CODE OF FEDERAL REGULATIONS21 Food and Drugs PARTS 600 TO 799 Revised as of April 1, 1999

CONTAINING

A CODIFICATION OF DOCUMENTS

OF GENERAL APPLICABILITY

AND FUTURE EFFECT

AS OF APRIL 1, 1999 With Ancillaries

Published by

the Office of the Federal Register

National Archives and Records

Administration

as a Special Edition of

the Federal Register

ARCHIVES.LI U.S. GOVERNMENT PRINTING OFFICE WASHINGTON : 1999

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 Table of Contents Page Explanation v Title 21: Chapter I—Food and Drug Administration, Department of Health and Human Services (Continued) 3 Finding Aids: Material Approved for Incorporation by Reference 151 Table of CFR Titles and Chapters 153 Alphabetical List of Agencies Appearing in the CFR 171 List of CFR Sections Affected 181

Cite this Code:CFR

To cite the regulations in this volume use title, part and section number. Thus, 21 CFR 600.3 refers to title 21, part 600, section 3. Explanation

The Code of Federal Regulations is a codification of the general and permanent rules published in the Federal Register by the Executive departments and agencies of the Federal Government. The Code is divided into 50 titles which represent broad areas subject to Federal regulation. Each title is divided into chapters which usually bear the name of the issuing agency. Each chapter is further subdivided into parts covering specific regulatory areas.

Each volume of the Code is revised at least once each calendar year and issued on a quarterly basis approximately as follows:

Title 1 through Title 16

as of January 1

Title 17 through Title 27

as of April 1

Title 28 through Title 41

as of July 1

Title 42 through Title 50

as of October 1

The appropriate revision date is printed on the cover of each volume.

LEGAL STATUS

The contents of the Federal Register are required to be judicially noticed (44 U.S.C. 1507). The Code of Federal Regulations is prima facie evidence of the text of the original documents (44 U.S.C. 1510).

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To determine whether a Code volume has been amended since its revision date (in this case, April 1, 1999), consult the “List of CFR Sections Affected (LSA),” which is issued monthly, and the “Cumulative List of Parts Affected,” which appears in the Reader Aids section of the daily Federal Register. These two lists will identify the Federal Register page number of the latest amendment of any given rule.

 EFFECTIVE AND EXPIRATION DATES

Each volume of the Code contains amendments published in the Federal Register since the last revision of that volume of the Code. Source citations for the regulations are referred to by volume number and page number of the Federal Register and date of publication. Publication dates and effective dates are usually not the same and care must be exercised by the user in determining the actual effective date. In instances where the effective date is beyond the cut-off date for the Code a note has been inserted to reflect the future effective date. In those instances where a regulation published in the Federal Register states a date certain for expiration, an appropriate note will be inserted following the text.

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 OBSOLETE PROVISIONS

Provisions that become obsolete before the revision date stated on the cover of each volume are not carried. Code users may find the text of provisions in effect on a given date in the past by using the appropriate numerical list of sections affected. For the period before January 1, 1986, consult either the List of CFR Sections Affected, 1949-1963, 1964-1972, or 1973-1985, published in seven separate volumes. For the period beginning January 1, 1986, a “List of CFR Sections Affected” is published at the end of each CFR volume.

 INCORPORATION BY REFERENCE

What is incorporation by reference? Incorporation by reference was established by statute and allows Federal agencies to meet the requirement to publish regulations in the Federal Register by referring to materials already published elsewhere. For an incorporation to be valid, the Director of the Federal Register must approve it. The legal effect of incorporation by reference is that the material is treated as if it were published in full in the Federal Register (5 U.S.C. 552(a)). This material, like any other properly issued regulation, has the force of law.

What is a proper incorporation by reference? The Director of the Federal Register will approve an incorporation by reference only when the requirements of 1 CFR part 51 are met. Some of the elements on which approval is based are:

(a) The incorporation will substantially reduce the volume of material published in the Federal Register.

(b) The matter incorporated is in fact available to the extent necessary to afford fairness and uniformity in the administrative process.

(c) The incorporating document is drafted and submitted for publication in accordance with 1 CFR part 51.

Properly approved incorporations by reference in this volume are listed in the Finding Aids at the end of this volume.

What if the material incorporated by reference cannot be found? If you have any problem locating or obtaining a copy of material listed in the Finding Aids of this volume as an approved incorporation by reference, please contact the agency that issued the regulation containing that incorporation. If, after contacting the agency, you find the material is not available, please notify the Director of the Federal Register, National Archives and Records Administration, Washington DC 20408, or call (202) 523-4534.

 CFR INDEXES AND TABULAR GUIDES

A subject index to the Code of Federal Regulations is contained in a separate volume, revised annually as of January 1, entitled CFR Index and Finding Aids. This volume contains the Parallel Table of Statutory Authorities and Agency Rules (Table I), and Acts Requiring Publication in the Federal Register (Table II). A list of CFR titles, chapters, and parts and an alphabetical list of agencies publishing in the CFR are also included in this volume.

An index to the text of “Title 3—The President” is carried within that volume.

The Federal Register Index is issued monthly in cumulative form. This index is based on a consolidation of the “Contents” entries in the daily Federal Register.

A List of CFR Sections Affected (LSA) is published monthly, keyed to the revision dates of the 50 CFR titles.

 REPUBLICATION OF MATERIAL

There are no restrictions on the republication of material appearing in the Code of Federal Regulations.

 INQUIRIES

For a legal interpretation or explanation of any regulation in this volume, contact the issuing agency. The issuing agency's name appears at the top of odd-numbered pages.

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The full text of the Code of Federal Regulations, the LSA (List of CFR Sections Affected), The United States Government Manual, the Federal Register, Public Laws, Weekly Compilation of Presidential Documents and the Privacy Act Compilation are available in electronic format at www.access.gpo.gov/nara (``GPO Access''). For more information, contact Electronic Information Dissemination Services, U.S. Government Printing Office. Phone 202-512-1530, or 888-293-6498 (toll-free). E-mail, gpoaccess@gpo.gov.

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 Raymond A. Mosley, Director, Office of the Federal Register. April 1, 1999. THIS TITLE

Title 21—Food and Drugs is composed of nine volumes. The parts in these volumes are arranged in the following order: Parts 1-99, 100-169, 170-199, 200-299, 300-499, 500-599, 600-799, 800-1299 and 1300-end. The first eight volumes, containing parts 1-1299, comprise Chapter I—Food and Drug Administration, Department of Health and Human Services. The ninth volume, containing part 1300 to end, includes Chapter II—Drug Enforcement Administration, Department of Justice, and Chapter III—Office of National Drug Control Policy. The contents of these volumes represent all current regulations codified under this title of the CFR as of April 1, 1999.

Redesignation tables for Chapter I—Food and Drug Administration appear in the Finding Aids section for the volumes containing parts 170-199 and 500-599.

For this volume, Carol Conroy was Chief Editor. The Code of Federal Regulations publication program is under the direction of Frances D. McDonald, assisted by Alomha S. Morris.

CFRORDR.FRM 21 CFR Ch. I (4-1-99 Edition) Food and Drug Administration, HHS <CHAPTER> <SUBCHAP TYPE="N"> <PRTPAGE P="5"/> <HD SOURCE="HED">SUBCHAPTER F—BIOLOGICS</HD> <PART> <EAR>Pt. 600</EAR> <HD SOURCE="HED">PART 600—BIOLOGICAL PRODUCTS: GENERAL</HD> <CONTENTS> <SUBPART> <HD SOURCE="HED">Subpart A—General Provisions</HD> <SECHD>Sec.</SECHD> <SECTNO>600.3</SECTNO> <SUBJECT>Definitions.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart B—Establishment Standards</HD> <SECTNO>600.10</SECTNO> <SUBJECT>Personnel.</SUBJECT> <SECTNO>600.11</SECTNO> <SUBJECT>Physical establishment, equipment, animals, and care.</SUBJECT> <SECTNO>600.12</SECTNO> <SUBJECT>Records.</SUBJECT> <SECTNO>600.13</SECTNO> <SUBJECT>Retention samples.</SUBJECT> <SECTNO>600.14</SECTNO> <SUBJECT>Reporting of errors.</SUBJECT> <SECTNO>600.15</SECTNO> <SUBJECT>Temperatures during shipment.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart C—Establishment Inspection</HD> <SECTNO>600.20</SECTNO> <SUBJECT>Inspectors.</SUBJECT> <SECTNO>600.21</SECTNO> <SUBJECT>Time of inspection.</SUBJECT> <SECTNO>600.22</SECTNO> <SUBJECT>Duties of inspector.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart D—Reporting of Adverse Experiences</HD> <SECTNO>600.80</SECTNO> <SUBJECT>Postmarketing reporting of adverse experiences.</SUBJECT> <SECTNO>600.81</SECTNO> <SUBJECT>Distribution reports.</SUBJECT> <SECTNO>600.90</SECTNO> <SUBJECT>Waivers.</SUBJECT> </SUBPART> </CONTENTS> <AUTH> <HD SOURCE="HED">Authority: </HD> <P>21 U.S.C. 321, 351, 352, 353, 355, 360, 360i, 371, 374; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.</P> </AUTH> <CROSSREF> <HD SOURCE="HED"> <E T="04">Cross References: </E> </HD> <P>For U.S. Customs Service regulations relating to viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal Service regulations relating to the admissibility to the United States mails see parts 124 and 125 of the Domestic Mail Manual, that is incorporated by reference in 39 CFR part 111.</P> </CROSSREF> <SUBPART> <HD SOURCE="HED">Subpart A—General Provisions</HD> <SECTION> <SECTNO>§ 600.3</SECTNO> <SUBJECT>Definitions.</SUBJECT> <P>As used in this subchapter:</P> <P>(a) <E T="03">Act</E> means the Public Health Service Act (58 Stat. 682), approved July 1, 1944.</P> <P>(b) <E T="03">Secretary</E> means the Secretary of Health and Human Services and any other officer or employee of the Department of Health and Human Services to whom the authority involved has been delegated.</P> <P>(c) <E T="03">Commissioner of Food and Drugs</E> means the Commissioner of the Food and Drug Administration.</P> <P>(d) <E T="03">Center for Biologics Evaluation and Research</E> means Center for Biologics Evaluation and Research of the Food and Drug Administration.</P> <P>(e) <E T="03">State</E> means a State or the District of Columbia, Puerto Rico, or the Virgin Islands.</P> <P>(f) <E T="03">Possession</E> includes among other possessions, Puerto Rico and the Virgin Islands.</P> <P>(g) <E T="03">Products</E> includes biological products and trivalent organic arsenicals.</P> <P>(h) <E T="03">Biological product</E> means any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment or cure of diseases or injuries of man:</P> <P>(1) A virus is interpreted to be a product containing the minute living cause of an infectious disease and includes but is not limited to filterable viruses, bacteria, rickettsia, fungi, and protozoa.</P> <P>(2) A therapeutic serum is a product obtained from blood by removing the clot or clot components and the blood cells.</P> <P>(3) A toxin is a product containing a soluble substance poisonous to laboratory animals or to man in doses of 1 milliliter or less (or equivalent in weight) of the product, and having the property, following the injection of non-fatal doses into an animal, of causing to be produced therein another soluble substance which specifically neutralizes the poisonous substance and which is demonstrable in the serum of the animal thus immunized.</P> <P>(4) An antitoxin is a product containing the soluble substance in serum or other body fluid of an immunized animal which specifically neutralizes the toxin against which the animal is immune.</P> <P>(5) A product is analogous:</P> <P>(i) To a virus if prepared from or with a virus or agent actually or potentially infectious, without regard to the degree of virulence or toxicogenicity of the specific strain used.</P> <P>(ii) To a therapeutic serum, if composed of whole blood or plasma or containing some organic constituent or product other than a hormone or an <PRTPAGE P="6"/>amino acid, derived from whole blood, plasma, or serum.</P> <P>(iii) To a toxin or antitoxin, if intended, irrespective of its source of origin, to be applicable to the prevention, treatment, or cure of disease or injuries of man through a specific immune process.</P> <P>(i) <E T="03">Trivalent organic arsenicals</E> means arsphenamine and its derivatives (or any other trivalent organic arsenic compound) applicable to the prevention, treatment, or cure of diseases or injuries of man.</P> <P>(j) A product is deemed <E T="03">applicable to the prevention, treatment, or cure of diseases or injuries of man</E> irrespective of the mode of administration or application recommended, including use when intended through administration or application to a person as an aid in diagnosis, or in evaluating the degree of susceptibility or immunity possessed by a person, and including also any other use for purposes of diagnosis if the diagnostic substance so used is prepared from or with the aid of a biological product.</P> <P>(k) <E T="03">Proper name</E>, as applied to a product, means the name designated in the license for use upon each package of the product.</P> <P>(l) <E T="03">Dating period</E> means the period beyond which the product cannot be expected beyond reasonable doubt to yield its specific results.</P> <P>(m) <E T="03">Expiration date</E> means the calendar month and year, and where applicable, the day and hour, that the dating period ends.</P> <P>(n) The word <E T="03">standards</E> means specifications and procedures applicable to an establishment or to the manufacture or release of products, which are prescribed in this subchapter and which are designed to insure the continued safety, purity and potency of such products.</P> <P>(o) The word <E T="03">continued</E> as applied to the safety, purity and potency of products is interpreted to apply to the dating period.</P> <P>(p) The word <E T="03">safety</E> means the relative freedom from harmful effect to persons affected, directly or indirectly, by a product when prudently administered, taking into consideration the character of the product in relation to the condition of the recipient at the time.</P> <P>(q) The word <E T="03">sterility</E> is interpreted to mean freedom from viable contaminating microorganisms, as determined by the tests prescribed in § 610.12 of this chapter.</P> <P>(r) <E T="03">Purity</E> means relative freedom from extraneous matter in the finished product, whether or not harmful to the recipient or deleterious to the product. <E T="03">Purity</E> includes but is not limited to relative freedom from residual moisture or other volatile substances and pyrogenic substances.</P> <P>(s) The word <E T="03">potency</E> is interpreted to mean the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result.</P> <P>(t) <E T="03">Manufacturer</E> means any legal person or entity engaged in the manufacture of a product subject to license under the act; “Manufacturer” also includes any legal person or entity who is an applicant for a license where the applicant assumes responsibility for compliance with the applicable product and establishment standards.</P> <P>(u) <E T="03">Manufacture</E> means all steps in propagation or manufacture and preparation of products and includes but is not limited to filling, testing, labeling, packaging, and storage by the manufacturer.</P> <P>(v) <E T="03">Location</E> includes all buildings, appurtenances, equipment and animals used, and personnel engaged by a manufacturer within a particular area designated by an address adequate for identification.</P> <P>(w) <E T="03">Establishment</E> includes all locations.</P> <P>(x) <E T="03">Lot</E> means that quantity of uniform material identified by the manufacturer as having been thoroughly mixed in a single vessel.</P> <P>(y) A <E T="03">filling</E> refers to a group of final containers identical in all respects, which have been filled with the same product from the same bulk lot without any change that will affect the integrity of the filling assembly.</P> <P>(z) <E T="03">Process</E> refers to a manufacturing step that is performed on the product <PRTPAGE P="7"/>itself which may affect its safety, purity or potency, in contrast to such manufacturing steps which do not affect intrinsically the safety, purity or potency of the product.</P> <P>(aa) <E T="03">Selling agent</E> or <E T="03">distributor</E> means any person engaged in the unrestricted distribution, other than by sale at retail, of products subject to license.</P> <P>(bb) <E T="03">Container</E> (referred to also as “final container”) is the immediate unit, bottle, vial, ampule, tube, or other receptacle containing the product as distributed for sale, barter, or exchange.</P> <P>(cc) <E T="03">Package</E> means the immediate carton, receptacle, or wrapper, including all labeling matter therein and thereon, and the contents of the one or more enclosed containers. If no package, as defined in the preceding sentence, is used, the container shall be deemed to be the package.</P> <P>(dd) <E T="03">Label</E> means any written, printed, or graphic matter on the container or package or any such matter clearly visible through the immediate carton, receptacle, or wrapper.</P> <P>(ee) <E T="03">Radioactive biological product</E> means a biological product which is labeled with a radionuclide or intended solely to be labeled with a radionuclide.</P> <P>(ff) <E T="03">Amendment</E> is the submission of information to a pending license application or supplement, to revise or modify the application as originally submitted.</P> <P>(gg) <E T="03">Supplement</E> is a request to the Director, Center for Biologics Evaluation and Research, to approve a change in an approved license application.</P> <CITA>[38 FR 32048, Nov. 20, 1973, as amended at 40 FR 31313, July 25, 1975; 55 FR 11014, Mar. 26, 1990; 61 FR 24232, May 14, 1996; 62 FR 39901, July 24, 1997]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart B—Establishment Standards</HD> <SECTION> <SECTNO>§ 600.10</SECTNO> <SUBJECT>Personnel.</SUBJECT> <P>(a) [Reserved]</P> <P>(b) <E T="03">Personnel.</E> Personnel shall have capabilities commensurate with their assigned functions, a thorough understanding of the manufacturing operations which they perform, the necessary training and experience relating to individual products, and adequate information concerning the application of the pertinent provisions of this subchapter to their respective functions. Personnel shall include such professionally trained persons as are necessary to insure the competent performance of all manufacturing processes.</P> <P>(c) <E T="03">Restrictions on personnel</E>—(1) <E T="03">Specific duties.</E> Persons whose presence can affect adversely the safety and purity of a product shall be excluded from the room where the manufacture of a product is in progress.</P> <P>(2) <E T="03">Sterile operations.</E> Personnel performing sterile operations shall wear clean or sterilized protective clothing and devices to the extent necessary to protect the product from contamination.</P> <P>(3) <E T="03">Pathogenic viruses and spore-bearing organisms.</E> Persons working with viruses pathogenic for man or with spore-bearing microorganisms, and persons engaged in the care of animals or animal quarters, shall be excluded from areas where other products are manufactured, or such persons shall change outer clothing, including shoes, or wear protective covering prior to entering such areas.</P> <P>(4) <E T="03">Live vaccine work areas.</E> Persons may not enter a live vaccine processing area after having worked with other infectious agents in any other laboratory during the same working day. Only persons actually concerned with propagation of the culture, production of the vaccine, and unit maintenance, shall be allowed in live vaccine processing areas when active work is in progress. Casual visitors shall be excluded from such units at all times and all others having business in such areas shall be admitted only under supervision. Street clothing, including shoes, shall be replaced or covered by suitable laboratory clothing before entering a live vaccine processing unit. Persons caring for animals used in the manufacture of live vaccines shall be excluded from other animal quarters and from contact with other animals during the same working day.</P> <CITA>[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55 FR 11014, Mar. 26, 1990; 62 FR 53538, Oct. 15, 1997]</CITA> </SECTION> <SECTION> <PRTPAGE P="8"/> <SECTNO>§ 600.11</SECTNO> <SUBJECT>Physical establishment, equipment, animals, and care.</SUBJECT> <P>(a) <E T="03">Work areas.</E> All rooms and work areas where products are manufactured or stored shall be kept orderly, clean, and free of dirt, dust, vermin and objects not required for manufacturing. Precautions shall be taken to avoid clogging and back-siphonage of drainage systems. Precautions shall be taken to exclude extraneous infectious agents from manufacturing areas. Work rooms shall be well lighted and ventilated. The ventilation system shall be arranged so as to prevent the dissemination of microorganisms from one manufacturing area to another and to avoid other conditions unfavorable to the safety of the product. Filling rooms, and other rooms where open, sterile operations are conducted, shall be adequate to meet manufacturing needs and such rooms shall be constructed and equipped to permit thorough cleaning and to keep air-borne contaminants at a minimum. If such rooms are used for other purposes, they shall be cleaned and prepared prior to use for sterile operations. Refrigerators, incubators and warm rooms shall be maintained at temperatures within applicable ranges and shall be free of extraneous material which might affect the safety of the product.</P> <P>(b) <E T="03">Equipment.</E> Apparatus for sterilizing equipment and the method of operation shall be such as to insure the destruction of contaminating microorganisms. The effectiveness of the sterilization procedure shall be no less than that achieved by an attained temperature of 121.5° C maintained for 20 minutes by saturated steam or by an attained temperature of 170° C maintained for 2 hours with dry heat. Processing and storage containers, filters, filling apparatus, and other pieces of apparatus and accessory equipment, including pipes and tubing, shall be designed and constructed to permit thorough cleaning and, where possible, inspection for cleanliness. All surfaces that come in contact with products shall be clean and free of surface solids, leachable contaminants, and other materials that will hasten the deterioration of the product or otherwise render it less suitable for the intended use. For products for which sterility is a factor, equipment shall be sterile, unless sterility of the product is assured by subsequent procedures.</P> <P>(c) <E T="03">Laboratory and bleeding rooms.</E> Rooms used for the processing of products, including bleeding rooms, shall be effectively fly-proofed and kept free of flies and vermin. Such rooms shall be so constructed as to insure freedom from dust, smoke and other deleterious substances and to permit thorough cleaning and disinfection. Rooms for animal injection and bleeding, and rooms for smallpox vaccine animals, shall be disinfected and be provided with the necessary water, electrical and other services.</P> <P>(d) <E T="03">Animal quarters and stables.</E> Animal quarters, stables and food storage areas shall be of appropriate construction, fly-proofed, adequately lighted and ventilated, and maintained in a clean, vermin-free and sanitary condition. No manure or refuse shall be stored as to permit the breeding of flies on the premises, nor shall the establishment be located in close proximity to off-property manure or refuse storage capable of engendering fly breeding.</P> <P>(e) <E T="03">Restrictions on building and equipment use</E>—(1) <E T="03">Work of a diagnostic nature.</E> Laboratory procedures of a clinical diagnostic nature involving materials that may be contaminated, shall not be performed in space used for the manufacture of products except that manufacturing space which is used only occasionally may be used for diagnostic work provided spore-bearing pathogenic microorganisms are not involved and provided the space is thoroughly cleaned and disinfected before the manufacture of products is resumed.</P> <P>(2) <E T="03">Spore-bearing organisms for supplemental sterilization procedure control test.</E> Spore-bearing organisms used as an additional control in sterilization procedures may be introduced into areas used for the manufacture of products, only for the purposes of the test and only immediately before use for such purposes: <E T="03">Provided,</E> That (i) the organism is not pathogenic for man or animals and does not produce pyrogens or toxins, (ii) the culture is demonstrated to be pure, (iii) transfer of test cultures to culture media shall be limited to the <PRTPAGE P="9"/>sterility test area or areas designated for work with spore-bearing organisms, (iv) each culture be labeled with the name of the microorganism and the statement “Caution: microbial spores. See directions for storage, use and disposition.”, and (v) the container of each culture is designed to withstand handling without breaking.</P> <P>(3) <E T="03">Work with spore-bearing organisms.</E> Except as provided in the previous paragraph, all work with spore-bearing microorganisms shall be done in an entirely separate building: <E T="03">Provided,</E> That such work may be done in a portion of a building used in the manufacture of products not containing spore-bearing microorganisms if such portion is completely walled-off and is constructed so as to prevent contamination of other areas and if entrances to such portion are independent of the remainder of the building. All vessels, apparatus and equipment used for spore-bearing microorganisms shall be permanently identified and reserved exclusively for use with those organisms. Materials destined for further manufacturing may be removed from such an area only under conditions which will prevent the introduction of spores into other manufacturing areas.</P> <P>(4) <E T="03">Live vaccine processing.</E> Space used for processing a live vaccine shall not be used for any other purpose during the processing period for that vaccine and such space shall be decontaminated prior to initiation of the processing. Live vaccine processing areas shall be isolated from and independent of any space used for any other purpose by being either in a separate building, in a separate wing of a building, or in quarters at the blind end of a corridor and shall include adequate space and equipment for all processing steps up to filling into final containers. Test procedures which potentially involve the presence of microorganisms other than the vaccine strains, or the use of tissue culture cell lines other than primary cultures, shall not be conducted in space used for processing live vaccine.</P> <P>(5) <E T="03">Equipment and supplies—contamination.</E> Equipment and supplies used in work on or otherwise exposed to any pathogenic or potentially pathogenic agent shall be kept separated from equipment and supplies used in the manufacture of products to the extent necessary to prevent cross-contamination.</P> <P>(f) <E T="03">Animals used in manufacture</E>—(1) <E T="03">Care of animals used in manufacturing.</E> Caretakers and attendants for animals used for the manufacture of products shall be sufficient in number and have adequate experience to insure adequate care. Animal quarters and cages shall be kept in sanitary condition. Animals on production shall be inspected daily to observe response to production procedures. Animals that become ill for reasons not related to production shall be isolated from other animals and shall not be used for production until recovery is complete. Competent veterinary care shall be provided as needed.</P> <P>(2) <E T="03">Quarantine of animals</E>—(i) <E T="03">General.</E> No animal shall be used in processing unless kept under competent daily inspection and preliminary quarantine for a period of at least 7 days before use, or as otherwise provided in this subchapter. Only healthy animals free from detectable communicable diseases shall be used. Animals must remain in overt good health throughout the quarantine periods and particular care shall be taken during the quarantine periods to reject animals of the equine genus which may be infected with glanders and animals which may be infected with tuberculosis.</P> <P>(ii) <E T="03">Quarantine of monkeys.</E> In addition to observing the pertinent general quarantine requirements, monkeys used as a source of tissue in the manufacture of vaccine shall be maintained in quarantine for at least 6 weeks prior to use, except when otherwise provided in this part. Only monkeys that have reacted negatively to tuberculin at the start of the quarantine period and again within 2 weeks prior to use shall be used in the manufacture of vaccine. Due precaution shall be taken to prevent cross-infection from any infected or potentially infected monkeys on the premises. Monkeys to be used in the manufacture of a live vaccine shall be maintained throughout the quarantine period in cages closed on all sides with solid materials except the front which shall be screened, with no more than <PRTPAGE P="10"/>two monkeys housed in one cage. Cage mates shall not be interchanged.</P> <P>(3) <E T="03">Immunization against tetanus.</E> Horses and other animals susceptible to tetanus, that are used in the processing steps of the manufacture of biological products, shall be treated adequately to maintain immunity to tetanus.</P> <P>(4) <E T="03">Immunization and bleeding of animals used as a source of products.</E> Toxins or other nonviable antigens administered in the immunization of animals used in the manufacture of products shall be sterile. Viable antigens, when so used, shall be free of contaminants, as determined by appropriate tests prior to use. Injections shall not be made into horses within 6 inches of bleeding site. Horses shall not be bled for manufacturing purposes while showing persistent general reaction or local reaction near the site of bleeding. Blood shall not be used if it was drawn within 5 days of injecting the animals with viable microorganisms. Animals shall not be bled for manufacturing purposes when they have an intercurrent disease. Blood intended for use as a source of a biological product shall be collected in clean, sterile vessels. When the product is intended for use by injection, such vessels shall also be pyrogen-free.</P> <P>(5) [Reserved]</P> <P>(6) <E T="03">Reporting of certain diseases.</E> In cases of actual or suspected infection with foot and mouth disease, glanders, tetanus, anthrax, gas gangrene, equine infectious anemia; equine encephalomyelitis, or any of the pock diseases among animals intended for use or used in the manufacture of products, the manufacturer shall immediately notify the Director, Center for Biologics Evaluation and Research.</P> <P>(7) <E T="03">Monkeys used previously for experimental or test purposes.</E> Monkeys that have been used previously for experimental or test purposes with live microbiological agents shall not be used as a source of kidney tissue for the manufacture of vaccine. Except as provided otherwise in this subchapter, monkeys that have been used previously for other experimental or test purposes may be used as a source of kidney tissue upon their return to a normal condition, provided all quarantine requirements have been met.</P> <P>(8) <E T="03">Necropsy examination of monkeys.</E> Each monkey used in the manufacture of vaccine shall be examined at necropsy under the direction of a qualified pathologist, physician, or veterinarian having experience with diseases of monkeys, for evidence of ill health, particularly for (i) evidence of tuberculosis, (ii) presence of herpes-like lesions, including eruptions or plaques on or around the lips, in the buccal cavity or on the gums, and (iii) signs of conjunctivitis. If there are any such signs or other significant gross pathological lesions, the tissue shall not be used in the manufacture of vaccine.</P> <P>(g) <E T="03">Filling procedures.</E> Filling procedures shall be such as will not affect adversely the safety, purity or potency of the product.</P> <P>(h) <E T="03">Containers and closures.</E> All final containers and closures shall be made of material that will not hasten the deterioration of the product or otherwise render it less suitable for the intended use. All final containers and closures shall be clean and free of surface solids, leachable contaminants and other materials that will hasten the deterioration of the product or otherwise render it less suitable for the intended use. After filling, sealing shall be performed in a manner that will maintain the integrity of the product during the dating period. In addition, final containers and closures for products intended for use by injection shall be sterile and free from pyrogens. Except as otherwise provided in the regulations of this subchapter, final containers for products intended for use by injection shall be colorless and sufficiently transparent to permit visual examination of the contents under normal light. As soon as possible after filling final containers shall be labeled as prescribed in § 610.60 <E T="03">et seq.</E> of this chapter, except that final containers may be stored without such prescribed labeling provided they are stored in a sealed receptacle labeled both inside and outside with at least the name of the product, the lot number, and the filling identification.</P> <CITA>[38 FR 32048, Nov. 20, 1973, as amended at 41 FR 10428, Mar. 11, 1976; 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <PRTPAGE P="11"/> <SECTNO>§ 600.12</SECTNO> <SUBJECT>Records.</SUBJECT> <P>(a) <E T="03">Maintenance of records.</E> Records shall be made, concurrently with the performance, of each step in the manufacture and distribution of products, in such a manner that at any time successive steps in the manufacture and distribution of any lot may be traced by an inspector. Such records shall be legible and indelible, shall identify the person immediately responsible, shall include dates of the various steps, and be as detailed as necessary for clear understanding of each step by one experienced in the manufacture of products.</P> <P>(b) <E T="03">Records retention</E>—(1) <E T="03">General.</E> Records shall be retained for such interval beyond the expiration date as is necessary for the individual product, to permit the return of any clinical report of unfavorable reactions. The retention period shall be no less than five years after the records of manufacture have been completed or six months after the latest expiration date for the individual product, whichever represents a later date.</P> <P>(2) <E T="03">Records of recall.</E> Complete records shall be maintained pertaining to the recall from distribution of any product upon notification by the Director, Center for Biologics Evaluation and Research, to recall for failure to conform with the standards prescribed in the regulations of this subchapter, because of deterioration of the product or for any other factor by reason of which the distribution of the product would constitute a danger to health.</P> <P>(3) <E T="03">Suspension of requirement for retention.</E> The Director, Center for Biologics Evaluation and Research, may authorize the suspension of the requirement to retain records of a specific manufacturing step upon a showing that such records no longer have significance for the purposes for which they were made: <E T="03">Provided,</E> That a summary of such records shall be retained.</P> <P>(c) <E T="03">Records of sterilization of equipment and supplies.</E> Records relating to the mode of sterilization, date, duration, temperature and other conditions relating to each sterilization of equipment and supplies used in the processing of products shall be made by means of automatic recording devices or by means of a system of recording which gives equivalent assurance of the accuracy and reliability of the record. Such records shall be maintained in a manner that permits an identification of the product with the particular manufacturing process to which the sterilization relates.</P> <P>(d) <E T="03">Animal necropsy records.</E> A necropsy record shall be kept on each animal from which a biological product has been obtained and which dies or is sacrificed while being so used.</P> <P>(e) <E T="03">Records in case of divided manufacturing responsibility.</E> If two or more establishments participate in the manufacture of a product, the records of each such establishment must show plainly the degree of its responsibility. In addition, each participating manufacturer shall furnish to the manufacturer who prepares the product in final form for sale, barter or exchange, a copy of all records relating to the manufacturing operations performed by such participating manufacturer insofar as they concern the safety, purity and potency of the lots of the product involved, and the manufacturer who prepares the product in final form shall retain a complete record of all the manufacturing operations relating to the product.</P> <CITA>[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 600.13</SECTNO> <SUBJECT>Retention samples.</SUBJECT> <P>Manufacturers shall retain for a period of at least 6 months after the expiration date, unless a different time period is specified in additional standards, a quantity of representative material of each lot of each product, sufficient for examination and testing for safety and potency, except Whole Blood, Cryoprecipitated AHF, Platelets, Red Blood Cells, Plasma, and Source Plasma and Allergenic Products prepared to a physician's prescription. Samples so retained shall be selected at random from either final container material, or from bulk and final containers, provided they include at least one final container as a final package, or package-equivalent of such filling of each lot of the product as intended for distribution. Such sample material shall be stored at temperatures and under conditions which will maintain <PRTPAGE P="12"/>the identity and integrity of the product. Samples retained as required in this section shall be in addition to samples of specific products required to be submitted to the Center for Biologics Evaluation and Research. Exceptions may be authorized by the Director, Center for Biologics Evaluation and Research, when the lot yields relatively few final containers and when such lots are prepared by the same method in large number and in close succession.</P> <CITA>[41 FR 10428, Mar. 11, 1976, as amended at 49 FR 23833, June 8, 1984; 50 FR 4133, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 600.14</SECTNO> <SUBJECT>Reporting of errors.</SUBJECT> <P>(a) The Director, Office of Compliance, Center for Biologics Evaluation and Research (HFB-100), 8800 Rockville Pike, Bethesda, MD 20892, shall be notified promptly of errors or accidents in the manufacture of products that may affect the safety, purity, or potency of any product.</P> <P>(b) Manufacturers of licensed in vitro diagnostic products, and manufacturers of unlicensed in vitro diagnostic products which are required to be registered under part 607 of this chapter, shall notify the Director in accordance with paragraph (a) of this section. Manufacturers of other in vitro diagnostic products which are required to be registered under part 807 of this chapter, shall report in accordance with part 803 of this chapter.</P> <CITA>[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 49 FR 36348, Sept. 14, 1984; 55 FR 11014, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 600.15</SECTNO> <SUBJECT>Temperatures during shipment.</SUBJECT> <P>The following products shall be maintained during shipment at the specified temperatures:</P> <P>(a) <E T="03">Products.</E> </P> <GPOTABLE CDEF="s50,r50" COLS="2" OPTS="L2"> <BOXHD> <CHED H="1">Product</CHED> <CHED H="1">Temperature</CHED> </BOXHD> <ROW> <ENT I="01">Cryoprecipitated AHF</ENT> <ENT>−18 <E T="61">°</E>C or colder.</ENT> </ROW> <ROW> <ENT I="01">Measles and Rubella Virus Vaccine Live</ENT> <ENT>10 <E T="61">°</E>C or colder.</ENT> </ROW> <ROW> <ENT I="01">Measles Live and Smallpox Vaccine</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Measles, Mumps, and Rubella Virus Vaccine Live</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Measles and Mumps Virus Vaccine Live</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Measles Virus Vaccine Live</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Mumps Virus Vaccine Live</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Fresh Frozen Plasma</ENT> <ENT>−18 <E T="61">°</E>C or colder.</ENT> </ROW> <ROW> <ENT I="01">Liquid Plasma</ENT> <ENT>1 to 10 <E T="61">°</E>C.</ENT> </ROW> <ROW> <ENT I="01">Plasma</ENT> <ENT>−18 <E T="61">°</E>C or colder.</ENT> </ROW> <ROW> <ENT I="01">Platelet Rich Plasma</ENT> <ENT>Between 1 and 10 <E T="61">°</E>C if the label indicates storage between 1 and 6 <E T="61">°</E>C, or all reasonable methods to maintain the temperature as close as possible to a range between 20 and 24 <E T="61">°</E>C, if the label indicates storage between 20 and 24 <E T="61">°</E>C.</ENT> </ROW> <ROW> <ENT I="01">Platelets</ENT> <ENT>Between 1 and 10 <E T="61">°</E>C if the label indicates storage between 1 and 6 <E T="61">°</E>C, or all reasonable methods to maintain the temperature as close as possible to a range between 20 to 24 <E T="61">°</E>C, if the label indicates storage between 20 and 24 <E T="61">°</E>C.</ENT> </ROW> <ROW> <ENT I="01">Poliovirus Vaccine Live Oral Trivalent</ENT> <ENT>0 <E T="61">°</E>C or colder.</ENT> </ROW> <ROW> <ENT I="01">Poliovirus Vaccine Live Oral Type I</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Poliovirus Vaccine Live Oral Type II</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Poliovirus Vaccine Live Oral Type III</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Red Blood Cells (liquid product)</ENT> <ENT>Between 1 and 10 <E T="61">°</E>C.</ENT> </ROW> <ROW> <ENT I="01">Red Blood Cells Frozen</ENT> <ENT>−65 <E T="61">°</E>C or colder.</ENT> </ROW> <ROW> <ENT I="01">Rubella and Mumps Virus Vaccine Live</ENT> <ENT>10 <E T="61">°</E>C or colder.</ENT> </ROW> <ROW> <ENT I="01">Rubella Virus Vaccine Live</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Smallpox Vaccine (Liquid Product)</ENT> <ENT>0 <E T="61">°</E>C or colder.</ENT> </ROW> <ROW> <ENT I="01">Source Plasma</ENT> <ENT>−5 <E T="61">°</E>C or colder.</ENT> </ROW> <ROW> <ENT I="01">Source Plasma Liquid</ENT> <ENT>10 <E T="61">°</E>C or colder.</ENT> </ROW> <ROW> <ENT I="01">Whole Blood</ENT> <ENT>Blood that is transported from the collecting facility to the processing facility shall be transported in an environment capable of continuously cooling the blood toward a temperature range of 1 to 10 <E T="61">°</E>C, or at a temperature as close as possible to 20 to 24 <E T="61">°</E>C for a period not to exceed 6 hours. Blood transported from the storage facility shall be placed in an appropriate environment to maintain a temperature range between 1 to 10 <E T="61">°</E>C during shipment.</ENT> </ROW> <ROW> <ENT I="01">Yellow Fever Vaccine</ENT> <ENT>0 <E T="61">°</E>C or colder.</ENT> </ROW> </GPOTABLE> <P>(b) <E T="03">Exemptions.</E> Exemptions or modifications shall be made only upon written approval, in the form of a supplement of the product license, issued by the Director, Center for Biologics Evaluation and Research.</P> <CITA>[39 FR 39872, Nov. 12, 1974, as amended at 49 FR 23833, June 8, 1984; 50 FR 4133, Jan. 29, 1985; 50 FR 9000, Mar. 6, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994]</CITA> </SECTION> </SUBPART> <SUBPART> <PRTPAGE P="13"/> <HD SOURCE="HED">Subpart C—Establishment Inspection</HD> <SECTION> <SECTNO>§ 600.20</SECTNO> <SUBJECT>Inspectors.</SUBJECT> <P>Inspections shall be made by an officer of the Food and Drug Administration having special knowledge of the methods used in the manufacture and control of products and designated for such purposes by the Commissioner of Food and Drugs, or by any officer, agent, or employee of the Department of Health and Human Services specifically designated for such purpose by the Secretary.</P> <CITA>[38 FR 32048, Nov. 20, 1973]</CITA> </SECTION> <SECTION> <SECTNO>§ 600.21</SECTNO> <SUBJECT>Time of inspection.</SUBJECT> <P>The inspection of an establishment for which a license is pending need not be made until the establishment is in operation and is manufacturing the complete product for which a product license is desired. In case the license is denied following inspection for the original license, no reinspection need be made until assurance has been received that the faulty conditions which were the basis of the denial have been corrected. An inspection of each licensed establishment and its additional location(s) shall be made at least once every 2 years. Inspections may be made with or without notice, and shall be made during regular business hours unless otherwise directed.</P> <CITA>[38 FR 32048, Nov. 20, 1973, as amended at 48 FR 26314, June 7, 1983]</CITA> </SECTION> <SECTION> <SECTNO>§ 600.22</SECTNO> <SUBJECT>Duties of inspector.</SUBJECT> <P>The inspector shall:</P> <P>(a) Call upon the active head of the establishment, stating the object of his visit,</P> <P>(b) Interrogate the proprietor or other personnel of the establishment as he may deem necessary,</P> <P>(c) Examine the details of location, construction, equipment and maintenance, including stables, barns, warehouses, manufacturing laboratories, bleeding clinics maintained for the collection of human blood, shipping rooms, record rooms, and any other structure or appliance used in any part of the manufacture of a product,</P> <P>(d) Investigate as fully as he deems necessary the methods of propagation, processing, testing, storing, dispensing, recording, or other details of manufacture and distribution of each licensed product, or product for which a license has been requested, including observation of these procedures in actual operation,</P> <P>(e) Obtain and cause to be sent to the Director, Center for Biologics Evaluation and Research, adequate samples for the examination of any product or ingredient used in its manufacture,</P> <P>(f) Bring to the attention of the manufacturer any fault observed in the course of inspection in location, construction, manufacturing methods, or administration of a licensed establishment which might lead to impairment of a product,</P> <P>(g) Inspect and copy, as circumstances may require, any records required to be kept pursuant to § 600.12,</P> <P>(h) Certify as to the condition of the establishment and of the manufacturing methods followed and make recommendations as to action deemed appropriate with respect to any application for license or any license previously issued.</P> <CITA>[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart D—Reporting of Adverse Experiences</HD> <SOURCE> <HD SOURCE="HED">Source: </HD> <P>59 FR 54042, Oct. 27, 1994, unless otherwise noted.</P> </SOURCE> <SECTION> <SECTNO>§ 600.80</SECTNO> <SUBJECT>Postmarketing reporting of adverse experiences.</SUBJECT> <P>(a) <E T="03">Definitions</E>. The following definitions of terms apply to this section:</P> <P> <E T="03">Adverse experience</E>. Any adverse event associated with the use of a biological product in humans, whether or not considered product related, including the following: An adverse event occurring in the course of the use of a biological product in professional practice; an adverse event occurring from overdose of the product whether accidental or intentional; an adverse event occurring from abuse of the product; an adverse event occurring from withdrawal of the product; and any failure of expected pharmacological action.</P> <P> <E T="03">Blood Component</E>. As defined in § 606.3(c) of this chapter.<PRTPAGE P="14"/> </P> <P> <E T="03">Disability</E>. A substantial disruption of a person's ability to conduct normal life functions.</P> <P> <E T="03">Life-threatening adverse experience</E>. Any adverse experience that places the patient, in the view of the initial reporter, at immediate risk of death from the adverse experience as it occurred, i.e., it does not include an adverse experience that, had it occurred in a more severe form, might have caused death.</P> <P> <E T="03">Serious adverse experience</E>. Any adverse experience occurring at any dose that results in any of the following outcomes: Death, a life-threatening adverse experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.</P> <P> <E T="03">Unexpected adverse experience</E>: Any adverse experience that is not listed in the current labeling for the biological product. This includes events that may be symptomatically and pathophysiologically related to an event listed in the labeling, but differ from the event because of greater severity or specificity. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the labeling only referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the labeling only listed cerebral vascular accidents. “Unexpected,” as used in this definition, refers to an adverse experience that has not been previously observed (i.e., included in the labeling) rather than from the perspective of such experience not being anticipated from the pharmacological properties of the pharmaceutical product.</P> <P>(b) <E T="03">Review of adverse experiences</E>. Any person having a product license under § 601.20 of this chapter shall promptly review all adverse experience information pertaining to its product obtained or otherwise received by the licensed manufacturer from any source, foreign or domestic, including information derived from commercial marketing experience, postmarketing clinical investigations, postmarketing epidemiological/surveillance studies, reports in the scientific literature, and unpublished scientific papers. Licensed manufacturers are not required to resubmit to FDA adverse product experience reports forwarded to the licensed manufacturer by FDA; licensed manufacturers, however, must submit all followup information on such reports to FDA. Any person subject to the reporting requirements under paragraph (c) of this section shall also develop written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse experiences to FDA.</P> <P>(c) <E T="03">Reporting requirements</E>. The licensed manufacturer shall report to FDA adverse experience information, as described in this section. The licensed manufacturer shall submit two copies of each report described in this section for nonvaccine biological products, to the Center for Biologics Evaluation and Research (HFM-210), Food and Drug Administration, 1401 Rockville Pike, suite 200 N., Rockville, MD 20852-1448. Submit all vaccine adverse experience reports to: Vaccine Adverse Event Reporting System (VAERS), P.O. Box 1100, Rockville, MD 20849-1100. FDA may waive the requirement for the second copy in appropriate instances.</P> <P>(1)(i) <E T="03">Postmarketing 15-day “Alert reports”</E>. The licensed manufacturer shall report each adverse experience that is both serious and unexpected, whether foreign or domestic, as soon as possible but in no case later than 15 calendar days of initial receipt of the information by the licensed manufacturer.<PRTPAGE P="15"/> </P> <P>(ii) <E T="03">Postmarketing 15-day “Alert reports”—followup</E>. The licensed manufacturer shall promptly investigate all adverse experiences that are the subject of these postmarketing 15-day Alert reports and shall submit followup reports within 15 calendar days of receipt of new information or as requested by FDA. If additional information is not obtainable, records should be maintained of the unsuccessful steps taken to seek additional information. Postmarketing 15-day Alert reports and followups to them shall be submitted under separate cover.</P> <P>(iii) <E T="03">Submission of reports</E>. The requirements of paragraphs (c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of postmarketing 15-day Alert reports, shall also apply to any person whose name appears on the label of a licensed biological product as a manufacturer, packer, distributor, shared manufacturer, joint manufacturer, or any other participant involved in divided manufacturing. To avoid unnecessary duplication in the submission to FDA of reports required by paragraphs (c)(1)(i) and (c)(1)(ii) of this section, obligations of persons other than the licensed manufacturer of the final biological product may be met by submission of all reports of serious adverse experiences to the licensed manufacturer of the final product. If a person elects to submit adverse experience reports to the licensed manufacturer of the final product rather than to FDA, the person shall submit each report to the licensed manufacturer of the final product within 5 calendar days of receipt of the report by the person, and the licensed manufacturer of the final product shall then comply with the requirements of this section. Under this circumstance, a person who elects to submit reports to the licensed manufacturer of the final product shall maintain a record of this action which shall include:</P> <P>(A) A copy of all adverse biological product experience reports submitted to the licensed manufacturer of the final product;</P> <P>(B) The date the report was received by the person;</P> <P>(C) The date the report was submitted to the licensed manufacturer of the final product; and-</P> <P>(D) The name and address of the licensed manufacturer of the final product.</P> <P>(iv) <E T="03">Report identification</E>. Each report submitted under this paragraph shall bear prominent identification as to its contents, i.e., “15-day Alert report,” or “15-day Alert report-followup.”</P> <P>(2) <E T="03">Periodic adverse experience reports</E>. (i) The licensed manufacturer shall report each adverse experience not reported under paragraph (c)(1)(i) of this section at quarterly intervals, for 3 years from the date of issuance of the product license, and then at annual intervals. The licensed manufacturer shall submit each quarterly report within 30 days of the close of the quarter (the first quarter beginning on the date of issuance of the product license) and each annual report within 60 days of the anniversary date of the issuance of the product license. Upon written notice, FDA may extend or reestablish the requirement that a licensed manufacturer submit quarterly reports, or require that the licensed manufacturer submit reports under this section at different times than those stated. Followup information to adverse experiences submitted in a periodic report may be submitted in the next periodic report.</P> <P>(ii) Each periodic report shall contain:</P> <P>(A) A narrative summary and analysis of the information in the report and an analysis of the 15-day Alert reports submitted during the reporting interval (all 15-day Alert reports being appropriately referenced by the licensed manufacturer's patient identification number, adverse reaction term(s), and date of submission to FDA);</P> <P>(B) A form designated for Adverse Experience Reporting by FDA for each adverse experience not reported under paragraph (c)(1)(i) of this section (with an index consisting of a line listing of the licensed manufacturer's patient identification number and adverse reaction term(s)); and</P> <P>(C) A history of actions taken since the last report because of adverse experiences (for example, labeling changes or studies initiated).<PRTPAGE P="16"/> </P> <P>(iii) Periodic reporting, except for information regarding 15-day Alert reports, does not apply to adverse experience information obtained from postmarketing studies (whether or not conducted under an investigational new drug application), from reports in the scientific literature, and from foreign marketing experience.</P> <P>(d) <E T="03">Scientific literature</E>. (1) A 15-day Alert report based on information from the scientific literature shall be accompanied by a copy of the published article. The 15-day Alert reporting requirements in paragraph (c)(1)(i) of this section (i.e., serious, unexpected adverse experiences) apply only to reports found in scientific and medical journals either as case reports or as the result of a formal clinical trial.</P> <P>(2) As with all reports submitted under paragraph (c)(1)(i) of this section, reports based on the scientific literature shall be submitted on the reporting form designated by FDA or comparable format as prescribed by paragraph (f) of this section. In cases where the licensed manufacturer believes that preparing the form designated by FDA constitutes an undue hardship, the licensed manufacturer may arrange with the Division of Biostatistics and Epidemiology (HFM-210) for an acceptable alternative reporting format.</P> <P>(e) <E T="03">Postmarketing studies</E>. (1) Licensed manufacturers are not required to submit a 15-day Alert report under paragraph (c) of this section for an adverse experience obtained from a postmarketing clinical study (whether or not conducted under a biological investigational new drug application) unless the licensed manufacturer concludes that there is a reasonable possibility that the product caused the adverse experience.</P> <P>(2) The licensed manufacturer shall separate and clearly mark reports of adverse experiences that occur during a postmarketing study as being distinct from those experiences that are being reported spontaneously to the licensed manufacturer.</P> <P>(f) <E T="03">Reporting forms</E>. (1) Except as provided in paragraph (f)(3) of this section, the licensed manufacturer shall complete the reporting form designated by FDA for each report of an adverse experience (FDA Form 3500A, or, for vaccines, a VAERS form; foreign events including those associated with the use of vaccines, may be submitted either on an FDA Form 3500A or, if preferred, on a CIOMS I form).</P> <P>(2) Each completed form should refer only to an individual patient or single attached publication.</P> <P>(3) Instead of using a designated reporting form, a licensed manufacturer may use a computer-generated form or other alternative format (e.g., a computer-generated tape or tabular listing) provided that:</P> <P>(i) The content of the alternative format is equivalent in all elements of information to those specified in the form designated by FDA; and</P> <P>(ii) the format is approved in advance by MEDWATCH: The FDA Medical Products Reporting Program; or, for alternatives to the VAERS Form, by the Division of Biostatistics and Epidemiology.</P> <P>(4) Copies of the reporting form designated by FDA (FDA-3500A) for nonvaccine biological products may be obtained from the Center for Biologics Evaluation and Research (address above). Additional supplies of the form may be obtained from the Consolidated Forms and Publications Distribution Center, 3222 Hubbard Rd., Landover, MD 20785. Supplies of the VAERS form may be obtained from VAERS by calling 1-800-822-7967.</P> <P>(g) <E T="03">Multiple reports</E>. A licensed manufacturer should not include in reports under this section any adverse experience that occurred in clinical trials if they were previously submitted as part of the license application. If a report refers to more than one biological product marketed by a licensed manufacturer, the licensed manufacturer should submit the report to the license for the product listed first in the report.</P> <P>(h) <E T="03">Patient privacy</E>. For nonvaccine biological products, a licensed manufacturer should not include in reports under this section the names and addresses of individual patients; instead, the licensed manufacturer should assign a unique code number to each report, preferably not more than eight characters in length. The licensed manufacturer should include the name of <PRTPAGE P="17"/>the reporter from whom the information was received. The names of patients, health care professionals, hospitals, and geographical identifiers in adverse experience reports are not releasable to the public under FDA's public information regulations in part 20 this of chapter. For vaccine adverse experience reports, these data will become part of the CDC Privacy Act System 09-20-0136, “Epidemiologic Studies and Surveillance of Disease Problems.” Information identifying the person who received the vaccine or that person's legal representative will not be made available to the public, but may be available to the vaccinee or legal representative.</P> <P>(i) <E T="03">Recordkeeping</E>. The licensed manufacturer shall maintain for a period of 10 years records of all adverse experiences known to the licensed manufacturer, including raw data and any correspondence relating to the adverse experiences.</P> <P>(j) <E T="03">Revocation of license</E>. If a licensed manufacturer fails to establish and maintain records and make reports required under this section with respect to a licensed biological product, FDA may revoke the product license for such a product in accordance with the procedures of § 601.5 of this chapter.</P> <P>(k) <E T="03">Exemptions</E>. Manufacturers of the following listed products are not required to submit adverse experience reports under this section:</P> <P>(1) Whole blood or components of whole blood.</P> <P>(2) In vitro diagnostic products, including assay systems for the detection of antibodies or antigens to retroviruses. These products are subject to the reporting requirements for devices.</P> <P>(l) <E T="03">Disclaimer</E>. A report or information submitted by a licensed manufacturer under this section (and any release by FDA of that report or information) does not necessarily reflect a conclusion by the licensed manufacturer or FDA that the report or information constitutes an admission that the biological product caused or contributed to an adverse effect. A licensed manufacturer need not admit, and may deny, that the report or information submitted under this section constitutes an admission that the biological product caused or contributed to an adverse effect. For purposes of this provision, this paragraph also includes any person reporting under paragraph (c)(1)(iii) of this section.</P> <CITA>[59 FR 54042, Oct. 27, 1994, as amended at 62 FR 34168, June 25, 1997; 62 FR 52252, Oct. 7, 1997; 63 FR 14612, Mar. 26, 1998]</CITA> </SECTION> <SECTION> <SECTNO>§ 600.81</SECTNO> <SUBJECT>Distribution reports.</SUBJECT> <P>The licensed manufacturer shall submit information about the quantity of the product distributed under the product license, including the quantity distributed to distributors. The interval between distribution reports shall be 6 months. Upon written notice, FDA may require that the licensed manufacturer submit distribution reports under this section at times other than every 6 months. The distribution report shall consist of the bulk lot number (from which the final container was filled), the fill lot numbers for the total number of dosage units of each strength or potency distributed (e.g., fifty thousand per 10-milliliter vials), the label lot number (if different from fill lot number), labeled date of expiration, number of doses in fill lot/label lot, date of release of fill lot/label lot for distribution at that time. If any significant amount of a fill lot/label lot is returned, include this information. Disclosure of financial or pricing data is not required. As needed, FDA may require submission of more detailed product distribution information. Upon written notice, FDA may require that the licensed manufacturer submit reports under this section at times other than those stated. Requests by a licensed manufacturer to submit reports at times other than those stated should be made as a request for a waiver under § 600.90.</P> </SECTION> <SECTION> <SECTNO>§ 600.90</SECTNO> <SUBJECT>Waivers.</SUBJECT> <P>(a) A licensed manufacturer may ask the Food and Drug Administration to waive under this section any requirement that applies to the licensed manufacturer under §§ 600.80 and 600.81. A waiver request under this section is required to be submitted with supporting documentation. The waiver request is required to contain one of the following:<PRTPAGE P="18"/> </P> <P>(1) An explanation why the licensed manufacturer's compliance with the requirement is unnecessary or cannot be achieved,</P> <P>(2) A description of an alternative submission that satisfies the purpose of the requirement, or</P> <P>(3) Other information justifying a waiver.</P> <P>(b) FDA may grant a waiver if it finds one of the following:</P> <P>(1) The licensed manufacturer's compliance with the requirement is unnecessary or cannot be achieved,</P> <P>(2) The licensed manufacturer's alternative submission satisfies the requirement, or</P> <P>(3) The licensed manufacturer's submission otherwise justifies a waiver.</P> </SECTION> </SUBPART> </PART> <PART> <EAR>Pt. 601</EAR> <HD SOURCE="HED">PART 601—LICENSING</HD> <CONTENTS> <SUBPART> <HD SOURCE="HED">Subpart A—General Provisions</HD> <SECHD>Sec.</SECHD> <SECTNO>601.1</SECTNO> <SUBJECT>Two forms of licenses.</SUBJECT> <SECTNO>601.2</SECTNO> <SUBJECT>Applications for establishment and product licenses; procedures for filing.</SUBJECT> <SECTNO>601.3</SECTNO> <SUBJECT>License forms.</SUBJECT> <SECTNO>601.4</SECTNO> <SUBJECT>Issuance and denial of license.</SUBJECT> <SECTNO>601.5</SECTNO> <SUBJECT>Revocation of license.</SUBJECT> <SECTNO>601.6</SECTNO> <SUBJECT>Suspension of license.</SUBJECT> <SECTNO>601.7</SECTNO> <SUBJECT>Procedure for hearings.</SUBJECT> <SECTNO>601.8</SECTNO> <SUBJECT>Publication of revocation.</SUBJECT> <SECTNO>601.9</SECTNO> <SUBJECT>Licenses; reissuance.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart B—Establishment Licensing</HD> <SECTNO>601.10</SECTNO> <SUBJECT>Establishment licenses; issuance and conditions.</SUBJECT> <SECTNO>601.12</SECTNO> <SUBJECT>Changes to an approved application.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart C—Product Licensing</HD> <SECTNO>601.20</SECTNO> <SUBJECT>Product licenses; issuance and conditions.</SUBJECT> <SECTNO>601.21</SECTNO> <SUBJECT>Products under development.</SUBJECT> <SECTNO>601.22</SECTNO> <SUBJECT>Products in short supply; initial manufacturing at other than licensed establishment.</SUBJECT> <SECTNO>601.25</SECTNO> <SUBJECT>Review procedures to determine that licensed biological products are safe, effective, and not misbranded under prescribed, recommended, or suggested conditions of use.</SUBJECT> <SECTNO>601.26</SECTNO> <SUBJECT>Reclassification procedures to determine that licensed biological products are safe, effective, and not misbranded under prescribed, recommended, or suggested conditions of use.</SUBJECT> <SECTNO>601.27</SECTNO> <SUBJECT>Pediatric studies.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart D—Licensing of Foreign Establishments and Products</HD> <SECTNO>601.33</SECTNO> <SUBJECT>Samples for each importation.</SUBJECT> <SECTNO>601.37</SECTNO> <SUBJECT>Annual reports of postmarketing pediatric studies.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart E—Accelerated Approval of Biological Products for Serious or Life-Threatening Illnesses</HD> <SECTNO>601.40</SECTNO> <SUBJECT>Scope.</SUBJECT> <SECTNO>601.41</SECTNO> <SUBJECT>Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity.</SUBJECT> <SECTNO>601.42</SECTNO> <SUBJECT>Approval with restrictions to assure safe use.</SUBJECT> <SECTNO>601.43</SECTNO> <SUBJECT>Withdrawal procedures.</SUBJECT> <SECTNO>601.44</SECTNO> <SUBJECT>Postmarketing safety reporting.</SUBJECT> <SECTNO>601.45</SECTNO> <SUBJECT>Promotional materials.</SUBJECT> <SECTNO>601.46</SECTNO> <SUBJECT>Termination of requirements.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart F—Confidentiality of Information</HD> <SECTNO>601.50</SECTNO> <SUBJECT>Confidentiality of data and information in an investigational new drug notice for a biological product.</SUBJECT> <SECTNO>601.51</SECTNO> <SUBJECT>Confidentiality of data and information in applications for establishment and product licenses.</SUBJECT> </SUBPART> </CONTENTS> <AUTH> <HD SOURCE="HED">Authority: </HD> <P>15 U.S.C. 1451-1461; 21 U.S.C. 321, 351, 352, 353, 355, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216, 241, 262, 263.</P> </AUTH> <SOURCE> <HD SOURCE="HED">Source: </HD> <P>38 FR 32052, Nov. 20, 1973, unless otherwise noted.</P> </SOURCE> <CROSSREF> <HD SOURCE="HED"> <E T="04">Cross References:</E> </HD> <P>For U.S. Customs Service regulations relating to viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal Service regulations relating to the admissibility to the United States mails see parts 124 and 125 of the Domestic Mail Manual, that is incorporated by reference in 39 CFR part 111.</P> </CROSSREF> <SUBPART> <HD SOURCE="HED">Subpart A—General Provisions</HD> <SECTION> <SECTNO>§ 601.1</SECTNO> <SUBJECT>Two forms of licenses.</SUBJECT> <P>There shall be two forms of licenses: establishment and product.</P> </SECTION> <SECTION> <SECTNO>§ 601.2</SECTNO> <SUBJECT>Applications for establishment and product licenses; procedures for filing.</SUBJECT> <P>(a) To obtain a license for any establishment or product, the manufacturer shall make application to the Director, Center for Biologics Evaluation and Research, on forms prescribed for such purposes, and in the case of an application for a product license, shall submit <PRTPAGE P="19"/>data derived from nonclinical laboratory and clinical studies which demonstrate that the manufactured product meets prescribed standards of safety, purity, and potency; with respect to each nonclinical laboratory study, either a statement that the study was conducted in compliance with the requirements set forth in part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance; statements regarding each clinical investigation involving human subjects contained in the application, that it either was conducted in compliance with the requirements for institutional review set forth in part 56 of this chapter or was not subject to such requirements in accordance with § 56.104 or § 56.105 of this chapter, and was conducted in compliance with requirements for informed consent set forth in part 50 of this chapter; a full description of manufacturing methods; data establishing stability of the product through the dating period; sample(s) representative of the product to be sold, bartered, or exchanged or offered, sent, carried, or brought for sale, barter, or exchange; summaries of results of tests performed on the lot(s) represented by the submitted sample(s); and specimens of the labels, enclosures, containers, and, if applicable, any Medication Guide required under part 208 of this chapter proposed to be used for the product. The applicant shall also include a financial certification or disclosure statement(s) or both for clinical investigators as required by part 54 of this chapter. An application for license shall not be considered as filed until all pertinent information and data have been received from the manufacturer by the Center for Biologics Evaluation and Research. The applicant shall also include either a claim for categorical exclusion under § 25.30 or 25.31 of this chapter or an environmental assessment under § 25.40 of this chapter. In lieu of the procedures described in this paragraph, applications for radioactive biological products shall be handled as set forth in paragraph (b) of this section. The applicant, or the applicant's attorney, agent, or other authorized official shall sign the application. In lieu of the procedures described in this paragraph, applications for the following specified categories of products shall be handled as set forth in paragraph (c) of this section:</P> <P>(1) Therapeutic DNA plasmid products;</P> <P>(2) Therapeutic synthetic peptide products of 40 or fewer amino acids;</P> <P>(3) Monoclonal antibody products for in vivo use; and</P> <P>(4) Therapeutic recombinant DNA-derived products.</P> <P>(b) <E T="03">Radioactive biological products.</E> In lieu of submitting an establishment and product license for the manufacture of a radioactive biological product, as defined in § 600.3(ee) of this chapter, the manufacturer of such a product shall submit a new drug application to the Director, Division of Medical Imaging, Surgical, and Dental Products (HFD-160), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, consistent with the procedures set forth in § 314.50 of this chapter. For such products, the approval of the new drug application will be in lieu of issuing a product and an establishment license. Compliance with the provisions of part 314 of this chapter shall be deemed to constitute compliance with the provisions of Subchapter F of this chapter unless the Commissioner makes a determination that a particular regulation from Subchapter F shall be applicable to radioactive drugs containing a biological product, e.g., § 610.2 of this chapter.</P> <P>(c)(1) To obtain marketing approval for a therapeutic DNA plasmid product, therapeutic synthetic peptide product of 40 or fewer amino acids, monoclonal antibody product for in vivo use, or therapeutic recombinant DNA-derived product, an applicant shall submit to the Director, Center for Biologics Evaluation and Research, a biologics license application on a form prescribed by the Director, Center for Biologics Evaluation and Research. For such products, a separate establishment license application shall not be required. An application for a license for such a product shall include:<PRTPAGE P="20"/> </P> <P>(i) Data derived from nonclinical laboratory and clinical studies that demonstrate that the manufactured product meets prescribed standards of safety, purity, and potency; with respect to each nonclinical laboratory study, either a statement that the study was conducted in compliance with the requirements set forth in part 58 of this chapter, or,</P> <P>(ii) If the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance;</P> <P>(iii) Statements regarding each clinical investigation involving human subjects contained in the application, that it either was conducted in compliance with the requirements for institutional review set forth in part 56 of this chapter or was not subject to such requirements in accordance with §§ 56.104 or 56.105 of this chapter, and was conducted in compliance with requirements for informed consent set forth in part 50 of this chapter;</P> <P>(iv) A full description of manufacturing methods;</P> <P>(v) Data establishing stability of the product through the dating period;</P> <P>(vi) Sample(s) representative of the product to be sold, bartered, or exchanged or offered, sent, carried or brought for sale, barter, or exchange;</P> <P>(vii) Summaries of results of tests performed on the lot(s) represented by the submitted samples; and</P> <P>(viii) Specimens of the labels, enclosures, containers, and, if applicable, any Medication Guide required under part 208 of this chapter proposed to be used for the product.</P> <P>(2) An application for license shall not be considered as filed until all pertinent information and data have been received from the applicant by the Center for Biologics Evaluation and Research. The applicant shall also include either a claim for categorical exclusion under § 25.30 or 25.31 of this chapter or an environmental assessment under § 25.40 of this chapter.</P> <P>(3) Approval of the biologics license application and issuance of the biologics license shall constitute a determination that the establishment and the product meet applicable standards established in this chapter to ensure the continued safety, purity, and potency of such products. Applicable standards for the maintenance of establishments for the manufacture of a product subject to this paragraph (c) shall include the good manufacturing practice requirements set forth in parts 210 and 211 of this chapter. The following sections in parts 600 through 680 of this chapter shall not be applicable to such products: §§ 600.10(b) and (c), 600.11, 600.12, 600.13, 601.1, 610.11, 610.53, and 610.62 of this chapter.</P> <P>(4) The term “product license application,” as it is used in those sections of parts 600 through 680 of this chapter that are applicable to products subject to this paragraph (c) shall include a biologics license application for a therapeutic DNA plasmid product, therapeutic synthetic peptide product of 40 or fewer amino acids, monoclonal antibody product for in vivo use, or therapeutic recombinant DNA-derived product.</P> <P>(5) To the extent that the requirements in this paragraph (c) conflict with other requirements in this subchapter, this paragraph (c) shall supersede such other requirements.</P> <P>(6) The applicant, or the applicant's attorney, agent, or other authorized official shall sign the application.</P> <CITA>[40 FR 31313, July 25, 1975, as amended at 46 FR 8955, Jan. 27, 1981; 47 FR 6618, Feb. 16, 1982; 49 FR 23833, June 8, 1984; 50 FR 7518, Feb. 22, 1985; 50 FR 16669, Apr. 26, 1985; 55 FR 11013 and 11014, Mar. 26, 1990; 61 FR 24232, May 14, 1996; 62 FR 11769, Mar. 13, 1997; 62 FR 40600, July 29, 1997; 62 FR 53538, Oct. 15, 1997; 63 FR 5253, Feb. 2, 1998; 63 FR 66399, Dec. 1, 1998]</CITA> <EFFDNOT> <HD SOURCE="HED">Effective Date Note:</HD> <P> At 63 FR 66399, Dec. 1, 1998, § 601.2 was amended by revising the first sentence in paragraph (a) and paragraph (c)(1)(viii), effective June 1, 1999. For the convenience of the user, the superseded text follows:</P> <SUPERSED> <SECTION> <SECTNO>§ 601.2</SECTNO> <SUBJECT>Applications for establishment and product licenses; procedures for filing.</SUBJECT> <P>(a) <E T="03">General.</E> To obtain a license for any establishment or product, the manufacturer shall make application to the Director, Center for Biologics Evaluation and Research, on forms prescribed for such purposes, and in the case of an application for a product license, shall submit data derived from nonclinical laboratory and clinical studies which demonstrate that the manufactured product meets prescribed standards of safety, purity, and potency; with respect to each <PRTPAGE P="21"/>nonclinical laboratory study, either a statement that the study was conducted in compliance with the requirements set forth in part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance; statements regarding each clinical investigation involving human subjects contained in the application, that it either was conducted in compliance with the requirements for institutional review set forth in part 56 of this chapter or was not subject to such requirements in accordance with § 56.104 or § 56.105, and was conducted in compliance with requirements for informed consent set forth in part 50 of this chapter; a full description of manufacturing methods; data establishing stability of the product through the dating period; sample(s) representative of the product to be sold, bartered, or exchanged or offered, sent, carried or brought for sale, barter, or exchange; summaries of results of tests performed on the lot(s) represented by the submitted sample(s); and specimens of the labels, enclosures, and containers proposed to be used for the product.<STARS/> </P> <P>(c)(1) * * *</P> <P>(viii) Specimens of the labels, enclosures, and containers proposed to be used for the product.<STARS/> </P> </SECTION> <SECTION> <SECTNO>§ 601.3</SECTNO> <SUBJECT>License forms.</SUBJECT> <P>(a) <E T="03">Establishment license.</E> The establishment license form shall be prescribed by the Director, Center for Biologics Evaluation and Research and shall include:</P> <P>(1) The name and address of the manufacturer.</P> <P>(2) The name and address of the establishment.</P> <P>(3) The names and addresses of all locations of the establishment.</P> <P>(4) The license number.</P> <P>(5) The date of issuance.</P> <P>(b) <E T="03">Product license.</E> The product license form shall be prescribed by the Director, Center for Biologics Evaluation and Research and shall include:</P> <P>(1) The name and address of the manufacturer.</P> <P>(2) The name and address of the establishment.</P> <P>(3) The name and address of each location at which the product is manufactured.</P> <P>(4) The license number of the establishment.</P> <P>(5) The proper name of the product, with additional specifications, if any, which may be approved or required for additional labeling purposes.</P> <CITA>[38 FR 32052, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 601.4</SECTNO> <SUBJECT>Issuance and denial of license.</SUBJECT> <P>(a) An establishment or product license shall be issued upon a determination by the Director, Center for Biologics Evaluation and Research that the establishment or the product, as the case may be, meets the applicable standards established in this chapter. Licenses shall be valid until suspended or revoked.</P> <P>(b) If the Commissioner determines that the establishment or product does not meet the standards established in this chapter, he shall deny the application and inform the applicant of the grounds for, and of an opportunity for a hearing on, his decision. If the applicant so requests, the Commissioner shall issue a notice of opportunity for hearing on the matter pursuant to § 12.21(b) of this chapter.</P> <CITA>[42 FR 4718, Jan. 25, 1977, as amended at 42 FR 15676, Mar. 22, 1977; 42 FR 19142, Apr. 12, 1977; 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 601.5</SECTNO> <SUBJECT>Revocation of license.</SUBJECT> <P>(a) An establishment or product license shall be revoked upon application of the manufacturer giving notice of intention to discontinue the manufacture of all products or to discontinue the manufacture of a particular product for which a license is held, and waiving an opportunity for a hearing on the matter.</P> <P>(b) If the Commissioner finds that (1) authorized Food and Drug Administration employees after reasonable efforts have been unable to gain access to an establishment or a location for the purpose of carrying out the inspection required under § 600.21 of this chapter, (2) manufacturing of products or of a product has been discontinued to an extent that a meaningful inspection or evaluation cannot be made, (3) the manufacturer has failed to report a change as <PRTPAGE P="22"/>required by § 601.12, (4) the establishment or any location thereof, or the product for which the license has been issued, fails to conform to the applicable standards established in the license and in this chapter designed to ensure the continued safety, purity, and potency of the manufactured product, (5) the establishment or the manufacturing methods have been so changed as to require a new showing that the establishment or product meets the standards established in this chapter in order to protect the public health, or (6) the licensed product is not safe and effective for all of its intended uses or is misbranded with respect to any such use, he shall notify the licensee of his intention to revoke the license, setting forth the grounds for, and offering an opportunity for a hearing on, the proposed revocation. Except as provided in § 601.6 or in cases involving willfulness, the notification required in this paragraph shall provide a reasonable period for the licensee to demonstrate or achieve compliance with the requirements of this chapter, before proceedings will be instituted for the revocation of the license. If compliance is not demonstrated or achieved and the licensee does not waive the opportunity for a hearing, the Commissioner shall issue a notice of opportunity for hearing on the matter pursuant to § 12.21(b) of this chapter.</P> <CITA>[42 FR 4718, Jan. 25, 1977, as amended at 42 FR 15676, Mar. 22, 1977; 42 FR 19143, Apr. 12, 1977; 49 FR 23833, June 8, 1984]</CITA> </SECTION> <SECTION> <SECTNO>§ 601.6</SECTNO> <SUBJECT>Suspension of license.</SUBJECT> <P>(a) Whenever the Commissioner has reasonable grounds to believe that any of the grounds for revocation of a license exist and that by reason thereof there is a danger to health, he may notify the licensee that his license for the establishment or the product is suspended and require that the licensee (1) notify the selling agents and distributors to whom such product or products have been delivered of such suspension, and (2) furnish to the Director, Center for Biologics Evaluation and Research, complete records of such deliveries and notice of suspension.</P> <P>(b) Upon suspension of a license, the Commissioner shall either (1) proceed pursuant to the provisions of § 601.5(b) to revoke the license, or (2) if the licensee agrees, hold revocation in abeyance pending resolution of the matters involved.</P> <CITA>[42 FR 4718, Jan. 25, 1977 as amended at 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 601.7</SECTNO> <SUBJECT>Procedure for hearings.</SUBJECT> <P>(a) A notice of opportunity for hearing, notice of appearance and request for hearing, and grant or denial of hearing for a biological drug pursuant to this part, for which the exemption from the Federal Food, Drug, and Cosmetic Act in § 310.4 of this chapter has been revoked, shall be subject to the provisions of § 314.200 of this chapter except to the extent that the notice of opportunity for hearing on the matter issued pursuant to § 12.21(b) of this chapter specifically provides otherwise.</P> <P>(b) Hearings pursuant to §§ 601.4 through 601.6 shall be governed by part 12 of this chapter.</P> <P>(c) When a license has been suspended pursuant to § 601.6 and a hearing request has been granted, the hearing shall proceed on an expedited basis.</P> <CITA>[42 FR 4718, Jan. 25, 1977, as amended at 42 FR 15676, Mar. 22, 1977; 42 FR 19143, Apr. 12, 1977]</CITA> </SECTION> <SECTION> <SECTNO>§ 601.8</SECTNO> <SUBJECT>Publication of revocation.</SUBJECT> <P>Notice of revocation of a license, with statement of the cause therefor, shall be issued by the Commissioner and published in the <E T="04">Federal Register</E>.</P> <CITA>[42 FR 4718, Jan. 25, 1977]</CITA> </SECTION> <SECTION> <SECTNO>§ 601.9</SECTNO> <SUBJECT>Licenses; reissuance.</SUBJECT> <P>(a) <E T="03">Compliance with standards.</E> An establishment or product license, previously suspended or revoked, may be reissued or reinstated upon a showing of compliance with required standards and upon such inspection and examination as may be considered necessary by the Director, Center for Biologics Evaluation and Research.</P> <P>(b) <E T="03">Exclusion of noncomplying location.</E> An establishment or product license, excluding a location or locations that fail to comply with required standards, may be issued without further application and concurrently with the suspension or revocation of the license for <PRTPAGE P="23"/>noncompliance at the excluded location or locations.</P> <CITA>[42 FR 4718, Jan. 25, 1977, as amemded at 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SUBPART> <HD SOURCE="HED">Subpart B—Establishment Licensing</HD> <SECTION> <SECTNO>§ 601.10</SECTNO> <SUBJECT>Establishment licenses; issuance and conditions.</SUBJECT> <P>(a) <E T="03">Inspection—compliance with standards.</E> An establishment license shall be issued only after inspection of the establishment and upon a determination that the establishment complies with the applicable standards prescribed in the regulations in this subchapter.</P> <P>(b) <E T="03">Availability of product; simultaneous request for and issuance of product license.</E> No establishment license shall be issued unless (1) a product intended for sale, barter or exchange or intended to be offered, sent, carried or brought for sale, barter or exchange is available for examination, (2) such product is available for inspection during all phases of manufacture and (3) a product license is requested and issued simultaneously with the establishment license.</P> <P>(c) <E T="03">One establishment license to cover all locations.</E> One establishment license shall be issued to cover all locations meeting the establishment standards.</P> </SECTION> <SECTION> <SECTNO>§ 601.12</SECTNO> <SUBJECT>Changes to an approved application.</SUBJECT> <P>(a) <E T="03">General</E>. As provided by this section, an applicant shall inform Food and Drug Administration (FDA) about each change in the product, production process, quality controls, equipment, facilities, responsible personnel, or labeling, established in the approved license application(s). Before distributing a product made using a change, an applicant shall demonstrate through appropriate validation and/or other clinical and/or non-clinical laboratory studies, the lack of adverse effect of the change on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product.</P> <P>(b) <E T="03">Changes requiring supplement submission and approval prior to distribution of the product made using the change (major changes)</E>. (1) A supplement shall be submitted for any change in the product, production process, quality controls, equipment, facilities, or responsible personnel that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product.</P> <P>(2) These changes include, but are not limited to:</P> <P>(i) Changes in the qualitative or quantitative formulation or other specifications as provided in the approved application or in the regulations;</P> <P>(ii) Changes requiring completion of an appropriate human study to demonstrate the equivalence of the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product;</P> <P>(iii) Changes in the virus or adventitious agent removal or inactivation method(s);</P> <P>(iv) Changes in the source material or cell line;</P> <P>(v) Establishment of a new master cell bank or seed; and</P> <P>(vi) Changes which may affect product sterility assurance, such as changes in product or component sterilization method(s), or an addition, deletion, or substitution of steps in an aseptic processing operation.</P> <P>(3) The applicant must obtain approval of the supplement from FDA prior to distribution of the product made using the change. Except for submissions under paragraph (e) of this section, the following shall be contained in the supplement:</P> <P>(i) A detailed description of the proposed change;</P> <P>(ii) The product(s) involved;</P> <P>(iii) The manufacturing site(s) or area(s) affected;</P> <P>(iv) A description of the methods used and studies performed to evaluate the effect of the change on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product;</P> <P>(v) The data derived from such studies;</P> <P>(vi) Relevant validation protocols and data; and<PRTPAGE P="24"/> </P> <P>(vii) A reference list of relevant standard operating procedures (SOP's).</P> <P>(c) <E T="03">Changes requiring supplement submission at least 30 days prior to distribution of the product made using the change</E>. (1) A supplement shall be submitted for any change in the product, production process, quality controls, equipment, facilities, or responsible personnel that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product. The supplement shall be labeled “Supplement—Changes Being Effected in 30 Days” or, if applicable under paragraph (c)(5) of this section, “Supplement—Changes Being Effected.”</P> <P>(2) These changes include, but are not limited to:</P> <P>(i) Change in the site of testing from one facility to another;</P> <P>(ii) An increase or decrease in production scale during finishing steps that involves new or different equipment; and</P> <P>(iii) Replacement of equipment with that of similar, but not identical, design and operating principle that does not affect the process methodology or process operating parameters.</P> <P>(3) Pending approval of the supplement by FDA, and except as provided in paragraph (c)(5) of this section, distribution of the product made using the change may begin not less than 30 days after receipt of the supplement by FDA. The information listed in paragraph (b)(3)(i) through (b)(3)(vii) of this section shall be contained in the supplement.</P> <P>(4) If within 30 days following FDA's receipt of the supplement, FDA informs the applicant that either:</P> <P>(i) The change requires approval prior to distribution of the product in accordance with paragraph (b) of this section; or</P> <P>(ii) Any of the information required under paragraph (c)(3) of this section is missing; the applicant shall not distribute the product made using the change until FDA determines that compliance with this section is achieved.</P> <P>(5) In certain circumstances, FDA may determine that, based on experience with a particular type of change, the supplement for such change is usually complete and provides the proper information, and on particular assurances that the proposed change has been appropriately submitted, the product made using the change may be distributed immediately upon receipt of the supplement by FDA. These circumstances may include substantial similarity with a type of change regularly involving a “Supplement—Changes Being Effected” supplement or a situation in which the applicant presents evidence that the proposed change has been validated in accordance with an approved protocol for such change under paragraph (e) of this section.</P> <P>(d) <E T="03">Changes to be described in an annual report (minor changes)</E>. (1) Changes in the product, production process, quality controls, equipment, facilities, or responsible personnel that have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product shall be documented by the applicant in an annual report submitted each year within 60 days of the anniversary date of approval of the application. The Director, Center for Biologics Evaluation and Research, may approve a written request for an alternative date to combine annual reports for multiple approved applications into a single annual report submission.</P> <P>(2) These changes include, but are not limited to:</P> <P>(i) Any change made to comply with an official compendium that is consistent with FDA requirements;</P> <P>(ii) The deletion of an ingredient intended only to affect the color of the product except that a change intended only to affect Blood Grouping Reagents requires supplement submission and approval prior to distribution of the product made using the change in accordance with the requirements set forth in paragraph (b) of this section;</P> <P>(iii) An extension of an expiration date based upon full shelf-life data obtained from a protocol approved in the application;</P> <P>(iv) A change within the container and closure system for solid dosage <PRTPAGE P="25"/>forms, based upon a showing of equivalency to the approved system under a protocol approved in the application or published in an official compendium;</P> <P>(v) A change in the size of a container for a solid dosage form, without a change from one container and closure system to another;</P> <P>(vi) The addition by embossing, debossing, or engraving of a code imprint to a solid dosage form biological product other than a modified release dosage form, or a minor change in an existing code imprint; and</P> <P>(vii) The addition or deletion of an alternate analytical method.</P> <P>(3) The following information for each change shall be contained in the annual report:</P> <P>(i) A list of all products involved; and</P> <P>(ii) A full description of the manufacturing and controls changes including: the manufacturing site(s) or area(s) involved; the date the change was made; a cross-reference to relevant validation protocols and/or SOP's; and relevant data from studies and tests performed to evaluate the effect of the change on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product.</P> <P>(4) The applicant shall submit the report to the FDA office responsible for reviewing the application. The report shall include all the information required under this paragraph for each change made during the annual reporting interval which ends on the anniversary date in the order in which they were implemented.</P> <P>(e) An applicant may submit one or more protocols describing the specific tests and validation studies and acceptable limits to be achieved to demonstrate the lack of adverse effect for specified types of manufacturing changes on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product. Any such protocols, or change to a protocol, shall be submitted as a supplement requiring approval from FDA prior to distribution of the product which, if approved, may justify a reduced reporting category for the particular change because the use of the protocol for that type of change reduces the potential risk of an adverse effect.</P> <P>(f) <E T="03">Labeling changes</E>. (1) Labeling changes requiring supplement submission—FDA approval must be obtained before distribution of the product with the labeling change. Except as described in paragraphs (f)(2) and (f)(3) of this section, an applicant shall submit a supplement describing a proposed change in the package insert, package label, container label, or, if applicable, a Medication Guide required under part 208 of this chapter, and include the information necessary to support the proposed change. The supplement shall clearly highlight the proposed change in the labeling. The applicant shall obtain approval from FDA prior to distribution of the product with the labeling change.</P> <P>(2) <E T="03">Labeling changes requiring supplement submission—product with a labeling change that may be distributed before FDA approval</E>. (i) An applicant shall submit, at the time such change is made, a supplement for any change in the package insert, package label, or container label to accomplish any of the following:</P> <P>(A) To add or strengthen a contraindication, warning, precaution, or adverse reaction;</P> <P>(B) To add or strengthen a statement about abuse, dependence, psychological effect, or overdosage;</P> <P>(C) To add or strengthen an instruction about dosage and administration that is intended to increase the safety of the use of the product; and</P> <P>(D) To delete false, misleading, or unsupported indications for use or claims for effectiveness.</P> <P>(ii) Pending approval of the supplement by FDA, the applicant may distribute a product with a package insert, package label, or container label bearing such change at the time the supplement is submitted. The supplement shall clearly identify the change being made and include necessary supporting data. The supplement and its mailing cover shall be plainly marked: “Special Labeling Supplement—Changes Being Effected.”</P> <P>(3) <E T="03">Labeling changes requiring submission in an annual report</E>. (i) An applicant shall submit any final printed <PRTPAGE P="26"/>package insert, package label, container label, or Medication Guide required under part 208 of this chapter incorporating the following changes in an annual report submitted to FDA each year as provided in paragraph (d)(1) of this section:</P> <P>(A) Editorial or similar minor changes;</P> <P>(B) A change in the information on how the product is supplied that does not involve a change in the dosage strength or dosage form; and</P> <P>(C) A change in the information specified in § 208.20(b)(8)(iii) and (b)(8)(iv) of this chapter for a Medication Guide.</P> <P>(ii) The applicant may distribute a product with a package insert, package label, or container label bearing such change at the time the change is made.</P> <P>(4) <E T="03">Advertisements and promotional labeling</E>. Advertisements and promotional labeling shall be submitted to the Center for Biologics Evaluation and Research in accordance with the requirements set forth in § 314.81(b)(3)(i) of this chapter, except that Form FDA-2567 (Transmittal of Labels and Circulars) or an equivalent form shall be used.</P> <P>(g) <E T="03">Failure to comply</E>. In addition to other remedies available in law and regulations, in the event of repeated failure of the applicant to comply with this section, FDA may require that the applicant submit a supplement for any proposed change and obtain approval of the supplement by FDA prior to distribution of the product made using the change.</P> <P>(h) <E T="03">Administrative review</E>. Under § 10.75 of this chapter, an applicant may request internal FDA review of FDA employee decisions under this section.</P> <CITA>[62 FR 39901, July 24, 1997, as amended at 63 FR 66399, Dec. 1, 1998]</CITA> <EFFDNOT> <HD SOURCE="HED">Effective Date Note:</HD> <P> At 63 FR 66399, Dec. 1, 1998, § 601.12 was amended by revising the second sentence of paragraph (f)(1) and paragraph (f)(3)(i), effective June 1, 1999. For the convenience of the user, the superseded text follows:</P> <SUPERSED> <SECTION> <SECTNO>§ 601.12</SECTNO> <SUBJECT>Changes to an approved application.</SUBJECT> <STARS/> <P>(f) * * *</P> <P>(1) * * * Except as described in paragraphs (f)(2) and (f)(3) of this section, an applicant shall submit a supplement describing a proposed change in the package insert, package label, or container label, and include the information necessary to support the proposed change. * * *<STARS/> </P> <P>(3) * * * (i) An applicant shall submit any final printed package insert, package label, or container label incorporating the following changes in an annual report submitted to FDA each year as provided in paragraph (d)(1) of this section:</P> <P>(A) Editorial or similar minor changes; and</P> <P>(B) A change in the information on how the product is supplied that does not involve a change in the dosage strength or dosage form.<STARS/> </P> </SECTION> <SUBPART> <HD SOURCE="HED">Subpart C—Product Licensing</HD> <SECTION> <SECTNO>§ 601.20</SECTNO> <SUBJECT>Product licenses; issuance and conditions.</SUBJECT> <P>(a) <E T="03">Examination—compliance with standards.</E> A product license shall be issued only upon examination of the product and upon a determination that the product complies with the standards prescribed in the regulations in this subchapter: <E T="03">Provided,</E> That no product license shall be issued except upon a determination that the establishment complies with the establishment standards prescribed in the regulations contained in this subchapter, applicable to the manufacture of such product.</P> <P>(b) <E T="03">Manufacturing process—impairment of assurances.</E> No product shall be licensed if any part of the process of or relating to the manufacture of such product, in the judgment of the Commissioner of Food and Drugs, would impair the assurances of continued safety, purity and potency as provided by the regulations contained in this subchapter.</P> </SECTION> <SECTION> <SECTNO>§ 601.21</SECTNO> <SUBJECT>Products under development.</SUBJECT> <P>A biological product undergoing development, but not yet ready for a product license, may be shipped or otherwise delivered from one State or possession into another State or possession provided such shipment or delivery is not for sale, barter, or exchange, except as provided in section 505(i) of the Federal Food, Drug, and Cosmetic <PRTPAGE P="27"/>Act, as amended, and the regulations thereunder (21 CFR part 312).</P> <CITA>[45 FR 73923, Nov. 7, 1980, as amended at 55 FR 11014, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 601.22</SECTNO> <SUBJECT>Products in short supply; initial manufacturing at other than licensed establishment.</SUBJECT> <P>Licenses issued to a manufacturer for an establishment shall authorize persons other than such manufacturer to conduct at places other than such establishment the initial, and partial manufacturing of a product for shipment solely to such manufacturer only to the extent that the names of such persons and places are registered with the Commissioner of Food and Drugs and he finds upon application of such manufacturer, that (a) the product is in short supply due either to the peculiar growth requirements of the organism involved or to the scarcity of the animal required for manufacturing purposes, and (b) such manufacturer has established with respect to such persons and places such procedures, inspections, tests or other arrangements as will assure full compliance with the applicable regulations of this subchapter related to continued safety, purity, and potency. Such persons and places shall be subject to all regulations of this subchapter except §§ 601.1 to 601.6, 601.9, 601.10, 601.20, 601.21, 601.30 to 601.33, and §§610.60 to 610.65 of this chapter. For persons and places authorized under this section to conduct the initial and partial manufacturing of a product for shipment solely to a manufacturer of a product subject to licensure under § 601.2(c), the following additional regulations shall not be applicable: §§ 600.10(b) and (c), 600.11, 600.12, 600.13, 610.11, and 610.53 of this chapter. Failure of such manufacturer to maintain such procedures, inspections, tests, or other arrangements, or failure of any person conducting such partial manufacturing to comply with applicable regulations shall constitute a ground for suspension or revocation of the authority conferred pursuant to this section on the same basis as provided in §§ 601.6 to 601.8 with respect to the suspension and the revocation of licenses.</P> <CITA>[42 FR 4718, Jan. 25, 1977, as amended at 61 FR 24233, May 14, 1996]</CITA> </SECTION> <SECTION> <SECTNO>§ 601.25</SECTNO> <SUBJECT>Review procedures to determine that licensed biological products are safe, effective, and not misbranded under prescribed, recommended, or suggested conditions of use.</SUBJECT> <P>For purposes of reviewing biological products that have been licensed prior to July 1, 1972, to determine that they are safe and effective and not misbranded, the following regulations shall apply. Prior administrative action exempting biological products from the provisions of the Federal Food, Drug, and Cosmetic Act is superseded to the extent that these regulations result in imposing requirements pursuant to provisions therein for a designated biological product or category of products.</P> <P>(a) <E T="03">Advisory review panels.</E> The Commissioner of Food and Drugs shall appoint advisory review panels (1) to evaluate the safety and effectiveness of biological products for which a license has been issued pursuant to section 351 of the Public Health Service Act, (2) to review the labeling of such biological products, and (3) to advise him on which of the biological products under review are safe, effective, and not misbranded. An advisory review panel shall be established for each designated category of biological product. The members of a panel shall be qualified experts, appointed by the Commissioner, and shall include persons from lists submitted by organizations representing professional, consumer, and industry interests. Such persons shall represent a wide divergence of responsible medical and scientific opinion. The Commissioner shall designate the chairman of each panel, and summary minutes of all meetings shall be made.</P> <P>(b) <E T="03">Request for data and views.</E> (1) The Commissioner of Food and Drugs will publish a notice in the <E T="04">Federal Register</E> requesting interested persons to submit, for review and evaluation by an advisory review panel, published and unpublished data and information pertinent to a designated category of biological products.</P> <P>(2) Data and information submitted pursuant to a published notice, and falling within the confidentiality provisions of 18 U.S.C. 1905, 5 U.S.C. 552(b), or 21 U.S.C. 331(j), shall be handled by <PRTPAGE P="28"/>the advisory review panel and the Food and Drug Administration as confidential until publication of a proposed evaluation of the biologics under review and the full report or reports of the panel. Thirty days thereafter such data and information shall be made publicly available and may be viewed at the Dockets Management Branch of the Food and Drug Administration, except to the extent that the person submitting it demonstrates that it still falls within the confidentiality provisions of one or more of those statutes.</P> <P>(3) To be considered, 12 copies of the submission on any marketed biological product within the class shall be submitted, preferably bound, indexed, and on standard sized paper, approximately 8<FR>1/2</FR> × 11 inches. The time allotted for submissions will be 60 days, unless otherwise indicated in the specific notice requesting data and views for a particular category of biological products. When requested, abbreviated submissions should be sent. All submissions shall be in the following format, indicating “none” or “not applicable” where appropriate, unless changed in the <E T="04">Federal Register</E> notice:</P> <EXTRACT> <HD SOURCE="HD1"> <E T="04">Biological Products Review Information</E> </HD> <P>I. Label or labels and all other labeling (preferably mounted. Facsimile labeling is acceptable in lieu of actual container labeling), including labeling for export.</P> <P>II. Representative advertising used during the past 5 years.</P> <P>III. The complete quantitative composition of the biological product.</P> <P>IV. Animal safety data.</P> <P>A. Individual active components.</P> <P>1. Controlled studies.</P> <P>2. Partially controlled or uncontrolled studies.</P> <P>B. Combinations of the individual active components.</P> <P>1. Controlled studies.</P> <P>2. Partially controlled or uncontrolled studies.</P> <P>C. Finished biological product.</P> <P>1. Controlled studies.</P> <P>2. Partially controlled or uncontrolled studies.</P> <P>V. Human safety data.</P> <P>A. Individual active components.</P> <P>1. Controlled studies.</P> <P>2. Partially controlled or uncontrolled studies.</P> <P>3. Documented case reports.</P> <P>4. Pertinent marketing experiences that may influence a determination as to the safety of each individual active component.</P> <P>5. Pertinent medical and scientific literature.</P> <P>B. Combinations of the individual active components.</P> <P>1. Controlled studies.</P> <P>2. Partially controlled or uncontrolled studies.</P> <P>3. Documented case reports.</P> <P>4. Pertinent marketing experiences that may influence a determination as to the safety of combinations of the individual active components.</P> <P>5. Pertinent medical and scientific literature.</P> <P>C. Finished biological product.</P> <P>1. Controlled studies.</P> <P>2. Partially controlled or uncontrolled studies.</P> <P>3. Documented case reports.</P> <P>4. Pertinent marketing experiences that may influence a determination as to the safety of the finished biological product.</P> <P>5. Pertinent medical and scientific literature.</P> <P>VI. Efficacy data.</P> <P>A. Individual active components.</P> <P>1. Controlled studies.</P> <P>2. Partially controlled or uncontrolled studies.</P> <P>3. Documented case reports.</P> <P>4. Pertinent marketing experiences that may influence a determination on the efficacy of each individual active component.</P> <P>5. Pertinent medical and scientific literature.</P> <P>B. Combinations of the individual active components.</P> <P>1. Controlled studies.</P> <P>2. Partially controlled or uncontrolled studies.</P> <P>3. Documented case reports.</P> <P>4. Pertinent marketing experiences that may influence a determination as to the effectiveness of combinations of the individual active components.</P> <P>5. Pertinent medical and scientific literature.</P> <P>C. Finished biological product.</P> <P>1. Controlled studies.</P> <P>2. Partially controlled or uncontrolled studies.</P> <P>3. Documented case reports.</P> <P>4. Pertinent marketing experiences that may influence a determination as to the effectiveness of the finished biological product.</P> <P>5. Pertinent medical and scientific literature.</P> <P>VII. A summary of the data and views setting forth the medical rational and purpose (or lack thereof) for the biological product and its components and the scientific basis (or lack thereof) for the conclusion that the biological product, including its components, has been proven safe and effective and is properly labeled for the intended use or uses. If there is an absence of controlled studies in <PRTPAGE P="29"/>the materials submitted, an explanation as to why such studies are not considered necessary or feasible shall be included.</P> <P>VIII. If the submission is by a licensee, a statement signed by an authorized official of the licensee shall be included, stating that to the best of his or her knowledge and belief, it includes all information, favorable and unfavorable, pertinent to an evaluation of the safety, effectiveness, and labeling of the product, including information derived from investigation, commercial marketing, or published literature. If the submission is by an interested person other than a licensee, a statement signed by the person responsible for such submission shall be included, stating that to the best of his knowledge and belief, it fairly reflects a balance of all the information, favorable and unfavorable, available to him pertinent to an evaluation of the safety, effectiveness, and labeling of the product. </P> </EXTRACT> <P>(c) <E T="03">Deliberations of an advisory review panel.</E> An advisory review panel will meet as often and for as long as is appropriate to review the data submitted to it and to prepare a report containing its conclusions and recommendations to the Commissioner of Food and Drugs with respect to the safety, effectiveness, and labeling of the biological products in the designated category under review.</P> <P>(1) A panel may also consult any individual or group.</P> <P>(2) Any interested person may request in writing an opportunity to present oral views to the panel. Such written requests for oral presentations should include a summarization of the data to be presented to the panel. Such request may be granted or denied by the panel.</P> <P>(3) Any interested person may present written data and views which shall be considered by the panel. This information shall be presented to the panel in the format set forth in paragraph (b)(3) of this section and within the time period established for the biological product category in the notice for review by a panel.</P> <P>(d) <E T="03">Standards for safety, effectiveness, and labeling.</E> The advisory review panel, in reviewing the submitted data and preparing the panel's conclusions and recommendations, and the Commissioner of Food and Drugs, in reviewing and implementing the conclusions and recommendations of the panel, shall apply the following standards to determine that a biological product is safe and effective and not misbranded.</P> <P>(1) Safety means the relative freedom from harmful effect to persons affected, directly or indirectly, by a product when prudently administered, taking into consideration the character of the product in relation to the condition of the recipient at the time. Proof of safety shall consist of adequate tests by methods reasonably applicable to show the biological product is safe under the prescribed conditions of use, including results of significant human experience during use.</P> <P>(2) Effectiveness means a reasonable expectation that, in a significant proportion of the target population, the pharmacological or other effect of the biological product, when used under adequate directions, for use and warnings against unsafe use, will serve a clinically significant function in the diagnosis, cure, mitigation, treatment, or prevention of disease in man. Proof of effectiveness shall consist of controlled clinical investigations as defined in § 314.126 of this chapter, unless this requirement is waived on the basis of a showing that it is not reasonably applicable to the biological product or essential to the validity of the investigation, and that an alternative method of investigation is adequate to substantiate effectiveness. Alternate methods, such as serological response evaluation in clinical studies and appropriate animal and other laboratory assay evaluations may be adequate to substantiate effectiveness where a previously accepted correlation between data generated in this way and clinical effectiveness already exists. Investigations may be corroborated by partially controlled or uncontrolled studies, documented clinical studies by qualified experts, and reports of significant human experience during marketing. Isolated case reports, random experience, and reports lacking the details which permit scientific evaluation will not be considered.</P> <P>(3) The benefit-to-risk ratio of a biological product shall be considered in determining safety and effectiveness.</P> <P>(4) A biological product may combine two or more safe and effective active components: (i) When each active component makes a contribution to the <PRTPAGE P="30"/>claimed effect or effects; (ii) when combining of the active ingredients does not decrease the purity, potency, safety, or effectiveness of any of the individual active components; and (iii) if the combination, when used under adequate directions for use and warnings against unsafe use, provides rational concurrent preventive therapy or treatment for a significant proportion of the target population.</P> <P>(5) Labeling shall be clear and truthful in all respects and may not be false or misleading in any particular. It shall comply with section 351 of the Public Health Service Act and sections 502 and 503 of the Federal Food, Drug, and Cosmetic Act, and in particular with the applicable requirements of §§ 610.60 through 610.65 and subpart D of part 201 of this chapter.</P> <P>(e) <E T="03">Advisory review panel report to the Commissioner.</E> An advisory review panel shall submit to the Commissioner of Food and Drugs a report containing the panel's conclusions and recommendations with respect to the biological products falling within the category covered by the panel. Included within this report shall be:</P> <P>(1) A statement which designates those biological products determined by the panel to be safe and effective and not misbranded. This statement may include any condition relating to active components, labeling, tests required prior to release of lots, product standards, or other conditions necessary or appropriate for their safety and effectiveness.</P> <P>(2) A statement which designates those biological products determined by the panel to be unsafe or ineffective, or to be misbranded. The statement shall include the panel's reasons for each such determination.</P> <P>(3) A statement which designates those biological products determined by the panel not to fall within either paragraph (e) (1) or (2) of this section on the basis of the panel's conclusion that the available data are insufficient to classify such biological products, and for which further testing is therefore required. The report shall recommend with as must specificity as possible the type of further testing required and the time period within which it might reasonably be concluded. The report shall also recommend whether the product license should or should not be revoked, thus permitting or denying continued manufacturing and marketing of the biological product pending completion of the testing. This recommendation will be based on an assessment of the present evidence of the safety and effectiveness of the product and the potential benefits and risks likely to result from the continued use of the product for a limited period of time while the questions raised concerning the product are being resolved by further study.<SU>2</SU> <FTREF/> </P> <FTNT> <P> <SU>2</SU> As of November 4, 1982, the provisions under paragraphs (e)(3) and (f)(3) of this section for the interim marketing of certain biological products pending completion of additional studies have been superseded by the review and reclassification procedures under § 601.26 of this chapter. The superseded text is included for the convenience of the user only.</P> </FTNT> <P>(f) <E T="03">Proposed order.</E> After reviewing the conclusions and recommendations of the advisory review panel, the Commissioner of Food and Drugs shall publish in the <E T="04">Federal Register</E> a proposed order containing:</P> <P>(1) A statement designating the biological products in the category under review that are determined by the Commissioner of Food and Drugs to be safe and effective and not misbranded. This statement may include any condition relating to active components, labeling, tests required prior to release of lots, product standards, or other conditions necessary or appropriate for their safety and effectiveness, and may propose corresponding amendments in other regulations under this subchapter F.</P> <P>(2) A statement designating the biological products in the category under review that are determined by the Commissioner of Food and Drugs to be unsafe or ineffective, or to be misbranded, together with the reasons therefor. All licenses for such products shall be proposed to be revoked.</P> <P>(3) A statement designating the biological products not included in either of the above two statements on the basis of the Commissioner of Food and Drugs determination that the available data are insufficient to classify such <PRTPAGE P="31"/>biological products under either paragraph (f) (1) or (2) of this section. Licenses for such products may be proposed to be revoked or to remain in effect on an interim basis. Where the Commissioner determines that the potential benefits outweigh the potential risks, the proposed order shall provide that the product license for any biological product, falling within this paragraph will not be revoked but will remain in effect on an interim basis while the data necessary to support its continued marketing are being obtained for evaluation by the Food and Drug Administration. The tests necessary to resolve whatever safety or effectiveness questions exist shall be described.<SU>2</SU> <FTREF/> </P> <FTNT> <P> <SU>2</SU> As of November 4, 1982, the provisions under paragraphs (e)(3) and (f)(3) of this section for the interim marketing of certain biological products pending completion of additional studies have been superseded by the review and reclassification procedures under § 601.26 of this chapter. The superseded text is included for the convenience of the user only.</P> </FTNT> <P>(4) The full report or reports of the panel to the Commissioner of Food and Drugs. </P> <EXTRACT> <P>The summary minutes of the panel meeting or meetings shall be made available to interested persons upon request. Any interested person may within 90 days after publication of the proposed order in the <E T="04">Federal Register,</E> file with the Hearing Clerk of the Food and Drug Administration written comments in quintuplicate. Comments may be accompanied by a memorandum or brief in support thereof. All comments may be reviewed at the office of the Dockets Management Branch during regular working hours, Monday through Friday. </P> </EXTRACT> <P>(g) <E T="03">Final order.</E> After reviewing the comments, the Commissioner of Food and Drugs shall publish in the <E T="04">Federal Register</E> a final order on the matters covered in the proposed order. The final order shall become effective as specified in the order.</P> <P>(h) [Reserved]</P> <P>(i) <E T="03">Court Appeal.</E> The final order(s) published pursuant to paragraph (g) of this section, and any notice published pursuant to paragraph (h) of this section, constitute final agency action from which appeal lies to the courts. The Food and Drug Administration will request consolidation of all appeals in a single court. Upon court appeal, the Commissioner of Food and Drugs may, at his discretion, stay the effective date for part or all of the final order or notice, pending appeal and final court adjudication.</P> <CITA>[38 FR 32052, Nov. 20, 1973, as amended at 39 FR 11535, Mar. 29, 1974; 40 FR 13498, Mar. 27, 1975; 43 FR 44838, Sept. 29, 1978; 47 FR 44071, Oct. 5, 1982; 47 FR 50211, Nov. 5, 1982; 51 FR 15607, Apr. 25, 1986; 55 FR 11014, Mar. 26, 1990; 62 FR 53538, Oct. 15, 1997]</CITA> </SECTION> <SECTION> <SECTNO>§ 601.26</SECTNO> <SUBJECT>Reclassification procedures to determine that licensed biological products are safe, effective, and not misbranded under prescribed, recommended, or suggested conditions of use.</SUBJECT> <P>This regulation establishes procedures for the reclassification of all biological products that have been classified into Category IIIA. A Category IIIA biological product is one for which an advisory review panel has recommended under § 601.25(e)(3), the Commissioner of Food and Drugs (Commissioner) has proposed under § 601.25(f)(3), or the Commissioner has finally decided under § 601.25(g) that available data are insufficient to determine whether the product license should be revoked or affirmed and which may be marketed pending the completion of further testing. All of these Category IIIA products will either be reclassified into Category I (safe, effective, and not misbranded) or Category II (unsafe, ineffective, or misbranded) in accordance with the procedures set forth below.</P> <P>(a) <E T="03">Advisory review panels.</E> The Commissioner will appoint advisory review panels and use existing advisory review panels to (1) evaluate the safety and effectiveness of all Category IIIA biological products; (2) review the labeling of such products; and (3) advise the Commissioner on which Category IIIA biological products are safe, effective, and not misbranded. These advisory review panels will be established in accordance with procedures set forth in § 601.25(a).</P> <P>(b) <E T="03">Deliberations of advisory review panels.</E> The deliberations of advisory review panels will be conducted in accordance with § 601.25(d).</P> <P>(c) <E T="03">Advisory review panel report to the Commissioner.</E> An advisory review panel <PRTPAGE P="32"/>shall submit to the Commissioner a report containing the panel's conclusions and recommendations with respect to the biological products falling within the category of products reviewed by the panel. The panel report shall include:</P> <P>(1) A statement designating the biological products in the category under review in accordance with either § 601.25(e)(1) or § 601.25(e)(2).</P> <P>(2) A statement identifying those biological products designated under § 601.25(e)(2) that the panel recommends should be designated as safe and presumptively effective and should remain on the market pending completion of further testing because there is a compelling medical need and no suitable alternative therapeutic, prophylactic, or diagnostic agent that is available in sufficient quantities to meet current medical needs. For the products or categories of products so recommended, the report shall include: </P> <P>(i) A description and evaluation of the available evidence concerning effectiveness and an explanation why the evidence shows that the product has any benefit; and</P> <P>(ii) A description of the alternative therapeutic, prophylactic, or diagnostic agents considered and a statement of why such alternatives are not suitable. In making this recommendation the panel shall also take into account the seriousness of the condition intended to be treated, prevented, or diagnosed by the product, the risks involved in the continued use of the product, and the likelihood that, based upon existing data, the effectiveness of the product can eventually be established by further testing and new test development. The report shall also recommend with as much specificity as possible the type of further testing required and the time period within which it might reasonably be concluded.</P> <P>(d) <E T="03">Proposed order.</E> After reviewing the conclusions and recommendations of the advisory review panels, the Commissioner shall publish in the <E T="04">Federal Register</E> a proposed order containing:</P> <P>(1) A statement designating the biological products in the category under review in accordance with either § 601.25(e)(1) or 601.25(e)(2);</P> <P>(2) A notice of availability of the full panel report or reports. The full panel report or reports shall be made publicly available at the time of publication of the proposed order.</P> <P>(3) A proposal to accept or reject the findings of the advisory review panel required by § 601.26(c)(2)(i) and (ii).</P> <P>(4) A statement identifying those biological products that the Commissioner proposes should be designated as safe and presumptively effective under § 601.26(c)(2) and should be permitted to remain on the market pending completion of further testing because there is a compelling medical need and no suitable alternative therapeutic, prophylactic, or diagnostic agent for the product that is available in sufficient quantities to meet current medical needs. In making this proposal, the Commissioner shall take into account the seriousness of the condition to be treated, prevented, or diagnosed by the product, the risks involved in the continued use of the product, and the likelihood that, based upon existing data, the effectiveness of the product can eventually be established by further testing.</P> <P>(e) <E T="03">Final order.</E> After reviewing the comments on the proposed order, the Commissioner shall publish in the <E T="04">Federal Register</E> a final order on the matters covered in the proposed order. Where the Commissioner determines that there is a compelling medical need and no suitable alternative therapeutic, prophylactic, or diagnostic agent for any biological product that is available in sufficient quantities to meet current medical needs, the final order shall provide that the product license for that biological product will not be revoked, but will remain in effect on an interim basis while the data necessary to support its continued marketing are being obtained for evaluation by the Food and Drug Administration. The final order shall describe the tests necessary to resolve whatever effectiveness questions exist.</P> <P>(f) <E T="03">Additional studies and labeling.</E> (1) Within 60 days following publication of the final order, each licensee for a biological product designated as requiring further study to justify continued marketing on an interim basis, pursuant to paragraph (e) of this section, shall submit to the Commissioner a written <PRTPAGE P="33"/>statement intended to show that studies adequate and appropriate to resolve the questions raised about the product have been undertaken. The Federal Government may undertake the studies. Any study involving a clinical investigation that involves human subjects shall be conducted in compliance with the requirements for informed consent under part 50 of this chapter. Such a study is also subject to the requirements for institutional review under part 56 of this chapter unless exempt under § 56.104 or § 56.105. The Commissioner may extend this 60-day period if necessary, either to review and act on proposed protocols or upon indication from the licensee that the studies will commence at a specified reasonable time. If no such commitment is made, or adequate and appropriate studies are not undertaken, the product license or licenses shall be revoked.</P> <P>(2) A progress report shall be filed on the studies by January 1 and July 1 until completion. If the progress report is inadequate or if the Commissioner concludes that the studies are not being pursued promptly and diligently, or if interim results indicate the product is not a medical necessity, the product license or licenses shall be revoked.</P> <P>(3) Promptly upon completion of the studies undertaken on the product, the Commissioner will review all available data and will either retain or revoke the product license or licenses involved. In making this review the Commissioner may again consult the advisory review panel which prepared the report on the product, or other advisory committees, professional organizations, or experts. The Commissioner shall take such action by notice published in the <E T="04">Federal Register</E>.</P> <P>(4) Labeling and promotional material for those biological products requiring additional studies shall bear a box statement in the following format:</P> <BOXTXT> <P SOURCE="P1-1">Based on a review by the (<E T="03">insert name of appropriate advisory review panel</E>) and other information, the Food and Drug Administration has directed that further investigation be conducted before this product is conclusively determined to be effective for labeled indication(s). </P> </BOXTXT> <P>(5) A written informed consent shall be obtained from participants in any additional studies required under paragraph (f)(1) of this section, explaining the nature of the product and the investigation. The explanation shall consist of such disclosure and be made so that intelligent and informed consent be given and that a clear opportunity to refuse is presented.</P> <P>(g) <E T="03">Court appeal.</E> The final order(s) published pursuant to paragraph (e) of this section constitute final agency action from which appeal lies to the courts. The Food and Drug Administration will request consolidation of all appeals in a single court. Upon court appeal, the Commissioner of Food and Drugs may, at the Commissioner's discretion, stay the effective date for part or all of the final order or notice, pending appeal and final court adjudication.</P> <P>(h) [Reserved]</P> <P>(i) <E T="03">Institutional review and informed consent.</E> Information and data submitted under this section after July 27, 1981, shall include statements regarding each clinical investigation involving human subjects, that it was conducted in compliance with the requirements for informed consent under part 50 of this chapter. Such a study is also subject to the requirements for institutional review under part 56 of this chapter, unless exempt under § 56.104 or § 56.105.</P> <CITA>[47 FR 44071, Oct. 5, 1982]</CITA> </SECTION> <SECTION> <SECTNO>§ 601.27</SECTNO> <SUBJECT>Pediatric studies.</SUBJECT> <P>(a) <E T="03">Required assessment.</E> Except as provided in paragraphs (b), (c), and (d) of this section, each application for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration shall contain data that are adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. Where the course of the disease and the effects of the product are similar in adults and pediatric patients, FDA may conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled effectiveness studies in adults, usually supplemented <PRTPAGE P="34"/>with other information in pediatric patients, such as pharmacokinetic studies. In addition, studies may not be needed in each pediatric age group, if data from one age group can be extrapolated to another. Assessments required under this section for a product that represents a meaningful therapeutic benefit over existing treatments must be carried out using appropriate formulations for the age group(s) for which the assessment is required.</P> <P>(b) <E T="03">Deferred submission.</E> (1) FDA may, on its own initiative or at the request of an applicant, defer submission of some or all assessments of safety and effectiveness described in paragraph (a) of this section until after licensing of the product for use in adults. Deferral may be granted if, among other reasons, the product is ready for approval in adults before studies in pediatric patients are complete, pediatric studies should be delayed until additional safety or effectiveness data have been collected. If an applicant requests deferred submission, the request must provide an adequate justification for delaying pediatric studies, a description of the planned or ongoing studies, and evidence that the studies are being or will be conducted with due diligence and at the earliest possible time.</P> <P>(2) If FDA determines that there is an adequate justification for temporarily delaying the submission of assessments of pediatric safety and effectiveness, the product may be licensed for use in adults subject to the requirement that the applicant submit the required assessments within a specified time.</P> <P>(c) <E T="03">Waivers</E>—(1) <E T="03">General.</E> FDA may grant a full or partial waiver of the requirements of paragraph (a) of this section on its own initiative or at the request of an applicant. A request for a waiver must provide an adequate justification.</P> <P>(2) <E T="03">Full waiver.</E> An applicant may request a waiver of the requirements of paragraph (a) of this section if the applicant certifies that:</P> <P>(i) The product does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients and is not likely to be used in a substantial number of pediatric patients;</P> <P>(ii) Necessary studies are impossible or highly impractical because, e.g., the number of such patients is so small or geographically dispersed; or</P> <P>(iii) There is evidence strongly suggesting that the product would be ineffective or unsafe in all pediatric age groups.</P> <P>(3) <E T="03">Partial waiver.</E> An applicant may request a waiver of the requirements of paragraph (a) of this section with respect to a specified pediatric age group, if the applicant certifies that:</P> <P>(i) The product does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients in that age group, and is not likely to be used in a substantial number of patients in that age group;</P> <P>(ii) Necessary studies are impossible or highly impractical because, e.g., the number of patients in that age group is so small or geographically dispersed;</P> <P>(iii) There is evidence strongly suggesting that the product would be ineffective or unsafe in that age group; or</P> <P>(iv) The applicant can demonstrate that reasonable attempts to produce a pediatric formulation necessary for that age group have failed.</P> <P>(4) <E T="03">FDA action on waiver.</E> FDA shall grant a full or partial waiver, as appropriate, if the agency finds that there is a reasonable basis on which to conclude that one or more of the grounds for waiver specified in paragraphs (c)(2) or (c)(3) of this section have been met. If a waiver is granted on the ground that it is not possible to develop a pediatric formulation, the waiver will cover only those pediatric age groups requiring that formulation. If a waiver is granted because there is evidence that the product would be ineffective or unsafe in pediatric populations, this information will be included in the product's labeling.</P> <P>(5) <E T="03">Definition of “meaningful therapeutic benefit”.</E> For purposes of this section, a product will be considered to offer a meaningful therapeutic benefit over existing therapies if FDA estimates that:</P> <P>(i) If approved, the product would represent a significant improvement in the treatment, diagnosis, or prevention of a disease, compared to marketed products adequately labeled for that <PRTPAGE P="35"/>use in the relevant pediatric population. Examples of how improvement might be demonstrated include, e.g., evidence of increased effectiveness in treatment, prevention, or diagnosis of disease; elimination or substantial reduction of a treatment-limiting drug reaction; documented enhancement of compliance; or evidence of safety and effectiveness in a new subpopulation; or</P> <P>(ii) The product is in a class of products or for an indication for which there is a need for additional therapeutic options.</P> <P>(d) <E T="03">Exemption for orphan drugs.</E> This section does not apply to any product for an indication or indications for which orphan designation has been granted under part 316, subpart C, of this chapter.</P> <CITA>[63 FR 66671, Dec. 2, 1998]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart D—Licensing of Foreign Establishments and Products</HD> <SECTION> <SECTNO>§ 601.33</SECTNO> <SUBJECT>Samples for each importation.</SUBJECT> <P>Random samples of each importation, obtained by the District Director of Customs and forwarded to the Director, Center for Biologics Evaluation and Research, shall be at least two final containers of each lot of product. A copy of the associated documents which describe and identify the shipment shall accompany the shipment for forwarding with the samples to the Director, Center for Biologics Evaluation and Research. For shipments of 20 or less final containers, samples need not be forwarded, provided a copy of an official release from the Center for Biologics Evaluation and Research accompanies each shipment.</P> <CITA>[38 FR 32052, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 601.37</SECTNO> <SUBJECT>Annual reports of postmarketing pediatric studies.</SUBJECT> <P>Sponsors of licensed biological products shall submit the following information each year within 60 days of the anniversary date of approval of the license, to the Director, Center for Biologics Evaluation and Research:</P> <P>(a) <E T="03">Summary.</E> A brief summary stating whether labeling supplements for pediatric use have been submitted and whether new studies in the pediatric population to support appropriate labeling for the pediatric population have been initiated. Where possible, an estimate of patient exposure to the drug product, with special reference to the pediatric population (neonates, infants, children, and adolescents) shall be provided, including dosage form.</P> <P>(b) <E T="03">Clinical data.</E> Analysis of available safety and efficacy data in the pediatric population and changes proposed in the labeling based on this information. An assessment of data needed to ensure appropriate labeling for the pediatric population shall be included.</P> <P>(c) <E T="03">Status reports.</E> A statement on the current status of any postmarketing studies in the pediatric population performed by, or on behalf of, the applicant. The statement shall include whether postmarketing clinical studies in pediatric populations were required or agreed to, and if so, the status of these studies, e.g., to be initiated, ongoing (with projected completion date), completed (including date), completed and results submitted to the BLA (including date).</P> <CITA>[63 FR 66672, Dec. 2, 1998]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart E—Accelerated Approval of Biological Products for Serious or Life-Threatening Illnesses</HD> <SOURCE> <HD SOURCE="HED">Source: </HD> <P>57 FR 58959, Dec. 11, 1992, unless otherwise noted.</P> </SOURCE> <SECTION> <SECTNO>§ 601.40</SECTNO> <SUBJECT>Scope.</SUBJECT> <P>This subpart applies to certain biological products that have been studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments (e.g., ability to treat patients unresponsive to, or intolerant of, available therapy, or improved patient response over available therapy).</P> </SECTION> <SECTION> <SECTNO>§ 601.41</SECTNO> <SUBJECT>Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity.</SUBJECT> <P>FDA may grant marketing approval for a biological product on the basis of <PRTPAGE P="36"/>adequate and well-controlled clinical trials establishing that the biological product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity. Approval under this section will be subject to the requirement that the applicant study the biological product further, to verify and describe its clinical benefit, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome. Postmarketing studies would usually be studies already underway. When required to be conducted, such studies must also be adequate and well-controlled. The applicant shall carry out any such studies with due diligence.</P> </SECTION> <SECTION> <SECTNO>§ 601.42</SECTNO> <SUBJECT>Approval with restrictions to assure safe use.</SUBJECT> <P>(a) If FDA concludes that a biological product shown to be effective can be safely used only if distribution or use is restricted, FDA will require such postmarketing restrictions as are needed to assure safe use of the biological product, such as:</P> <P>(1) Distribution restricted to certain facilities or physicians with special training or experience; or</P> <P>(2) Distribution conditioned on the performance of specified medical procedures.</P> <P>(b) The limitations imposed will be commensurate with the specific safety concerns presented by the biological product.</P> </SECTION> <SECTION> <SECTNO>§ 601.43</SECTNO> <SUBJECT>Withdrawal procedures.</SUBJECT> <P>(a) For biological products approved under §§ 601.40 and 601.42, FDA may withdraw approval, following a hearing as provided in part 15 of this chapter, as modified by this section, if:</P> <P>(1) A postmarketing clinical study fails to verify clinical benefit;</P> <P>(2) The applicant fails to perform the required postmarketing study with due diligence;</P> <P>(3) Use after marketing demonstrates that postmarketing restrictions are inadequate to ensure safe use of the biological product;</P> <P>(4) The applicant fails to adhere to the postmarketing restrictions agreed upon;</P> <P>(5) The promotional materials are false or misleading; or</P> <P>(6) Other evidence demonstrates that the biological product is not shown to be safe or effective under its conditions of use.</P> <P>(b) <E T="03">Notice of opportunity for a hearing</E>. The Director of the Center for Biologics Evaluation and Research will give the applicant notice of an opportunity for a hearing on the Center's proposal to withdraw the approval of an application approved under § 601.40 or § 601.41. The notice, which will ordinarily be a letter, will state generally the reasons for the action and the proposed grounds for the order.</P> <P>(c) <E T="03">Submission of data and information</E>. (1) If the applicant fails to file a written request for a hearing within 15 days of receipt of the notice, the applicant waives the opportunity for a hearing.</P> <P>(2) If the applicant files a timely request for a hearing, the agency will publish a notice of hearing in the <E T="04">Federal Register</E> in accordance with §§ 12.32(e) and 15.20 of this chapter.</P> <P>(3) An applicant who requests a hearing under this section must, within 30 days of receipt of the notice of opportunity for a hearing, submit the data and information upon which the applicant intends to rely at the hearing.</P> <P>(d) <E T="03">Separation of functions</E>. Separation of functions (as specified in § 10.55 of this chapter) will not apply at any point in withdrawal proceedings under this section.</P> <P>(e) <E T="03">Procedures for hearings</E>. Hearings held under this section will be conducted in accordance with the provisions of part 15 of this chapter, with the following modifications:</P> <P>(1) An advisory committee duly constituted under part 14 of this chapter will be present at the hearing. The committee will be asked to review the issues involved and to provide advice and recommendations to the Commissioner of Food and Drugs.</P> <P>(2) The presiding officer, the advisory committee members, up to three representatives of the applicant, and up to three representatives of the Center <PRTPAGE P="37"/>may question any person during or at the conclusion of the person's presentation. No other person attending the hearing may question a person making a presentation. The presiding officer may, as a matter of discretion, permit questions to be submitted to the presiding officer for response by a person making a presentation.</P> <P>(f) <E T="03">Judicial review</E>. The Commissioner's decision constitutes final agency action from which the applicant may petition for judicial review. Before requesting an order from a court for a stay of action pending review, an applicant must first submit a petition for a stay of action under § 10.35 of this chapter.</P> </SECTION> <SECTION> <SECTNO>§ 601.44</SECTNO> <SUBJECT>Postmarketing safety reporting.</SUBJECT> <P>Biological products approved under this program are subject to the postmarketing recordkeeping and safety reporting applicable to all approved biological products.</P> </SECTION> <SECTION> <SECTNO>§ 601.45</SECTNO> <SUBJECT>Promotional materials.</SUBJECT> <P>For biological products being considered for approval under this subpart, unless otherwise informed by the agency, applicants must submit to the agency for consideration during the preapproval review period copies of all promotional materials, including promotional labeling as well as advertisements, intended for dissemination or publication within 120 days following marketing approval. After 120 days following marketing approval, unless otherwise informed by the agency, the applicant must submit promotional materials at least 30 days prior to the intended time of initial dissemination of the labeling or initial publication of the advertisement.</P> </SECTION> <SECTION> <SECTNO>§ 601.46</SECTNO> <SUBJECT>Termination of requirements.</SUBJECT> <P>If FDA determines after approval that the requirements established in § 601.42, § 601.43, or § 601.45 are no longer necessary for the safe and effective use of a biological product, it will so notify the applicant. Ordinarily, for biological products approved under § 601.41, these requirements will no longer apply when FDA determines that the required postmarketing study verifies and describes the biological product's clinical benefit and the biological product would be appropriate for approval under traditional procedures. For biological products approved under § 601.42, the restrictions would no longer apply when FDA determines that safe use of the biological product can be assured through appropriate labeling. FDA also retains the discretion to remove specific postapproval requirements upon review of a petition submitted by the sponsor in accordance with § 10.30.</P> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart F—Confidentiality of Information</HD> <SECTION> <SECTNO>§ 601.50</SECTNO> <SUBJECT>Confidentiality of data and information in an investigational new drug notice for a biological product.</SUBJECT> <P>(a) The existence of an IND notice for a biological product will not be disclosed by the Food and Drug Administration unless it has previously been publicly disclosed or acknowledged.</P> <P>(b) The availability for public disclosure of all data and information in an IND file for a biological product shall be handled in accordance with the provisions established in § 601.51.</P> <P>(c) Notwithstanding the provisions of § 601.51, the Food and Drug Administration shall disclose upon request to an individual on whom an investigational biological product has been used a copy of any adverse reaction report relating to such use.</P> <CITA>[39 FR 44656, Dec. 24, 1974]</CITA> </SECTION> <SECTION> <SECTNO>§ 601.51</SECTNO> <SUBJECT>Confidentiality of data and information in applications for establishment and product licenses.</SUBJECT> <P>(a) For purposes of this section the <E T="03">biological product file</E> includes all data and information submitted with or incorporated by reference in any application for an establishment or product license, IND's incorporated into any such application, master files, and other related submissions. The availability for public disclosure of any record in the biological product file shall be handled in accordance with the provisions of this section.</P> <P>(b) The existence of a biological product file will not be disclosed by the Food and Drug Administration before a product license has been sent to the applicant, unless it has previously been <PRTPAGE P="38"/>publicly disclosed or acknowledged. The Director of the Center for Biologics Evaluation and Research will maintain a list available for public disclosure of biological products for which a license has been issued.</P> <P>(c) If the existence of a biological product file has not been publicly disclosed or acknowledged, no data or information in the biological product file is available for public disclosure.</P> <P>(d)(1) If the existence of a biological product file has been publicly disclosed or acknowledged before a license has been issued, no data or information contained in the file is available for public disclosure before such license is issued, but the Commissioner may, in his discretion, disclose a summary of such selected portions of the safety and effectiveness data as are appropriate for public consideration of a specific pending issue, e.g., at an open session of a Food and Drug Administration advisory committee or pursuant to an exchange of important regulatory information with a foreign government.</P> <P>(2) Notwithstanding paragraph (d)(1) of this section, FDA will make available to the public upon request the information in the IND that was required to be filed in Docket Number 95S-0158 in the Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857, for investigations involving an exception from informed consent under § 50.24 of this chapter. Persons wishing to request this information shall submit a request under the Freedom of Information Act.</P> <P>(e) After a license has been issued, the following data and information in the biological product file are immediately available for public disclosure unless extraordinary circumstances are shown:</P> <P>(1) All safety and effectiveness data and information.</P> <P>(2) A protocol for a test or study, unless it is shown to fall within the exemption established for trade secrets and confidential commercial or financial information in § 20.61 of this chapter.</P> <P>(3) Adverse reaction reports, product experience reports, consumer complaints, and other similar data and information, after deletion of:</P> <P>(i) Names and any information that would identify the person using the product.</P> <P>(ii) Names and any information that would identify any third party involved with the report, such as a physician or hospital or other institution.</P> <P>(4) A list of all active ingredients and any inactive ingredients previously disclosed to the public, as defined in § 20.81 of this chapter.</P> <P>(5) An assay method or other analytical method, unless it serves no regulatory or compliance purpose and it is shown to fall within the exemption established in § 20.61 of this chapter.</P> <P>(6) All correspondence and written summaries of oral discussions relating to the biological product file, in accordance with the provisions of part 20 of this chapter.</P> <P>(7) All records showing the manufacturer's testing of a particular lot, after deletion of data or information that would show the volume of the drug produced, manufacturing procedures and controls, yield from raw materials, costs, or other material falling within § 20.61 of this chapter.</P> <P>(8) All records showing the testing of and action on a particular lot by the Food and Drug Administration.</P> <P>(f) The following data and information in a biological product file are not available for public disclosure unless they have been previously disclosed to the public as defined in § 20.81 of this chapter or they relate to a product or ingredient that has been abandoned and they no longer represent a trade secret or confidential commercial or financial information as defined in § 20.61 of this chapter:</P> <P>(1) Manufacturing methods or processes, including quality control procedures.</P> <P>(2) Production, sales, distribution, and similar data and information, except that any compilation of such data and information aggregated and prepared in a way that does not reveal data or information which is not available for public disclosure under this provision is available for public disclosure.</P> <P>(3) Quantitative or semiquantitative formulas.</P> <P>(g) For purposes of this regulation, safety and effectiveness data include <PRTPAGE P="39"/>all studies and tests of a biological product on animals and humans and all studies and tests on the drug for identity, stability, purity, potency, and bioavailability.</P> <CITA>[39 FR 44656, Dec. 24, 1974, as amended at 42 FR 15676, Mar. 22, 1977; 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 61 FR 51530, Oct. 2, 1996]</CITA> </SECTION> </SUBPART> <PART> <EAR>Pt. 606</EAR> <HD SOURCE="HED">PART 606—CURRENT GOOD MANUFACTURING PRACTICE FOR BLOOD AND BLOOD COMPONENTS</HD> <CONTENTS> <SUBPART> <HD SOURCE="HED">Subpart A—General Provisions</HD> <SECHD>Sec.</SECHD> <SECTNO>606.3</SECTNO> <SUBJECT>Definitions.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart B—Organization and Personnel</HD> <SECTNO>606.20</SECTNO> <SUBJECT>Personnel.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart C—Plant and Facilities</HD> <SECTNO>606.40</SECTNO> <SUBJECT>Facilities.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart D—Equipment</HD> <SECTNO>606.60</SECTNO> <SUBJECT>Equipment.</SUBJECT> <SECTNO>606.65</SECTNO> <SUBJECT>Supplies and reagents.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart E[Reserved]</HD> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart F—Production and Process Controls</HD> <SECTNO>606.100</SECTNO> <SUBJECT>Standard operating procedures.</SUBJECT> <SECTNO>606.110</SECTNO> <SUBJECT>Plateletpheresis, leukapheresis, and plasmapheresis.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart G—Finished Product Control</HD> <SECTNO>606.120</SECTNO> <SUBJECT>Labeling, general requirements.</SUBJECT> <SECTNO>606.121</SECTNO> <SUBJECT>Container label.</SUBJECT> <SECTNO>606.122</SECTNO> <SUBJECT>Instruction circular.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart H—Laboratory Controls</HD> <SECTNO>606.140</SECTNO> <SUBJECT>Laboratory controls.</SUBJECT> <SECTNO>606.151</SECTNO> <SUBJECT>Compatibility testing.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart I—Records and Reports</HD> <SECTNO>606.160</SECTNO> <SUBJECT>Records.</SUBJECT> <SECTNO>606.165</SECTNO> <SUBJECT>Distribution and receipt; procedures and records.</SUBJECT> <SECTNO>606.170</SECTNO> <SUBJECT>Adverse reaction file.</SUBJECT> </SUBPART> </CONTENTS> <AUTH> <HD SOURCE="HED">Authority: </HD> <P>21 U.S.C. 321, 331, 351, 352, 355, 360, 360j, 371, 374; 42 U.S.C. 216, 262, 263a, 264.</P> </AUTH> <SOURCE> <HD SOURCE="HED">Source: </HD> <P>40 FR 53532, Nov. 18, 1975, unless otherwise noted.</P> </SOURCE> <SUBPART> <HD SOURCE="HED">Subpart A—General Provisions</HD> <SECTION> <SECTNO>§ 606.3</SECTNO> <SUBJECT>Definitions.</SUBJECT> <P>As used in this part:</P> <P>(a) <E T="03">Blood</E> means whole blood collected from a single donor and processed either for transfusion or further manufacturing.</P> <P>(b) <E T="03">Unit</E> means the volume of blood or one of its components in a suitable volume of anticoagulant obtained from a single collection of blood from one donor.</P> <P>(c) <E T="03">Component</E> means that part of a single-donor unit of blood separated by physical or mechanical means.</P> <P>(d) <E T="03">Plasma for further manufacturing</E> means that liquid portion of blood separated and used as material to prepare another product.</P> <P>(e) <E T="03">Plasmapheresis</E> means the procedure in which blood is removed from the donor, the plasma is separated from the formed elements and at least the red blood cells are returned to the donor. This process may be immediately repeated, once.</P> <P>(f) <E T="03">Plateletpheresis</E> means the procedure in which blood is removed from the donor, a platelet concentrate is separated, and the remaining formed elements and residual plasma are returned to the donor.</P> <P>(g) <E T="03">Leukapheresis</E> means the procedure in which blood is removed from the donor, a leukocyte concentrate is separated, and the remaining formed elements and residual plasma are returned to the donor.</P> <P>(h) <E T="03">Facilities</E> means any area used for the collection, processing, compatibility testing, storage or distribution of blood and blood components.</P> <P>(i) <E T="03">Processing</E> means any procedure employed after collection and before compatibility testing of blood and includes the identification of a unit of donor blood, the preparation of components from such unit of donor blood, serological testing, labeling and associated recordkeeping.</P> <P>(j) <E T="03">Compatibility testing</E> means the in vitro serological tests performed on donor and recipient blood samples to establish the serological matching of a donor's blood or blood components with that of a potential recipient.</P> </SECTION> </SUBPART> <SUBPART> <PRTPAGE P="40"/> <HD SOURCE="HED">Subpart B—Organization and Personnel</HD> <SECTION> <SECTNO>§ 606.20</SECTNO> <SUBJECT>Personnel.</SUBJECT> <P>(a) [Reserved]</P> <P>(b) The personnel responsible for the collection, processing, compatibility testing, storage or distribution of blood or blood components shall be adequate in number, educational background, training and experience, including professional training as necessary, or combination thereof, to assure competent performance of their assigned functions, and to ensure that the final product has the safety, purity, potency, identity and effectiveness it purports or is represented to possess. All personnel shall have capabilities commensurate with their assigned functions, a thorough understanding of the procedures or control operations they perform, the necessary training or experience, and adequate information concerning the application of pertinent provisions of this part to their respective functions.</P> <P>(c) Persons whose presence can adversely affect the safety and purity of the products shall be excluded from areas where the collection, processing, compatibility testing, storage or distribution of blood or blood components is conducted.</P> <CITA>[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 55 FR 11014, Mar. 26, 1990; 62 FR 53538, Oct. 15, 1997]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart C—Plant and Facilities</HD> <SECTION> <SECTNO>§ 606.40</SECTNO> <SUBJECT>Facilities.</SUBJECT> <P>Facilities shall be maintained in a clean and orderly manner, and shall be of suitable size, construction and location to facilitate adequate cleaning, maintenance and proper operations. The facilities shall:</P> <P>(a) Provide adequate space for the following when applicable:</P> <P>(1) Private and accurate examinations of individuals to determine their suitability as blood donors.</P> <P>(2) The withdrawal of blood from donors with minimal risk of contamination, or exposure to activities and equipment unrelated to blood collection.</P> <P>(3) The storage of blood or blood components pending completion of tests.</P> <P>(4) The quarantine storage of blood or blood components in a designated location pending repetition of those tests that initially gave questionable serological results.</P> <P>(5) The storage of finished products prior to distribution.</P> <P>(6) The quarantine storage, handling and disposition of products and reagents not suitable for use.</P> <P>(7) The orderly collection, processing, compatibility testing, storage and distribution of blood and blood components to prevent contamination.</P> <P>(8) The adequate and proper performance of all steps in plasmapheresis, plateletpheresis and leukapheresis procedures.</P> <P>(9) The orderly conduction of all packaging, labeling and other finishing operations.</P> <P>(b) Provide adequate lighting, ventilation and screening of open windows and doors.</P> <P>(c) Provide adequate, clean, and convenient handwashing facilities for personnel, and adequate, clean, and convenient toilet facilities for donors and personnel. Drains shall be of adequate size and, where connected directly to a sewer, shall be equipped with traps to prevent back-siphonage.</P> <P>(d) Provide for safe and sanitary disposal for the following:</P> <P>(1) Trash and items used during the collection, processing and compatibility testing of blood and blood components.</P> <P>(2) Blood and blood components not suitable for use or distribution.</P> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart D—Equipment</HD> <SECTION> <SECTNO>§ 606.60</SECTNO> <SUBJECT>Equipment.</SUBJECT> <P>(a) Equipment used in the collection, processing, compatibility testing, storage and distribution of blood and blood components shall be maintained in a clean and orderly manner and located so as to facilitate cleaning and maintenance. The equipment shall be observed, standardized and calibrated on a regularly scheduled basis as prescribed in the Standard Operating Procedures Manual and shall perform in the manner for which it was designed <PRTPAGE P="41"/>so as to assure compliance with the official requirements prescribed in this chapter for blood and blood products.</P> <P>(b) Equipment that shall be observed, standardized and calibrated with at least the following frequency, include but are not limited to:</P> <GPOTABLE CDEF="s60,r100,r45,r100" COLS="4" OPTS="L2"> <BOXHD> <CHED H="1">Equipment</CHED> <CHED H="1">Performance check</CHED> <CHED H="1">Frequency</CHED> <CHED H="1">Frequency of calibration</CHED> </BOXHD> <ROW> <ENT I="01">Temperature recorder</ENT> <ENT>Compare against thermometer</ENT> <ENT>Daily</ENT> <ENT>As necessary.</ENT> </ROW> <ROW> <ENT I="01">Refrigerated centrifuge</ENT> <ENT>Observe speed and temperature</ENT> <ENT>Each day of use</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Hematocrit centrifuge</ENT> <ENT/> <ENT/> <ENT>Standardize before initial use, after repairs or adjustments, and annually. Timer every 3 mo.</ENT> </ROW> <ROW> <ENT I="01">General lab centrifuge</ENT> <ENT/> <ENT/> <ENT>Tachometer every 6 mo.</ENT> </ROW> <ROW> <ENT I="01">Automated blood-typing machine</ENT> <ENT>Observe controls for correct results</ENT> <ENT>Each day of use</ENT> </ROW> <ROW> <ENT I="01">Hemoglobinometer</ENT> <ENT>Standardize against cyanmethemoglobin standard</ENT> <ENT>......do</ENT> <ENT/> </ROW> <ROW> <ENT I="01">Refractometer</ENT> <ENT>Standardize against distilled water</ENT> <ENT>......do</ENT> <ENT/> </ROW> <ROW> <ENT I="01">Blood container scale</ENT> <ENT>Standardize against container of known weight</ENT> <ENT>......do</ENT> <ENT>As necessary.</ENT> </ROW> <ROW> <ENT I="01">Water bath</ENT> <ENT>Observe temperature</ENT> <ENT>......do</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Rh view box</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Autoclave</ENT> <ENT>......do</ENT> <ENT>Each time of use</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Serologic rotators</ENT> <ENT>Observe controls for correct results</ENT> <ENT>Each day of use</ENT> <ENT>Speed as necessary.</ENT> </ROW> <ROW> <ENT I="01">Laboratory thermometers</ENT> <ENT/> <ENT/> <ENT>Before initial use.</ENT> </ROW> <ROW> <ENT I="01">Electronic thermometers</ENT> <ENT/> <ENT/> <ENT>Monthly.</ENT> </ROW> <ROW> <ENT I="01">Vacuum blood agitator</ENT> <ENT>Observe weight of the first container of blood filled for correct results</ENT> <ENT>Each day of use</ENT> <ENT>Standardize with container of known mass or volume before initial use, and after repairs or adjustments.</ENT> </ROW> </GPOTABLE> <P>(c) Equipment employed in the sterilization of materials used in blood collection or for disposition of contaminated products shall be designed, maintained and utilized to ensure the destruction of contaminating microorganisms. The effectiveness of the sterilization procedure shall be no less than that achieved by an attained temperature of 121.5 °C (251 °F) maintained for 20 minutes by saturated steam or by an attained temperature of 170 °C (338 °F) maintained for 2 hours with dry heat.</P> <CITA>[40 FR 53532, Nov. 18, 1975; 40 FR 55849, Dec. 2, 1975, as amended at 45 FR 9261, Feb. 12, 1980; 57 FR 11263, Apr. 2, 1992; 57 FR 12862, Apr. 13, 1992]</CITA> </SECTION> <SECTION> <SECTNO>§ 606.65</SECTNO> <SUBJECT>Supplies and reagents.</SUBJECT> <P>All supplies and reagents used in the collection, processing, compatibility testing, storage and distribution of blood and blood components shall be stored in a safe, sanitary and orderly manner.</P> <P>(a) All surfaces coming in contact with blood and blood components intended for transfusion shall be sterile, pyrogen-free, and shall not interact with the product in such a manner as to have an adverse effect upon the safety, purity, potency or effectiveness of the product. All final containers and closures for blood and blood components not intended for transfusion shall be clean and free of surface solids and other contaminants.</P> <P>(b) Each blood collecting container and its satellite container(s), if any, shall be examined visually for damage or evidence of contamination prior to its use and immediately after filling. Such examination shall include inspection for breakage of seals, when indicated, and abnormal discoloration. Where any defect is observed, the container shall not be used, or, if detected after filling, shall be properly discarded.</P> <P>(c) Representative samples of each lot of the following reagents or solutions shall be tested on a regularly scheduled basis by methods described in the Standard Operating Procedures Manual to determine their capacity to perform as required:</P> <GPOTABLE CDEF="s50,xl50" COLS="2" OPTS="L2"> <BOXHD> <CHED H="1">Reagent or solution</CHED> <CHED H="1">Frequency of testing</CHED> </BOXHD> <ROW> <ENT I="01">Anti-human globulin</ENT> <ENT>Each day of use.</ENT> </ROW> <ROW> <ENT I="01">Blood grouping reagents</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Lectins</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Antibody screening and reverse grouping cells</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Hepatitis test reagents</ENT> <ENT>Each run.</ENT> </ROW> <ROW> <ENT I="01">Syphilis serology reagents</ENT> <ENT>Do.</ENT> </ROW> <ROW> <PRTPAGE P="42"/> <ENT I="01">Enzymes</ENT> <ENT>Each day of use.</ENT> </ROW> </GPOTABLE> <P>(d) Supplies and reagents that do not bear an expiration date shall be stored in such a manner that the oldest is used first.</P> <P>(e) Supplies and reagents shall be used in a manner consistent with instructions provided by the manufacturer.</P> <P>(f) Items that are required to be sterile and come into contact with blood should be disposable whenever possible.</P> <CITA>[40 FR 53532, Nov. 18, 1975, as amended at 59 FR 23636, May 6, 1994]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart E[Reserved]</HD> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart F—Production and Process Controls</HD> <SECTION> <SECTNO>§ 606.100</SECTNO> <SUBJECT>Standard operating procedures.</SUBJECT> <P>(a) In all instances, except clinical investigations, standard operating procedures shall comply with published additional standards in part 640 of this chapter for the products being processed; except that, references in part 640 relating to licenses, licensed establishments and submission of material or data to or approval by the Director, Center for Biologics Evaluation and Research, are not applicable to establishments not subject to licensure under section 351 of the Public Health Service Act.</P> <P>(b) Written standard operating procedures shall be maintained and shall include all steps to be followed in the collection, processing, compatibility testing, storage and distribution of blood and blood components for homologous transfusion, autologous transfusion and further manufacturing purposes. Such procedures shall be available to the personnel for use in the areas where the procedures are performed, unless this is impractical. The written standard operating procedures shall include, but are not limited to, descriptions of the following, when applicable:</P> <P>(1) Criteria used to determine donor suitability, including acceptable medical history criteria.</P> <P>(2) Methods of performing donor qualifying tests and measurements, including minimum and maximum values for a test or procedure when a factor in determining acceptability.</P> <P>(3) Solutions and methods used to prepare the site of phlebotomy to give maximum assurance of a sterile container of blood.</P> <P>(4) Method of accurately relating the product(s) to the donor.</P> <P>(5) Blood collection procedure, including in-process precautions taken to measure accurately the quantity of blood removed from the donor.</P> <P>(6) Methods of component preparation, including any time restrictions for specific steps in processing.</P> <P>(7) All tests and repeat tests performed on blood and blood components during processing, including testing for hepatitis B surface antigen as prescribed in § 610.40 of this chapter.</P> <P>(8) Pretransfusion testing, where applicable, including precautions to be taken to identify accurately the recipient blood samples and crossmatched donor units.</P> <P>(9) Procedures for investigating adverse donor and recipient reactions.</P> <P>(10) Storage temperatures and methods of controlling storage temperatures for all blood products and reagents as prescribed in §§ 600.15 and 610.53 of this chapter.</P> <P>(11) Length of expiration dates, if any, assigned for all final products as prescribed in § 610.53 of this chapter.</P> <P>(12) Criteria for determining whether returned blood is suitable for reissue.</P> <P>(13) Procedures used for relating a unit of blood or blood component from the donor to its final disposition.</P> <P>(14) Quality control procedures for supplies and reagents employed in blood collection, processing and pretransfusion testing.</P> <P>(15) Schedules and procedures for equipment maintenance and calibration.</P> <P>(16) Labeling procedures, including safeguards to avoid labeling mixups.</P> <P>(17) Procedures of plasmapheresis, plateletpheresis, and leukapheresis, if performed, including precautions to be taken to ensure reinfusion of a donor's own cells.</P> <P>(18) Procedure for preparing recovered (salvaged) plasma, if performed, <PRTPAGE P="43"/>including details of separation, pooling, labeling, storage and distribution.</P> <P>(19) Procedures in accordance with § 610.46 of this chapter to look at prior donations of Whole Blood, blood components, Source Plasma and Source Leukocytes from a donor who has donated blood and subsequently tests repeatedly reactive for antibody to human immunodeficiency virus (HIV) or otherwise is determined to be unsuitable when tested in accordance with § 610.45 of this chapter. Procedures to quarantine in-house Whole Blood, blood components, Source Plasma and Source Leukocytes intended for further manufacture into injectable products that were obtained from such donors; procedures to notify consignees regarding the need to quarantine such products; procedures to determine the suitability for release of such products from quarantine; procedures to notify consignees of Whole Blood, blood components, Source Plasma and Source Leukocytes from such donors of the results of the antibody testing of such donors; and procedures in accordance with § 610.47 of this chapter to notify attending physicians so that transfusion recipients are informed that they may have received Whole Blood and, blood components at increased risk for transmitting human immunodeficiency virus.</P> <P>(c) All records pertinent to the lot or unit maintained pursuant to these regulations shall be reviewed before the release or distribution of a lot or unit of final product. The review or portions of the review may be performed at appropriate periods during or after blood collecting, processing, compatibility testing and storing. A thorough investigation, including the conclusions and followup, of any unexplained discrepancy or the failure of a lot or unit to meet any of its specifications shall be made and recorded.</P> <P>(d) In addition to the requirements of this subpart and in conformity with this section, any facility may utilize current standard operating procedures such as the manuals of the following organizations, as long as such specific procedures are consistent with, and at least as stringent as, the requirements contained in this part.</P> <P>(1) American Association of Blood Banks.</P> <P>(2) American National Red Cross.</P> <P>(3) Other organizations or individual blood banks, subject to approval by the Director, Center for Biologics Evaluation and Research.</P> <CITA>[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 61 FR 47422, Sept. 9, 1996]</CITA> </SECTION> <SECTION> <SECTNO>§ 606.110</SECTNO> <SUBJECT>Plateletpheresis, leukapheresis, and plasmapheresis.</SUBJECT> <P>(a) The use of plateletpheresis and leukapheresis procedures to obtain a product for a specific recipient may be at variance with the additional standards for specific products prescribed in this part provided that: (1) A physician has determined that the recipient must be transfused with the leukocytes or platelets from a specific donor, and (2) the procedure is performed under the supervision of a qualified licensed physician who is aware of the health status of the donor, and the physician has certified in writing that the donor's health permits plateletpheresis or leukapheresis.</P> <P>(b) Plasmapheresis of donors who do not meet the donor requirements of §§ 640.63, 640.64 and 640.65 of this chapter for the collection of plasma containing rare antibodies shall be permitted only with the prior approval of the Director, Center for Biologics Evaluation and Research.</P> <CITA>[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart G—Finished Product Control</HD> <SECTION> <SECTNO>§ 606.120</SECTNO> <SUBJECT>Labeling, general requirements.</SUBJECT> <P>(a) Labeling operations shall be separated physically or spatially from other operations in a manner adequate to prevent mixups.</P> <P>(b) The labeling operation shall include the following labeling controls:</P> <P>(1) Labels shall be held upon receipt, pending review and proofing against an approved final copy, to ensure accuracy regarding identity, content, and conformity with the approved copy.<PRTPAGE P="44"/> </P> <P>(2) Each type of label representing different products shall be stored and maintained in a manner to prevent mixups, and stocks of obsolete labels shall be destroyed.</P> <P>(3) All necessary checks in labeling procedures shall be utilized to prevent errors in translating test results to container labels.</P> <P>(c) All labeling shall be clear and legible.</P> <CITA>[50 FR 35469, Aug. 30, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 606.121</SECTNO> <SUBJECT>Container label.</SUBJECT> <P>(a) The container label requirements are designed to facilitate the use of a uniform container label for blood and blood components (except Source Plasma) by all blood establishments. Single copies of an FDA guideline entitled “Guideline for the Uniform Labeling of Blood and Blood Components” are available upon request (under Docket No. 80N-0120) from the Dockets Management Branch (HFA-305), Food and Drug Administration, Rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857 (copies of the guideline are available also from the American Blood Commission, 1901 North Ft. Myer Drive, Suite 300, Arlington, VA 22209).</P> <P>(b) The label provided by the collecting facility and the initial processing facility shall not be removed, altered, or obscured, except that the label may be altered to indicate the proper name and other information required to identify accurately the contents of a container after blood components have been prepared.</P> <P>(c) The container label shall include the following information, as well as other specialized information as required in this section for specific products:</P> <P>(1) The proper name of the product in a prominent position, and modifier(s), if appropriate.</P> <P>(2) The name, address, registration number, and, if a licensed product, the license number of each manufacturer.</P> <P>(3) The donor, pool, or lot number relating the unit to the donor.</P> <P>(4) The expiration date, including the day, month, and year, and, if the dating period for the product is 72 hours or less, the hour of expiration.</P> <P>(5) If the product is intended for transfusion, the appropriate donor classification statement, i.e., “paid donor” or “volunteer donor”, in no less prominence than the proper name of the product.</P> <P>(i) A paid donor is a person who receives monetary payment for a blood donation.</P> <P>(ii) A volunteer donor is a person who does not receive monetary payment for a blood donation.</P> <P>(iii) Benefits, such as time off from work, membership in blood assurance programs, and cancellation of nonreplacement fees that are not readily convertible to cash, do not constitute monetary payment within the meaning of this paragraph.</P> <P>(6) For Whole Blood, Plasma, Platelets, and partial units of Red Blood Cells, the volume of the product, accurate to within <E T="61">±</E>10 percent; or optionally for Platelets, the volume range within reasonable limits.</P> <P>(7) The recommended storage temperature (in degrees Celsius).</P> <P>(8) If the product is intended for transfusion, the statements:</P> <P>(i) “Caution: Federal law prohibits dispensing without prescription.”</P> <P>(ii) “See circular of information for indications, contraindications, cautions, and methods of infusion.”</P> <P>(iii) “Properly identify intended recipient.”</P> <P>(9) The statement: “This product may transmit infectious agents.”</P> <P>(10) Where applicable, the name and volume of source material.</P> <P>(11) The statement: “Caution: For Manufacturing Use Only”, when applicable.</P> <P>(12) If the product is intended for transfusion, the ABO and Rh groups of the donor shall be designated conspicuously. For Cryoprecipitated AHF, the Rh group may be omitted. The Rh group shall be designated as follows:</P> <P>(i) If the test using Anti-D Blood Grouping Reagent is positive, the product shall be labeled: “Rh positive.”</P> <P>(ii) If the test using Anti-D Blood Grouping Reagent is negative but the test for D<E T="51">u</E> is positive, the product shall be labeled: “Rh positive.”</P> <P>(iii) If the test using Anti-D Blood Grouping Reagent is negative and the test for D<E T="51">u</E> is negative, the product shall be labeled: “Rh negative.”<PRTPAGE P="45"/> </P> <P>(13) The container label may bear encoded information in the form of machine-readable symbols approved for use by the Director, Center for Biologics Evaluation and Research (HFB-1).</P> <P>(d) Except for recovered plasma intended for manufacturing use or as otherwise approved by the Director, Center for Biologics Evaluation and Research (HFB-1), the paper of the container label shall be white and print shall be solid black, with the following additional exceptions:</P> <P>(1) The Rh blood group shall be printed as follows:</P> <P>(i) Rh positive: Use black print on white background.</P> <P>(ii) Rh negative: Use white print on black background.</P> <P>(2) The proper name of the product, any appropriate modifier(s), the donor classification statement, and the statement “properly identify intended recipient” shall be printed in solid red.</P> <P>(3) The following color scheme may be used optionally for differentiating ABO Blood groups:</P> <GPOTABLE CDEF="xl50,r50" COLS="2" OPTS="L2"> <BOXHD> <CHED H="1">Blood group</CHED> <CHED H="1">Color of label paper</CHED> </BOXHD> <ROW> <ENT I="01">O </ENT> <ENT>Blue</ENT> </ROW> <ROW> <ENT I="01">A </ENT> <ENT>Yellow</ENT> </ROW> <ROW> <ENT I="01">B </ENT> <ENT>Pink</ENT> </ROW> <ROW> <ENT I="01">AB </ENT> <ENT>White</ENT> </ROW> </GPOTABLE> <P>(4) Ink colors used for the optional color coding system described in paragraph (d)(3) of this section shall be a visual match to specific color samples designated by the Director, Center for Biologics Evaluation and Research (HFB-1).</P> <P>(5) Special labels, such as those described in paragraphs (h) and (i) of this section, may be color coded using the colors recommended in the guideline (see paragraph (a) of this section), or colors otherwise approved for use by the Director, Center for Biologics Evaluation and Research (HFB-1).</P> <P>(e) Container label requirements for particular products or groups of products.</P> <P>(1) Whole Blood labels shall include:</P> <P>(i) The volume of anticoagulant.</P> <P>(ii) The name of the applicable anticoagulant immediately preceding and of no less prominence than the proper name and expressed as follows: (<E T="03">a</E>) ACD, (<E T="03">b</E>) CPD, (<E T="03">c</E>) Heparin, (<E T="03">d</E>) CPDA-1, (<E T="03">e</E>) CP2D, or by other nomenclature approved for use by the Director, Office of Biologics Research and Review (HFN-800), Center for Drugs and Biologics.</P> <P>(iii) If tests for unexpected antibodies are positive, blood intended for transfusion shall be labeled: “Contains (<E T="03">name of antibody</E>).”</P> <P>(2) Except for frozen, deglycerolized, or washed Red Blood Cell products, red blood cell labels shall include:</P> <P>(i) The volume and kind of Whole Blood, including the type of anticoagulant, from which the product was prepared.</P> <P>(ii) If tests for unexpected antibodies are positive and the product is intended for transfusion, the statement: “Contains (<E T="03">name of antibody</E>).”</P> <P>(3) Labels for products with a dating period of 72 hours or less, including any product prepared in a system that may compromise sterility, shall bear the hour of expiration.</P> <P>(4) If tests for unexpected antibodies are positive, Plasma intended for transfusion shall be labeled: “Contains (<E T="03">name of antibody</E>).”</P> <P>(5) Recovered plasma labels shall include:</P> <P>(i) In lieu of an expiration date, the date of collection of the oldest material in the container.</P> <P>(ii) The statement: “Caution: For Manufacturing Use Only”; or “Caution: For Use in Manufacturing Noninjectable Products Only”, as applicable.</P> <P>(iii) For recovered plasma not meeting the requirements for manufacture into licensable products, the statement: “Not for Use in Products Subject to License Under Section 351 of the Public Health Service Act.”</P> <P>(f) Blood and blood components determined to be unsuitable for transfusion shall be prominently labeled: “NOT FOR TRANSFUSION”, and the label shall state the reason the unit is considered unsuitable. The provision does not apply to recovered plasma labeled according to paragraph (e)(5) of this section.</P> <P>(g) As required under § 610.40 of this chapter, labels for blood and blood components that are reactive for Hepatitis B Surface Antigen, but that are intended for further manufacturing, <PRTPAGE P="46"/>shall state conspicuously that the material is reactive when tested for hepatitis B surface antigen and may transmit viral hepatitis or, as applicable, that blood was collected from a donor known to be reactive for hepatitis B surface antigen and is presumed to be infectious, although confirmatory hepatitis testing has not been done.</P> <P>(h) The following additional information shall appear on the label for blood or blood components shipped in an emergency, prior to completion of required tests, in accordance with § 640.2(f) of this chapter:</P> <P>(1) The statement: “FOR EMERGENCY USE ONLY BY <E T="72">____</E>.”</P> <P>(2) Results of any tests prescribed under §§ 610.40, 610.45, and 640.5 (a), (b), or (c) of this chapter completed before shipment.</P> <P>(3) Indication of any tests prescribed under §§ 610.40, 610.45, and 640.5 (a), (b), or (c) of this chapter and not completed before shipment.</P> <P>(i) The following additional information shall appear on the label for Whole Blood or Red Blood Cells intended for autologous infusion:</P> <P>(1) Information adequately identifying the patient, e.g., name, blood group, hospital, and identification number.</P> <P>(2) Date of donation.</P> <P>(3) The statement: “FOR AUTOLOGOUS USE ONLY.”</P> <P>(4) In place of the blood group label, each container of blood intended for autologous use and obtained from a donor who fails to meet any of the donor suitability requirements under § 640.3 of this chapter or who is reactive in the hepatitis tests prescribed under § 610.40 of this chapter shall be prominently and permanently labeled: “FOR AUTOLOGOUS USE ONLY.”</P> <P>(5) Units of blood originally intended for autologous use, except those labeled as prescribed under paragraph (i)(4) of this section, may be issued for homologous transfusion provided the container label complies with all applicable provisions of paragraphs (b) through (e) of this section. In such case, the special label required under paragraph (i) (1), (2), and (3) of this section shall be removed or otherwise obscured.</P> <P>(j) A tie-tag attached to the container may be used for providing the information required by paragraph (e) (1)(iii), (2)(ii), and (4), (h), or (i)(1), (2), and (3) of this section.</P> <CITA>[50 FR 35469, Aug. 30, 1985, as amended at 53 FR 116, Jan. 5, 1988; 55 FR 11014, Mar. 26, 1990; 57 FR 10814, Mar. 31, 1992; 59 FR 23636, May 6, 1994; 63 FR 16685, Apr. 6, 1998]</CITA> <EFFDNOT> <HD SOURCE="HED">Effective Date Note: </HD> <P> The information collection requirements contained in § 606.121 will not become effective until OMB approval has been obtained. FDA will publish a notice of OMB approval in the <E T="04">Federal Register</E>. </P> </EFFDNOT> </SECTION> <SECTION> <SECTNO>§ 606.122</SECTNO> <SUBJECT>Instruction circular.</SUBJECT> <P>An instruction circular shall be available for distribution if the product is intended for transfusion. The instruction circular shall provide adequate directions for use, including the following information:</P> <P>(a) Instructions to mix the product before use.</P> <P>(b) Instructions to use a filter in the administration equipment.</P> <P>(c) The statement “Do Not Add Medications” or an explanation concerning allowable additives.</P> <P>(d) A description of the product, its source, and preparation, including the name and proportion of the anticoagulant used in collecting the Whole Blood from each product is prepared.</P> <P>(e) Statements that the product was prepared from blood that was negative when tested for antibody to Human Immunodeficiency Virus (HIV) and nonreactive for hepatitis B surface antigen by FDA required tests and nonreactive when tested for syphilis by a serologic test for syphilis (STS).</P> <P>(f) The statements: “Warning. The risk of transmitting hepatitis is present. Careful donor selection and available laboratory tests do not eliminate the hazard.”</P> <P>(g) The names of cryoprotective agents and other additives that may still be present in the product.</P> <P>(h) The names and results of all tests performed when necessary for safe and effective use.</P> <P>(i) The use of the product, indications, contradications, side effects and hazards, dosage and administration recommendations.</P> <P>(j) [Reserved]<PRTPAGE P="47"/> </P> <P>(k) For Red Blood Cells, the instruction circular shall contain:</P> <P>(1) Instructions to administer a suitable plasma volume expander if Red Blood Cells are substituted when Whole Blood is the indicated product.</P> <P>(2) A warning not to add Lactated Ringer's Injection U.S.P. solution to Red Blood Cell products.</P> <P>(l) For Platelets, the instruction circular shall contain:</P> <P>(1) The approximate volume of plasma from which a sample unit of Platelets is prepared.</P> <P>(2) Instructions to begin administration as soon as possible, but not more than 4 hours after entering the container.</P> <P>(m) For Plasma, the instruction circular shall contain:</P> <P>(1) A warning against further processing of the frozen product if there is evidence of breakage or thawing.</P> <P>(2) Instructions to thaw the frozen product at a temperature between 30 and 37 <E T="61">°</E>C.</P> <P>(3) When applicable, instructions to begin administration of the product within 6 hours after thawing.</P> <P>(4) Instructions to administer to ABO-group-compatible recipients.</P> <P>(5) A statement that this product has the same hepatitis risk as Whole Blood; other plasma volume expanders without this risk are available for treating hypovolemia.</P> <P>(n) For Cryoprecipitated AHF, the instruction circular shall contain:</P> <P>(1) A statement that the average potency is 80 or more International Units of antihemophilic factor.</P> <P>(2) The statement: “Usually contains at least 150 milligrams of fibrinogen”; or, alternatively, the average fibrinogen level determined by assay of representative units.</P> <P>(3) A warning against further processing of the product if there is evidence of breakage or thawing.</P> <P>(4) Instructions to thaw the product for no more than 15 minutes at a temperature of 37 <E T="61">°</E>C.</P> <P>(5) Instructions to store at room temperature after thawing and to begin administration as soon as possible but no more than 4 hours after entering the container or after pooling and within 6 hours after thawing.</P> <P>(6) A statement that 0.9 percent Sodium Chloride Injection U.S.P. is the preferred diluent.</P> <P>(7) Adequate instructions for pooling to ensure complete removal of all concentrated material from each container.</P> <P>(8) The statement: “Good patient management requires monitoring treatment responses to Cryoprecipitated AHF transfusions with periodic plasma factor VIII or fibrinogen assays in hemophilia A and hypofibrinogenemic recipients, respectively.”</P> <CITA>[50 FR 35470, Aug. 30, 1985, as amended at 53 FR 116, Jan. 5, 1988]</CITA> <EFFDNOT> <HD SOURCE="HED">Effective Date Note: </HD> <P> The information collection requirements contained in § 606.122 will not become effective until OMB approval has been obtained. FDA will publish a notice of OMB approval in the <E T="04">Federal Register</E>. </P> </EFFDNOT> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart H—Laboratory Controls</HD> <SECTION> <SECTNO>§ 606.140</SECTNO> <SUBJECT>Laboratory controls.</SUBJECT> <P>Laboratory control procedures shall include:</P> <P>(a) The establishment of scientifically sound and appropriate specifications, standards and test procedures to assure that blood and blood components are safe, pure, potent and effective.</P> <P>(b) Adequate provisions for monitoring the reliability, accuracy, precision and performance of laboratory test procedures and instruments.</P> <P>(c) Adequate identification and handling of all test samples so that they are accurately related to the specific unit of product being tested, or to its donor, or to the specific recipient, where applicable.</P> </SECTION> <SECTION> <SECTNO>§ 606.151</SECTNO> <SUBJECT>Compatibility testing.</SUBJECT> <P>Standard operating procedures for compatibility testing shall include the following:</P> <P>(a) A method of collecting and identifying the blood samples of recipients to ensure positive identification.</P> <P>(b) The use of fresh recipient serum samples less than 48 hours old for all pretransfusion testing.</P> <P>(c) The testing of the donor's cells with the recipient's serum (major crossmatch) by a method that will <PRTPAGE P="48"/>demonstrate agglutinating, coating and hemolytic antibodies, which shall include the antiglobulin method.</P> <P>(d) A provision that, if the unit of donor's blood has not been screened by a method that will demonstrate agglutinating, coating and hemolytic antibodies, the recipient's cells shall be tested with the donor's serum (minor crossmatch) by a method that will so demonstrate.</P> <P>(e) Procedures to expedite transfusions in life-threatening emergencies. Records of all such incidents shall be maintained, including complete documentation justifying the emergency action, which shall be signed by the physician requesting the procedure.</P> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart I—Records and Reports</HD> <SECTION> <SECTNO>§ 606.160</SECTNO> <SUBJECT>Records.</SUBJECT> <P>(a)(1) Records shall be maintained concurrently with the performance of each significant step in the collection, processing, compatibility testing, storage and distribution of each unit of blood and blood components so that all steps can be clearly traced. All records shall be legible and indelible, and shall identify the person performing the work, include dates of the various entries, show test results as well as the interpretation of the results, show the expiration date assigned to specific products, and be as detailed as necessary to provide a complete history of the work performed.</P> <P>(2) Appropriate records shall be available from which to determine lot numbers of supplies and reagents used for specific lots or units of the final product.</P> <P>(b) Records shall be maintained that include, but are not limited to, the following when applicable:</P> <P>(1) Donor records:</P> <P>(i) Donor selection, including medical interview and examination and where applicable, informed consent.</P> <P>(ii) Permanent and temporary deferrals for health reasons including reason(s) for deferral.</P> <P>(iii) Donor adverse reaction complaints and reports, including results of all investigations and followup.</P> <P>(iv) Therapeutic bleedings, including signed requests from attending physicians, the donor's disease and disposition of units.</P> <P>(v) Immunization, including informed consent, identification of the antigen, dosage and route of administration.</P> <P>(vi) Blood collection, including identification of the phlebotomist.</P> <P>(vii) Records to relate the donor with the unit number of each previous donation from that donor.</P> <P>(viii) Records of quarantine, notification, testing, and disposition performed pursuant to §§ 610.46 and 610.47 of this chapter.</P> <P>(2) Processing records:</P> <P>(i) Blood processing, including results and interpretation of all tests and retests.</P> <P>(ii) Component preparation, including all relevant dates and times.</P> <P>(iii) Separation and pooling of recovered plasma.</P> <P>(iv) Centrifugation and pooling of source plasma.</P> <P>(v) Labeling, including initials of person(s) responsible.</P> <P>(3) Storage and distribution records:</P> <P>(i) Distribution and disposition, as appropriate, of blood and blood products.</P> <P>(ii) Visual inspection of whole blood and red blood cells during storage and immediately before distribution.</P> <P>(iii) Storage temperature, including initialed temperature recorder charts.</P> <P>(iv) Reissue, including records of proper temperature maintenance.</P> <P>(v) Emergency release of blood, including signature of requesting physician obtained before or after release.</P> <P>(4) Compatibility test records:</P> <P>(i) Results of all compatibility tests, including crossmatching, testing of patient samples, antibody screening and identification.</P> <P>(ii) Results of confirmatory testing.</P> <P>(5) Quality control records:</P> <P>(i) Calibration and standardization of equipment.</P> <P>(ii) Performance checks of equipment and reagents.</P> <P>(iii) Periodic check on sterile technique.</P> <P>(iv) Periodic tests of capacity of shipping containers to maintain proper temperature in transit.</P> <P>(v) Proficiency test results.<PRTPAGE P="49"/> </P> <P>(6) Transfusion reaction reports and complaints, including records of investigations and followup.</P> <P>(7) General records:</P> <P>(i) Sterilization of supplies and reagents prepared within the facility, including date, time interval, temperature and mode.</P> <P>(ii) Responsible personnel.</P> <P>(iii) Errors and accidents.</P> <P>(iv) Maintenance records for equipment and general physical plant.</P> <P>(v) Supplies and reagents, including name of manufacturer or supplier, lot numbers, expiration date and date of receipt.</P> <P>(vi) Disposition of rejected supplies and reagents used in the collection, processing and compatibility testing of blood and blood components.</P> <P>(c) A donor number shall be assigned to each accepted donor, which relates the unit of blood collected to that donor, to his medical record, to any component or blood product from that donor's unit of blood, and to all records describing the history and ultimate disposition of these products.</P> <P>(d) Records shall be retained for such interval beyond the expiration date for the blood or blood component as necessary to facilitate the reporting of any unfavorable clinical reactions. The retention period shall be no less than 5 years after the records of processing have been completed or 6 months after the latest expiration date for the individual product, whichever is a later date. When there is no expiration date, records shall be retained indefinitely.</P> <P>(e) A record shall be available from which unsuitable donors may be identified so that products from such individuals will not be distributed.</P> <CITA>[40 FR 53532, Nov. 18, 1975, as amended at 61 FR 47422, Sept. 9, 1996]</CITA> </SECTION> <SECTION> <SECTNO>§ 606.165</SECTNO> <SUBJECT>Distribution and receipt; procedures and records.</SUBJECT> <P>(a) Distribution and receipt procedures shall include a system by which the distribution or receipt of each unit can be readily determined to facilitate its recall, if necessary.</P> <P>(b) Distribution records shall contain information to readily facilitate the identification of the name and address of the consignee, the date and quantity delivered, the lot number of the unit(s), the date of expiration or the date of collection, whichever is applicable, or for crossmatched blood and blood components, the name of the recipient.</P> <P>(c) Receipt records shall contain the name and address of the collecting facility, date received, donor or lot number assigned by the collecting facility and the date of expiration or the date of collection, whichever is applicable.</P> </SECTION> <SECTION> <SECTNO>§ 606.170</SECTNO> <SUBJECT>Adverse reaction file.</SUBJECT> <P>(a) Records shall be maintained of any reports of complaints of adverse reactions regarding each unit of blood or blood product arising as a result of blood collection or transfusion. A thorough investigation of each reported adverse reaction shall be made. A written report of the investigation of adverse reactions, including conclusions and followup, shall be prepared and maintained as part of the record for that lot or unit of final product by the collecting or transfusing facility. When it is determined that the product was at fault in causing a transfusion reaction, copies of all such written reports shall be forwarded to and maintained by the manufacturer or collecting facility.</P> <P>(b) When a complication of blood collection or transfusion is confirmed to be fatal, the Director, Office of Compliance, Center for Biologics Evaluation and Research, shall be notified by telephone or telegraph as soon as possible; a written report of the investigation shall be submitted to the Director, Office of Compliance, Center for Biologics Evaluation and Research, within 7 days after the fatality by the collecting facility in the event of a donor reaction, or by the facility that performed the compatibility tests in the event of a transfusion reaction. </P> <EXTRACT> <FP>(Information collection requirements approved by the Office of Management and Budget under control number 0910-0116)</FP> </EXTRACT> <CITA>[40 FR 53532, Nov. 18, 1975, as amended at 49 FR 23833, June 8, 1984; 50 FR 35471, Aug. 30, 1985; 55 FR 11014, Mar. 26, 1990]</CITA> </SECTION> </SUBPART> </PART> <PART> <PRTPAGE P="50"/> <EAR>Pt. 607</EAR> <HD SOURCE="HED">PART 607—ESTABLISHMENT REGISTRATION AND PRODUCT LISTING FOR MANUFACTURERS OF HUMAN BLOOD AND BLOOD PRODUCTS</HD> <CONTENTS> <SUBPART> <HD SOURCE="HED">Subpart A—General Provisions</HD> <SECHD>Sec.</SECHD> <SECTNO>607.3</SECTNO> <SUBJECT>Definitions.</SUBJECT> <SECTNO>607.7</SECTNO> <SUBJECT>Establishment registration and product listing of blood banks and other firms manufacturing human blood and blood products.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart B—Procedures for Domestic Blood Product Establishments</HD> <SECTNO>607.20</SECTNO> <SUBJECT>Who must register and submit a blood product list.</SUBJECT> <SECTNO>607.21</SECTNO> <SUBJECT>Times for establishment registration and blood product listing.</SUBJECT> <SECTNO>607.22</SECTNO> <SUBJECT>How and where to register establishments and list blood products.</SUBJECT> <SECTNO>607.25</SECTNO> <SUBJECT>Information required for establishment registration and blood product listing.</SUBJECT> <SECTNO>607.26</SECTNO> <SUBJECT>Amendments to establishment registration.</SUBJECT> <SECTNO>607.30</SECTNO> <SUBJECT>Updating blood product listing information.</SUBJECT> <SECTNO>607.31</SECTNO> <SUBJECT>Additional blood product listing information.</SUBJECT> <SECTNO>607.35</SECTNO> <SUBJECT>Notification of registrant; blood product establishment registration number and NDC Labeler Code.</SUBJECT> <SECTNO>607.37</SECTNO> <SUBJECT>Inspection of establishment registrations and blood product listings.</SUBJECT> <SECTNO>607.39</SECTNO> <SUBJECT>Misbranding by reference to establishment registration or to registration number.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart C—Procedures for Foreign Blood Product Establishments</HD> <SECTNO>607.40</SECTNO> <SUBJECT>Blood product listing requirements for foreign blood product establishments.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart D—Exemptions</HD> <SECTNO>607.65</SECTNO> <SUBJECT>Exemptions for blood product establishments.</SUBJECT> </SUBPART> </CONTENTS> <AUTH> <HD SOURCE="HED">Authority: </HD> <P>21 U.S.C. 321, 331, 351, 352, 355, 360, 371, 374; 42 U.S.C. 216, 262.</P> </AUTH> <SOURCE> <HD SOURCE="HED">Source: </HD> <P>40 FR 52788, Nov. 12, 1975, unless otherwise noted.</P> </SOURCE> <SUBPART> <HD SOURCE="HED">Subpart A—General Provisions</HD> <SECTION> <SECTNO>§ 607.3</SECTNO> <SUBJECT>Definitions.</SUBJECT> <P>(a) The term <E T="03">act</E> means the Federal Food, Drug, and Cosmetic Act approved June 25, 1938 (52 Stat. 1040 et seq., as amended, 21 U.S.C. 301-392).</P> <P>(b) <E T="03">Blood and blood product</E> means a drug which consists of human whole blood, plasma, or serum or any product derived from human whole blood, plasma or serum, hereinafter referred to as “blood product.”</P> <P>(c) <E T="03">Establishment</E> means a place of business under one management at one general physical location. The term includes, among others, human blood and plasma donor centers, blood banks, transfusion services, other blood product manufacturers and independent laboratories that engage in quality control and testing for registered blood product establishments.</P> <P>(d) <E T="03">Manufacture</E> means the collection, preparation, processing or compatibility testing by chemical, physical, biological, or other procedures of any blood product which meets the definition of a drug as defined in section 201(g) of the act, and including manipulation, sampling, testing, or control procedures applied to the final product or to any part of the process. The term includes packaging, labeling, repackaging or otherwise changing the container, wrapper, or labeling of any blood product package in furtherance of the distribution of the blood product from the original place of manufacture to the person who makes final delivery or sale to the ultimate consumer.</P> <P>(e) <E T="03">Commercial distribution</E> means any distribution of a blood product except pursuant to the investigational use provisions of part 312 of this chapter, but does not include internal or interplant transfer of a bulk product substance between registered domestic establishments within the same parent, subsidiary, and/or affiliate company.</P> <P>(f) <E T="03">Any material change</E> includes but is not limited to any change in the name of the blood product, in the quantity or identity of the active ingredient(s) or in the quantity or identity of the inactive ingredient(s) where quantitative listing of all ingredients is required pursuant to § 607.31(a)(2) and any significant change in the labeling of a blood product. Changes that are not significant include changes in arrangement or printing or changes of an editorial nature.</P> <P>(g) <E T="03">Bulk product substance</E> means any substance that is represented for use in a blood product and when used in the <PRTPAGE P="51"/>manufacturing of a blood product becomes an active ingredient or a finished dosage form of such product.</P> <P>(h) <E T="03">Advertising</E> and <E T="03">labeling</E> include the promotional material described in § 202.1(l) (1) and (2) of this chapter, respectively.</P> <P>(i) The definitions and interpretations contained in sections 201 and 510 of the act shall be applicable to such terms when used in this part 607.</P> <CITA>[40 FR 52788, Nov. 12, 1975, as amended at 55 FR 11014, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 607.7</SECTNO> <SUBJECT>Establishment registration and product listing of blood banks and other firms manufacturing human blood and blood products.</SUBJECT> <P>(a) All owners or operators of establishments that engage in the manufacturing of blood products are required to register, pursuant to section 510 of the Federal Food, Drug, and Cosmetic Act. Registration and listing of blood products shall comply with this part. Registration does not permit any blood bank or similar establishment to ship blood products in interstate commerce.</P> <P>(b) Forms for registration of an establishment are obtainable on request from the Center for Biologics Evaluation and Research (HFB-240), 8800 Rockville Pike, Bethesda, MD 20892 or at any of the Food and Drug Administration district offices.</P> <P>(c) The completed form should be mailed to the Center for Biologics Evaluation and Research (HFB-240), 8800 Rockville Pike, Bethesda, MD 20892.</P> <CITA>[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984; 55 FR 11014, Mar. 26, 1990]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart B—Procedures for Domestic Blood Product Establishments</HD> <SECTION> <SECTNO>§ 607.20</SECTNO> <SUBJECT>Who must register and submit a blood product list.</SUBJECT> <P>(a) Owners or operators of all establishments, not exempt under section 510(g) of the act or subpart D of this part 607, that engage in the manufacture of blood products are required to register and to submit a list of every blood product in commercial distribution (except that listing information may be submitted by the parent, subsidiary, and/or affiliate company for all establishments when operations are conducted at more than one establishment and there exists joint ownership and control among all the establishments), whether or not the output of such blood product establishment or any particular blood product so listed enters interstate commerce.</P> <P>(b) Preparatory to engaging in the manufacture of blood products, owners or operators of establishments who are submitting an establishment license application to manufacture blood products are required to register before the establishment license application is approved.</P> <P>(c) No registration fee is required. Establishment registration and blood product listing do not constitute an admission or agreement or determination that a blood product is a “drug” within the meaning of section 201(g) of the act.</P> </SECTION> <SECTION> <SECTNO>§ 607.21</SECTNO> <SUBJECT>Times for establishment registration and blood product listing.</SUBJECT> <P>The owner or operator of an establishment entering into an operation defined in § 607.3(d) shall register such establishment within 5 days after the beginning of such operation and submit a list of every blood product in commercial distribution at the time. If the owner or operator of the establishment has not previously entered into such operation (defined in § 607.3(d)) for which a license is required, registration shall follow within 5 days after the submission of an establishment and product license application in order to manufacture blood products. Owners or operators of all establishments so engaged shall register annually between November 15 and December 31 and shall update their blood product listing information every June and December.</P> </SECTION> <SECTION> <SECTNO>§ 607.22</SECTNO> <SUBJECT>How and where to register establishments and list blood products.</SUBJECT> <P>(a) The first registration of an establishment shall be on Form FD-2830 (Blood Establishment Registration and Product Listing) obtainable on request from the Department of Health and Human Services, Food and Drug Administration, Center for Biologics <PRTPAGE P="52"/>Evaluation and Research (HFB-240), 8800 Rockville Pike, Bethesda, MD 20892, or from Food and Drug Administration district offices. Subsequent annual registration shall also be accomplished on Form FD-2830 which will be furnished by the Food and Drug Administration before November 15 of each year to establishments whose product registration for that year was validated pursuant to § 607.35. The completed form shall be mailed to the above address before December 31 of that year.</P> <P>(b) The first list of blood products and subsequent June and December updatings shall be on Form FD-2830, obtainable upon request as described in paragraph (a) of this section. In lieu of Form FD-2830, tapes for computer input may be submitted if equivalent in all elements of information as specified in Form FD-2830. All formats proposed for such use will require initial review and approval by the Office of Compliance, Center for Biologics Evaluation and Research, Food and Drug Administration.</P> <CITA>[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984; 55 FR 11014, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 607.25</SECTNO> <SUBJECT>Information required for establishment registration and blood product listing.</SUBJECT> <P>(a) Form FD-2830 (Blood Establishment Registration and Product Listing) requires furnishing or confirming registration information required by the act. This information includes the name and street address of the establishment, including post office ZIP code; all trade names used by the establishment; the kind of ownership or operation (that is, individually owned partnership, or corporation); and the name of the owner or operator of such establishment. The term “name of the owner or operator” shall include in the case of a partnership the name of each partner, and in the case of a corporation the name and title of each corporate officer and director and the name of the State of incorporation. The information required shall be given separately for each establishment, as defined in § 607.3(c).</P> <P>(b) Form FD-2830 also requires furnishing blood product listing information required by the act as follows:</P> <P>(1) A list of blood products, including bulk product substances as well as finished dosage forms, by established name as defined in section 502(e) of the act and by proprietary name, which are being manufactured for commercial distribution and which have not been included in any list previously submitted on Form FD-2830 (Blood Establishment Registration and Product Listing) or Form FD-2250 (National Drug Code Directory Input).</P> <P>(2) For each blood product so listed which is subject to section 351 of the Public Health Service Act, the license number of the manufacturer issued by the Center for Biologics Evaluation and Research, Food and Drug Administration.</P> <P>(3) For each blood product listed, the registration number of every blood product establishment within the parent company at which it is manufactured.</P> <CITA>[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 607.26</SECTNO> <SUBJECT>Amendments to establishment registration.</SUBJECT> <P>Changes in individual ownership, corporate or partnership structure location or blood-product-handling activity, shall be submitted on Form FD-2830 (Blood Establishment Registration and Product Listing) as amendment to registration within 5 days of such changes. Changes in the names of officers and directors of the corporations do not require such amendment but must be shown at time of annual registration.</P> </SECTION> <SECTION> <SECTNO>§ 607.30</SECTNO> <SUBJECT>Updating blood product listing information.</SUBJECT> <P>(a) After submission of the initial blood product listing information, every person who is required to list blood products pursuant to § 607.20 shall submit on Form FD-2830 (Blood Establishment Registration and Product Listing) during each subsequent June and December, or at the discretion of the registrant at the time the change occurs, the following information:<PRTPAGE P="53"/> </P> <P>(1) A list of each blood product introduced by the registrant for commercial distribution which has not been included in any list previously submitted. All of the information required by § 607.25(b) shall be provided for each such blood product.</P> <P>(2) A list of each blood product formerly listed pursuant to § 607.25(b) for which commercial distribution has been discontinued, including for each blood product so listed the identity by established name and proprietary name, and date of discontinuance. It is requested but not required that the reason for discontinuance of distribution be included with this information.</P> <P>(3) A list of each blood product for which a notice of discontinuance was submitted pursuant to paragraph (a)(2) of this section and for which commercial distribution has been resumed, including for each blood product so listed the identity by established name as defined in section 502(e) of the act and by any proprietary name, the date of resumption, and any other information required by § 607.25(b) not previously submitted.</P> <P>(4) Any material change in any information previously submitted.</P> <P>(b) When no changes have occurred since the previously submitted list, no listing information is required.</P> </SECTION> <SECTION> <SECTNO>§ 607.31</SECTNO> <SUBJECT>Additional blood product listing information.</SUBJECT> <P>(a) In addition to the information routinely required by §§ 607.25 and 607.30, the Commissioner may require submission of the following information by letter or by <E T="04">Federal Register</E> notice:</P> <P>(1) For a particular blood product so listed, upon request made by the Commissioner for good cause, a copy of all advertisements.</P> <P>(2) For a particular blood product so listed, upon a finding by the Commissioner that it is necessary to carry out the purposes of the act, a quantitative listing of all ingredients.</P> <P>(3) For each registrant, upon a finding by the Commissioner that it is necessary to carry out the purposes of the act, a list of each listed blood product containing a particular ingredient.</P> <P>(b) It is requested but not required that information concerning the quantity of blood product distributed be submitted in conjunction with the annual registration in the format prescribed in a section of Form FD-2831 (Blood Establishment Resource Summary), for each blood product currently listed.</P> </SECTION> <SECTION> <SECTNO>§ 607.35</SECTNO> <SUBJECT>Notification of registrant; blood product establishment registration number and NDC Labeler Code.</SUBJECT> <P>(a) The Commissioner will provide to the registrant a validated copy of Form FD-2830 (Blood Establishment Registration and Product Listing) as evidence of registration. This validated copy will be sent only to the location shown for the registering establishment. A permanent registration number will be assigned to each blood product establishment registered in accordance with these regulations.</P> <P>(b) If a registered blood product establishment has not previously participated in the National Drug Code system, or in the National Health Related Items Code system, the National Drug Code (NDC) numbering system shall be used in assigning the first five numeric characters, otherwise known as the Labeler Code, of the 10-character NDC Code. The Labeler Code identifies the manufacturer.</P> <P>(c) Although establishment registration and blood product listing are required as described in § 607.20, validation of registration and the assignment of a NDC Labeler Code do not, in themselves, establish that the holder of the registration is legally qualified to deal in such products.</P> <CITA>[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984]</CITA> </SECTION> <SECTION> <SECTNO>§ 607.37</SECTNO> <SUBJECT>Inspection of establishment registrations and blood product listings.</SUBJECT> <P>(a) A copy of the Form FD-2830 (Blood Establishment Registration and Product Listing) filed by the registrant will be available for inspection pursuant to section 510(f) of the act, at the Department of Health and Human Services, Food and Drug Administration, Office of Compliance, Center for Biologics Evaluation and Research (HFB-100), 8800 Rockville Pike, Bethesda, MD 20892. In addition, there <PRTPAGE P="54"/>will be available for inspection at each of the Food and Drug Administration district offices the same information for firms within the geographical area of such district office. Upon request and receipt of a self-addressed stamped envelope, verification of registration number, or location of a registered establishment will be provided. The following information submitted pursuant to the blood product listing requirements is illustrative of the type of information that will be available for public disclosure when it is compiled:</P> <P>(1) A list of all blood products.</P> <P>(2) A list of all blood products manufactured by each establishment.</P> <P>(3) A list of blood products discontinued.</P> <P>(4) All data or information that has already become a matter of public knowledge.</P> <P>(b) Requests for information regarding blood establishment registrations and blood product listings should be directed to the Department of Health and Human Services, Food and Drug Administration, Office of Compliance, Center for Biologics Evaluation and Research (HFB-100), 8800 Rockville Pike, Bethesda, MD 20892.</P> <CITA>[40 FR 52788, Nov. 12, 1975, as amended at 49 FR 23833, June 8, 1984; 55 FR 11014, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 607.39</SECTNO> <SUBJECT>Misbranding by reference to establishment registration or to registration number.</SUBJECT> <P>Registration of an establishment or assignment of a registration number or assignment of a NDC number does not in any way denote approval of the firm or its products. Any representation that creates an impression of official approval because of establishment registration or possession of registration number or NDC number is misleading and constitutes misbranding.</P> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart C—Procedures for Foreign Blood Product Establishments</HD> <SECTION> <SECTNO>§ 607.40</SECTNO> <SUBJECT>Blood product listing requirements for foreign blood product establishments.</SUBJECT> <P>(a) Every foreign establishment shall comply with the blood product listing requirements contained in Subpart B of this part, unless exempt under Subpart D of this part, whether or not it is also registered.</P> <P>(b) No blood product may be imported from a foreign establishment into the United States except a blood product imported or offered for import pursuant to the investigational use provisions of part 312 of this chapter, unless it is first the subject of a blood product listing as required in Subpart B of this part. The blood product listing information shall be in the English language.</P> <P>(c) Foreign establishments shall submit, as part of the blood product listing, the name and address of the establishment and the name of the individual responsible for submitting blood product listing information. Any changes in this information shall be reported to the Food and Drug Administration at the intervals specified for updating blood product listing information in § 607.30(a).</P> <CITA>[40 FR 52788, Nov. 12, 1975, as amended at 55 FR 11014, Mar. 26, 1990]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart D—Exemptions</HD> <SECTION> <SECTNO>§ 607.65</SECTNO> <SUBJECT>Exemptions for blood product establishments.</SUBJECT> <P>The following classes of persons are exempt from registration and blood product listing in accordance with this part 607 under the provisions of section 510(g) (1), (2), and (3) of the act, or because the Commissioner has found, under section 510(g)(4), that such registration is not necessary for the protection of the public health.</P> <P>(a) Pharmacies that are operating under applicable local laws regulating dispensing of prescription drugs and that are not manufacturing blood products for sale other than in the regular course of the practice of the profession of pharmacy including the business of dispensing and selling blood products at retail. The supplying by such pharmacies of blood products to a practitioner licensed to administer such blood products for his use in the course of his professional practice or to other pharmacies to meet temporary inventory shortages are not acts which require such pharmacies to register.</P> <P>(b) Practitioners who are licensed by law to prescribe or administer drugs and who manufacture blood products <PRTPAGE P="55"/>solely for use in the course of their professional practice.</P> <P>(c) Persons who manufacture blood products which are not for sale, rather, are solely for use in research, teaching, or analysis, including laboratory samples.</P> <P>(d) Carriers, by reason of their receipt, carriage, holding, or delivery of blood products in the usual course of business as carriers.</P> <P>(e) Persons who engage solely in the manufacture of in vitro diagnostic blood products and reagents not subject to licensing under section 351 of the Public Health Service Act (42 U.S.C. 262). This paragraph does not exempt such persons from registration and listing for medical devices required under part 807 of this chapter.</P> <P>(f) Transfusion services which are a part of a facility approved for Medicare reimbursement and engaged in the compatibility testing and transfusion of blood and blood components, but which neither routinely collect nor process blood and blood components. The collection and processing of blood and blood components in an emergency situation as determined by a responsible person and documented in writing, therapeutic collection of blood or plasma, the preparation of recovered human plasma for further manufacturing use, or preparation of red blood cells for transfusion are not acts requiring such transfusion services to register.</P> <P>(g) Clinical laboratories that are approved for Medicare reimbursement and are engaged in the testing of blood products in support of other registered blood establishments.</P> <CITA>[40 FR 52788, Nov. 12, 1975, as amended at 43 FR 37997, Aug. 25, 1978; 45 FR 85729, Dec. 30, 1980; 49 FR 34449, Aug. 31, 1984]</CITA> </SECTION> </SUBPART> </PART> <PART> <EAR>Pt. 610</EAR> <HD SOURCE="HED">PART 610—GENERAL BIOLOGICAL PRODUCTS STANDARDS</HD> <CONTENTS> <SUBPART> <HD SOURCE="HED">Subpart A—Release Requirements</HD> <SECHD>Sec.</SECHD> <SECTNO>610.1</SECTNO> <SUBJECT>Tests prior to release required for each lot.</SUBJECT> <SECTNO>610.2</SECTNO> <SUBJECT>Requests for samples and protocols; official release.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart B—General Provisions</HD> <SECTNO>610.9</SECTNO> <SUBJECT>Equivalent methods and processes.</SUBJECT> <SECTNO>610.10</SECTNO> <SUBJECT>Potency.</SUBJECT> <SECTNO>610.11</SECTNO> <SUBJECT>General safety.</SUBJECT> <SECTNO>610.11a</SECTNO> <SUBJECT>Inactivated influenza vaccine, general safety test.</SUBJECT> <SECTNO>610.12</SECTNO> <SUBJECT>Sterility.</SUBJECT> <SECTNO>610.13</SECTNO> <SUBJECT>Purity.</SUBJECT> <SECTNO>610.14</SECTNO> <SUBJECT>Identity.</SUBJECT> <SECTNO>610.15</SECTNO> <SUBJECT>Constituent materials.</SUBJECT> <SECTNO>610.16</SECTNO> <SUBJECT>Total solids in serums.</SUBJECT> <SECTNO>610.17</SECTNO> <SUBJECT>Permissible combinations.</SUBJECT> <SECTNO>610.18</SECTNO> <SUBJECT>Cultures.</SUBJECT> <SECTNO>610.19</SECTNO> <SUBJECT>Status of specific products; Group A streptococcus.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart C—Standard Preparations and Limits of Potency</HD> <SECTNO>610.20</SECTNO> <SUBJECT>Standard preparations.</SUBJECT> <SECTNO>610.21</SECTNO> <SUBJECT>Limits of potency.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart D—Mycoplasma</HD> <SECTNO>610.30</SECTNO> <SUBJECT>Test for <E T="03">Mycoplasma.</E> </SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart E—Hepatitis Requirements</HD> <SECTNO>610.40</SECTNO> <SUBJECT>Test for hepatitis B surface antigen.</SUBJECT> <SECTNO>610.41</SECTNO> <SUBJECT>History of hepatitis B surface antigen.</SUBJECT> <SECTNO>610.45</SECTNO> <SUBJECT>Human Immunodeficiency Virus (HIV) requirements.</SUBJECT> <SECTNO>610.46</SECTNO> <SUBJECT>“Lookback” requirements.</SUBJECT> <SECTNO>610.47</SECTNO> <SUBJECT>“Lookback” notification requirements for transfusion services.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart F—Dating Period Limitations</HD> <SECTNO>610.50</SECTNO> <SUBJECT>Date of manufacture.</SUBJECT> <SECTNO>610.53</SECTNO> <SUBJECT>Dating periods for licensed biological products .</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart G—Labeling Standards</HD> <SECTNO>610.60</SECTNO> <SUBJECT>Container label.</SUBJECT> <SECTNO>610.61</SECTNO> <SUBJECT>Package label.</SUBJECT> <SECTNO>610.62</SECTNO> <SUBJECT>Proper name; package label; legible type.</SUBJECT> <SECTNO>610.63</SECTNO> <SUBJECT>Divided manufacturing responsibility to be shown.</SUBJECT> <SECTNO>610.64</SECTNO> <SUBJECT>Name and address of distributor.</SUBJECT> <SECTNO>610.65</SECTNO> <SUBJECT>Products for export.</SUBJECT> </SUBPART> </CONTENTS> <AUTH> <HD SOURCE="HED">Authority: </HD> <P>21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 U.S.C. 216, 262, 263, 263a, 264.</P> </AUTH> <SOURCE> <HD SOURCE="HED">Source: </HD> <P>38 FR 32056, Nov. 20, 1973, unless otherwise noted.</P> </SOURCE> <CROSSREF> <HD SOURCE="HED"> <E T="04">Cross References:</E> </HD> <P>For U.S. Customs Service regulations relating to viruses, serums, and toxins, see 19 CFR 12.21—12.23. For U.S. Postal Service regulations relating to the admissibility to the United States mails see parts 124 and 125 of the Domestic Mail Manual, that is incorporated by reference in 39 CFR part 111.</P> </CROSSREF> <SUBPART> <PRTPAGE P="56"/> <HD SOURCE="HED">Subpart A—Release Requirements</HD> <SECTION> <SECTNO>§ 610.1</SECTNO> <SUBJECT>Tests prior to release required for each lot.</SUBJECT> <P>No lot of any licensed product shall be released by the manufacturer prior to the completion of tests for conformity with standards applicable to such product. Each applicable test shall be made on each lot after completion of all processes of manufacture which may affect compliance with the standard to which the test applies. The results of all tests performed shall be considered in determining whether or not the test results meet the test objective, except that a test result may be disregarded when it is established that the test is invalid due to causes unrelated to the product.</P> </SECTION> <SECTION> <SECTNO>§ 610.2</SECTNO> <SUBJECT>Requests for samples and protocols; official release.</SUBJECT> <P>(a) <E T="03">General.</E> Samples of any lot of any licensed product, except for radioactive biological products, together with the protocols showing results of applicable tests, may at any time be required to be sent to the Director, Center for Biologics Evaluation and Research. Upon notification by the Director, Center for Biologics Evaluation and Research, a manufacturer shall not distribute a lot of a product until the lot is released by the Director, Center for Biologics Evaluation and Research: <E T="03">Provided,</E> That the Director, Center for Biologics Evaluation and Research, shall not issue such notification except when deemed necessary for the safety, purity, or potency of the product.</P> <P>(b) <E T="03">Radioactive biological products.</E> Samples of any lot of a radioactive biological product, as defined in § 600.3(ee) of this chapter, together with the protocols showing results of applicable tests, may at any time be required to be sent to the Food and Drug Administration for official release. Upon notification by the Director, Center for Drug Evaluation and Research, a manufacturer shall not distribute a lot of a radioactive biological product until the lot is released by the Director, Center for Drug Evaluation and Research: <E T="03">Provided,</E> That the Director, Center for Drug Evaluation and Research shall not issue such notification except when deemed necessary for the safety, purity, or potency of the product. </P> <EXTRACT> <FP>(Information collection requirements approved by the Office of Management and Budget under control number 0910-0206)</FP> </EXTRACT> <CITA>[40 FR 31313, July 25, 1975, as amended by 49 FR 23834, June 8, 1984; 50 FR 10941, Mar. 19, 1985; 55 FR 11013 and 11014, Mar. 26, 1990]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart B—General Provisions</HD> <SECTION> <SECTNO>§ 610.9</SECTNO> <SUBJECT>Equivalent methods and processes.</SUBJECT> <P>Modification of any particular test method or manufacturing process or the conditions under which it is conducted as required in this part or in the additional standards for specific biological products in parts 620 through 680 of this chapter shall be permitted only under the following conditions:</P> <P>(a) The applicant presents evidence, in the form of a license application, or a supplement to the application submitted in accordance with § 601.12(b) or (c), demonstrating that the modification will provide assurances of the safety, purity, potency, and effectiveness of the biological product equal to or greater than the assurances provided by the method or process specified in the general standards or additional standards for the biological product; and</P> <P>(b) Approval of the modification is received in writing from the Director, Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852-1448.</P> <CITA>[62 FR 39903, July 24, 1997]</CITA> </SECTION> <SECTION> <SECTNO>§ 610.10</SECTNO> <SUBJECT>Potency.</SUBJECT> <P>Tests for potency shall consist of either in vitro or in vivo tests, or both, which have been specifically designed for each product so as to indicate its potency in a manner adequate to satisfy the interpretation of potency given by the definition in § 600.3(s) of this chapter.</P> </SECTION> <SECTION> <SECTNO>§ 610.11</SECTNO> <SUBJECT>General safety.</SUBJECT> <P>A general safety test for the detection of extraneous toxic contaminants <PRTPAGE P="57"/>shall be performed on biological products intended for administration to humans. The general safety test is required in addition to other specific tests prescribed in the additional standards for individual products in this subchapter, except that, the test need not be performed on those products listed in paragraph (g) of this section. The general safety test shall be performed as specified in this section, unless: Modification is prescribed in the additional standards for specific products, or variation is approved as a supplement to the product license under § 610.9.</P> <P>(a) <E T="03">Product to be tested.</E> The general safety test shall be conducted upon a representative sample of the product in the final container from every final filling of each lot of the product. If any product is processed further after filling, such as by freeze-drying, sterilization, or heat treatment, the test shall be conducted upon a sample from each filling of each drying chamber run, sterilization chamber, or heat treatment bath.</P> <P>(b) <E T="03">Test animals.</E> Only overtly healthy guinea pigs weighing less than 400 grams each and mice weighing less than 22 grams each shall be used. The animals shall not have been used previously for any test purpose.</P> <P>(c) <E T="03">Procedure.</E> The duration of the general safety test shall be 7 days for both species, except that a longer period may be established for specific products in accordance with § 610.9. Once the manufacturer has established a specific duration of the test period for a specific product, it cannot be varied subsequently, except, in accordance with § 610.9. Each test animal shall be weighed and the individual weights recorded immediately prior to injection and on the last day of the test. Each animal shall be observed every working day. Any animal response including any which is not specific for or expected from the product and which may indicate a difference in its quality shall be recorded on the day such response is observed. The test product shall be administered as follows:</P> <P>(1) <E T="03">Liquid product or freeze-dried product which has been reconstituted as directed on the label.</E> Inject intraperitoneally 0.5 milliliter of the liquid product or the reconstituted product into each of at least two mice, and 5.0 milliliters of the liquid product or the reconstituted product into each of at least two guinea pigs.</P> <P>(2) <E T="03">Freeze-dried product for which the volume of reconstitution is not indicated on the label.</E> The route of administration, test dose, and diluent shall be as approved by the Director, Center for Biologics Evaluation and Research, in accordance with § 610.9. Administer the test product as approved on at least two mice and at least two guinea pigs.</P> <P>(3) <E T="03">Nonliquid products other than freeze-dried product.</E> The route of administration, test dose, and diluent shall be as approved by the Director, Center for Biologics Evaluation and Research, in accordance with § 610.9. Dissolve or grind and suspend the product in the approved diluent. Administer the test product as approved on at least two mice and at least two guinea pigs.</P> <P>(d) <E T="03">Test requirements.</E> A safety test is satisfactory if all animals meet all of the following requirements:</P> <P>(1) They survive the test period.</P> <P>(2) They do not exhibit any response which is not specific for or expected from the product and which may indicate a difference in its quality.</P> <P>(3) They weigh no less at the end of the test period than at the time of injection.</P> <P>(e) <E T="03">Repeat tests</E>—(1) <E T="03">First repeat test.</E> If a filling fails to meet the requirements of paragraph (d) of this section in the initial test, a repeat test may be conducted on the species which failed the initial test, as prescribed in paragraph (c) of this section. The filling is satisfactory only if each retest animal meets the requirements prescribed in paragraph (d) of this section.</P> <P>(2) <E T="03">Second repeat test.</E> If a filling fails to meet the requirements of the first repeat test, a second repeat test may be conducted on the species which failed the test: <E T="03">Provided,</E> That 50 percent of the total number of animals in that species has survived the initial and first repeat tests. The second repeat test shall be conducted as prescribed in paragraph (c) of this section, except that the number of animals shall be twice that used in the first repeat test. The filling is satisfactory <PRTPAGE P="58"/>only if each second repeat test animal meets the requirements prescribed in paragraph (d) of this section.</P> <P>(f) [Reserved]</P> <P>(g) <E T="03">Exceptions</E>—(1) The test prescribed in this section need not be performed for Whole Blood, Red Blood Cells, Cryoprecipitated AHF, Platelets, Plasma, or Cellular Therapy Products.</P> <P>(2) [Reserved]</P> <CITA>[41 FR 10891, Mar. 15, 1976, as amended at 49 FR 15187, Apr. 18, 1984; 49 FR 23834, June 8, 1984; 50 FR 4133, Jan. 29, 1985; 51 FR 15607, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 63 FR 19403, Apr. 20, 1998; 63 FR 41718, Aug. 5, 1998]</CITA> </SECTION> <SECTION> <SECTNO>§ 610.11a</SECTNO> <SUBJECT>Inactivated influenza vaccine, general safety test.</SUBJECT> <P>For inactivated influenza vaccine, the general safety test shall be conducted in the manner indicated in § 610.11 of this chapter except that, with reference to guinea pigs, the test shall be satisfied if the product provides satisfactory results using either the subcutaneous or intraperitoneal injection of 5.0 milliliters of inactivated influenza vaccine into each guinea pig. The requirements for general safety for inactivated influenza vaccine shall not be considered to be satisfied unless each lot of influenza vaccine is assayed for endotoxin in comparison to a reference preparation provided by the Food and Drug Administration, and such lot is found to contain no more endotoxin than the reference preparation.</P> <CITA>[39 FR 40016, Nov. 13, 1974]</CITA> </SECTION> <SECTION> <SECTNO>§ 610.12</SECTNO> <SUBJECT>Sterility.</SUBJECT> <P>Except as provided in paragraphs (f) and (g) of this section, the sterility of each lot of each product shall be demonstrated by the performance of the tests prescribed in paragraphs (a) and (b) of this section for both bulk and final container material.</P> <P>(a) <E T="03">The test.</E> Bulk material shall be tested separately from final container material and material from each final container shall be tested in individual test vessels as follows:</P> <P>(1) <E T="03">Using Fluid Thioglycollate Medium—</E>(i) <E T="03">Bulk and final container material.</E> The volume of product, as required by paragraph (d) of this section (hereinafter referred to also as the “inoculum”), from samples of both bulk and final container material, shall be inoculated into test vessels of Fluid Thioglycollate Medium. The inoculum and medium shall be mixed thoroughly and incubated at a temperature of 30 to 35 °C for a test period of no less than 14 days and examined visually for evidence of growth on the third, fourth, or fifth day, and on the seventh or eighth day, and on the last day of the test period. Results of each examination shall be recorded. If the inoculum renders the medium turbid so that the absence of growth cannot be determined reliably by visual examination, portions of this turbid medium in amounts of no less than 1.0 milliliter shall be transferred on the third, fourth, or fifth day of incubation, from each of the test vessels and inoculated into additional vessels of the medium. The material in the additional vessels shall be incubated at a temperature of 30 to 35 °C for no less than 14 days. Notwithstanding such transfer of material, examination of the original vessels shall be continued as prescribed above. The additional test vessels shall be examined visually for evidence of growth on the third, fourth, or fifth day of incubation, and on the seventh or eighth day, and on the last day of the incubation period. If growth appears, repeat tests may be performed as prescribed in paragraph (b) of this section and interpreted as specified in paragraph (c) of this section.</P> <P>(ii) <E T="03">Final container material containing a mercurial preservative.</E> In addition to the test prescribed in paragraph (a)(1)(i) of this section, final container material containing a mercurial preservative shall be tested using Fluid Thioglycollate Medium following the procedures prescribed in such subparagraph, except that the incubation shall be at a temperature of 20 to 25 °C.</P> <P>(2) <E T="03">Using Soybean-Casein Digest Medium.</E> Except for products containing a mercurial preservative, a test shall be made on final container material, following the procedures prescribed in paragraph (a)(1)(i) of this section, except that the medium shall be Soybean-Casein Digest Medium and the incubation shall be at a temperature of 20 to 25 °C.<PRTPAGE P="59"/> </P> <P>(b) <E T="03">Repeat tests.</E> If growth appears in any of the test media during testing of either bulk or final container material, the test may be repeated to rule out faulty test procedures as follows:</P> <P>(1) <E T="03">Repeat bulk test.</E> Only one repeat bulk test may be conducted. The volume of inoculum to be used for the repeat bulk test shall be as prescribed in paragraph (d)(1) of this section. The repeat test shall be performed using the procedure prescribed in paragraph (a)(1)(i) of this section.</P> <P>(2) <E T="03">First repeat final container test.</E> The number of test samples and the volumes of product used for the first repeat test shall be as prescribed in paragraph (d)(2) of this section. For products that do not contain a mercurial preservative, the repeat test shall be performed, using both Fluid Thioglycollate Medium and Soybean-Casein Digest Medium, following the procedures prescribed in paragraphs (a)(1)(i) and (a)(2), respectively, of this section. If the product contains a mercurial preservative, the repeat test shall be performed using Fluid Thioglycollate Medium and the procedures prescribed in paragraphs (a)(1) (i) and (ii) of this section.</P> <P>(3) <E T="03">Second repeat final container test.</E> If growth appears in any of the first repeat final container tests, all tests of the first repeat final container test shall be repeated, provided there was no evidence of growth in any test of the bulk material. The test samples used for the second repeat final container test shall be twice the number used for the first repeat final container test.</P> <P>(c) <E T="03">Interpretation of test results.</E> The results of all tests performed on a lot shall be considered in determining whether or not the lot meets the requirements for sterility, except that tests may be excluded when demonstrated by adequate controls to be invalid. The lot meets the test requirements if no growth appears in the tests prescribed in paragraph (a) of this section. If repeat tests are performed, the lot meets the test requirements if no growth appears in the tests prescribed in paragraph (b)(2) or (3) of this section, whichever is applicable.</P> <P>(d) <E T="03">Test samples and volumes</E>—(1) <E T="03">Bulk.</E> Each sample for the bulk sterility test shall be representative of the bulk material and the volume tested shall be no less than 10 ml. (Note exceptions in paragraph (g) of this section.)</P> <P>(2) <E T="03">Final containers.</E> The sample used for each test medium or each incubation temperature of a test medium for the final container and first repeat final container test shall be no less than 20 final containers from each filling of each lot, selected to represent all stages of filling from the bulk vessel. If the amount of material in the final container is 1.0 milliliter or less, the entire contents shall be tested. If the amount of material in the final container is more than 1.0 milliliter, the volume tested shall be the largest single dose recommended by the manufacturer or 1.0 milliliter, whichever is larger, but no more than 10 milliliters of material or the entire contents from a single final container need be tested. If more than 2 filling machines, each with either single or multiple filling stations, are used for filling one lot, no less than 10 filled containers shall be tested from each filling machine for each test medium or each incubation temperature condition, but no more than 100 containers of each lot need be tested. The items tested shall be representative of each filling assembly and shall be selected to represent all stages of the filling operation. (Note exceptions in paragraph (g) of this section.)</P> <P>(e) <E T="03">Culture medium</E>—(1) <E T="03">Formulae.</E> (i) The formula for Fluid Thioglycollate Medium is as follows:</P> <GPOTABLE CDEF="s50,xs48" COLS="2" OPTS="L0,6/7,g1,t1"> <TTITLE> <E T="04">Fluid Thioglycollate Medium</E> </TTITLE> <ROW> <ENT I="01">1-cystine</ENT> <ENT>0.5 gm.</ENT> </ROW> <ROW> <ENT I="01">Sodium chloride</ENT> <ENT>2.5 gm.</ENT> </ROW> <ROW> <ENT I="01">Dextrose (C<E T="22">6</E> <E T="31">H</E> <E T="22">1</E> <E T="22">2</E> <E T="31">O</E> <E T="22">6</E> <E T="01">·</E> <E T="31">H</E> <E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>5.5 gm.</ENT> </ROW> <ROW> <ENT I="01">Granular agar (less than 15% moisture by weight) </ENT> <ENT>0.75 gm.</ENT> </ROW> <ROW> <ENT I="01">Yeast extract (water-soluble)</ENT> <ENT>5.0 gm.</ENT> </ROW> <ROW> <ENT I="01">Pancreatic digest of casein</ENT> <ENT>15.0 gm.</ENT> </ROW> <ROW> <ENT I="01">Purified water</ENT> <ENT>1,000.0 ml.</ENT> </ROW> <ROW> <ENT I="01">Sodium thioglycollate (or thioglycolic acid—0.3 ml) </ENT> <ENT>0.5 gm.</ENT> </ROW> <ROW> <ENT I="01">Resazurin (0.10% solution, 1.0 ml. freshly prepared)</ENT> </ROW> <ROW> <ENT I="11">pH after sterilization 7.1<E T="21">±</E> <E T="31">0.2.</E> </ENT> </ROW> </GPOTABLE> <P>(ii) The formula for Soybean-Casein Digest Medium is as follows:</P> <GPOTABLE CDEF="s50,xs48" COLS="2" OPTS="L0,6/7,g1,t1"> <TTITLE> <E T="04">Soybean-Casein Digest Medium</E> </TTITLE> <ROW> <ENT I="01">Pancreatic Digest of Casein</ENT> <ENT>17.0 gm.</ENT> </ROW> <ROW> <ENT I="01">Papaic Digest of Soybean Meal</ENT> <ENT>3.0 gm.</ENT> </ROW> <ROW> <ENT I="01">Sodium Chloride</ENT> <ENT>5.0 gm.</ENT> </ROW> <ROW> <ENT I="01">Dibasic Potassium Phosphate</ENT> <ENT>2.5 gm.</ENT> </ROW> <ROW> <PRTPAGE P="60"/> <ENT I="01">Dextrose (C<E T="22">6</E> <E T="31">H</E> <E T="22">12</E> <E T="31">O</E> <E T="22">6</E> <E T="01">·</E> <E T="31">H</E> <E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>2.5 gm.</ENT> </ROW> <ROW> <ENT I="01">Purified water</ENT> <ENT>1,000.0 ml.</ENT> </ROW> <ROW> <ENT I="11">pH after sterilization 7.3<E T="21">±</E> <E T="31">0.2.</E> </ENT> </ROW> </GPOTABLE> <P>(2) <E T="03">Culture media requirements—</E>(i) <E T="03">Definition of a lot of culture medium and test requirements.</E> A lot of culture medium is that quantity of uniform material identified as having been thoroughly mixed in a single vessel, dispensed into a group of vessels of the same composition and design, sterilized in a single autoclave run, and identified in a manner to distinguish one lot from another. Each lot of culture medium shall be tested for its growth-promoting qualities unless it meets the exception for dehydrated culture medium described in this subpart. The growth-promoting quality test shall be performed on the smallest sized vessel used in an autoclave run. When using a single batch of dehydrated culture medium, a manufacturer need not perform growth-promoting tests on each lot of prepared liquid medium, provided that a validation program exists for autoclaves used to sterilize the culture medium, and the manufacturer has received approval for this practice from the Director, Center for Biologics Evaluation and Research.</P> <P>(ii) <E T="03">Test organisms, strains, characteristics, identity, and verification.</E> Two or more strains of microorganisms that are exacting in their nutritive and aerobic/anaerobic requirements shall be used to test the growth-promoting qualities of each lot of test medium. When using Fluid Thioglycollate medium, both an aerobic and an anaerobic test microorganism shall be chosen. When using Soybean Casein Digest Medium, the yeast, <E T="03">Candida albicans,</E> shall be one of the two test microorganisms chosen. Manufacturers shall choose the strains of microorganisms from the chart in this paragraph.</P> <GPOTABLE CDEF="s100,r100,xs40" COLS="3" OPTS="L2,i1"> <BOXHD> <CHED H="1">Medium</CHED> <CHED H="1">Test microorganisms</CHED> <CHED H="1">Incubation temperature</CHED> </BOXHD> <ROW> <ENT I="22"/> <ENT O="xl"> <E T="03">Spore-formers</E> </ENT> </ROW> <ROW> <ENT I="01">Fluid Thioglycollate</ENT> <ENT>1. <E T="03">Bacillus subtilis</E> (ATCC No. 6633) </ENT> <ENT>30 to 35 °C.</ENT> </ROW> <ROW> <ENT I="22"/> <ENT>2. <E T="03">Clostridium sporogenes</E> (ATCC No. 11437)</ENT> <ENT>Do. </ENT> </ROW> <ROW> <ENT I="22"/> <ENT O="xl"> <E T="03">Non-spore-formers</E> </ENT> </ROW> <ROW> <ENT I="22"/> <ENT>3. <E T="03">Candida albicans</E> (ATCC No. 10231)</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="22"/> <ENT>4. <E T="03">Micrococcus luteus</E> (ATCC No. 9341)</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="22"/> <ENT>5. <E T="03">Bacteroides vulgatus</E> (ATCC No. 8482)</ENT> <ENT>Do. </ENT> </ROW> <ROW> <ENT I="22"/> <ENT O="xl"> <E T="03">Spore-formers</E> </ENT> </ROW> <ROW> <ENT I="01">Soybean-Casein Digest </ENT> <ENT>1. <E T="03">Bacillus subtilis</E> (ATCC No. 6633)</ENT> <ENT>20 to 25 °C. </ENT> </ROW> <ROW> <ENT I="22"/> <ENT O="xl"> <E T="03">Non-spore-formers</E> </ENT> </ROW> <ROW> <ENT I="22"/> <ENT>2. <E T="03">Candida albicans</E> (ATCC No. 10231)</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="22"/> <ENT>3. <E T="03">Micrococcus luteus</E> (ATCC No. 9341)</ENT> <ENT>Do.</ENT> </ROW> </GPOTABLE> <P>ATCC strains of microorganisms described in this section are available from the American Type Culture Collection, 12301 Parklawn Dr., Rockville, MD 20852. Periodic tests shall be performed to verify the integrity of the test organisms in accordance with § 610.18 (a) and (b). The results of these periodic tests shall be recorded and retained in accordance with § 600.12(b) of this chapter.</P> <P>(iii) <E T="03">Storage and maintenance of cultures of test organisms.</E> Cultures of the test organisms used to determine the growth-promoting qualities of the medium shall be stored in a manner that will prevent cross contamination or loss of identity, at a temperatre and by a method that will retain the initial characteristics of the organisms and ensure freedom from contamination and deterioration. If the test organisms are stored in the freeze-dried state, or frozen, they shall be reconstituted or thawed, whichever is applicable, and plated periodically to verify the colony count of the suspension. If the test suspensions are stored in a state other than freeze-dried or frozen, they shall be plated, and a colony count shall be performed at the time of each growth-promoting quality test to assure that not more than 100 organisms are used per test vessel. The results of tests for verification of the colony count shall <PRTPAGE P="61"/>be recorded and retained in accordance with § 600.12(b) of this chapter.</P> <P>(iv) <E T="03">Storage and condition of media.</E> A medium shall not be used if the extent of evaporation affects its fluidity, nor shall it be reused in a sterility test of the product. Fluid Thioglycollate Medium shall be stored in the dark at room temperature if the vessels are unsealed. Sealed vessels shall be stored at the manufacturer's specified storage temperature.</P> <P>Fluid Thioglycollate Medium shall not be used if more than the upper one-third of the medium has acquired a pink color. The medium may be restored once by heating on a steam bath or in free-flowing steam until the pink color disappears. The design of the test vessel for Fluid Thioglycollate Medium shall provide favorable aerobic and anaerobic conditions for growth of the microorganisms throughout the test period. Soybean-Casein Digest Medium shall be stored in the dark at 20 to 25 °C. Unsealed vessels of either medium may be stored for more than 10 days at the proper temperature, provided they are tested monthly for growth-promotion and found to be satisfactory. Sealed vessels of either medium may be stored at the proper temperature for a period of time not to exceed 1 year, provided they are tested for growth-promotion every 3 months and found to be satisfactory. The results of such testing shall be recorded and retained in accordance with § 600.12(b) of this chapter.</P> <P>(v) <E T="03">Criteria for a satisfactory growth-promoting quality test.</E> (<E T="03">a</E>) One hundred or fewer organisms of each strain tested shall be used. The test is satisfactory if evidence of growth appears within 7 days in all vessels inoculated. If a lot of medium fails to support the growth of any test organism, or if the test results show that more than 100 organisms of a strain were used or are necessary to promote growth in the lot of medium being tested, or if the growth is not a pure culture of the test organism, a second test may be performed. If it fails the second test, the lot of medium shall be rejected.</P> <P>(<E T="03">b</E>) Inoculated Fluid Thioglycollate Medium shall be incubated at 30 to 35 °C for 7 days. If the test medium is to be used in determining the sterility of a product containing a mercurial preservative, a second test shall be performed in accordance with paragraph (e)(2)(v)(<E T="03">a</E>) of this section, except that the test shall be incubated at 20 to 25 °C for 7 days. Inoculated Soybean-Casein Digest Medium shall be incubated at 20 to 25 °C for 7 days. The sterility of each lot of medium shall be confirmed by the incubation of uninoculated control test vessels for 7 days at the temperature(s) for that particular medium. The lot of medium is satisfactory if no growth is observed in the control test vessels within the incubation period. The tests for growth-promoting qualities of culture media may be performed simultaneously with sterility testing of biological products, provided the sterility test is considered invalid if the test medium shows no growth response.</P> <P>(vi) <E T="03">Volume of culture medium.</E> The volume of each culture medium shall be determined for each bulk and final container sterility test required for each product. The ratio of the volume of inoculum to the volume of culture medium shall result in a dilution of the product that is not bacteriostatic or fungistatic, except for products to be tested by membrane filtration. The volume of inhibitors or neutralizers of preservatives added should be considered in determining the proper ratio of inoculum/medium. Vessels of the product-medium mixture(s) and control vessels of the medium shall be inoculated with dilutions of cultures of bacteria or fungi which are viable in the product being tested, and incubated at the appropriate temperature for no less than 7 days.</P> <P>(f) <E T="03">Membrane filtration</E>. Bulk and final container material or products containing oil products in water-insoluble ointments may be tested for sterility using the membrane filtration procedure set forth in the United States Pharmacopeia (23d Revision, 1995), section entitled “Test Procedures Using Membrane Filtration,” pp. 1689 to 1690, which is incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies are available from the United States Pharmacopeial Convention, Inc., 12601 Twinbrook Pkwy., <PRTPAGE P="62"/>Rockville, MD 20852, or available for inspection at the Center for Drug Evaluation and Research's Division of Medical Library, 5600 Fishers Lane, rm. 11B-40, Rockville, MD, or at the Office of the Federal Register, 800 North Capitol St. NW., suite 700, Washington, DC, except that:</P> <P>(1) The test samples shall conform with paragraph (d) of this section; and</P> <P>(2) In addition, for products containing a mercurial preservative, the product shall be tested in a second test using Fluid Thioglycollate Medium incubated at 20 to 25 <E T="81">½</E>C in lieu of the test in Soybean-Casein Digest Medium.</P> <P>(g) <E T="03">Exceptions.</E> Bulk and final container material shall be tested for sterility as described above in this section, except as follows:</P> <P>(1) <E T="03">Different sterility tests prescribed.</E> When different sterility tests are prescribed for a product in this subchapter.</P> <P>(2) <E T="03">Alternate incubation temperatures.</E> Two tests may be performed as prescribed in paragraph (a)(1)(i) of this section, one test using an incubation temperature of 18 to 22 °C, the other test using an incubation temperature of 30 to 37 °C, in lieu of performing one test using an incubation temperature of 30 to 35 °C, provided that growth-promoting quality tests have been performed at these temperatures.</P> <P>(3) [Reserved]</P> <P>(4) <E T="03">Test precluded or not required.</E> (i) The tests prescribed in this section need not be performed for Whole Blood, Cryoprecipitated AHF, Platelets, Red Blood Cells, Plasma, Source Plasma, Smallpox Vaccine, Reagent Red Blood Cells, Anti-Human Globulin, or Blood Grouping Reagent.</P> <P>(ii) Where a manufacturer submits data which the Director, Center for Biologics Evaluation and Research, finds adequate to establish that the mode of administration, the method of preparation, or the special nature of the product precludes or does not require a sterility test or that the sterility of the lot is not necessary to assure the safety, purity, and potency of the product, the Director may exempt a product from the sterility requirements of this section subject to any conditions necessary to assure the safety, purity, and potency of the product.</P> <P>(5) <E T="03">Number of final containers more than 20, less than 200.</E> If the number of final containers in the filling is more than 20 or less than 200, the sample shall be no less than 10 percent of the containers.</P> <P>(6) <E T="03">Number of final containers—20 or less.</E> If the number of final containers in a filling is 20 or less, the sample shall be two final containers, or the sample need be no more than one final container, provided (i) the bulk material met the sterility test requirements and (ii) after filling, it is demonstrated by testing a simulated sample that all surfaces to which the product was exposed were free of contaminating microorganisms. The simulated sample shall be prepared by rinsing the filling equipment with sterile 1.0 percent peptone solution, pH 7.1<E T="21">±</E>0.1, which shall be discharged into a final container by the same method used for filling the final containers with the product.</P> <P>(7) <E T="03">Samples—large volume of product in final containers.</E> For Albumin (Human) and Plasma Protein Fraction (Human), when the volume of product in the final container is 50 milliliters or more, the final containers selected as the test sample may contain less than the full volume of product in the final containers of the filling from which the sample is taken: <E T="03">Provided,</E> That the containers and closures of the sample are identical with those used for the filling to which the test applies, and the sample represents all stages of that filling.</P> <P>(8) <E T="03">Diagnostic biological products not intended for injection.</E> For diagnostic biological products not intended for injection, (i) only the Fluid Thioglycollate Medium test incubated at 30 to 35 °C is required, (ii) the volume of material for the bulk test shall be no less than 2.0 milliliters, and (iii) the sample for the final container test shall be no less than three final containers if the total number filled is 100 or less, and, if greater, one additional container for each additional 50 containers or fraction thereof, but the sample need be no more than 10 containers.</P> <P>(9) <E T="03">Immune globulin preparations.</E> For immune globulin preparations, the test samples from the bulk material and <PRTPAGE P="63"/>from each final container need be no more than 2.0 ml.</P> <P>(h) <E T="03">Records.</E> The records related to the testing requirements of this section shall be prepared and maintained as required by §§ 211.167 and 211.194 of this chapter. </P> <EXTRACT> <FP>(Information collection requirements approved by the Office of Management and Budget under control number 0910-0139)</FP> </EXTRACT> <CITA>[38 FR 32056, Nov. 20, 1973, as amended at 41 FR 4015, Jan. 28, 1976; 41 FR 10428, Mar. 11, 1976; 44 FR 11754, Mar. 2, 1979; 49 FR 15187, Apr. 18, 1984; 49 FR 23834, June 8, 1984; 50 FR 4133, Jan. 29, 1985; 51 FR 44906, Dec. 15, 1986; 53 FR 12764, Apr. 19, 1988; 55 FR 11013, Mar. 26, 1990; 62 FR 48175, Sept. 15, 1997]</CITA> </SECTION> <SECTION> <SECTNO>§ 610.13</SECTNO> <SUBJECT>Purity.</SUBJECT> <P>Products shall be free of extraneous material except that which is unavoidable in the manufacturing process described in the approved license. In addition, products shall be tested as provided in paragraphs (a) and (b) of this section.</P> <P>(a)(1) <E T="03">Test for residual moisture.</E> Each lot of dried product shall be tested for residual moisture and shall meet and not exceed established limits as specified by an approved method on file in the product license application. The test for residual moisture may be exempted by the Director, Center for Biologics Evaluation and Research, when deemed not necessary for the continued safety, purity, and potency of the product.</P> <P>(2) <E T="03">Records.</E> Appropriate records for residual moisture under paragraph (a)(1) of this section shall be prepared and maintained as required by the applicable provisions of §§ 211.188 and 211.194 of this chapter.</P> <P>(b) <E T="03">Test for pyrogenic substances.</E> Each lot of final containers of any product intended for use by injection shall be tested for pyrogenic substances by intravenous injection into rabbits as provided in paragraphs (b) (1) and (2) of this section: <E T="03">Provided,</E> That notwithstanding any other provision of Subchapter F of this chapter, the test for pyrogenic substances is not required for the following products: Products containing formed blood elements; Cryoprecipitate; Plasma; Source Plasma; Normal Horse Serum; bacterial, viral, and rickettsial vaccines and antigens; toxoids; toxins; allergenic extracts; venoms; diagnostic substances and trivalent organic arsenicals.</P> <P>(1) <E T="03">Test dose.</E> The test dose for each rabbit shall be at least 3 milliliters per kilogram of body weight of the rabbit and also shall be at least equivalent proportionately, on a body weight basis, to the maximum single human dose recommended, but need not exceed 10 milliliters per kilogram of body weight of the rabbit, except that: (i) Regardless of the human dose recommended, the test dose per kilogram of body weight of each rabbit shall be at least 1 milliliter for immune globulins derived from human blood; (ii) for Streptokinase, the test dose shall be at least equivalent proportionately, on a body weight basis, to the maximum single human dose recommended.</P> <P>(2) <E T="03">Test procedure, results, and interpretation; standards to be met.</E> The test for pyrogenic substances shall be performed according to the requirements specified in United States Pharmacopeia XX.</P> <P>(3) <E T="03">Retest.</E> If the lot fails to meet the test requirements prescribed in paragraph (b)(2) of this section, the test may be repeated once using five other rabbits. The temperature rises recorded for all eight rabbits used in testing shall be included in determining whether the requirements are met. The lot meets the requirements for absence of pyrogens if not more than three of the eight rabbits show individual rises in temperature of 0.6 °C or more, and if the sum of the eight individual maximum temperature rises does not exceed 3.7 °C. </P> <EXTRACT> <FP>(Information collection requirements were approved by the Office of Management and Budget (OMB) and assigned OMB control number 0910-0139)</FP> </EXTRACT> <CITA>[38 FR 32056, Nov. 20, 1973, as amended at 40 FR 29710, July 15, 1975; 41 FR 10429, Mar. 11, 1976; 41 FR 41424, Sept. 22, 1976; 44 FR 40289, July 10, 1979; 46 FR 62845, Dec. 29, 1981; 49 FR 15187, Apr. 18, 1984; 50 FR 4134, Jan. 29, 1985; 55 FR 28381, July 11, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 610.14</SECTNO> <SUBJECT>Identity.</SUBJECT> <P>The contents of a final container of each filling of each lot shall be tested for identity after all labeling operations shall have been completed. The <PRTPAGE P="64"/>identity test shall be specific for each product in a manner that will adequately identify it as the product designated on final container and package labels and circulars, and distinguish it from any other product being processed in the same laboratory. Identity may be established either through the physical or chemical characteristics of the product, inspection by macroscopic or microscopic methods, specific cultural tests, or in vitro or in vivo immunological tests.</P> </SECTION> <SECTION> <SECTNO>§ 610.15</SECTNO> <SUBJECT>Constituent materials.</SUBJECT> <P>(a) <E T="03">Ingredients, preservatives, diluents, adjuvants.</E> All ingredients used in a licensed product, and any diluent provided as an aid in the administration of the product, shall meet generally accepted standards of purity and quality. Any preservative used shall be sufficiently nontoxic so that the amount present in the recommended dose of the product will not be toxic to the recipient, and in the combination used it shall not denature the specific substances in the product to result in a decrease below the minimum acceptable potency within the dating period when stored at the recommended temperature. Products in multiple-dose containers shall contain a preservative, except that a preservative need not be added to Yellow Fever Vaccine; Poliovirus Vaccine Live Oral; viral vaccines labeled for use with the jet injector; dried vaccines when the accompanying diluent contains a preservative; or to an Allergenic Product in 50 percent or more volume in volume (v/v) glycerin. An adjuvant shall not be introduced into a product unless there is satisfactory evidence that it does not affect adversely the safety or potency of the product. The amount of aluminum in the recommended individual dose of a biological product shall not exceed:</P> <P>(1) 0.85 milligrams if determined by assay;</P> <P>(2) 1.14 milligrams if determined by calculation on the basis of the amount of aluminum compound added; or</P> <P>(3) 1.25 milligrams determined by assay provided that data demonstrating that the amount of aluminum used is safe and necessary to produce the intended effect are submitted to and approved by the Director, Center for Biologics Evaluation and Research.</P> <P>(b) <E T="03">Extraneous protein; cell culture produced vaccines.</E> Extraneous protein known to be capable of producing allergenic effects in human subjects shall not be added to a final virus medium of cell culture produced vaccines intended for injection. If serum is used at any stage, its calculated concentration in the final medium shall not exceed 1:1,000,000.</P> <P>(c) <E T="03">Antibiotics.</E> A minimum concentration of antibiotics, other than penicillin, may be added to the production substrate of viral vaccines.</P> <CITA>[38 FR 32056, Nov. 20, 1973, as amended at 46 FR 51903, Oct. 23, 1981; 48 FR 13025, Mar. 29, 1983; 48 FR 37023, Aug. 16, 1983; 49 FR 23834, June 8, 1984; 50 FR 4134, Jan. 29, 1985; 51 FR 15607, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 610.16</SECTNO> <SUBJECT>Total solids in serums.</SUBJECT> <P>Except as otherwise provided by regulation, no liquid serum or antitoxin shall contain more than 20 percent total solids.</P> </SECTION> <SECTION> <SECTNO>§ 610.17</SECTNO> <SUBJECT>Permissible combinations.</SUBJECT> <P>Licensed products may not be combined with other licensed products either therapeutic, prophylactic or diagnostic, except as a license is obtained for the combined product. Licensed products may not be combined with nonlicensable therapeutic, prophylactic, or diagnostic substances except as a license is obtained for such combination.</P> </SECTION> <SECTION> <SECTNO>§ 610.18</SECTNO> <SUBJECT>Cultures.</SUBJECT> <P>(a) <E T="03">Storage and maintenance.</E> Cultures used in the manufacture of products shall be stored in a secure and orderly manner, at a temperature and by a method that will retain the initial characteristics of the organisms and insure freedom from contamination and deterioration.</P> <P>(b) <E T="03">Identity and verification.</E> Each culture shall be clearly identified as to source strain. A complete identification of the strain shall be made for each new stock culture preparation. Primary and subsequent seed lots shall be identified by lot number and date of preparation. Periodic tests shall be performed as often as necessary to verify <PRTPAGE P="65"/>the integrity of the strain characteristics and freedom from extraneous organisms. Results of all periodic tests for verification of cultures and determination of freedom from extraneous organisms shall be recorded and retained.</P> <P>(c) <E T="03">Cell lines used for manufacturing biological products</E>—(1) <E T="03">General requirements.</E> Cell lines used for manufacturing biological products shall be:</P> <P>(i) Identified by history;</P> <P>(ii) Described with respect to cytogenetic characteristics and tumorigenicity;</P> <P>(iii) Characterized with respect to in vitro growth characteristics and life potential; and</P> <P>(iv) Tested for the presence of detectable microbial agents.</P> <P>(2) <E T="03">Tests.</E> Tests that are necessary to assure the safety, purity, and potency of a product may be required by the Director, Center for Biologics Evaluation and Research.</P> <P>(3) <E T="03">Applicability.</E> This paragraph applies to diploid and nondiploid cell lines. Primary cell cultures that are not subcultivated and primary cell cultures that are subsequently subcultivated for only a very limited number of population doublings are not subject to the provisions of this paragraph (c).</P> <P>(d) <E T="03">Records.</E> The records appropriate for cultures under this section shall be prepared and maintained as required by the applicable provisions of §§ 211.188 and 211.194 of this chapter.</P> <APPRO>(Approved by the Office of Management and Budget under control number 0910-0139)</APPRO> <CITA>[38 FR 32056, Nov. 20, 1973, as amended at 51 FR 44453, Dec. 10, 1986; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 610.19</SECTNO> <SUBJECT>Status of specific products; Group A streptococcus.</SUBJECT> <P>The presence of Group A streptococcus organisms and derivatives of Group A streptococcus in Bacterial Vaccines and Bacterial Antigens with “No U.S. Standard of Potency” may induce dangerous tissue reactions in humans. Available data demonstrate that they are unsafe as ingredients in products for human use. Group A streptococcus organisms and derivatives of Group A streptococcus are prohibited from Bacterial Vaccines and Bacterial Antigens with “No U.S. Standard of Potency.” Any Bacterial Vaccine or Bacterial Antigen with “No U.S. Standard of Potency” containing Group A streptococcus organisms or derivatives of Group A streptococcus in interstate commerce is in violation of section 351 of the Public Health Service Act (42 U.S.C. 262).</P> <CITA>[44 FR 1549, Jan. 5, 1979]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart C—Standard Preparations and Limits of Potency</HD> <SECTION> <SECTNO>§ 610.20</SECTNO> <SUBJECT>Standard preparations.</SUBJECT> <P>Standard preparations made available by the Center for Biologics Evaluation and Research shall be applied in testing, as follows:</P> <P>(a) <E T="03">Potency standards.</E> Potency standards shall be applied in testing for potency all forms of the following:</P> <EXTRACT> <HD SOURCE="HD1"> <E T="04">Antibodies</E> </HD> <FP SOURCE="FP-1">Botulism Antitoxin, Type A.</FP> <FP SOURCE="FP-1">Botulism Antitoxin, Type B.</FP> <FP SOURCE="FP-1">Botulism Antitoxin, Type E.</FP> <FP SOURCE="FP-1">Diphtheria Antitoxin.</FP> <FP SOURCE="FP-1">Histolyticus Antitoxin.</FP> <FP SOURCE="FP-1">Oedematiens Antitoxin.</FP> <FP SOURCE="FP-1">Perfringens Antitoxin.</FP> <FP SOURCE="FP-1">Antipertussis Serum.</FP> <FP SOURCE="FP-1">Antirabies Serum.</FP> <FP SOURCE="FP-1">Sordellii Antitoxin.</FP> <FP SOURCE="FP-1">Staphylococcus Antitoxin.</FP> <FP SOURCE="FP-1">Tetanus Antitoxin.</FP> <FP SOURCE="FP-1">Vibrion Septique Antitoxin.</FP> <HD SOURCE="HD1"> <E T="04">Antigens</E> </HD> <FP SOURCE="FP-1">Cholera Vaccine, Inaba serotype.</FP> <FP SOURCE="FP-1">Cholera Vaccine, Ogawa serotype.</FP> <FP SOURCE="FP-1">Diphtheria Toxin for Schick Test.</FP> <FP SOURCE="FP-1">Pertussis Vaccine.</FP> <FP SOURCE="FP-1">Tuberculin, Old.</FP> <FP SOURCE="FP-1">Tuberculin, Purified Protein Derivative.</FP> <FP SOURCE="FP-1">Typhoid Vaccine.</FP> <HD SOURCE="HD1"> <E T="04">Blood Derivative</E> </HD> <FP SOURCE="FP-1">Thrombin. </FP> </EXTRACT> <P>(b) <E T="03">Opacity standard.</E> The U.S. Opacity Standard shall be applied in estimating the bacterial concentration of all bacterial vaccines. The assigned value of the standard when observed visually is 10 units. The assigned value of the standard when observed with a photometer is (1) 10 units when the wavelength of the filter is 530 millimicrons, (2) 10.6 units when the wavelength of the filter is 650 millimicrons, <PRTPAGE P="66"/>and (3) 9 units when the wavelength of the filter is 420 millimicrons.</P> <CITA>[38 FR 32056, Nov. 20, 1973, as amended at 41 FR 10429, Mar. 11, 1976; 41 FR 18295, May 3, 1976; 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 610.21</SECTNO> <SUBJECT>Limits of potency.</SUBJECT> <P>The potency of the following products shall be not less than that set forth below and products dispensed in the dried state shall represent liquid products having the stated limitations.</P> <HD SOURCE="HD1"> <E T="04">Antibodies</E> </HD> <EXTRACT> <FP SOURCE="FP-1">Diphtheria Antitoxin, 500 units per milliliter.</FP> <FP SOURCE="FP-1">Tetanus Antitoxin, 400 units per milliliter.</FP> <FP SOURCE="FP-1">Tetanus Immune Globulin (Human), 50 units of tetanus antitoxin per milliliter.</FP> <HD SOURCE="HD1"> <E T="04">Antigens</E> </HD> <FP SOURCE="FP-1">Cholera Vaccine, 8 units each of Inaba and Ogawa serotype antigens per milliliter.</FP> <FP SOURCE="FP-1">Pertussis Vaccine, 12 units per total human immunizing dose.</FP> <FP SOURCE="FP-1">Typhoid Vaccine, 8 units per milliliter.</FP> </EXTRACT> <CITA>[41 FR 10429, Mar. 11, 1976, as amended at 41 FR 18295, May 3, 1976]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart D—Mycoplasma</HD> <SECTION> <SECTNO>§ 610.30</SECTNO> <SUBJECT>Test for Mycoplasma.</SUBJECT> <P>Except as provided otherwise in this subchapter, prior to clarification or filtration in the case of live virus vaccines produced from in vitro living cell cultures, and prior to inactivation in the case of inactivated virus vaccines produced from such living cell cultures, each virus harvest pool and control fluid pool shall be tested for the presence of <E T="03">Mycoplasma,</E> as follows: </P> <EXTRACT> <P>Samples of the virus for this test shall be stored either (1) between 2 and 8 °C for no longer than 24 hours, or (2) at −20 °C or lower if stored for longer than 24 hours. The test shall be performed on samples of the viral harvest pool and on control fluid pool obtained at the time of viral harvest, as follows: No less than 2.0 ml. of each sample shall be inoculated in evenly distributed amounts over the surface of no less than 10 plates of at least two agar media. No less than 1.0 ml. of sample shall be inoculated into each of four tubes containing 10 ml. of a semisolid broth medium. The media shall be such as have been shown to be capable of detecting known <E T="03">Mycoplasma</E> and each test shall include control cultures of at least two known strains of <E T="03">Mycoplasma,</E> one of which must be <E T="03">M. pneumoniae.</E> One half of the plates and two tubes of broth shall be incubated aerobically at 36 °C <E T="21">±</E>1 °C and the remaining plates and tubes shall be incubated anaerobically at 36 °C <E T="21">±</E>1 °C in an environment of 5-10 percent CO<E T="22">2</E> in N<E T="22">2</E>. Aerobic incubation shall be for a period of no less than 14 days and the broth in the two tubes shall be tested after 3 days and 14 days, at which times 0.5 ml. of broth from each of the two tubes shall be combined and subinoculated on to no less than 4 additional plates and incubated aerobically. Anaerobic incubation shall be for no less than 14 days and the broth in the two tubes shall be tested after 3 days and 14 days, at which times 0.5 ml. of broth from each of the two tubes shall be combined and subinoculated onto no less than four additional plates and incubated anaerobically. All inoculated plates shall be incubated for no less than 14 days, at which time observation for growth of <E T="03">Mycoplasma</E> shall be made at a magnification of no less than 300×. If the Dienes Methylene Blue-Azure dye or an equivalent staining procedure is used, no less than a one square cm. plug of the agar shall be excised from the inoculated area and examined for the presence of <E T="03">Mycoplasma.</E> The presence of the <E T="03">Mycoplasma</E> shall be determined by comparison of the growth obtained from the test samples with that of the control cultures, with respect to typical colonial and microscopic morphology. The virus pool is satisfactory for vaccine manufacture if none of the tests on the samples show evidence of the presence of <E T="03">Mycoplasma.</E> </P> </EXTRACT> <CITA>[38 FR 32056, Nov. 20, 1973, as amended at 63 FR 16685, Apr. 6, 1998]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart E—Hepatitis Requirements</HD> <SECTION> <SECTNO>§ 610.40</SECTNO> <SUBJECT>Test for hepatitis B surface antigen.</SUBJECT> <P>(a) <E T="03">Test sensitivity.</E> Each donation of blood, plasma, or serum to be used in preparing a biological product shall be tested for the presence of hepatitis B surface antigen by a method of sufficient sensitivity to detect all sera labeled A, (A), B, (B), and C in the Reference Hepatitis B Surface Antigen Panel distributed by the Center for Biologics Evaluation and Research; except that, in emergency situations, a test method of sufficient sensitivity to detect all sera labeled A, (A), and B in the Reference Hepatitis B Surface Antigen Panel may be used and, in dire emergency situations, blood and blood products may be issued without any HB<E T="22">8</E> Ag testing, provided that a test <PRTPAGE P="67"/>otherwise required by this paragraph is performed as soon as possible after issuance of the blood and blood product.</P> <P>(b) <E T="03">Procedures.</E> Only Antibody to Hepatitis B Surface Antigen licensed under this subchapter shall be used in performing the test and the test method(s) used shall be that for which the antibody product is specifically designed to be effective as recommended by the manufacturer in the package insert. The sample of blood, plasma, or serum to be tested shall have been taken from the donor at the time of donation of that unit. The test need not be performed on the day of the withdrawal of the sample. If the radioimmunoassay method is used, it must be performed in one of the following ways:</P> <P>(1) The complete test is performed at the collection facility.</P> <P>(2) The test is performed at the collection facility up to the point of counting the radioactivity of the samples, which counting, thereafter, is performed at another facility by personnel from the collection facility or by personnel from the counting facility.</P> <P>(3) The complete test is performed by the personnel at an establishment licensed to manufacture blood or blood derivatives under section 351(a) of the Public Health Service Act (42 U.S.C. 262(a)), or by a clinical laboratory which meets the standards of the Clinical Laboratories Improvement Act of 1967 (CLIA) (42 U.S.C. 263a), provided the establishment or the clinical laboratory is qualified to perform radioimmunoassay testing for the presence of hepatitis B surface antigen.</P> <P>(4) Except as provided in this paragraph (b)(4), a collection facility shall not ship any blood product as a biological product or ship such a blood product where it is intended for use in manufacturing a biological product until the test for hepatitis B surface antigen is completed and the written test results are received by the collection facility. Notwithstanding the provisions of § 610.1 of this chapter, in the case of an emergency, or as otherwise approved in writing by the Director, Center for Biologics Evaluation and Research, a collection facility may ship a blood product before the test for hepatitis B surface antigen is completed. To obtain approval for such shipments, the collection facility shall submit a description of the control procedures to be used by both the collection facility and the manufacturing facility to the Director, Center for Biologics Evaluation and Research (HFB-1), Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892. The control procedures to be used by the collection facility and the manufacturing facility shall include, but may not be limited to, a system of communicating the test results to the manufacturing facility, use of specific labeling warnings for the product to ensure that persons handling the shipment know that it may be infectious, procedures for quarantine of the untested or incompletely tested product both at the collection facility and at the manufacturing facility, and a procedure at the manufacturing facility to identify, preclude use of, and dispose of any blood product that is received and later found to be reactive for hepatitis B surface antigen.</P> <P>(c) <E T="03">Materials in storage.</E> All blood, plasma, or serum in storage which has not been tested for the presence of the hepatitis B surface antigen shall be tested as required in paragraphs (a) and (b) of this section before use as a biological product, or before use in the manufacture of a biological product. All blood, plasma, or serum in storage which has been tested for the presence of the hepatitis B surface antigen by a method of second generation sensitivity may be used as a biological product or in manufacture of a biological product, provided it is used on or before March 15, 1976.</P> <P>(d) <E T="03">Restrictions on use.</E> Blood, plasma, or serum that is reactive when tested for hepatitis B surface antigen or that was collected from a donor known to be reactive for hepatitis B surface antigen shall not be used in manufacturing biological products except as provided in paragraphs (d) (1) and (2) of this section.</P> <P>(1) <E T="03">Injectable biological products and licensed in vitro diagnostic biological products.</E> Blood, plasma, or serum that is reactive when tested for hepatitis B surface antigen or that was collected from a donor known to be reactive for hepatitis B surface antigen may be <PRTPAGE P="68"/>used in manufacturing hepatitis B vaccine and licensed in vitro diagnostic biological products if all of the following conditions are met:</P> <P>(i) The final product cannot be prepared from blood, plasma, or serum that is nonreactive when tested for hepatitis B surface antigen, due either to the nature or to the scarcity of the final product.</P> <P>(ii) The label of the source blood, plasma, or serum conspicuously states either that it is reactive when tested for hepatitis B surface antigen and it may transmit viral hepatitis; or that the source blood, plasma, or serum was collected from a donor known to be reactive for hepatitis B surface antigen and it may transmit viral hepatitis, although confirmatory hepatitis testing has not been done.</P> <P>(iii) The package label of the licensed in vitro diagnostic biological product prepared from such blood, plasma, or serum states conspicuously that either the product was prepared from source material that was reactive when tested for hepatitis B surface antigen and it may transmit viral hepatitis; or that the source material was collected from a donor known to be reactive for hepatitis B surface antigen and it may transmit viral hepatitis, although confirmatory hepatitis testing has not been done.</P> <P>(iv) The package label of the licensed injectable biological product prepared from such blood, plasma, or serum states that the product has been inactivated.</P> <P>(v) The Director, Center for Biologics Evaluation and Research (HFB-1), Food and Drug Administration, 8800 Rockville Pike, Bethesda MD 20892, is notified in writing at the time of the shipment, or in the case of repetitive shipments, or April 1 and October 1 of each year, of each shipment of source blood, plasma, or serum for manufacture into hepatitis B vaccine or into a licensed in vitro diagnostic biological product. Such shipments shall not be subject to the requirements of paragraph (b)(3) of this section. Each notification shall identify the kind and amount of source material shipped, the name and address of the consignee, the date of shipment, and the manner in which the source material is labeled.</P> <P>(2) <E T="03">Unlicensed in vitro diagnostic biological products.</E> Blood, plasma, or serum that is reactive when tested for hepatitis B surface antigen or that was collected from a donor known to be reactive for hepatitis B surface antigen may be used in manufacturing unlicensed in vitro diagnostic biological products including clinical chemistry control reagents if all of the following conditions are met:</P> <P>(i) The final product cannot be prepared from blood, plasma, or serum that is nonreactive when tested for hepatitis B surface antigen, due either to the nature or to the scarcity of the final product.</P> <P>(ii) The label of the source blood, plasma, or serum states conspicuously that either it is reactive when tested for hepatitis B surface antigen and it may transmit viral hepatitis; or that the source blood, plasma, or serum was collected from a donor known to be reactive for hepatitis B surface antigen and it may transmit viral hepatitis, although confirmatory hepatitis testing has not been done.</P> <P>(iii) The manufacturer of the source blood, plasma, or serum obtains written assurance from the manufacturer(s) of the final unlicensed product that package labels of all unlicensed products will conspicuously state, as required by § 809.10(a)(4) of this chapter, that the product was prepared from blood, plasma, or serum that was reactive when tested for hepatitis B surface antigen and it may transmit viral hepatitis; or that the source material was collected from a donor known to be reactive for hepatitis B surface antigen and it may transmit viral hepatitis, although confirmatory hepatitis testing has not been done.</P> <P>(iv) At the time of shipment, the Director, Center for Biologics Evaluation and Research (HFB-1), Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892, is notified in writing of each shipment of source blood, plasma, or serum signifying the kind and the amount of source material shipped, the name and address of the consignee, the date of shipment, and the manner in which such source material was labeled. Such shipments shall not be subject to the requirements of paragraph (b)(3) of this section.<PRTPAGE P="69"/> </P> <P>(e) <E T="03">Manufacturing responsibility.</E> When the radioimmunoassay method for hepatitis B surface antigen testing is performed by personnel other than those of the facility collecting the blood, plasma, or serum, as provided in paragraph (b) of this section, it shall not be considered as divided manufacturing as described in § 610.63, provided the following conditions are met:</P> <P>(1) The collecting facility has obtained a written agreement that the testing laboratory will permit authorized representatives of the Food and Drug Administration to inspect its testing procedures and facilities during reasonable business hours.</P> <P>(2) The testing laboratory will participate in any proficiency testing programs undertaken by the Center for Biologics Evaluation and Research, Food and Drug Administration.</P> <P>(f) The information collection requirements in paragraph (d) of this section were approved by the Office of Management and Budget and assigned OMB control number 0910-0136. </P> <EXTRACT> <FP>(Information collection requirements contained in paragraph (b)(4) were approved by the Office of Management and Budget under control number 0910-0168)</FP> </EXTRACT> <CITA>[40 FR 29710, July 15, 1975, as amended at 48 FR 23181, May 24, 1983; 49 FR 23834, June 8, 1984; 49 FR 26718, June 29, 1984; 51 FR 15607, Apr. 25, 1986; 55 FR 11013 and 11014, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 610.41</SECTNO> <SUBJECT>History of hepatitis B surface antigen.</SUBJECT> <P>A person known to have previously tested positive for hepatitis B surface antigen, testing positive, or both, may not serve as a donor of human blood, plasma, or serum, except that under § 640.120 of this chapter, such a donor may serve as a source of hepatitis B surface antigen for the manufacture of hepatitis B vaccine or the preparation of a diagnostic product for laboratory tests, or a person known to have previously tested positive for hepatitis B surface antigen may serve as a source of antibody to hepatitis B surface antigen for the preparation of a biological product or a diagnostic product for laboratory tests.</P> <CITA>[48 FR 23182, May 24, 1983, as amended at 57 FR 10814, Mar. 31, 1992]</CITA> </SECTION> <SECTION> <SECTNO>§ 610.45</SECTNO> <SUBJECT>Human Immunodeficiency Virus (HIV) requirements.</SUBJECT> <P>(a) <E T="03">Testing requirements.</E> (1) Each donation of human blood or blood components intended for use in preparing a product shall be tested for antibody to HIV by a test approved for such use by FDA, except as otherwise approved in writing by FDA. When the test for antibody to HIV is required, blood and blood products may be issued before the results of the test for antibody to HIV are available only in dire emergency situations or as otherwise approved in writing by FDA and, provided the test required by this paragraph is performed as soon as possible after issuance of the blood or blood product.</P> <P>(2) Tests approved by FDA for the screening of blood and blood components for evidence of HIV may only be used in place of a test for antibody to HIV to satisfy the requirements of this section and related sections if so specified by FDA.</P> <P>(b) <E T="03">Testing responsibility.</E> The test for antibody to HIV shall be performed by the collection facility, by personnel of an establishment licensed to manufacture blood or blood derivatives under section 351(a) of the Public Health Service Act (42 U.S.C. 262(a)), or by a clinical laboratory which meets the standards of the Clinical Laboratory Improvement Act of 1967 (CLIA) (42 U.S.C. 263a), provided the establishment or clinical laboratory is qualified to perform the test.</P> <P>(c) <E T="03">Restrictions on use.</E> (1) Blood, plasma, or other blood components that are repeatably reactive to a test for antibody to HIV or that were collected from a donor whose blood is known to be repeatably reactive to a test for antibody to HIV, shall not be shipped or used to prepare any product, including products not subject to licensure; except that such blood and blood components shall be shipped or used only for purposes and under conditions specifically approved in writing by FDA.</P> <P>(2) The restrictions on use contained in this paragraph shall not apply in the following cases:</P> <P>(i) Blood and blood components testing repeatably reactive or from a donor whose blood is known to be repeatably reactive that are shown to be negative for evidence of HIV infection by a <PRTPAGE P="70"/>method or process approved for such use by FDA;</P> <P>(ii) The distribution of blood, plasma, or serum samples, except when intended for use in the manufacture of a product;</P> <P>(iii) The in-house use of blood and blood components for research purposes; or</P> <P>(iv) The distribution of blood and blood components for research purposes, if not distributed by sale, barter, or exchange.</P> <P>(d) For a donor whose test results for antibody to HIV are repeatedly reactive or otherwise determined to be unsuitable when tested in accordance with paragraph (a) of this section, the blood establishment shall comply, as applicable, with §§ 610.46 and 610.47.</P> <CITA>[53 FR 116, Jan. 5, 1988, as amended at 61 FR 47423, Sept. 9, 1996]</CITA> </SECTION> <SECTION> <SECTNO>§ 610.46</SECTNO> <SUBJECT>“Lookback” requirements.</SUBJECT> <P>(a) <E T="03">Quarantine and notification.</E> (1) All blood and plasma establishments are required to take appropriate action when a donor of Whole Blood, blood components, Source Plasma and Source Leukocytes tests repeatedly reactive for antibody to human immunodeficiency virus (HIV), or otherwise is determined to be unsuitable when tested in accordance with § 610.45. For Whole Blood, blood components, Source Plasma and Source Leukocytes collected from that donor within the 5 years prior to the repeatedly reactive test, if intended for transfusion, or collected within the 6 months prior to the repeatedly reactive test, if intended for further manufacture into injectable products, except those products exempt from quarantine in accordance with § 610.46(c), the blood establishment shall promptly, within 72 hours:</P> <P>(i) Quarantine all such Whole Blood, blood components, Source Plasma and Source Leukocytes from previous collections held at that establishment; and</P> <P>(ii) Notify consignees of the repeatedly reactive HIV screening test results so that all Whole Blood, blood components, Source Plasma and Source Leukocytes from previous collections they hold are quarantined.</P> <P>(2) Consignees notified in accordance with paragraph (a)(1)(ii) of this section shall quarantine Whole Blood, blood components, Source Plasma and Source Leukocytes held at that establishment except as provided in paragraph (c) of this section.</P> <P>(b) <E T="03">Further testing and notification of consignees of results.</E> Blood establishments that have collected Whole Blood, blood components, Source Plasma or Source Leukocytes from a donor as described in paragraph (a) of this section shall perform a licensed, more specific test for HIV on the donor's blood, and in the case of distributed products, further shall notify the consignee(s) of the results of this test, within 30 calendar days after the donor's repeatedly reactive test. Pending the availability of a licensed, more specific test for HIV-2, a second, different screening test for antibody to HIV-2 shall be used along with a licensed, more specific test for HIV-1.</P> <P>(c) <E T="03">Exemption from quarantine.</E> Products intended for transfusion need not be held in quarantine if a determination has been made that the Whole Blood, blood components, Source Plasma or Source Leukocytes was collected more than 12 months prior to the donor's most recent negative antibody screening test when tested in accordance with § 610.45. Pooled Source Plasma and Source Leukocytes are exempt from quarantine.</P> <P>(d) <E T="03">Release from quarantine.</E> Whole Blood, blood components, Source Plasma and Source Leukocytes intended for transfusion or further manufacture which have been quarantined under paragraph (a) of this section may be released if the donor is subsequently tested for antibody to HIV as provided in paragraph (b) of this section and the test result is negative, absent other informative test results.</P> <P>(e) Actions under this section do not constitute a product recall as defined in § 7.3(g) of this chapter.</P> <CITA>[61 FR 47423, Sept. 9, 1996]</CITA> </SECTION> <SECTION> <SECTNO>§ 610.47</SECTNO> <SUBJECT>“Lookback” notification requirements for transfusion services.</SUBJECT> <P>(a) Transfusion services that are not subject to the Health Care Financing Administration's regulations on conditions of Medicare participation for hospitals (42 CFR part 482) are required to take appropriate action in accordance <PRTPAGE P="71"/>with paragraphs (b) and (c) of this section when a recipient has received Whole Blood or blood components from a donor determined to be unsuitable when tested for human immunodeficiency virus (HIV) infection in accordance with § 610.45 and the results of the additional tests as provided for in § 610.46(b) are positive.</P> <P>(b) <E T="03">Notification of recipients of prior transfusion.</E> If the transfusion service has administered Whole Blood or blood components as described in paragraph (a) of this section, the transfusion service shall notify the recipient's attending physician (physician of record) and ask him or her to inform the recipient of the need for HIV testing and counseling. If the physician is unavailable or declines to notify the recipient, the transfusion service shall notify the recipient and inform the recipient of the need for HIV testing and counseling. The notification process shall include a minimum of three attempts to notify the recipient and be completed within a maximum 8 weeks of receipt of the result of the licensed, more specific test for HIV. The transfusion service is responsible for notification, including basic explanations to the recipient and referral for counseling, and shall document the notification or attempts to notify the attending physician or the recipient, pursuant to § 606.160 of this chapter.</P> <P>(c) <E T="03">Notification to legal representative or relative.</E> If the transfusion recipient has been adjudged incompetent by a State court, the transfusion service or physician must notify a legal representative designated in accordance with State law. If the transfusion recipient is competent, but State law permits a legal representative or relative to receive the information on the recipient's behalf, the transfusion service or physician must notify the recipient or his or her legal representative or relative. If the transfusion recipient is deceased, the transfusion service or physician must continue the notification process and inform the deceased recipient's legal representative or relative. Reasons for notifying the recipient's relative or legal representative on his or her behalf shall be documented pursuant to § 606.160 of this chapter.</P> <CITA>[61 FR 47423, Sept. 9, 1996]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart F—Dating Period Limitations</HD> <SECTION> <SECTNO>§ 610.50</SECTNO> <SUBJECT>Date of manufacture.</SUBJECT> <P>The date of manufacture shall be determined as follows:</P> <P>(a) For products for which an official standard of potency is prescribed in either § 610.20 or § 610.21, or which are subject to official potency tests, the date of initiation by the manufacturer of the last valid potency test.</P> <P>(b) For products that are not subject to official potency tests, (1) the date of removal from animals, (2) the date of extraction, (3) the date of solution, (4) the date of cessation of growth, or (5) the date of final sterile filtration of a bulk solution, whichever is applicable.</P> <CITA>[38 FR 32056, Nov. 20, 1973, as amended at 42 FR 27582, May 31, 1977]</CITA> </SECTION> <SECTION> <SECTNO>§ 610.53</SECTNO> <SUBJECT>Dating periods for licensed biological products.</SUBJECT> <P>(a) <E T="03">General.</E> The minimum dating periods in paragraph (c) of this section are based on data relating to usage, clinical experience, or laboratory tests that establish the reasonable period beyond which the product cannot be expected to yield its specific results and retain its safety, purity, and potency, provided the product is maintained at the recommended temperatures. The standards prescribed by the regulations in this subchapter are designed to ensure the continued safety, purity, and potency of the products and are based on the dating periods set forth in paragraph (c) of this section. Package labels for each product shall recommend storage at the stated temperatures.</P> <P>(b) <E T="03">When the dating period begins.</E> The dating period for a product shall begin on the date of manufacture, as prescribed in § 610.50. The dating period for a combination of two or more products shall be no longer than the dating period of the component with the shortest dating period.</P> <P>(c) <E T="03">Table of dating periods.</E> In using the table in this paragraph, a product in column A may be stored by the manufacturer at the prescribed temperature and length of time in either column B or C, plus the length of time in column D. The dating period in column D shall be applied from the day the <PRTPAGE P="72"/>product leaves the manufacturer's storage, provided the product has not exceeded its maximum storage period, as prescribed in column B or C. If a product is held in the manufacturer's storage beyond the period prescribed, the dating period for the product being distributed shall be reduced by a corresponding period.</P> <GPOTABLE CDEF="s100,xs50,xs50,r100" COLS="4" OPTS="L2,i1"> <BOXHD> <CHED H="1">A</CHED> <CHED H="2">Product</CHED> <CHED H="1">B</CHED> <CHED H="2">Manufacturer's storage period 1 to 5 <E T="61">°</E>C (unless otherwise stated)</CHED> <CHED H="1">C</CHED> <CHED H="2">Manufacturer's storage period 0 <E T="61">°</E>C or colder (unless otherwise stated)</CHED> <CHED H="1">D</CHED> <CHED H="2">Dating period after leaving manufacturer's storage when stored at 2 to 8 <E T="61">°</E>C (unless otherwise stated)</CHED> </BOXHD> <ROW> <ENT I="01">Adenovirus Vaccine Live Oral</ENT> <ENT>6 months</ENT> <ENT>Not applicable</ENT> <ENT>6 months.</ENT> </ROW> <ROW> <ENT I="01">Albumin (Human)</ENT> <ENT>3 years</ENT> <ENT>......do</ENT> <ENT>(a) 5 years.</ENT> </ROW> <ROW> <ENT I="22"/> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>(b) 3 years, provided labeling recommends storage at room temperature, no warmer than 37 <E T="61">°</E>C.</ENT> </ROW> <ROW> <ENT I="22"/> <ENT>Not applicable</ENT> <ENT>......do</ENT> <ENT>(c) 10 years, if in a hermetically sealed metal container and provided labeling recommends storage between 2 and 8 <E T="61">°</E>C.</ENT> </ROW> <ROW> <ENT I="11">Allergenic Extracts labeled “No U.S. Standard of Potency”:</ENT> </ROW> <ROW> <ENT I="03">1. With 50 percent or more glycerin</ENT> <ENT>3 years</ENT> <ENT>......do</ENT> <ENT>3 years.</ENT> </ROW> <ROW> <ENT I="03">2. With less than 50 percent glycerin</ENT> <ENT>18 months</ENT> <ENT>......do</ENT> <ENT>18 months.</ENT> </ROW> <ROW> <ENT I="03">3. Products for which cold storage conditions are inappropriate</ENT> <ENT>Not applicable</ENT> <ENT>......do</ENT> <ENT>18 months (from date of manufacture), provided labeling recommends storage at 30 <E T="61">°</E>C or colder.</ENT> </ROW> <ROW> <ENT I="03">4. Powders and tablets</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>5 years (from date of manufacture), provided labeling recommends storage at 30 <E T="61">°</E>C or colder.</ENT> </ROW> <ROW> <ENT I="13">5. Freeze-dried products:</ENT> </ROW> <ROW> <ENT I="04">a. Unreconstituted</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>4 years (from date of manufacture).</ENT> </ROW> <ROW> <ENT I="04">b. Reconstituted</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>18 months (cannot exceed 4-year unreconstituted dating period plus an additional 12 months).</ENT> </ROW> <ROW> <ENT I="01">Allergenic Extracts, Alum Precipitated labeled “No U.S. Standard of Potency”</ENT> <ENT>18 months</ENT> <ENT>......do</ENT> <ENT>18 months.</ENT> </ROW> <ROW> <ENT I="01">Anthrax Vaccine Adsorbed</ENT> <ENT>2 years</ENT> <ENT>......do</ENT> <ENT>1 year.</ENT> </ROW> <ROW> <ENT I="11">Antibody to Hepatitis B Surface Antigen:</ENT> </ROW> <ROW> <ENT I="03">1. Antibody to Hepatitis B Surface Antigen</ENT> <ENT>6 months</ENT> <ENT>......do</ENT> <ENT>6 months.</ENT> </ROW> <ROW> <ENT I="03">2. Lyophilized coated red blood cells</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="03">3. Enzyme conjugated products</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Iodinated (<SU>125</SU>l) products</ENT> <ENT>Not applicable</ENT> <ENT>......do</ENT> <ENT>45 days (from date of manufacture).</ENT> </ROW> <ROW> <ENT I="01">Antihemophilic Factor (Human)</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>1 year (from date of manufacture).</ENT> </ROW> <ROW> <ENT I="01">Anti-Human Globulin Liquid</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>2 years.</ENT> </ROW> <ROW> <ENT I="01">Anti-Inhibitor Coagulant Complex</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Antirabies Serum</ENT> <ENT>1 year</ENT> <ENT>......do</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Antivenin (<E T="03">Crotalidae</E>) Polyvalent</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>5 years with an initial 10 percent excess of potency, provided labeling recommends storage at 37 <E T="61">°</E> C or colder.</ENT> </ROW> <ROW> <ENT I="01">Antivenin (<E T="03">Latrodectus Mactans</E>)</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>5 years with an initial 10 percent excess of potency.</ENT> </ROW> <ROW> <ENT I="01">Antivenin (<E T="03">Micurus fulvius</E>)</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Asparaginase</ENT> <ENT>Not applicable</ENT> <ENT>......do</ENT> <ENT>18 months from the date of the last valid potency test.</ENT> </ROW> <ROW> <ENT I="01">BCG Vaccine</ENT> <ENT>1 year</ENT> <ENT>Not applicable</ENT> <ENT>6 months.</ENT> </ROW> <ROW> <ENT I="11">Blood Grouping Reagents</ENT> </ROW> <ROW> <ENT I="03">1. Liquid</ENT> <ENT>Not applicable</ENT> <ENT>Not applicable</ENT> <ENT>2 years.</ENT> </ROW> <ROW> <ENT I="03">2. Dried</ENT> <ENT>1 year</ENT> <ENT>2 years</ENT> <ENT>5 years.</ENT> </ROW> <ROW> <ENT I="01">Blood Group Substance AB</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>2 years.</ENT> </ROW> <ROW> <ENT I="01">Blood Group Substance A</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Blood Group Substance B</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Botulism Antitoxin</ENT> <ENT>......do</ENT> <ENT>Not applicable</ENT> <ENT>5 years with an initial 20 percent excess of potency.</ENT> </ROW> <ROW> <ENT I="01">Cholera Vaccine</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>18 months.</ENT> </ROW> <ROW> <ENT I="01">Coccidioidin</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>3 years.</ENT> </ROW> <ROW> <ENT I="01">Collagenase</ENT> <ENT>Not applicable</ENT> <ENT>......do</ENT> <ENT>4 years (from date of manufacture), provided labeling recommends storage at 37 <E T="61">°</E>C or colder.</ENT> </ROW> <ROW> <ENT I="01">Cryoprecipitated AFH</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>12 months from the date of collection of source blood, provided labeling recommends storage at −18 <E T="61">°</E>C or colder.</ENT> </ROW> <ROW> <PRTPAGE P="73"/> <ENT I="11">Diphtheria Antitoxin:</ENT> </ROW> <ROW> <ENT I="03">1. Liquid</ENT> <ENT>1 year</ENT> <ENT>......do</ENT> <ENT>5 years with an initial 20 percent excess of potency.</ENT> </ROW> <ROW> <ENT I="03">2. Dried</ENT> <ENT>......do</ENT> <ENT>2 years</ENT> <ENT>5 years with an initial 10 percent excess of potency.</ENT> </ROW> <ROW> <ENT I="01">Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed</ENT> <ENT>......do</ENT> <ENT>Not applicable</ENT> <ENT>18 months.</ENT> </ROW> <ROW> <ENT I="01">Diphtheria and Tetanus Toxoids, Adsorbed</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>2 years.</ENT> </ROW> <ROW> <ENT I="01">Diphtheria Toxin for Schick Test</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>1 year.</ENT> </ROW> <ROW> <ENT I="01">Diphtheria Toxoid</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>2 years.</ENT> </ROW> <ROW> <ENT I="01">Diphtheria Toxoid Adsorbed</ENT> <ENT>......do</ENT> <ENT>2 years</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Diphtheria Toxoid-Schick Test Control</ENT> <ENT>Not applicable</ENT> <ENT>Not applicable</ENT> <ENT>1 year.</ENT> </ROW> <ROW> <ENT I="01">Factor IX Complex</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>1 year (from date of manufacture).</ENT> </ROW> <ROW> <ENT I="01">Fibrinolysin (Human)</ENT> <ENT>1 year</ENT> <ENT>2 years</ENT> <ENT>2 years.</ENT> </ROW> <ROW> <ENT I="01">Fibrinolysin and Desoxyribonuclease Combined (Bovine)</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>3 years, provided labeling recommends storage at 30 <E T="61">°</E>C or colder.</ENT> </ROW> <ROW> <ENT I="01">Fibrinolysin and Desoxyribonuclease Combined (Bovine) with Chloramphenicol</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="11">Hepatitis B Surface Antigen:</ENT> </ROW> <ROW> <ENT I="03">1. Unlyophilized coated red blood cells</ENT> <ENT>Not applicable</ENT> <ENT>......do</ENT> <ENT>14 days (from date of manufacture).</ENT> </ROW> <ROW> <ENT I="03">2. Iodinated (<SU>125</SU> l) product</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>45 days (from date of manufacture).</ENT> </ROW> <ROW> <ENT I="03">3. Enzyme conjugated product</ENT> <ENT>6 months</ENT> <ENT>......do</ENT> <ENT>6 months.</ENT> </ROW> <ROW> <ENT I="01">Histoplasmin</ENT> <ENT>1 year</ENT> <ENT>Not applicable</ENT> <ENT>2 years.</ENT> </ROW> <ROW> <ENT I="11">Immunoglobulins:</ENT> </ROW> <ROW> <ENT I="03">1. Hepatitis B Immune Globulin (Human)</ENT> <ENT>Not applicable</ENT> <ENT>......do</ENT> <ENT>1 year.</ENT> </ROW> <ROW> <ENT I="03">2. Immune Globulin (Human)</ENT> <ENT>3 years </ENT> <ENT>......do</ENT> <ENT>3 years.</ENT> </ROW> <ROW> <ENT I="03">3. Immune Globulin Intravenous (Human)</ENT> <ENT>Not applicable</ENT> <ENT>......do</ENT> <ENT>1 year.</ENT> </ROW> <ROW> <ENT I="03">4. Lymphocyte Immune Globulin, Anti-Thymocyte Globulin (Equine)</ENT> <ENT>......do</ENT> <ENT>Not applicable</ENT> <ENT>2 years.</ENT> </ROW> <ROW> <ENT I="03">5. Pertussis Immune Globulin (Human)</ENT> <ENT>3 years</ENT> <ENT>......do</ENT> <ENT>3 years from date the dried or frozen bulk product is placed in final solution.</ENT> </ROW> <ROW> <ENT I="03">6. Rabies Immune Globulin (Human)</ENT> <ENT>1 year</ENT> <ENT>......do</ENT> <ENT>1 year.</ENT> </ROW> <ROW> <ENT I="03">7. Rh<E T="22">o</E>(D) Immune Globulin (Human)</ENT> <ENT>6 months</ENT> <ENT>......do</ENT> <ENT>6 months.</ENT> </ROW> <ROW> <ENT I="03">8. Tetanus Immune Globulin (Human)</ENT> <ENT>1 year</ENT> <ENT>......do</ENT> <ENT>3 years with an initial 10 percent excess of potency.</ENT> </ROW> <ROW> <ENT I="03">9. Vaccinia Immune Globulin (Human)</ENT> <ENT>3 years</ENT> <ENT>......do</ENT> <ENT>3 years.</ENT> </ROW> <ROW> <ENT I="03">10. Varicella-Zoster Immune Globulin (Human)</ENT> <ENT>Not applicable</ENT> <ENT>......do</ENT> <ENT>1 year.</ENT> </ROW> <ROW> <ENT I="01">Hepatitis B Vaccine</ENT> <ENT>2 years at 2 to 8 <E T="61">°</E>C</ENT> <ENT>Not applicable</ENT> <ENT>3 years.</ENT> </ROW> <ROW> <ENT I="01">Influenza Virus Vaccine</ENT> <ENT>1 year</ENT> <ENT>......do</ENT> <ENT>18 months.</ENT> </ROW> <ROW> <ENT I="01">Limulus Amebocyte Lysate</ENT> <ENT>Not applicable</ENT> <ENT>Not applicable</ENT> <ENT>18 months (from date of manufacture).</ENT> </ROW> <ROW> <ENT I="01">Measles, Mumps, and Rubella Virus Vaccine Live</ENT> <ENT>......do</ENT> <ENT>1 year (−20 <E T="61">°</E>C or colder)</ENT> <ENT>1 year.</ENT> </ROW> <ROW> <ENT I="01">Measles and Mumps Virus Vaccine Live</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>1 year.</ENT> </ROW> <ROW> <ENT I="01">Measles and Rubella Virus Vaccine Live</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Measles Live and Smallpox Vaccine</ENT> <ENT>Not applicable</ENT> <ENT>......do</ENT> <ENT>1 year (from date of manufacture).</ENT> </ROW> <ROW> <ENT I="01">Measles Virus Vaccine Live</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>1 year.</ENT> </ROW> <ROW> <ENT I="11">Meningococcal Polysaccharide Vaccine Group A:</ENT> </ROW> <ROW> <ENT I="03">1. Final bulk powder</ENT> <ENT>......do</ENT> <ENT>2 years (−20 <E T="61">°</E>C or colder)</ENT> <ENT>Not applicable.</ENT> </ROW> <ROW> <ENT I="03">2. Final container</ENT> <ENT>Not applicable</ENT> <ENT>3 years (−20 <E T="61">°</E>C or colder)</ENT> <ENT>2 years.</ENT> </ROW> <ROW> <ENT I="11">Meningococcal Polysaccharide Vaccine Group C:</ENT> </ROW> <ROW> <ENT I="03">1. Final bulk powder</ENT> <ENT>......do</ENT> <ENT>2 years (−20 <E T="61">°</E>C or colder)</ENT> <ENT>Not applicable.</ENT> </ROW> <ROW> <ENT I="03">2. Final container</ENT> <ENT>......do</ENT> <ENT>3 years (−20 <E T="61">°</E>C or colder)</ENT> <ENT>2 years.</ENT> </ROW> <ROW> <ENT I="11">Meningococcal Polysaccharide Vaccine Groups A and C combined:</ENT> </ROW> <ROW> <ENT I="03">1. Final bulk powder</ENT> <ENT>......do</ENT> <ENT>2 years (−20 <E T="61">°</E>C or colder)</ENT> <ENT>Not applicable.</ENT> </ROW> <ROW> <PRTPAGE P="74"/> <ENT I="03">2. Final container</ENT> <ENT>......do</ENT> <ENT>3 years (−20 <E T="61">°</E>C or colder)</ENT> <ENT>2 years.</ENT> </ROW> <ROW> <ENT I="11">Meningococcal Polysaccharide Vaccine Groups A, C, Y, and W135 combined:</ENT> </ROW> <ROW> <ENT I="03">1. Final bulk power</ENT> <ENT>......do</ENT> <ENT>2 years (−20 <E T="61">°</E>C or colder)</ENT> <ENT>Not applicable.</ENT> </ROW> <ROW> <ENT I="03">2. Final container</ENT> <ENT>......do</ENT> <ENT>3 years (−20 <E T="61">°</E>C or colder)</ENT> <ENT>2 years.</ENT> </ROW> <ROW> <ENT I="01">Mumps Skin Test Antigen</ENT> <ENT>6 months</ENT> <ENT>Not applicable</ENT> <ENT>18 months.</ENT> </ROW> <ROW> <ENT I="01">Mumps Virus Vaccine Live</ENT> <ENT>Not applicable</ENT> <ENT>1 year (−20 <E T="61">°</E>C or colder)</ENT> <ENT>1 year.</ENT> </ROW> <ROW> <ENT I="01">Normal Horse Serum</ENT> <ENT>1 year</ENT> <ENT>2 years</ENT> <ENT>5 years.</ENT> </ROW> <ROW> <ENT I="01">Pertussis Vaccine</ENT> <ENT>......do</ENT> <ENT>Not applicable</ENT> <ENT>18 months.</ENT> </ROW> <ROW> <ENT I="01">Pertussis Vaccine Adsorbed</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Plague Vaccine</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="11">Plasma products:</ENT> </ROW> <ROW> <ENT I="03">1. Fresh Frozen Plasma</ENT> <ENT>Not applicable</ENT> <ENT>......do</ENT> <ENT>1 year from date of collection of source blood (−18 <E T="61">°</E>C or colder).</ENT> </ROW> <ROW> <ENT I="03">2. Liquid Plasma</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>(a) 26 days from date of collection of source blood (between 1 and 6 <E T="61">°</E>C).</ENT> </ROW> <ROW> <ENT I="22"/> <ENT O="xl"/> <ENT O="xl"/> <ENT>(b) 40 days from date of collection of source blood only when CPDA-1 solution is used as the anticoagulant (between 1 and 6 <E T="61">°</E>C).</ENT> </ROW> <ROW> <ENT I="03">3. Plasma</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>5 years from date of collection of source blood (−18 <E T="61">°</E>C or colder).</ENT> </ROW> <ROW> <ENT I="03">4. Platelet Rich Plasma</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>72 hours from time of collection of source blood, provided labeling recommends storage (20 to 24 <E T="61">°</E>C or between 1 and 6 <E T="61">°</E>C). 5 days if certain approved containers are used (20 to 24 <E T="61">°</E>C).</ENT> </ROW> <ROW> <ENT I="03">5. Source Leukocytes</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>In lieu of expiration date, the collection date shall appear on the label.</ENT> </ROW> <ROW> <ENT I="03">6. Source Plasma</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>10 years (at the recommended storage temperature stated on the label).</ENT> </ROW> <ROW> <ENT I="03">7. Therapeutic Exchange Plasma</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>10 years.</ENT> </ROW> <ROW> <ENT I="01">Plasma Protein Fraction (Human)</ENT> <ENT>1 year</ENT> <ENT>......do</ENT> <ENT>(a) 5 years.<LI>(b) 3 years provided labeling recommends storage at room temperature, no warmer than 30 <E T="61">°</E>C).</LI> </ENT> </ROW> <ROW> <ENT I="01">Platelets</ENT> <ENT>Not applicable</ENT> <ENT>......do</ENT> <ENT>72 hours from time of collection of source blood, provided labeling recommends storage at 20 to 24 <E T="61">°</E>C or between 1 and 6 <E T="61">°</E>C. 5 days if certain approved containers are used (20 to 24 <E T="61">°</E>C).</ENT> </ROW> <ROW> <ENT I="11">Pneumococcal Vaccine Polyvalent:</ENT> </ROW> <ROW> <ENT I="03">1. Final bulk powder</ENT> <ENT>......do</ENT> <ENT>24 months after potency assay (−20 <E T="61">°</E>C or colder)</ENT> <ENT>Not applicable.</ENT> </ROW> <ROW> <ENT I="03">2. Final container</ENT> <ENT>......do</ENT> <ENT>Not applicable</ENT> <ENT>2 years (from date of manufacture).</ENT> </ROW> <ROW> <ENT I="01">Poliovirus Vaccine Inactivated</ENT> <ENT>1 year</ENT> <ENT>......do</ENT> <ENT>1 year.</ENT> </ROW> <ROW> <ENT I="11">Poliovirus Vaccine Live Oral Trivalent:</ENT> </ROW> <ROW> <ENT I="03">1. Frozen</ENT> <ENT>Not applicable</ENT> <ENT>1 year (−10 <E T="61">°</E>C or colder)</ENT> <ENT>1 year, provided labeling recommends storage at a temperature which will maintain ice continuously in a solid state.</ENT> </ROW> <ROW> <ENT I="03">2. Liquid</ENT> <ENT>......do</ENT> <ENT>Not applicable</ENT> <ENT>30 days, provided labeling recommends storage between 2 and 8 <E T="61">°</E>C and container has been unopened.</ENT> </ROW> <ROW> <ENT I="11">Poliovirus Vaccine Live Oral Type I:</ENT> </ROW> <ROW> <ENT I="03">1. Frozen</ENT> <ENT>......do</ENT> <ENT>1 year (−10 <E T="61">°</E>C or colder)</ENT> <ENT>1 year, provided labeling recommends storage at a temperature which will maintain ice continuously in a solid state.</ENT> </ROW> <ROW> <ENT I="03">2. Liquid</ENT> <ENT>......do</ENT> <ENT>Not applicable</ENT> <ENT>30 days, provided labeling recommends storage between 2 and 8 <E T="61">°</E>C and container has been unopened.</ENT> </ROW> <ROW> <PRTPAGE P="75"/> <ENT I="11">Poliovirus Vaccine Live Oral Type II:</ENT> </ROW> <ROW> <ENT I="03">1. Frozen</ENT> <ENT>......do</ENT> <ENT>1 year (−10 <E T="61">°</E>C or colder)</ENT> <ENT>1 year, provided labeling recommends storage at a temperature which will maintain ice continuously in a solid state.</ENT> </ROW> <ROW> <ENT I="03">2. Liquid</ENT> <ENT>......do</ENT> <ENT>Not applicable</ENT> <ENT>30 days, provided labeling recommends storage between 2 and 8 <E T="61">°</E>C and container has been unopened.</ENT> </ROW> <ROW> <ENT I="11">Poliovirus Vaccine Live Oral Type III:</ENT> </ROW> <ROW> <ENT I="03">1. Frozen</ENT> <ENT>......do</ENT> <ENT>1 year (−10 <E T="61">°</E>C or colder)</ENT> <ENT>1 year, provided labeling recommends storage at a temperature which will maintain ice continuously in a solid state.</ENT> </ROW> <ROW> <ENT I="03">2. Liquid</ENT> <ENT>......do</ENT> <ENT>Not applicable</ENT> <ENT>30 days, provided labeling recommends storage between 2 and 8 <E T="61">°</E>C and container has been unopened.</ENT> </ROW> <ROW> <ENT I="01">Polyvalent bacterial antigens with “No U.S. Standard of Potency” liquid</ENT> <ENT>1 year</ENT> <ENT>......do</ENT> <ENT>18 months.</ENT> </ROW> <ROW> <ENT I="01">Polyvalent bacterial vaccines with “No U.S. Standard of Potency” liquid</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="11">Rabies Vaccine:</ENT> </ROW> <ROW> <ENT I="03">1. Dried</ENT> <ENT>......do</ENT> <ENT>2 years</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="03">2. Liquid</ENT> <ENT>3 months</ENT> <ENT>Not applicable</ENT> <ENT>6 months.</ENT> </ROW> <ROW> <ENT I="01">Reagent red blood cells </ENT> <ENT>Not applicable </ENT> <ENT>Not applicable </ENT> <ENT>Thirty-five days from earliest date of collection if kept in liquid form (indefinite storage of reagent red blood cell source material at −65 <E T="61">°</E>C or colder).</ENT> </ROW> <ROW> <ENT I="01">ACD Red Blood Cells</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>(a) 21 days from date of collection of source blood, provided labeling recommends storage between 1 and 6 <E T="61">°</E>C and the hermetic seal is not broken during processing.<LI>(b) 24 hours after plasma removal, provided labeling recommends storage between 1 and 6 <E T="61">°</E>C and the hermetic seal is broken during processing.</LI> </ENT> </ROW> <ROW> <ENT I="01">CPD Red Blood Cells</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>(a) 21 days from date of collection of source blood, provided labeling recommends storage between 1 and 6 <E T="61">°</E>C and the hermetic seal is not broken during processing.<LI>(b) 24 hours after plasma removal, provided labeling recommends storage between 1 and 6 <E T="61">°</E>C and the hermetic seal is broken during processing.</LI> </ENT> </ROW> <ROW> <ENT I="01">CPDA-1 Red Blood Cells</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>(a) 35 days from date of collection of source blood, provided labeling recommends storage between 1 and 6 <E T="61">°</E>C and the hermetic seal is not broken during processing.<LI>(b) 24 hours after plasma removal, provided labeling recommends storage between 1 and 6 <E T="61">°</E>C and the hermetic seal is broken during processing.</LI> </ENT> </ROW> <ROW> <ENT I="01">Red Blood Cells Deglycerolized</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>24 hours after removal from storage at −65 <E T="61">°</E>C or colder, provided labeling recommends storage between 1 and 6 <E T="61">°</E>C.</ENT> </ROW> <ROW> <ENT I="01">Red Blood Cells Frozen</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>3 years from date of collection of source blood, provided labeling recommends storage at −65 <E T="61">°</E>C or colder.</ENT> </ROW> <ROW> <ENT I="01">Rubella and Mumps Virus Vaccine Live</ENT> <ENT>......do</ENT> <ENT>1 year (−20 <E T="61">°</E>C or colder)</ENT> <ENT>1 year.</ENT> </ROW> <ROW> <ENT I="01">Rubella Virus Vaccine Live</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Skin Test Antigens for Cellular Hypersensitivity</ENT> <ENT>6 months</ENT> <ENT>Not applicable</ENT> <ENT>Do.</ENT> </ROW> <ROW> <PRTPAGE P="76"/> <ENT I="11">Smallpox Vaccine:</ENT> </ROW> <ROW> <ENT I="03">1. Liquid</ENT> <ENT>Not applicable</ENT> <ENT>9 months (−10 <E T="61">°</E>C or colder, if product is maintained as glycerinated or equivalent vaccine in bulk or final containers)</ENT> <ENT>3 months, provided labeling recommends storage at 0 <E T="61">°</E>C or colder.</ENT> </ROW> <ROW> <ENT I="03">2. Dried</ENT> <ENT>6 months</ENT> <ENT>Not applicable</ENT> <ENT>18 months.</ENT> </ROW> <ROW> <ENT I="01">Streptokinase</ENT> <ENT>Not applicable</ENT> <ENT>......do</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Tetanus and Diphtheria Toxoids Adsorbed for Adult Use</ENT> <ENT>1 year</ENT> <ENT>......do</ENT> <ENT>2 years.</ENT> </ROW> <ROW> <ENT I="11">Tetanus Antitoxin:</ENT> </ROW> <ROW> <ENT I="03">1. Liquid</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>5 years with an initial 20 percent excess or potency.</ENT> </ROW> <ROW> <ENT I="03">2. Dried</ENT> <ENT>......do</ENT> <ENT>2 years</ENT> <ENT>5 years with an initial 10 percent excess or potency.</ENT> </ROW> <ROW> <ENT I="01">Tetanus Toxoid</ENT> <ENT>......do</ENT> <ENT>Not applicable</ENT> <ENT>2 years.</ENT> </ROW> <ROW> <ENT I="01">Tetanus Toxoid Adsorbed</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Thrombin</ENT> <ENT>......do</ENT> <ENT>2 year</ENT> <ENT>3 years.</ENT> </ROW> <ROW> <ENT I="01">Thrombin Impregnated Pad</ENT> <ENT>Not applicable</ENT> <ENT>Not applicable</ENT> <ENT>1 year, or 6 months at 20 to 24 <E T="61">°</E>C.</ENT> </ROW> <ROW> <ENT I="11">Tuberculin:</ENT> </ROW> <ROW> <ENT I="03">1. Purified Protein Derivative, diluted</ENT> <ENT>6 months</ENT> <ENT>......do</ENT> <ENT>1 year.</ENT> </ROW> <ROW> <ENT I="03">2. Old or Purified Protein Derivative dried on multiple puncture device</ENT> <ENT>1 year (not to exceed 30 <E T="61">°</E>C; do not refrigerate)</ENT> <ENT>......do</ENT> <ENT>2 years, provided labeling recommends storage at a temperature not to exceed 30 <E T="61">°</E>C. Do not refrigerate.</ENT> </ROW> <ROW> <ENT I="03">3. Old on multiple puncture device</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">Typhoid Vaccine</ENT> <ENT>1 year</ENT> <ENT>......do</ENT> <ENT>18 months.</ENT> </ROW> <ROW> <ENT I="01">ACD Whole Blood</ENT> <ENT>Not applicable</ENT> <ENT>......do</ENT> <ENT>21 days from date of collection, provided labeling recommends storage between 1 and 6 <E T="61">°</E>C.</ENT> </ROW> <ROW> <ENT I="01">CPD Whole Blood</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>Do.</ENT> </ROW> <ROW> <ENT I="01">CPDA-1 Whole Blood</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>35 days from date of collection, provided labeling recommends storage between 1 and 6 <E T="61">°</E>C.</ENT> </ROW> <ROW> <ENT I="01">Heparin Whole Blood</ENT> <ENT>......do</ENT> <ENT>......do</ENT> <ENT>48 hours from date of collection, provided labeling recommends storage between 1 and 6 <E T="61">°</E>C.</ENT> </ROW> <ROW> <ENT I="01">Yellow Fever Vaccine</ENT> <ENT>......do</ENT> <ENT>1 year (−20 <E T="61">°</E>C or colder)</ENT> <ENT>1 year, provided labeling recommends storage at 5 <E T="61">°</E>C or colder.</ENT> </ROW> </GPOTABLE> <P>(d) <E T="03">Exemptions.</E> Exemptions or modifications shall be made only upon written approval, in the form of a supplement of the product license, issued by the Director, Center for Biologics Evaluation and Research (HFB-1).</P> <CITA>[50 FR 4134, Jan. 29, 1985, as amended at 51 FR 15607, Apr. 25, 1986; 51 FR 19750, June 2, 1986; 52 FR 37450, Oct. 7, 1987; 53 FR 12764, Apr. 19, 1988; 55 FR 11014, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 62 FR 15110, Mar. 31, 1997]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart G—Labeling Standards</HD> <SECTION> <SECTNO>§ 610.60</SECTNO> <SUBJECT>Container label.</SUBJECT> <P>(a) <E T="03">Full label.</E> The following items shall appear on the label affixed to each container of a product capable of bearing a full label:</P> <P>(1) The proper name of the product;</P> <P>(2) The name, address, and license number of manufacturer;</P> <P>(3) The lot number or other lot identification;</P> <P>(4) The expiration date;</P> <P>(5) The recommended individual dose, for multiple dose containers.</P> <P>(6) The statement: “Caution: Federal law prohibits dispensing without prescription,” for prescription biologicals.</P> <P>(7) If a Medication Guide is required under part 208 of this chapter, the statement required under § 208.24(d) of this chapter instructing the authorized dispenser to provide a Medication Guide to each patient to whom the <PRTPAGE P="77"/>drug is dispensed and stating how the Medication Guide is provided, except where the container label is too small, the required statement may be placed on the package label.</P> <P>(b) <E T="03">Package label information.</E> If the container is not enclosed in a package, all the items required for a package label shall appear on the container label.</P> <P>(c) <E T="03">Partial label.</E> If the container is capable of bearing only a partial label, the container shall show as a minimum the name (expressed either as the proper or common name), the lot number or other lot identification and the name of the manufacturer; in addition, for multiple dose containers, the recommended individual dose. Containers bearing partial labels shall be placed in a package which bears all the items required for a package label.</P> <P>(d) <E T="03">No container label.</E> If the container is incapable of bearing any label, the items required for a container label may be omitted, provided the container is placed in a package which bears all the items required for a package label.</P> <P>(e) <E T="03">Visual inspection.</E> When the label has been affixed to the container a sufficient area of the container shall remain uncovered for its full length or circumference to permit inspection of the contents.</P> <CITA>[38 FR 32056, Nov. 20, 1973, as amended at 47 FR 22518, May 25, 1982; 63 FR 66400, Dec. 1, 1998]</CITA> <EFFDNOT> <HD SOURCE="HED">Effective Date Note:</HD> <P> At 63 FR 66400, Dec. 1, 1998, § 610.60 was amended by adding paragraph (a)(7), effective June 1, 1999.</P> </EFFDNOT> </SECTION> <SECTION> <SECTNO>§ 610.61</SECTNO> <SUBJECT>Package label.</SUBJECT> <P>The following items shall appear on the label affixed to each package containing a product:</P> <P>(a) The proper name of the product;</P> <P>(b) The name, address, and license number of manufacturer;</P> <P>(c) The lot number or other lot identification;</P> <P>(d) The expiration date;</P> <P>(e) The preservative used and its concentration, or if no preservative is used and the absence of a preservative is a safety factor, the words “no preservative”;</P> <P>(f) The number of containers, if more than one;</P> <P>(g) The amount of product in the container expressed as (1) the number of doses, (2) volume, (3) units of potency, (4) weight, (5) equivalent volume (for dried product to be reconstituted), or (6) such combination of the foregoing as needed for an accurate description of the contents, whichever is applicable;</P> <P>(h) The recommended storage temperature;</P> <P>(i) The words “Shake Well”, “Do not Freeze” or the equivalent, as well as other instructions, when indicated by the character of the product;</P> <P>(j) The recommended individual dose if the enclosed container(s) is a multiple-dose container;</P> <P>(k) The route of administration recommended, or reference to such directions in an enclosed circular;</P> <P>(l) Known sensitizing substances, or reference to an enclosed circular containing appropriate information;</P> <P>(m) The type and calculated amount of antibiotics added during manufacture;</P> <P>(n) The inactive ingredients when a safety factor, or reference to an enclosed circular containing appropriate information;</P> <P>(o) The adjuvant, if present;</P> <P>(p) The source of the product when a factor in safe administration;</P> <P>(q) The identity of each microorganism used in manufacture, and, where applicable, the production medium and the method of inactivation, or reference to an enclosed circular containing appropriate information;</P> <P>(r) Minimum potency of product expressed in terms of official standard of potency or, if potency is a factor and no U.S. standard of potency has been prescribed, the words “No U.S. standard of potency.”</P> <P>(s) The statement: “Caution: Federal law prohibits dispensing without prescription,” for prescription biologicals.</P> <CITA>[38 FR 32056, Nov. 20, 1973, as amended at 47 FR 22518, May 25, 1982; 55 FR 10423, Mar. 21, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 610.62</SECTNO> <SUBJECT>Proper name; package label; legible type.</SUBJECT> <P>(a) <E T="03">Position.</E> The proper name of the product on the package label shall be placed above any trademark or trade <PRTPAGE P="78"/>name identifying the product and symmetrically arranged with respect to other printing on the label.</P> <P>(b) <E T="03">Prominence.</E> The point size and typeface of the proper name shall be at least as prominent as the point size and typeface used in designating the trademark and trade name. The contrast in color value between the proper name and the background shall be at least as great as the color value between the trademark and trade name and the background. Typography, layout, contrast, and other printing features shall not be used in a manner that will affect adversely the prominence of the proper name.</P> <P>(c) <E T="03">Legible type.</E> All items required to be on the container label and package label shall be in legible type. “Legible type” is type of a size and character which can be read with ease when held in a good light and with normal vision.</P> </SECTION> <SECTION> <SECTNO>§ 610.63</SECTNO> <SUBJECT>Divided manufacturing responsibility to be shown.</SUBJECT> <P>If two or more establishments participate in the manufacture of a product, the name, address, and license number of each must appear on the package label, and on the label of the container if capable of bearing a full label.</P> </SECTION> <SECTION> <SECTNO>§ 610.64</SECTNO> <SUBJECT>Name and address of distributor.</SUBJECT> <P>The name and address of the distributor of a product may appear on the label provided that the name, address, and license number of the manufacturer also appears on the label and the name of the distributor is qualified by one of the following phrases: “Manufactured for<E T="72">XXXXXXX</E>”, “Distributed by <E T="72">XXXXXX</E>”, “Manufactured by <E T="72">XXXXX</E> for <E T="72">XXXXX</E>”, “Manufactured for <E T="72">XXXXX</E> by <E T="72">XXXX</E>”, “Distributor: <E T="72">XXXXX</E>”, or “Marketed by <E T="72">XXXXX</E>”. The qualifying phrases may be abbreviated.</P> <CITA>[61 FR 57330, Nov. 6, 1996]</CITA> </SECTION> <SECTION> <SECTNO>§ 610.65</SECTNO> <SUBJECT>Products for export.</SUBJECT> <P>Labels on packages or containers of products for export may be adapted to meet specific requirements of the regulations of the country to which the product is to be exported provided that in all such cases the minimum label requirements prescribed in § 610.60 are observed.</P> </SECTION> </SUBPART> </PART> <PART> <EAR>Pt. 640</EAR> <HD SOURCE="HED">PART 640—ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS</HD> <CONTENTS> <SUBPART> <HD SOURCE="HED">Subpart A—Whole Blood</HD> <SECHD>Sec.</SECHD> <SECTNO>640.1</SECTNO> <SUBJECT>Whole Blood.</SUBJECT> <SECTNO>640.2</SECTNO> <SUBJECT>General requirements.</SUBJECT> <SECTNO>640.3</SECTNO> <SUBJECT>Suitability of donor.</SUBJECT> <SECTNO>640.4</SECTNO> <SUBJECT>Collection of the blood.</SUBJECT> <SECTNO>640.5</SECTNO> <SUBJECT>Testing the blood.</SUBJECT> <SECTNO>640.6</SECTNO> <SUBJECT>Modifications of Whole Blood.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart B—Red Blood Cells</HD> <SECTNO>640.10</SECTNO> <SUBJECT>Red Blood Cells.</SUBJECT> <SECTNO>640.11</SECTNO> <SUBJECT>General requirements.</SUBJECT> <SECTNO>640.12</SECTNO> <SUBJECT>Suitability of donor.</SUBJECT> <SECTNO>640.13</SECTNO> <SUBJECT>Collection of the blood.</SUBJECT> <SECTNO>640.14</SECTNO> <SUBJECT>Testing the blood.</SUBJECT> <SECTNO>640.15</SECTNO> <SUBJECT>Pilot samples.</SUBJECT> <SECTNO>640.16</SECTNO> <SUBJECT>Processing.</SUBJECT> <SECTNO>640.17</SECTNO> <SUBJECT>Modifications for specific products.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart C—Platelets</HD> <SECTNO>640.20</SECTNO> <SUBJECT>Platelets.</SUBJECT> <SECTNO>640.21</SECTNO> <SUBJECT>Suitability of donors.</SUBJECT> <SECTNO>640.22</SECTNO> <SUBJECT>Collection of source material.</SUBJECT> <SECTNO>640.23</SECTNO> <SUBJECT>Testing the blood.</SUBJECT> <SECTNO>640.24</SECTNO> <SUBJECT>Processing.</SUBJECT> <SECTNO>640.25</SECTNO> <SUBJECT>General requirements.</SUBJECT> <SECTNO>640.27</SECTNO> <SUBJECT>Emergency provisions.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart D—Plasma</HD> <SECTNO>640.30</SECTNO> <SUBJECT>Plasma.</SUBJECT> <SECTNO>640.31</SECTNO> <SUBJECT>Suitability of donors.</SUBJECT> <SECTNO>640.32</SECTNO> <SUBJECT>Collection of source material.</SUBJECT> <SECTNO>640.33</SECTNO> <SUBJECT>Testing the blood.</SUBJECT> <SECTNO>640.34</SECTNO> <SUBJECT>Processing.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart E[Reserved]</HD> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart F—Cryoprecipitate</HD> <SECTNO>640.50</SECTNO> <SUBJECT>Cryoprecipitate AHF.</SUBJECT> <SECTNO>640.51</SECTNO> <SUBJECT>Suitability of donors.</SUBJECT> <SECTNO>640.52</SECTNO> <SUBJECT>Collection of source material.</SUBJECT> <SECTNO>640.53</SECTNO> <SUBJECT>Testing the blood.</SUBJECT> <SECTNO>640.54</SECTNO> <SUBJECT>Processing.</SUBJECT> <SECTNO>640.55</SECTNO> <SUBJECT>U.S. Standard preparation.</SUBJECT> <SECTNO>640.56</SECTNO> <SUBJECT>Quality control test for potency.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart G—Source Plasma</HD> <SECTNO>640.60</SECTNO> <SUBJECT>Source Plasma.</SUBJECT> <SECTNO>640.61</SECTNO> <SUBJECT>Informed consent.</SUBJECT> <SECTNO>640.62</SECTNO> <SUBJECT>Medical supervision.</SUBJECT> <SECTNO>640.63</SECTNO> <SUBJECT>Suitability of donor.</SUBJECT> <SECTNO>640.64</SECTNO> <SUBJECT>Collection of blood for Source Plasma.</SUBJECT> <SECTNO>640.65</SECTNO> <SUBJECT>Plasmapheresis.<PRTPAGE P="79"/> </SUBJECT> <SECTNO>640.66</SECTNO> <SUBJECT>Immunization of donors.</SUBJECT> <SECTNO>640.67</SECTNO> <SUBJECT>Laboratory tests.</SUBJECT> <SECTNO>640.68</SECTNO> <SUBJECT>Processing.</SUBJECT> <SECTNO>640.69</SECTNO> <SUBJECT>General requirements.</SUBJECT> <SECTNO>640.70</SECTNO> <SUBJECT>Labeling.</SUBJECT> <SECTNO>640.71</SECTNO> <SUBJECT>Manufacturing responsibility.</SUBJECT> <SECTNO>640.72</SECTNO> <SUBJECT>Records.</SUBJECT> <SECTNO>640.73</SECTNO> <SUBJECT>Reporting of fatal donor reactions.</SUBJECT> <SECTNO>640.74</SECTNO> <SUBJECT>Modification of Source Plasma.</SUBJECT> <SECTNO>640.76</SECTNO> <SUBJECT>Products stored or shipped at unacceptable temperatures.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart H—Albumin (Human)</HD> <SECTNO>640.80</SECTNO> <SUBJECT>Albumin (Human).</SUBJECT> <SECTNO>640.81</SECTNO> <SUBJECT>Processing.</SUBJECT> <SECTNO>640.82</SECTNO> <SUBJECT>Tests on final product.</SUBJECT> <SECTNO>640.83</SECTNO> <SUBJECT>General requirements.</SUBJECT> <SECTNO>640.84</SECTNO> <SUBJECT>Labeling.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart I—Plasma Protein Fraction (Human)</HD> <SECTNO>640.90</SECTNO> <SUBJECT>Plasma Protein Fraction (Human).</SUBJECT> <SECTNO>640.91</SECTNO> <SUBJECT>Processing.</SUBJECT> <SECTNO>640.92</SECTNO> <SUBJECT>Tests on final product.</SUBJECT> <SECTNO>640.93</SECTNO> <SUBJECT>General requirements.</SUBJECT> <SECTNO>640.94</SECTNO> <SUBJECT>Labeling.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart J—Immune Globulin (Human)</HD> <SECTNO>640.100</SECTNO> <SUBJECT>Immune Globulin (Human).</SUBJECT> <SECTNO>640.101</SECTNO> <SUBJECT>General requirements.</SUBJECT> <SECTNO>640.102</SECTNO> <SUBJECT>Manufacture of Immune Globulin (Human).</SUBJECT> <SECTNO>640.103</SECTNO> <SUBJECT>The final product.</SUBJECT> <SECTNO>640.104</SECTNO> <SUBJECT>Potency.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart K[Reserved]</HD> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart L—Alternative Procedures</HD> <SECTNO>640.120</SECTNO> <SUBJECT>Alternative procedures.</SUBJECT> </SUBPART> </CONTENTS> <AUTH> <HD SOURCE="HED">Authority: </HD> <P>21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 U.S.C. 216, 262, 263, 263a, 264.</P> </AUTH> <SOURCE> <HD SOURCE="HED">Source: </HD> <P>38 FR 32089, Nov. 20, 1973, unless otherwise noted.</P> </SOURCE> <CROSSREF> <HD SOURCE="HED"> <E T="04">Cross References:</E> </HD> <P>For U.S. Customs Service regulations relating to viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal Service regulations relating to the admissibility to the United States mails see parts 124 and 125 of the Domestic Mail Manual, that is incorporated by reference in 39 CFR part 111.</P> </CROSSREF> <SUBPART> <HD SOURCE="HED">Subpart A—Whole Blood</HD> <SECTION> <SECTNO>§ 640.1</SECTNO> <SUBJECT>Whole Blood.</SUBJECT> <P>The proper name of this product shall be Whole Blood. Whole Blood is defined as blood collected from human donors for transfusion to human recipients.</P> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.2</SECTNO> <SUBJECT>General requirements.</SUBJECT> <P>(a) <E T="03">Manufacturing responsibility.</E> All manufacturing of Whole Blood, including donor examination, blood collection, laboratory tests, labeling, storage and issue, shall be done under the supervision and control of the same licensed establishment except that the Director, Center for Biologics Evaluation and Research, may approve arrangements, upon joint request of two or more licensed establishments, which he finds are of such a nature as to assure compliance otherwise with the provisions of this subchapter.</P> <P>(b) <E T="03">Periodic check on sterile technique.</E> Where blood is collected in an open system, that is, where the blood container is entered, at least one container of such blood that upon visual examination appears normal shall be tested each month between the 18th and 24th day after collection (between the 32d and 38th day after collection when CPDA-1 solution is used as the anticoagulant), as a continuing check on technique of blood collection, as follows: The test shall be performed with a total sample of no less than 10 milliliters of blood and a total volume of fluid thioglycollate medium 10 times the volume of the sample of blood. The test sample shall be inoculated into one or more test vessels in a ratio of blood to medium of 1 to 10 for each vessel, mixed thoroughly, incubated for 7 to 9 days at a temperature of 30 to 32 °C, and examined for evidence of growth of microorganisms every workday throughout the test period. On the third, fourth, or fifth day, at least 1 milliliter of material from each test vessel shall be subcultured in additional test vessels containing the same culture medium and in such proportion as will permit significant visual inspection, mixed thoroughly, incubated for 7 to 9 days at a temperature of 30 to 32 °C, and examined for evidence of growth of microorganisms every workday throughout the test period. If growth is observed in any test vessel, the test shall be repeated to rule out faulty test procedure, using another <PRTPAGE P="80"/>sample of blood from either, (1) the container from which the initial test sample was taken; (2) the residual cells or plasma from that blood; or (3) two different containers of blood, each 18 to 24 days old (32 to 38 days old when CPDA-1 solution is used as the anticoagulant) and each tested separately. The formula for Fluid Thioglycollate Medium shall be as prescribed in § 610.12(e)(1) of this chapter. Media and design of container shall meet the requirements prescribed in § 610.12(e)(2) (i) and (ii) of this chapter. In lieu of performing one test using an incubation temperature of 30 to 32 °C, two tests may be performed: Each in all respects as prescribed in this paragraph, one at an incubation temperature of 18 to 22 °C and one at an incubation temperature of 35 to 37 °C.</P> <P>(c) <E T="03">Final container.</E> The original blood container shall be the final container and shall not be entered prior to issue for any purpose except for blood collection. Such container shall be uncolored and transparent to permit visual inspection of the contents and any closure shall be such as will maintain an hermetic seal and prevent contamination of the contents. The container material shall not interact with the contents under the customary conditions of storage and use, in such a manner as to have an adverse effect upon the safety, purity, or potency of the blood.</P> <P>(d) [Reserved]</P> <P>(e) <E T="03">Reissue of blood.</E> Blood that has been removed from storage controlled by a licensed establishment shall not be reissued by a licensed establishment unless the following conditions are observed:</P> <P>(1) The container has a tamper-proof seal when originally issued and this seal remains unbroken;</P> <P>(2) An original pilot sample is properly attached and has not been removed, except that blood lacking a pilot sample may be reissued in an emergency provided it is accompanied by instructions for sampling and for use within six hours after entering the container for sampling;</P> <P>(3) The blood has been stored continuously at 1 to 6 °C and shipped between 1 and 10 °C;</P> <P>(4) The blood is held for observation until a significant inspection consistent with the requirements of § 640.5(e) can be made.</P> <P>(f) <E T="03">Issue prior to determination of test results.</E> Notwithstanding the provisions of § 610.1 of this chapter, blood may be issued by the manufacturer on the request of a physician, hospital, or other medical facility before results of all tests prescribed in § 640.5, the test for hepatitis B surface antigen prescribed in § 610.40(a) of this chapter, and a test for antibody to Human Immunodeficiency Virus (HIV) prescribed in § 610.45(a) of this chapter have been completed, where such issue is essential to allow time for transportation to ensure arrival of the blood by the time it is needed for transfusion: <E T="03">Provided,</E> That (1) the blood is shipped directly to such physician or medical facility, (2) the records of the manufacturer contain a full explanation of the need for such issue, and (3) the label on each container of such blood bears the information required by § 606.121(h) of this chapter. </P> <EXTRACT> <FP>(Information collection requirements approved by the Office of Management and Budget under number 0910-0227)</FP> </EXTRACT> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 4015, Jan. 28, 1976; 42 FR 59878, Nov. 22, 1977; 43 FR 34460, Aug. 4, 1978; 49 FR 15187, Apr. 18, 1984; 49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 29, 1985; 53 FR 116, Jan. 5, 1988; 55 FR 11013, Mar. 26, 1990; 63 FR 16685, Apr. 6, 1998]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.3</SECTNO> <SUBJECT>Suitability of donor.</SUBJECT> <P>(a) <E T="03">Method of determining.</E> The suitability of a donor as a source of Whole Blood shall be determined by a qualified physician or by persons under his supervision and trained in determining suitability. Such determination shall be made on the day of collection from the donor by means of medical history, a test for hemoglobin level, and such physical examination as appears necessary to a physician who shall be present on the premises when examinations are made, except that the suitability of donors may be determined when a physician is not present on the premises, provided the establishment (1) maintains on the premises, and files with the Center for Biologics Evaluation and Research, a manual of standard procedures and methods, approved <PRTPAGE P="81"/>by the Director of the Center for Biologics Evaluation and Research, that shall be followed by employees who determine suitability of donors, and (2) maintains records indicating the name and qualifications of the person immediately in charge of the employees who determine the suitability of donors when a physician is not present on the premises.</P> <P>(b) <E T="03">Qualifications of donor; general.</E> Except as provided in paragraph (f), a person may not serve as a source of Whole Blood more than once in 8 weeks. In addition, donors shall be in good health, as indicated in part by:</P> <P>(1) Normal temperature;</P> <P>(2) Demonstration that systolic and diastolic blood pressures are within normal limits, unless the examining physician is satisfied that an individual with blood pressures outside these limits is an otherwise qualified donor under the provisions of this section;</P> <P>(3) A blood hemoglobin level which shall be demonstrated to be no less than 12.5 gm. of hemoglobin per 100 ml. of blood;</P> <P>(4) Freedom from acute respiratory diseases;</P> <P>(5) Freedom from any infectious skin disease at the site of phlebotomy and from any such disease generalized to such an extent as to create a risk of contamination of the blood;</P> <P>(6) Freedom from any disease transmissible by blood transfusion, insofar as can be determined by history and examinations indicated above; and</P> <P>(7) Freedom of the arms and forearms from skin punctures or scars indicative of addiction to self-injected narcotics.</P> <P>(c) <E T="03">Additional qualifications of donor; viral hepatitis.</E> No individual shall be used as a source of Whole Blood if he has—</P> <P>(1) A history of viral hepatitis;</P> <P>(2) A history of close contact within six months of donation with an individual having viral hepatitis;</P> <P>(3) A history of having received within six months human blood, or any derivative of human blood which the Food and Drug Administration has advised the licensed establishment is a possible source of viral hepatitis.</P> <P>(d) <E T="03">Therapeutic bleedings.</E> Blood withdrawn in order to promote the health of a donor otherwise qualified under the provisions of this section, shall not be used as a source of Whole Blood unless the container label conspicuously indicates the donor's disease that necessitated withdrawal of blood.</P> <P>(e) <E T="03">Immunized donors.</E> Blood withdrawn from donors known to have been immunized to human blood cell antigens shall not be used for Whole Blood unless the container label conspicuously indicates such information.</P> <P>(f) <E T="03">Qualifications; donations within less than 8 weeks.</E> A person may serve as a source of Whole Blood more than once in 8 weeks only if at the time of donation the person is examined and certified by a physician to be in good health, as indicated in part in paragraph (b) of this section.</P> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 29, 1985; 51 FR 15611, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.4</SECTNO> <SUBJECT>Collection of the blood.</SUBJECT> <P>(a) <E T="03">Supervision.</E> Blood shall be drawn from the donor by a qualified physician or under his supervision by assistants trained in the procedure. A physician shall be present on the premises when blood is being collected, except that blood may be collected when a physician is not present on the premises, provided the establishment (1) maintains on the premises, and files with the Center for Biologics Evaluation and Research, a manual of standard procedures and methods, approved by the Director of the Center for Biologics Evaluation and Research, that shall be followed by employees who collect blood, and (2) maintains records indicating the name and qualifications of the person immediately in charge of the employees who collect blood when a physician is not present on the premises.</P> <P>(b) <E T="03">The donor clinic.</E> The pertinent requirements of §§ 600.10 and 600.11 of this chapter shall apply at both the licensed establishment and at any other place where the bleeding is performed.</P> <P>(c) <E T="03">Blood containers.</E> Blood containers and donor sets shall be pyrogen-free, sterile and identified by lot number. The amount of anticoagulant required for the quantity of blood to be collected shall be in the blood container <PRTPAGE P="82"/>when it is sterilized. In addition, all container and donor set surfaces that come in contact with blood used in the processing of Heparin Whole Blood shall be water repellent.</P> <P>(d) <E T="03">The anticoagulant solution.</E> The anticoagulant solution shall be sterile and pyrogen-free. One of the following formulae shall be used in the indicated volumes:</P> <P>(1) <E T="03">Anticoagulant citrate dextrose solution (ACD).</E> </P> <GPOTABLE CDEF="s50,xs30,xs30" COLS="3" OPTS="L2"> <BOXHD> <CHED H="1"/> <CHED H="1">Solution A</CHED> <CHED H="1">Solution B</CHED> </BOXHD> <ROW> <ENT I="01">Tri-sodium citrate (Na<E T="22">3</E> <E T="31">C</E> <E T="22">6</E> <E T="31">H</E> <E T="22">5</E> <E T="31">O</E> <E T="22">7</E> <E T="01">·</E> <E T="31">2H</E> <E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>22.0 gm</ENT> <ENT>13.2 gm.</ENT> </ROW> <ROW> <ENT I="01">Citric acid (C<E T="22">6</E> <E T="31">H</E> <E T="22">8</E> <E T="31">O</E> <E T="22">7</E> <E T="01">·</E> <E T="31">H</E> <E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>8.0 gm</ENT> <ENT>4.8 gm.</ENT> </ROW> <ROW> <ENT I="01">Dextrose (C<E T="22">6</E> <E T="31">H</E> <E T="22">1</E> <E T="22">2</E> <E T="31">O</E> <E T="22">6</E> <E T="01">·</E> <E T="31">H</E> <E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>24.5 gm</ENT> <ENT>14.7 gm.</ENT> </ROW> <ROW> <ENT I="01">Water for injection (U.S.P.) to make</ENT> <ENT>1,000 ml</ENT> <ENT>1,000 ml.</ENT> </ROW> <ROW> <ENT I="01">Volume per 100 ml. blood</ENT> <ENT>15 ml</ENT> <ENT>25 ml.</ENT> </ROW> </GPOTABLE> <P>(2) <E T="03">Anticoagulant heparin solution.</E> </P> <GPOTABLE CDEF="s50,xs42" COLS="2" OPTS="L0,6/7,g1,t1"> <ROW> <ENT I="01">Heparin sodium (U.S.P.)</ENT> <ENT>75,000 units.</ENT> </ROW> <ROW> <ENT I="01">Sodium chloride injection (U.S.P.) to make</ENT> <ENT>1,000 ml.</ENT> </ROW> <ROW> <ENT I="01">Volume per 100 ml. blood</ENT> <ENT>6 ml.</ENT> </ROW> </GPOTABLE> <FP>A buffer to maintain stability shall be added, if necessary.</FP> <P>(3) <E T="03">Anticoagulant citrate phosphate dextrose solution (CPD).</E> </P> <GPOTABLE CDEF="s50,xs42" COLS="2" OPTS="L0,6/7,g1,t1"> <ROW> <ENT I="01">Tri-sodium citrate (Na<E T="22">3</E> <E T="31">C</E> <E T="22">6</E> <E T="31">H</E> <E T="22">5</E> <E T="31">O</E> <E T="22">7</E> <E T="01">·</E> <E T="31">2H</E> <E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>26.3 gm.</ENT> </ROW> <ROW> <ENT I="01">Citric acid (C<E T="22">6</E> <E T="31">H</E> <E T="22">8</E> <E T="31">O</E> <E T="22">7</E> <E T="01">·</E> <E T="31">H</E> <E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>3.27 gm.</ENT> </ROW> <ROW> <ENT I="01">Dextrose (C<E T="22">6</E> <E T="31">H</E> <E T="22">1</E> <E T="22">2</E> <E T="31">O</E> <E T="22">6</E> <E T="01">·</E> <E T="31">H</E> <E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>25.5 gm.</ENT> </ROW> <ROW> <ENT I="01">Monobasic sodium phosphate (NaH<E T="22">2</E> <E T="31">PO</E> <E T="22">4</E> <E T="01">·</E> <E T="31">H</E> <E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>2.22 gm.</ENT> </ROW> <ROW> <ENT I="01">Water for injection (U.S.P.) to make</ENT> <ENT>1,000 ml.</ENT> </ROW> <ROW> <ENT I="01">Volume per 100 ml. blood</ENT> <ENT>14 ml.</ENT> </ROW> </GPOTABLE> <P>(4) <E T="03">Anticoagulant citrate phosphate dextrose adenine solution (CPDA-1).</E> </P> <GPOTABLE CDEF="s50,xs42" COLS="2" OPTS="L0,6/7,g1,t1"> <ROW> <ENT I="01">Tri-sodium citrate (Na<E T="22">3</E> <E T="31">C</E> <E T="22">6</E> <E T="31">H</E> <E T="22">5</E> <E T="31">O</E> <E T="22">7</E> <E T="01">·</E> <E T="31">2H</E> <E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>26.3 gm.</ENT> </ROW> <ROW> <ENT I="01">Citric acid (C<E T="22">6</E> <E T="31">H</E> <E T="22">8</E> <E T="31">O</E> <E T="22">7</E> <E T="01">·</E> <E T="31">H</E> <E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>3.27 gm.</ENT> </ROW> <ROW> <ENT I="01">Dextrose (C<E T="22">6</E> <E T="31">H</E> <E T="22">12</E> <E T="31">O</E> <E T="22">6</E> <E T="01">·</E>H<E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>31.9 gm.</ENT> </ROW> <ROW> <ENT I="01">Monobasic sodium phosphate (NaH<E T="22">2</E> <E T="31">PO</E> <E T="22">4</E> <E T="01">·</E>H<E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>2.22 gm.</ENT> </ROW> <ROW> <ENT I="01">Adenine (C<E T="22">5</E> <E T="31">H</E> <E T="22">5</E> <E T="31">N</E> <E T="22">5</E> <E T="31">)</E> </ENT> <ENT>0.275 gm.</ENT> </ROW> <ROW> <ENT I="01">Water for injection (U.S.P.) to make </ENT> <ENT>1,000 ml.</ENT> </ROW> <ROW> <ENT I="01">Volume per 100 ml blood</ENT> <ENT>14 ml.</ENT> </ROW> </GPOTABLE> <P>(e) <E T="03">Donor identification.</E> Each unit of blood shall be so marked or identified by number or other symbol as to relate it to the individual donor whose identity shall be established to the extent necessary for compliance with § 640.3.</P> <P>(f) <E T="03">Prevention of contamination of the blood.</E> The skin of the donor at the site of phlebotomy shall be prepared thoroughly and carefully by a method that gives maximum assurance of a sterile container of blood. The blood shall be collected by aseptic methods in a sterile system which may be closed or may be vented if the vent protects the blood against contamination.</P> <P>(g) <E T="03">Pilot samples for laboratory tests.</E> Pilot samples for laboratory tests shall meet the following standards:</P> <P>(1) One or more pilot samples shall be provided with each unit of blood when issued or reissued except as provided in § 640.2(e)(2) and all pilot samples shall be from the donor who is the source of the unit of blood.</P> <P>(2) All samples for laboratory tests performed by the manufacturer and all pilot samples accompanying a unit of blood shall be collected at the time of filling the final container by the person who collects the unit of blood.</P> <P>(3) All containers for all samples shall bear the donor's identification before collecting the samples.</P> <P>(4) All containers for pilot samples accompanying a unit of blood shall be attached to the whole blood container before blood collection, in a tamperproof manner that will conspicuously indicate removal and reattachment.</P> <P>(5) When CPDA-1 is used, pilot samples for compatibility testing shall contain blood mixed with CPDA-1.</P> <P>(h) <E T="03">Phlebotomy for Heparin Whole Blood</E>. Heparin Whole Blood shall be collected with minimal damage to and minimal manipulation of the donor's tissue, and with a single, uninterrupted, freeflowing venipuncture.</P> <P>(i) <E T="03">Storage.</E> Immediately after collection, unless the blood is to be used as a source for Platelets, it shall be placed in storage at a temperature between 1 and 6 °C unless it must be transported from the donor clinic to the processing laboratory. In the latter case, the blood shall be placed in temporary storage having sufficient refrigeration capacity to cool the blood continuously toward a range between 1 and 6 °C until it arrives at the processing laboratory, where it shall be stored at a temperature between 1 and 6 °C. Blood from which Platelets is to be prepared shall be held in an environment maintained at a temperature range 20 to 24 °C until the platelets are separated. The red blood cells shall be placed in storage at <PRTPAGE P="83"/>a temperature between 1 and 6 °C immediately after the platelets are separated.</P> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 42 FR 59878, Nov. 22, 1977; 43 FR 34460, Aug. 4, 1978; 49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.5</SECTNO> <SUBJECT>Testing the blood.</SUBJECT> <P>All laboratory tests shall be made on a pilot sample specimen of blood taken from the donor at the time of collecting the unit of blood, and these tests shall include the following:</P> <P>(a) <E T="03">Serological test for syphilis.</E> Whole Blood shall be negative to a serological test for syphilis.</P> <P>(b) <E T="03">Determination of blood group.</E> Each container of Whole Blood shall be classified as to ABO blood group. At least two blood group tests shall be made and the unit shall not be issued until grouping tests by different methods or with different lots of antiserums are in agreement. Only those Anti-A and Anti-B Blood Grouping Reagents licensed under, or that otherwise meet the requirements of, the regulations of this subchapter shall be used, and the technique used shall be that for which the serum is specifically designed to be effective.</P> <P>(c) <E T="03">Determination of the Rh factors.</E> Each container of Whole Blood shall be classified as to Rh type on the basis of tests done on the pilot sample. The label shall indicate the extent of typing and the results of all tests performed. If the test, using Anti-D Blood Grouping Reagent, is positive, the container may be labeled “Rh Positive”. If this test is negative, the results shall be confirmed by further testing which may include tests for the Rh<E T="22">o</E> variant (D<E T="21">u</E>) and for other Rh-Hr factors. Blood maybe labeled “Rh Negative” if negative to tests for the Rh<E T="22">o</E> (D) and Rh<E T="22">o</E> variant (D<E T="21">u</E>) factors. If the test using Anti-D Blood Grouping Reagent is negative, but not tested for the Rh<E T="22">o</E> variant (D<E T="21">u</E>), the label must indicate that this test was not done. Only Anti-Rh Blood Grouping Reagents licensed under, or that otherwise meet the requirements of, the regulations of this subchapter shall be used, and the technique used shall be that for which the serum is specifically designed to be effective.</P> <P>(d) <E T="03">Sterility test.</E> Whole Blood intended for transfusion shall not be tested for sterility by a method that entails entering the final container before the blood is used for transfusion.</P> <P>(e) <E T="03">Inspection.</E> Whole Blood shall be inspected visually during storage and immediately prior to issue. If the color or physical appearance is abnormal or there is any indication or suspicion of microbial contamination the unit of Whole Blood shall not be issued for transfusion.</P> <P>(f) <E T="03">Test for antibody to HIV.</E> Whole Blood shall be tested for antibody to HIV as prescribed in § 610.45 of this chapter.</P> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 53 FR 12764, Apr. 19, 1988]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.6</SECTNO> <SUBJECT>Modifications of Whole Blood.</SUBJECT> <P>Upon approval by the Director, Center for Biologics Evaluation and Research, of a supplement to the product license application for Whole Blood a manufacturer may prepare Whole Blood from which the antihemophilic factor has been removed, provided the Whole Blood meets the applicable requirements of this subchapter and the following conditions are met:</P> <P>(a) The antihemophilic factor shall be removed in accordance with paragraphs (a), (b), and (c) of § 640.52.</P> <P>(b) Although the closed system between the red blood cells and plasma shall be maintained, the red blood cells shall be maintained between 1 and 6° C at all times, including that time when the plasma is being frozen for removal of the antihemophilic factor.</P> <P>(c) If containers for pilot samples are detached from the blood container during removal of the antihemophilic factor the pilot samples shall be reattached to the unit of Whole Blood Cryoprecipitate Removed as soon as the plasma is returned to the red blood cells. The reattachment of the pilot samples shall be in a tamperproof manner that will conspicuously indicate removal and reattachment.</P> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994]</CITA> </SECTION> </SUBPART> <SUBPART> <PRTPAGE P="84"/> <HD SOURCE="HED">Subpart B—Red Blood Cells</HD> <SECTION> <SECTNO>§ 640.10</SECTNO> <SUBJECT>Red Blood Cells.</SUBJECT> <P>The proper name of this product shall be Red Blood Cells. The product is defined as red blood cells remaining after separating plasma from human blood.</P> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.11</SECTNO> <SUBJECT>General requirements.</SUBJECT> <P>(a) <E T="03">Storage.</E> Immediately after processing, the Red Blood Cells shall be placed in storage and maintained at a temperature between 1 and 6 °C.</P> <P>(b) <E T="03">Inspection.</E> The product shall be inspected immediately after separation of the plasma, periodically during storage, and at the time of issue. The product shall not be issued if there is any abnormality in color or physical appearance or if there is any indication of microbial contamination.</P> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 18292, May 3, 1976; 42 FR 59878, Nov. 11, 1977; 50 FR 4139, Jan. 29, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.12</SECTNO> <SUBJECT>Suitability of donor.</SUBJECT> <P>The source blood for Red Blood Cells shall be obtained from a donor who meets the criteria for donor suitability prescribed in § 640.3.</P> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4139, Jan. 29, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.13</SECTNO> <SUBJECT>Collection of the blood.</SUBJECT> <P>(a) The source blood shall be collected as prescribed in § 640.4, except that paragraphs (d)(2), and (g), and (h) shall not apply.</P> <P>(b) Source blood may also be derived from Whole Blood manufactured in accordance with applicable provisions of this subchapter.</P> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4139, Jan. 29, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.14</SECTNO> <SUBJECT>Testing the blood.</SUBJECT> <P>Blood from which Red Blood Cells are prepared shall be tested as prescribed in §§ 610.40 and 610.45 of this chapter and § 640.5 (a), (b), and (c).</P> <CITA>[53 FR 117, Jan. 5, 1988]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.15</SECTNO> <SUBJECT>Pilot samples.</SUBJECT> <P>Pilot samples collected in integral tubing or in separate pilot tubes shall meet the following standards:</P> <P>(a) One or more pilot samples of either the original blood or of the Red Blood Cells being processed shall be provided with each unit of Red Blood Cells when issued or reissued.</P> <P>(b) Before they are filled, all pilot sample tubes shall be marked or identified so as to relate them to the donor of that unit of red cells.</P> <P>(c) Before the final container is filled or at the time the final product is prepared, the pilot sample tubes to accompany a unit of cells shall be attached securely to the final container in a tamper proof manner that will conspicuously indicate removal and reattachment.</P> <P>(d) All pilot sample tubes accompanying a unit of Red Blood Cells shall be filled at the time the blood is collected or at the time the final product is prepared, in each instance by the person who performs the collection or preparation.</P> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4139, Jan. 29, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.16</SECTNO> <SUBJECT>Processing.</SUBJECT> <P>(a) <E T="03">Separation.</E> Within 21 days from date of blood collection (within 35 days from date of blood collection when CPDA-1 solution is used as the anticoagulant), Red Blood Cells may be prepared either by centrifugation done in a manner that will not tend to increase the temperature of the blood or by normal undisturbed sedimentation. A portion of the plasma sufficient to insure optimal cell preservation shall be left with the red cells except when a cryoprotective substance is added for prolonged storage.</P> <P>(b) <E T="03">Sterile system.</E> All surfaces that come in contact with the red cells shall be sterile and pyrogen-free. If an open system is used, that is, where the transfer container is not integrally attached to the blood container, and the blood container is entered after blood collection, the plasma shall be separated from the red blood cells with positive pressure maintained on the original container until completely <PRTPAGE P="85"/>sealed. If the method of separation involves a vented system, that is, when an airway must be inserted in the container for withdrawal of the plasma, the airway and vent shall be sterile and constructed so as to exclude microorganisms and maintain a sterile system.</P> <P>(c) <E T="03">Final containers.</E> Final containers used for Red Blood Cells shall be the original blood containers unless the method of processing requires a different container. The final container shall meet the requirements for blood containers prescribed in § 640.2(c). At the time of filing, if a different container is used, it shall be marked or identified by number or other symbol so as to relate it to the donor of that unit of red cells.</P> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 43 FR 34460, Aug. 4, 1978; 50 FR 4139, Jan. 29, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.17</SECTNO> <SUBJECT>Modifications for specific products.</SUBJECT> <P>Red Blood Cells Frozen: A cryophylactic substance may be added to the Red Blood Cells for extended manufacturers' storage at −65° C or colder, provided the manufacturer submits data considered by the Director, Center for Biologics Evaluation and Research, as adequately demonstrating through in vivo cell survival and other appropriate tests that the addition of the substance, the materials used and the processing methods results in a final product that meets the required standards of safety, purity, and potency for Red Blood Cells, and that the frozen product will maintain those properties for the prescribed dating period. Section 640.11 (a) and (b) do not apply while a cryophylactic substance is present.</P> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 18292, May 3, 1976; 49 FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 63 FR 16685, Apr. 6, 1998]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart C—Platelets</HD> <SECTION> <SECTNO>§ 640.20</SECTNO> <SUBJECT>Platelets.</SUBJECT> <P>(a) <E T="03">Proper name and definition.</E> The proper name of this product shall be Platelets. The product is defined as platelets collected from one unit of blood and resuspended in an appropriate volume of original plasma, as prescribed in § 640.24(d).</P> <P>(b) <E T="03">Source.</E> The source material for Platelets shall be plasma which may be obtained by whole blood collection, by plasmapheresis, or by plateletpheresis.</P> <CITA>[40 FR 4304, Jan. 29, 1975, as amended at 47 FR 49021, Oct. 29, 1982; 50 FR 4139, Jan. 29, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.21</SECTNO> <SUBJECT>Suitability of donors.</SUBJECT> <P>(a) Whole blood donors shall meet the criteria for suitability prescribed in § 640.3.</P> <P>(b) Plasmapheresis donors shall meet the criteria for suitability prescribed in § 640.63, excluding the phrase “other than malaria” in paragraph (c)(9). Informed consent shall be required as prescribed in § 640.61.</P> <P>(c) Plateletpheresis donors shall meet criteria for suitability as described in a license application or a supplement to the product license, and must have the written approval of the Director, Center for Biologics Evaluation and Research, Food and Drug Administration.</P> <CITA>[40 FR 4304, Jan. 29, 1975, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.22</SECTNO> <SUBJECT>Collection of source material.</SUBJECT> <P>(a) Whole blood used as the source of Platelets shall be collected as prescribed in § 640.4, except that paragraphs (d)(2) and (h) shall not apply.</P> <P>(b) If plasmapheresis is used, the procedure for collection shall be prescribed in §§ 640.62, 640.64 (except paragraph (c)(3)), and 640.65.</P> <P>(c) If plateletpheresis is used, the procedure for collection shall be as described in a license application or a supplement to a product license, and must have the written approval of the Director, Center for Biologics Evaluation and Research, Food and Drug Administration.</P> <P>(d) The phlebotomy shall be performed by a single uninterrupted venipuncture with minimal damage to, and minimal manipulation of, the donor's tissue.</P> <CITA>[40 FR 4304, Jan. 29, 1975, as amended at 45 FR 27927, Apr. 25, 1980; 49 FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994]</CITA> </SECTION> <SECTION> <PRTPAGE P="86"/> <SECTNO>§ 640.23</SECTNO> <SUBJECT>Testing the blood.</SUBJECT> <P>(a) Blood from which plasma is separated for the preparation of Platelets shall be tested as prescribed in §§ 610.40 and 610.45 of this chapter and § 640.5 (a), (b), and (c).</P> <P>(b) The tests shall be performed on a sample of blood collected at the time of collecting the source blood, and such sample container shall be labeled with the donor's number before the container is filled.</P> <CITA>[40 FR 4304, Jan. 29, 1975, as amended at 50 FR 4139, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.24</SECTNO> <SUBJECT>Processing.</SUBJECT> <P>(a) Separation of plasma and platelets and resuspension of the platelets shall be in a closed system. Platelets shall not be pooled during processing.</P> <P>(b) Immediately after collection, the whole blood or plasma shall be held in storage between 20 and 24 °C, unless it must be transported from the donor clinic to the processing laboratory. During such transport, all reasonable methods shall be used to maintain the temperature as close as possible to a range between 20 and 24 °C until it arrives at the processing laboratory where it shall be held between 20 and 24 °C until the platelets are separated. The platelet concentrate shall be separated within 4 hours after the collection of the unit of whole blood or plasma.</P> <P>(c) The time and speed of centrifugation must have been demonstrated to produce an unclumped product, without visible hemolysis, that yields a count of not less than 5.5×10<E T="21"> 1</E> <E T="21"> 0</E> platelets per unit in at least 75 percent of the units tested.</P> <P>(d) The volume of original plasma used for resuspension of the platelets shall be determined by the maintenance of a pH of not less than 6.0 during the storage period. The pH shall be measured on a sample of platelets which has been stored for the maximum dating period at the selected storage temperature. One of the following storage temperatures shall be used continuously:</P> <P>(1) 20 to 24 °C.</P> <P>(2) 1 to 6 °C.</P> <P>(e) Final containers used for Platelets shall be colorless and transparent to permit visual inspection of the contents; any closure shall maintain a hermetic seal and prevent contamination of the contents. The container material shall not interact with the contents, under the customary conditions of storage and use, in such a manner as to have an adverse effect upon the safety, purity, potency, or efficacy of the product. At the time of filling, the final container shall be marked or identified by number so as to relate it to the donor.</P> <CITA>[40 FR 4304, Jan. 29, 1975, as amended at 42 FR 10983, Feb. 25, 1977; 47 FR 49021, Oct. 29, 1982; 50 FR 4139, Jan. 29, 1985; 63 FR 16685, Apr. 6, 1998]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.25</SECTNO> <SUBJECT>General requirements.</SUBJECT> <P>(a) <E T="03">Storage</E>. Immediately after resuspension, Platelets shall be placed in storage at the selected temperature range. If stored at 20 to 24 °C, a continuous gentle agitation of the platelet concentrate shall be maintained throughout the storage period. Agitation is optional if stored at a temperature between 1 and 6 °C.</P> <P>(b) <E T="03">Quality control testing.</E> Each month four units prepared from different donors shall be tested at the end of the storage period as follows:</P> <P>(1) Platelet count.</P> <P>(2) pH of not less than 6.0 measured at the storage temperature of the unit.</P> <P>(3) Measurement of actual plasma volume.</P> <P>(4) If the results of the quality control testing indicate that the product does not meet the prescribed requirements, immediate corrective action shall be taken and a record maintained of such action.</P> <P>(c) <E T="03">Manufacturing responsibility.</E> All manufacturing of Platelets shall be performed at the same licensed establishment, except that the quality control testing under paragraph (b) of this section may be performed by a clinical laboratory which meets the standards of the Clinical Laboratories Improvement Act of 1967 (CLIA) (42 U.S.C. 263a) and is qualified to perform platelet counts. Such arrangements must be approved by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration. Such testing shall not be considered as divided manufacturing, as described in § 610.63 of <PRTPAGE P="87"/>this chapter, provided the following conditions are met:</P> <P>(1) The results of each test are received within 10 days of the preparation of the platelet concentrate, and are maintained by the establishment licensed for Platelets so that they may be reviewed by an authorized representative of the Food and Drug Administration.</P> <P>(2) The licensed Platelets manufacturer has obtained a written agreement that the testing laboratory will permit an authorized representative of the Food and Drug Administration to inspect its testing procedures and facilities during reasonable business hours.</P> <P>(3) The testing laboratory will participate in any proficiency testing programs undertaken by the Center for Biologics Evaluation and Research, Food and Drug Administration.</P> <CITA>[40 FR 4304, Jan. 29, 1975, as amended at 47 FR 49021, Oct. 29, 1982; 49 FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.27</SECTNO> <SUBJECT>Emergency provisions.</SUBJECT> <P>The use of the plateletpheresis procedure to obtain a product for a specific recipient may be at variance with §§ 640.21(c) and 640.22(c): <E T="03">Provided,</E> That: (a) A licensed physician has determined that the recipient must be transfused with the platelets from a specific donor, and (b) the plateletpheresis procedure is performed under the supervision of a qualified licensed physician who is aware of the health status of the donor and the physician has certified in writing that the donor's health permits plateletpheresis.</P> <CITA>[40 FR 53544, Nov. 18, 1975]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart D—Plasma</HD> <SECTION> <SECTNO>§ 640.30</SECTNO> <SUBJECT>Plasma.</SUBJECT> <P>(a) <E T="03">Proper name and definition.</E> The proper name of this product shall be Plasma. The product is defined as the fluid portion of one unit of human blood intended for intravenous use which in a closed system, has been collected, stabilized against clotting, and separated from the red blood cells.</P> <P>(b) <E T="03">Source.</E> (1) Plasma shall be obtained by separating plasma from blood collected from blood donors or by plasmapheresis.</P> <P>(2) Plasma may be obtained from a unit of Whole Blood collected by another licensed establishment.</P> <CITA>[42 FR 59878, Nov. 22, 1977; 48 FR 13026, Mar. 29, 1983, as amended at 50 FR 4139, Jan. 29, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.31</SECTNO> <SUBJECT>Suitability of donors.</SUBJECT> <P>(a) Whole blood donors shall meet the criteria for donor suitability prescribed in § 640.3.</P> <P>(b) Plasmapheresis donors shall meet the criteria for donor suitability prescribed in § 640.63, excluding the phrase “other than malaria” in paragraph (c)(9) of that section. Informed consent shall be required as prescribed in § 640.61.</P> <P>(c) Donors shall not be suitable if they are known to have been immunized within the past 6 months by injection with human red blood cells.</P> <CITA>[42 FR 59878, Nov. 22, 1977]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.32</SECTNO> <SUBJECT>Collection of source material.</SUBJECT> <P>(a) Whole blood shall be collected, transported, and stored as prescribed in § 640.4, except that paragraphs (d)(2) and (h) of that section shall not apply. When whole blood is intended for Plasma, Fresh Frozen Plasma, and Liquid Plasma, it shall be maintained at a temperature between 1 and 6 °C until the plasma is removed. Whole blood intended for Platelet Rich Plasma, shall be maintained as prescribed in § 640.24 until the plasma is removed. The red blood cells shall be placed in storage at a temperature between 1 and 6 °C immediately after the plasma is separated.</P> <P>(b) Plasma obtained by plasmapheresis shall be collected as prescribed in §§ 640.62, 640.64 (except that paragraph (c)(3) of § 640.64 shall not apply), and § 640.65.</P> <CITA>[42 FR 59878, Nov. 22, 1977, as amended at 45 FR 27927, Apr. 25, 1980; 50 FR 4139, Jan. 29, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.33</SECTNO> <SUBJECT>Testing the blood.</SUBJECT> <P>(a) Blood from which plasma is separated shall be tested as prescribed in §§ 610.40 and 610.45 of this chapter and § 640.5 (a), (b), and (c).<PRTPAGE P="88"/> </P> <P>(b) Manufacturers of Plasma collected by plasmapheresis shall have testing and recordkeeping responsibilities equivalent to those prescribed in §§ 640.71 and 640.72.</P> <CITA>[42 FR 59878, Nov. 22, 1977, as amended at 44 FR 17658, Mar. 23, 1979; 50 FR 4139, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.34</SECTNO> <SUBJECT>Processing.</SUBJECT> <P>(a) <E T="03">Plasma.</E> Plasma shall be separated from the red blood cells within 26 days after phlebotomy (within 40 days after phlebotomy when CPDA-1 solution is used as the anticoagulant), and shall be stored at <E T="02">−</E>18 °C or colder within 6 hours after transfer to the final container, unless the product is to be stored as Liquid Plasma .</P> <P>(b) <E T="03">Fresh Frozen Plasma.</E> Fresh Frozen Plasma shall be prepared from blood collected by a single uninterrupted venipuncture with minimal damage to and minimal manipulation of the donor's tissue. The plasma shall be separated from the red blood cells, frozen solid within 6 hours after phlebotomy, and stored at −18 °C or colder.</P> <P>(c) <E T="03">Liquid Plasma.</E> Liquid Plasma shall be separated from the red blood cells within 26 days after phlebotomy (within 40 days after phlebotomy when CPDA-1 solution is used as the anticoagulant) and shall be stored at a temperature of 1 to 6 °C within 4 hours after filling the final container.</P> <P>(d) <E T="03">Platelet Rich Plasma.</E> Platelet Rich Plasma shall be prepared from blood collected by a single uninterrupted venipuncture with minimal damage to and manipulation of the donor's tissue. The plasma shall be separated from the red blood cells by centrifugation within 4 hours after phlebotomy. The time and speed of centrifugation shall have been shown to produce a product with at least 250,000 platelets per microliter. The plasma shall be stored at a temperature between 20 to 24 °C or between 1 and 6 °C, immediately after filling the final container. A gentle and continuous agitation of the product shall be maintained throughout the storage period, if stored at a temperature of 20 to 24 °C.</P> <P>(e) <E T="03">Modifications of Plasma.</E> It is possible to separate Platelets and/or Cryoprecipitated AHF from Plasma. When these components are to be separated, the plasma shall be collected as described in § 640.32 for Plasma.</P> <P>(1) Platelets shall be separated as prescribed in subpart C of part 640, prior to freezing the plasma. The remaining plasma may be labeled as Fresh Frozen Plasma, if frozen solid within 6 hours after phlebotomy.</P> <P>(2) Cryoprecipitated AHF shall be removed as prescribed in Subpart F of part 640. The remaining plasma may be labeled Plasma.</P> <P>(3) Plasma remaining after both Platelets and Cryoprecipitated AHF have been removed may be labeled Plasma.</P> <P>(f) <E T="03">The final container.</E> (1) The final container shall have no color added to the plastic and shall be transparent to permit visual inspection of the contents; any closure shall maintain a hermetic seal and prevent contamination of the contents.</P> <P>(2) The final container material shall not interact with the contents, under the customary conditions of storage and use, in such a manner as to have an adverse effect upon the safety, purity, potency, and effectiveness of the product.</P> <P>(3) Prior to filling, the final container shall be identified by number so as to relate it to the donor.</P> <P>(g) <E T="03">The final product.</E> (1) The final product shall be inspected immediately after separation of the plasma and shall not be issued for transfusion if there is (i) any abnormality in color or physical appearance, or (ii) any indication of contamination.</P> <P>(2) With the exception of Platelet Rich Plasma and Liquid Plasma, the final product shall be stored in a manner that will show evidence of thawing and shall not be issued if there is any evidence of thawing of the product during storage or breakage of the container.</P> <P>(3) No preservative shall be added to the final product.</P> <CITA>[42 FR 59878, Nov. 22, 1977, as amended at 43 FR 34460, Aug. 4 1978; 48 FR 13026, Mar. 29, 1983; 50 FR 4139, Jan. 29, 1985]</CITA> </SECTION> </SUBPART> <SUBPART> <PRTPAGE P="89"/> <HD SOURCE="HED">Subpart E[Reserved]</HD> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart F—Cryoprecipitate</HD> <SECTION> <SECTNO>§ 640.50</SECTNO> <SUBJECT>Cryoprecipitated AHF.</SUBJECT> <P>(a) <E T="03">Proper name and definition.</E> The proper name of this product shall be Cryoprecipitated AHF. The product is defined as a preparation of antihemophilic factor, which is obtained from a single unit of plasma collected and processed in a closed system.</P> <P>(b) <E T="03">Source.</E> The source material for Cryoprecipitated AHF shall be plasma which may be obtained by whole blood collection or by plasmapheresis.</P> <CITA>[42 FR 21774, Apr. 29, 1977; 48 FR 13026, Mar. 29, 1983; as amended at 50 FR 4139, Jan. 29, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.51</SECTNO> <SUBJECT>Suitability of donors.</SUBJECT> <P>(a) Whole blood donors shall meet the criteria for suitability prescribed in § 640.3.</P> <P>(b) Plasmaphersis donors shall meet the criteria for suitability prescribed in § 640.63, excluding the phrase “other than malaria” in paragraph (c) (9) of that section. Informed consent shall be required as prescribed in § 640.61.</P> <P>(c) Donors shall not be suitable if they are known to have been immunized by injection with human red blood cells within the last 6 months.</P> <CITA>[42 FR 21774, Apr. 29, 1977]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.52</SECTNO> <SUBJECT>Collection of source material.</SUBJECT> <P>(a) Whole blood used as a source of Cryoprecipitated AHF shall be collected as prescribed in § 640.4, except that paragraphs (d) (2), (g), and (h) of that section shall not apply. Whole blood from which both Platelets and Cryoprecipitated AHF is derived shall be maintained as required under § 640.24 until the platelets are removed.</P> <P>(b) If plasmapheresis is used, the procedure for collection shall be as prescribed in §§ 640.62, 640.64 (except that paragraph (c)(3) of that section shall not apply), and 640.65.</P> <CITA>[42 FR 21774, Apr. 29, 1977, as amended by 50 FR 4139, Jan. 29, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.53</SECTNO> <SUBJECT>Testing the blood.</SUBJECT> <P>(a) Blood from which plasma is separated for the preparation of Cryoprecipitated AHF shall be tested as prescribed in §§ 610.40 and 610.45 of this chapter and § 640.5 (a), (b), and (c).</P> <P>(b) The tests shall be performed on a sample of blood collected at the time of collecting the source blood, and such sample container shall be labeled with the donor's number before the container is filled.</P> <P>(c) Manufacturers of Cryoprecipitated AHF obtained from plasma collected by plasmapheresis shall have testing and record-keeping responsibilities equivalent to those prescribed in §§ 640.71 and 640.72.</P> <CITA>[42 FR 21774, Apr. 29, 1977, as amended at 42 FR 37546, July 22, 1977; 42 FR 43063, Aug. 26, 1977; 50 FR 4139, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.54</SECTNO> <SUBJECT>Processing.</SUBJECT> <P>(a) <E T="03">Processing the plasma.</E> (1) The plasma shall be separated from the red blood cells by centrifugation to obtain essentially cell-free plasma.</P> <P>(2) The plasma shall be frozen solid within 6 hours after blood collection. A combination of dry ice and organic solvent may be used for freezing: <E T="03">Provided,</E> That the procedure has been shown not to cause the solvent to penetrate the container or leach plasticizer from the container into the plasma.</P> <P>(3) Immediately after separation and freezing of the plasma, the plasma shall be stored and maintained at −18 °C or colder until thawing of the plasma for further processing to remove the Cryoprecipitated AHF.</P> <P>(b) <E T="03">Processing the final product.</E> (1) The Cryoprecipitated AHF shall be separated from the plasma by a procedure that has been shown to produce an average of no less than 80 units of antihemophilic factor per final container.</P> <P>(2) No diluent shall be added to the product by the manufacturer prior to freezing.</P> <P>(3) The final container used for Cryoprecipitated AHF shall be colorless and transparent to permit visual inspection of the contents; any closure shall maintain a hermetic seal and prevent contamination of the contents. <PRTPAGE P="90"/>The container material shall not interact with the contents under customary conditions of storage and use in such a manner as to have an adverse effect upon the safety, purity, potency and effectiveness of the product. At the time of filling, the final container shall be identified by a number so as to relate it to the donor.</P> <CITA>[42 FR 21774, Apr. 29, 1977, as amended at 47 FR 15330, Apr. 9, 1982; 50 FR 4139, Jan. 29, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.55</SECTNO> <SUBJECT>U.S. Standard preparation.</SUBJECT> <P>A U.S. Standard Antihemophilic Factor (Factor VIII) preparation may be obtained from the Center for Biologics Evaluation and Research, Food and Drug Administration, for use in the preparation of a working reference to be employed in a quality control potency test of Cryoprecipitated AHF.</P> <CITA>[42 FR 21774, Apr. 29, 1977, as amended at 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.56</SECTNO> <SUBJECT>Quality control test for potency.</SUBJECT> <P>(a) Quality control tests for potency of antihemophilic factor shall be conducted each month on at least four representative containers of Cryoprecipitated AHF.</P> <P>(b) The results of each test are received by the establishment licensed for Cryoprecipitated AHF within 30 days of the preparation of the cryoprecipitated antihemophilic factor and are maintained at that establishment so that they may be reviewed by an authorized representative of the Food and Drug Administration.</P> <P>(c) The quality control test for potency may be performed by a clinical laboratory which meets the standards of the Clinical Laboratories Improvement Act of 1967 (CLIA) (42 U.S.C. 263a) and is qualified to perform potency tests for antihemophilic factor. Such arrangements must be approved by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration. Such testing shall not be considered as divided manufacturing, as described in § 610.63 of this chapter, provided the following conditions are met:</P> <P>(1) The establishment licensed for Cryoprecipitated AHF has obtained a written agreement that the testing laboratory will permit an authorized representative of the Food and Drug Administration to inspect its testing procedures and facilities during reasonable business hours.</P> <P>(2) The testing laboratory will participate in any proficiency testing programs undertaken by the Center for Biologics Evaluation and Research, Food and Drug Administration.</P> <P>(d) If the average potency level of antihemophilic factor in the containers tested is less than 80 units of antihemophilic factor per container, immediate corrective actions shall be taken and a record maintained of such action.</P> <CITA>[42 FR 21774, Apr. 29, 1977, as amended at 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart G—Source Plasma</HD> <SECTION> <SECTNO>§ 640.60</SECTNO> <SUBJECT>Source Plasma.</SUBJECT> <P>The proper name of the product shall be Source Plasma. The product is defined as the fluid portion of human blood collected by plasmapheresis and intended as source material for further manufacturing use. The definition excludes single donor plasma products intended for intravenous use.</P> <CITA>[41 FR 10768, Mar. 12, 1976, as amended at 50 FR 4140, Jan. 29, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.61</SECTNO> <SUBJECT>Informed consent.</SUBJECT> <P>The written consent of a prospective donor shall be obtained after a qualified licensed physician has explained the hazards of the procedure to the prospective donor. The explanation shall include the risks of a hemolytic transfusion reaction if he is given the cells of another donor, and the hazards involved if he is hyperimmunized. The explanation shall consist of such disclosure and be made in such a manner that intelligent and informed consent be given and that a clear opportunity to refuse is presented.</P> </SECTION> <SECTION> <SECTNO>§ 640.62</SECTNO> <SUBJECT>Medical supervision.</SUBJECT> <P>A qualified licensed physician shall be on the premises when donor suitability is being determined, immunizations are being made, whole blood is <PRTPAGE P="91"/>being collected, and red blood cells are being returned to the donor.</P> </SECTION> <SECTION> <SECTNO>§ 640.63</SECTNO> <SUBJECT>Suitability of donor.</SUBJECT> <P>(a) <E T="03">Method of determining.</E> The suitability of a donor for Source Plasma shall be determined by a qualified licensed physician or by persons under his supervision and trained in determining donor suitability. Such determination shall be made on the day of collection from the donor by means of a medical history, tests, and such physical examination as appears necessary to the qualified licensed physician.</P> <P>(b) <E T="03">Initial medical examinations.</E> (1) Each donor shall be examined by a qualified licensed physician on the day of the first donation or no more than 1 week before the first donation and at subsequent intervals of no longer than 1 year.</P> <P>(2)(i) A donor who is to be immunized for the production of high-titer plasma shall be examined by a qualified licensed physician. The medical examination shall be performed within no more than 1 week before the first immunization injection. The medical examination for plasmapheresis need not be repeated, if the first donation occurs within 3 weeks after the first injection.</P> <P>(ii) A donor who is an active participant in a plasmapheresis program, and has been examined in accordance with paragraph (b)(1) of this section, need not be reexamined before immunization for the production of high-titer plasma.</P> <P>(3) Each donor shall be certified to be in good health by the examining physician. The certification of good health shall be on a form supplied by the licensed establishment and shall indicate that the certification applies to the suitability of the individual to be a plasmapheresis donor and, when applicable, an immunized donor.</P> <P>(c) <E T="03">Qualification of donor.</E> Donors shall be in good health on the day of donation, as indicated in part by:</P> <P>(1) Normal temperature;</P> <P>(2) Demonstration that systolic and diastolic blood pressures are within normal limits, unless the examining physician is satisfied that an individual with blood pressures outside these limits is an otherwise qualified donor under the provisions of this section;</P> <P>(3) A blood hemoglobin level of no less than 12.5 grams of hemoglobin per 100 milliliters of blood;</P> <P>(4) A normal pulse rate;</P> <P>(5) A total serum protein of no less than 6.0 grams per 100 milliliters of serum;</P> <P>(6) Weight, which shall be at least 110 pounds;</P> <P>(7) Freedom from acute respiratory diseases;</P> <P>(8) Freedom from any infectious skin disease at the site of phlebotomy and from any such disease generalized to such an extent as to create a risk of contamination of the plasma;</P> <P>(9) Freedom from any disease, other than malaria, transmissible by blood transfusion, insofar as can be determined by history and examinations indicated in this section;</P> <P>(10) Freedom of the arms and forearms from skin punctures or scars indicative of addiction to self-injected narcotics;</P> <P>(11) Freedom from a history of viral hepatitis;</P> <P>(12) Freedom from a history of close contact within six months of donation with an individual having viral hepatitis;</P> <P>(13) Freedom from a history of having received, within six months, human blood or any derivative of human blood which the Food and Drug Administration has advised the licensed establishment is a possible source of viral hepatitis, except for specific immunization performed in accordance with § 640.66 of this part.</P> <P>(d) <E T="03">General.</E> Any donor who, in the opinion of the interviewer, appears to be under the influence of any drug, alcohol, or for any reason does not appear to be providing reliable answers to medical history questions, shall not be considered a suitable donor.</P> <P>(e) <E T="03">Failure to return red blood cells.</E> Any donor who has not had the red blood cells returned from a unit of blood collected during a plasmapheresis procedure or who has been a donor of a unit of whole blood shall not be subjected to plasmapheresis for a period of 8 weeks, unless:<PRTPAGE P="92"/> </P> <P>(1) The donor has been examined by a qualified licensed physician and certified by the physician to be acceptable for further plasmapheresis before expiration of the 8-week period;</P> <P>(2) The donor possesses an antibody that is (i) transitory, (ii) of a highly unusual or infrequent specificity, or (iii) of an unusually high titer; and</P> <P>(3) The special characteristics of the antibody and the need for plasmapheresing the donor are documented.</P> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10768, Mar. 12, 1976; 43 FR 9805, Mar. 10, 1978; 43 FR 12311, Mar. 24, 1978; 46 FR 57480, Nov. 24, 1981; 50 FR 4140, Jan. 29, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.64</SECTNO> <SUBJECT>Collection of blood for Source Plasma.</SUBJECT> <P>(a) <E T="03">Supervision.</E> All blood for the collection of Source Plasma shall be drawn from the donor by a qualified licensed physician or by persons under his supervision trained in the procedure.</P> <P>(b) <E T="03">Blood containers.</E> Blood containers and donor sets shall be pyrogen-free, sterile and identified by lot number. The amount of anticoagulant required for the quantity of blood to be collected shall be in the blood container when it is sterilized.</P> <P>(c) <E T="03">The anticoagulant solution.</E> The anticoagulant solution shall be sterile and pyrogen-free. One of the following formulas shall be used in the indicated volumes, except that a different formula may be used for plasma for manufacture into noninjectable products if prior written approval is obtained from the Director of the Center for Biologics Evaluation and Research at the time of licensing or in the form of a supplement to the Source Plasma product license.</P> <P>(1) <E T="03">Anticoagulant citrate dextrose solution (ACD).</E> </P> <GPOTABLE CDEF="s50,xs48" COLS="2" OPTS="L0,6/7,g1,t1"> <ROW> <ENT I="01">Tri-sodium citrate (Na<E T="22">3</E> <E T="31">C</E> <E T="22">6</E> <E T="31">H</E> <E T="22">5</E> <E T="31">O</E> <E T="22">7</E> <E T="01">·</E> <E T="31">2H</E> <E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>22.0 grams.</ENT> </ROW> <ROW> <ENT I="01">Citric acid (C<E T="22">6</E> <E T="31">H</E> <E T="22">8</E> <E T="31">O</E> <E T="22">7</E> <E T="01">·</E> <E T="31">H</E> <E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>8.0 grams.</ENT> </ROW> <ROW> <ENT I="01">Dextrose (C<E T="22">6</E> <E T="31">H</E> <E T="22">1</E> <E T="22">2</E> <E T="31">O</E> <E T="22">6</E> <E T="31">H</E> <E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>24.5 grams.</ENT> </ROW> <ROW> <ENT I="01">Water for injection (U.S.P.) to make</ENT> <ENT>1,000 milliliters.</ENT> </ROW> <ROW> <ENT I="01">Volume per 100 milliliters blood</ENT> <ENT>15 milliliters.</ENT> </ROW> </GPOTABLE> <P>(2) <E T="03">Anticoagulant citrate phosphate dextrose solution (CPD).</E> </P> <GPOTABLE CDEF="s50,xs48" COLS="2" OPTS="L0,6/7,g1,t1"> <ROW> <ENT I="01">Tri-sodium citrate (Na<E T="22">3</E> <E T="31">C</E> <E T="22">6</E> <E T="31">H</E> <E T="22">5</E> <E T="31">O</E> <E T="22">7</E> <E T="01">·</E> <E T="31">2H</E> <E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>26.3 grams.</ENT> </ROW> <ROW> <ENT I="01">Citric acid (C<E T="22">6</E> <E T="31">H</E> <E T="22">8</E> <E T="31">O</E> <E T="22">7</E> <E T="21">·</E> <E T="31">H</E> <E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>3.27 grams.</ENT> </ROW> <ROW> <ENT I="01">Dextrose (C<E T="22">6</E> <E T="31">H</E> <E T="22">1</E> <E T="22">2</E> <E T="31">O</E> <E T="22">6</E> <E T="31">H</E> <E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>25.5 grams.</ENT> </ROW> <ROW> <ENT I="01">Monobasic sodium phosphate (NaH<E T="22">2</E> <E T="31">PO</E> <E T="22">4</E> <E T="01">·</E> <E T="31">H</E> <E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>2.22 grams.</ENT> </ROW> <ROW> <ENT I="01">Water for injection (U.S.P.) to make</ENT> <ENT>1,000 milliliters.</ENT> </ROW> <ROW> <ENT I="01">Volume per 100 milliliters blood</ENT> <ENT>14 milliliters.</ENT> </ROW> </GPOTABLE> <P>(3) <E T="03">Anticoagulant sodium citrate solution.</E> </P> <GPOTABLE CDEF="s50,xs48" COLS="2" OPTS="L0,6/7,g1,t1"> <ROW> <ENT I="01">Tri-sodium citrate (Na<E T="22">3</E> <E T="31">C</E> <E T="22">6</E> <E T="31">H</E> <E T="22">5</E> <E T="31">O</E> <E T="22">7</E> <E T="01">·</E> <E T="31">2H</E> <E T="22">2</E> <E T="31">O)</E> </ENT> <ENT>40 grams.</ENT> </ROW> <ROW> <ENT I="01">Water for injection (U.S.P.) to make</ENT> <ENT>1,000 milliliters.</ENT> </ROW> <ROW> <ENT I="01">Volume per 100 milliliters of blood</ENT> <ENT>10 milliliters.</ENT> </ROW> </GPOTABLE> <P>(d) <E T="03">Donor identification.</E> Each unit of blood and plasma shall be so marked or identified by number or other symbol so as to relate it directly to the donor.</P> <P>(e) <E T="03">Prevention of contamination of the blood and plasma.</E> The skin of the donor at the site of phlebotomy shall be prepared thoroughly and carefully by a method that gives maximum assurance of a sterile container of blood. The blood shall be collected, the plasma separated, and the cells returned to the donor by aseptic methods in a sterile system which may be closed, or may be vented if the vent protects the blood cells and plasma against contamination.</P> <CITA>[38 FR 32089, Nov. 20, 1973; 39 FR 13632, Apr. 16, 1974, as amended at 41 FR 10768, Mar. 12, 1976; 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 63 FR 16685, Apr. 6, 1998]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.65</SECTNO> <SUBJECT>Plasmapheresis.</SUBJECT> <P>(a) <E T="03">Procedure-general.</E> The plasmapheresis procedure is a procedure in which, during a single visit to the establishment, blood is removed from a donor, the plasma separated from the formed elements, and at least the red blood cells returned to the donor. This procedure shall be described in detail in the product license application.</P> <P>(b) <E T="03">Procedures-specific requirements.</E> The plasmapheresis procedure shall meet the following requirements:</P> <P>(1)(i) A sample of blood shall be drawn from each donor on the day of the first medical examination or plasmapheresis, whichever comes first and at least every 4 months thereafter by a qualified licensed physician or by persons under his supervision and trained in such procedure. A serologic test for syphilis, a total plasma or serum protein determination, and a plasma or serum protein electrophoresis or quantitative immuno-diffusion test or an <PRTPAGE P="93"/>equivalent test to determine immunoglobulin composition of the plasma or serum shall be performed on the sample.</P> <P>(ii) A repeat donor who does not return for plasmapheresis at the time the 4-month sample is due to be collected may be plasmapheresed on the day he appears: <E T="03">Provided,</E> That no longer than 6 months has elapsed since the last sample was collected, and the physician on the premises approves the plasmapheresis procedure and so indicates by signing the donor's record before such procedure is performed. The sample for the 4-month tests shall be collected on the day of the donor's return.</P> <P>(iii) A repeat donor from whom the plasmapheresis center is unable to obtain a sample for testing as prescribed in paragraph (b)(1)(i) of this section for a total period exceeding 6 months shall be processed as a new donor.</P> <P>(2)(i) The accumulated laboratory data, including tracings, if any, of the plasma or serum protein electrophoresis pattern, the calculated values of each component, and the collection records shall be reviewed by a qualified licensed physician within 21 days after the sample is drawn to determine whether or not the donor may continue in the program. The review shall be signed by the reviewing physician. If the protein composition is not within normal limits established by the testing laboratory, or if the total protein is less than 6.0 grams per 100 milliliters of samples, the donor shall be removed from the program until these values return to normal.</P> <P>(ii) A donor with a reactive serologic test for syphilis shall not be plasmapheresed again until the donor's serum is tested and found to be nonreactive to a serologic test for syphilis, except as provided in paragraph (b)(2) (iii) and (iv) of this section.</P> <P>(iii) A donor whose serum is determined to have a biologic false-positive reaction to a serologic test for syphilis may be plasmapheresed: <E T="03">Provided,</E> That the donor's file identifies the serologic test for syphilis and results used to confirm the biologic false-positive reaction and indicates that the physician on the premises has determined the false-positive reaction is not the result of an underlying disorder that would disqualify the donor from participation in the plasmapheresis program. If the serologic test for syphilis is performed at a facility other than the plasmapheresis center, all applicable provisions of § 640.71 shall be met.</P> <P>(iv) A donor with a reactive serologic test for syphilis may be plasmapheresed only to obtain plasma to be used for further manufacturing into control serum for the serologic test for syphilis: <E T="03">Provided,</E> That the physician on the premises approves the donation, the donor's file contains a signed statement from a physician or clinic establishing that treatment for syphilis has been initiated and that continuance in the plasmapheresis program will not interfere with or jeopardize the treatment of the syphilitic donor.</P> <P>(3) A donor identification system shall be established that positively identifies each donor and relates such donor directly to his blood and its components as well as to his accumulated records and laboratory data. Such system shall include either a photograph of each donor which shall be used on each visit to confirm the donor's identity, or some other method that provides equal or greater assurance of positively identifying the donor.</P> <P>(4) The amount of whole blood, not including anticoagulant, removed from a donor during a plasmapheresis procedure or in any 48-hour period shall not exceed 1,000 milliliters unless the donor's weight is 175 pounds or greater, in which case the amount of whole blood, not including anticoagulant, removed from the donor during a plasmapheresis procedure or in any 48-hour period shall not exceed 1,200 milliliters.</P> <P>(5) The amount of whole blood, not including anticoagulant, removed from a donor within a seven-day period shall not exceed 2,000 milliliters unless the donor's weight is 175 pounds or greater, in which case the amount of whole blood, not including anticoagulant, removed from the donor during a seven-day period shall not exceed 2,400 milliliters.</P> <P>(6) No more than 500 milliliters of whole blood shall be removed from a donor at one time, unless the donor's weight is 175 pounds or greater, in which case no more than 600 milliliters <PRTPAGE P="94"/>of whole blood shall be removed from the donor at one time.</P> <P>(7) The plasma shall be separated from the red blood cells immediately after blood collection. The maximum feasible volume of red blood cells shall be returned to the donor before another unit is collected.</P> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.66</SECTNO> <SUBJECT>Immunization of donors.</SUBJECT> <P>If specific immunization of a donor is to be performed, the selection and scheduling of the injection of the antigen, and the evaluation of each donor's clinical response, shall be by a qualified licensed physician or physicians. The administration of the antigen may be performed by a licensed physician or a trained person under his supervision. Any material used for immunization shall be either a product licensed under section 351 of the Public Health Service Act for such purpose or one specifically approved by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration. Immunization procedures shall be on file at each plasmapheresis center where immunizations are performed.</P> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.67</SECTNO> <SUBJECT>Laboratory tests.</SUBJECT> <P>(a) <E T="03">Hepatitis B surface antigen.</E> Each unit of Source Plasma shall be nonreactive to a test for hepatitis B surface antigen as prescribed in §§ 610.40 and 610.41 of this chapter, except insofar as permitted in § 610.40(d)(1) and (d)(2) of this chapter.</P> <P>(b) <E T="03">Antibody to HIV.</E> Each unit of Source Plasma shall be negative by a test for antibody to HIV as prescribed in § 610.45 of this chapter, except as provided in § 610.45(c) of this chapter.</P> <CITA>[53 FR 117, Jan. 5, 1988, as amended at 57 FR 10814, Mar. 31, 1992]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.68</SECTNO> <SUBJECT>Processing.</SUBJECT> <P>(a) <E T="03">Sterile system.</E> All administration and transfer sets inserted into blood containers used for processing Source Plasma intended for manufacturing into injectable or noninjectable products and all interior surfaces of plasma containers used for processing Source Plasma intended for manufacturing into injectable products shall be sterile, pyrogen-free, nontoxic, and compatible with the contents under normal conditions of use. Only Sodium Chloride Injection USP shall be used as a red blood cell diluent. If the method of separation of the plasma intended for injectable products involves a system in which an airway must be inserted into the plasma container, the airway shall be sterile and constructed so as to exclude microorganisms and maintain a sterile system.</P> <P>(b) <E T="03">Final containers.</E> Final containers used for Source Plasma, whether integrally attached or separated from the original blood container, shall not be entered prior to issuance for any purpose except for filling with the plasma. Such containers shall be uncolored and hermetically sealed, and shall permit clear visibility of the contents. Final containers and their components shall not interact with the plasma contents under conditions of storage and use so as to alter the safety, quality, purity, or potency of the plasma and shall provide adequate protection against external factors that may cause deterioration or contamination. Prior to filling, the final container shall be marked or identified by number or other symbol which will relate it directly to the donor.</P> <P>(c) <E T="03">Preservative.</E> Source Plasma shall not contain a preservative.</P> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976; 50 FR 4140, Jan. 29, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.69</SECTNO> <SUBJECT>General requirements.</SUBJECT> <P>(a) <E T="03">Pooling.</E> Two units of Source Plasma from the same donor may be pooled if such units are collected during one plasmapheresis procedure: <E T="03">Provided,</E> That the pooling is done by a procedure that does not introduce a risk of contamination of the red blood cells and, for plasma intended for injectable products, gives maximum assurance of a sterile container of plasma.</P> <P>(1) The pooling of plasma from two or more donors is not permitted in the manufacture of Source Plasma intended for manufacturing into injectable products.<PRTPAGE P="95"/> </P> <P>(2) The pooling of plasma from two or more donors by the manufacturer of Source Plasma intended for manufacturing into noninjectable products is permitted: <E T="03">Provided,</E> That the plasma from two or more donors is pooled after the plasma has been removed from the red blood cells, and after the red blood cell containers are sealed.</P> <P>(b) <E T="03">Storage.</E> Immediately after filling, plasma intended for manufacturing into injectable products shall be stored at a temperature not warmer than −20 °C, except for plasma collected as provided in § 640.74. Plasma intended for manufacturing into noninjectable products may be stored at temperatures appropriate for the intended use of the final product, provided these temperatures are included in the Source Plasma license application.</P> <P>(c) <E T="03">Inspection.</E> Source Plasma intended for manufacturing into injectable products shall be inspected for evidence of thawing at the time of issuance, except that inspection of individual plasma containers need not be made if the records of continuous monitoring of the storage temperature establish that the temperature remained at −20 °C or colder. If there is evidence that the storage temperature has not been maintained at −20 °C or colder, the plasma may be relabeled and issued as provided in § 640.76(a).</P> <P>(d) <E T="03">Pilot samples.</E> If pilot samples are provided, they shall meet the following standards:</P> <P>(1) Prior to filling, all pilot samples shall be marked or identified so as to relate them directly to the donor of that unit of plasma.</P> <P>(2) All pilot samples shall be filled at the time the final product is prepared by the person who prepares the final product.</P> <P>(3) All pilot samples shall be representative of the contents of the final product.</P> <P>(4) All pilot samples shall be collected in a manner that does not contaminate the contents of the final container.</P> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976; 41 FR 14367, Apr. 5, 1976; 50 FR 4140, Jan. 29, 1985; 63 FR 16685, Apr. 6, 1998]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.70</SECTNO> <SUBJECT>Labeling.</SUBJECT> <P>(a) In addition to the labeling requirements of § 610.62 of this chapter, and in lieu of the requirements in §§ 606.121, 610.60, and 610.61 of this chapter, the following information shall appear on the label affixed to each container of Source Plasma:</P> <P>(1) The proper name of the product.</P> <P>(2) The statement “Caution: For Manufacturing Use Only” for products intended for further manufacturing into injectable products, or the statement, “Caution: For Use In Manufacturing Noninjectable Products Only”, for products intended for further manufacturing into noninjectable products. The statement shall follow the proper name in the same size and type of print as the proper name.</P> <P>(3) The statement “Store at −20 °C or colder”: <E T="03">Provided,</E> That where plasma is intended for manufacturing into noninjectable products, this statement may be omitted if replaced by a statement of the temperature appropriate for the final product to be prepared from the plasma.</P> <P>(4) The total volume or weight of plasma and total quantity and type of anticoagulant used.</P> <P>(5) The donor number or individual bleed number, or both. If plasma is pooled from two or more donors, either all donor numbers, all bleed numbers, or a pool number that is traceable to each individual unit comprising the pool.</P> <P>(6) The expiration date of the plasma. If plasma intended for manufacturing into noninjectable products is pooled from two or more donors the expiration date is determined from the collection date of the oldest unit in the pool, and the pooling records shall show the collection date for each unit constituting the pool.</P> <P>(7) A statement as to whether the plasma was collected from normal donors or from immunized donors. In the case of immunized donors, the label shall state the immunizing antigen.</P> <P>(8) The test for hepatitis B surface antigen used for the results, or the statement “Nonreactive for HB<E T="22">s</E> Ag by FDA required test”.</P> <P>(9) When plasma collected from a donor is reactive for the serologic test <PRTPAGE P="96"/>for syphilis, a statement that the plasma is reactive and must be used only for the manufacturing of positive control reagents for the serologic test for syphilis.</P> <P>(10) Name, address, and license number of the manufacturer.</P> <P>(11) The statement “Negative by a test for antibody to HIV”, or equivalent statement.</P> <P>(b) Source Plasma diverted for Source Plasma Salvaged shall be relabeled “Source Plasma Salvaged” as prescribed in § 640.76. Immediately following the proper name of the product, the labeling shall conspicuously state as applicable, “STORAGE TEMPERATURE EXCEEDED −20 °C” or “SHIPPING TEMPERATURE EXCEEDED −5 °C”.</P> <CITA>[41 FR 10770, Mar. 12, 1976, as amended at 41 FR 27034, July 1, 1976; 41 FR 35062, Aug. 19, 1976; 47 FR 30969, July 16, 1982; 50 FR 4140, Jan. 29, 1985; 50 FR 35471, Aug. 30, 1985; 53 FR 117, Jan. 5, 1988; 63 FR 16685, Apr. 6, 1998]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.71</SECTNO> <SUBJECT>Manufacturing responsibility.</SUBJECT> <P>(a) All steps in the manufacture of Source Plasma, including donor examination, blood collection, plasmapheresis, laboratory testing, labeling, storage, and issuing shall be performed by personnel of the establishment licensed to manufacture Source Plasma, except that the following tests may be performed by personnel of an establishment licensed for blood or blood derivatives under section 351(a) of the Public Health Service Act, or by a clinical laboratory that meets the standards of the Clinical Laboratories Improvement Act of 1967 (CLIA) (42 U.S.C. 263a): <E T="03">Provided,</E> The establishment or the clinical laboratory is qualified to perform the assigned test(s).</P> <P>(1) The test for hepatitis B surface antigen.</P> <P>(2) The total plasma or serum protein and the quantitative test for plasma or serum proteins or for immunoglobulins.</P> <P>(3) The serologic test for syphilis.</P> <P>(4) A test for antibody to HIV.</P> <P>(b) Such testing shall not be considered divided manufacturing, which requires two product licenses for Source Plasma: <E T="03">Provided,</E> That</P> <P>(1) The results of such tests are maintained by the establishment licensed for Source Plasma whereby such results may be reviewed by a licensed physician as required in § 640.65(b)(2) and by an authorized representative of the Food and Drug Administration.</P> <P>(2) The Source Plasma manufacturer has obtained a written agreement that the testing laboratory will permit authorized representatives of the Food and Drug Administration to inspect its testing procedures and facilities during reasonable business hours.</P> <P>(3) The testing laboratory will participate in any proficiency testing programs undertaken by the Center for Biologics Evaluation and Research, Food and Drug Administration.</P> <CITA>[41 FR 10770, Mar. 12, 1976, as amended at 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.72</SECTNO> <SUBJECT>Records.</SUBJECT> <P>(a) In addition to the recordkeeping requirements of this subchapter, the following records shall be maintained:</P> <P>(1) Documentation compiled every 3 months establishing that the shipping temperature requirements of § 600.15 of this title and § 640.74(b)(2) are being met for Source Plasma intended for manufacture into injectable products.</P> <P>(2) For each donor, a separate and complete record of all initial and periodic examinations, tests, laboratory data, interviews, etc., undertaken pursuant to §§ 640.63, 640.65, 640.66, and 640.67, except that negative test results for hepatitis B surface antigen, negative test results for antibody to HIV, and the volume or weight of plasma withdrawn from a donor need not be kept on the individual donor record: <E T="03">Provided,</E> That such information is maintained on the premises of the plasmapheresis center where the donor's plasma has been collected.</P> <P>(3) The original or a clear copy of the donor's written consent for participation in the plasmapheresis program or for immunization.</P> <P>(4) The certification of the donor's good health as prescribed in § 640.63(b)(3).</P> <P>(5) If plasma that is reactive to a serologic test for syphilis is issued as prescribed in § 640.65(b)(2)(iv), the distribution records shall indicate by number those units that are reactive.<PRTPAGE P="97"/> </P> <P>(b) Each donor record must be directly cross-referenced to the unit(s) of Source Plasma associated with the donor.</P> <P>(c) If a repeat donor is rejected or a donor's plasma is found unsuitable, the donor's record shall contain a full explanation for the rejection.</P> <P>(d) If a donor has a reaction while on the plasmapheresis premises, or a donor reaction is reported to the center after the donor has left the premises, the donor's record shall contain a full explanation of the reaction, including the measures taken to assist the donor and the outcome of the incident. </P> <EXTRACT> <FP>(Collection of information requirements approved by the Office of Management and Budget under control number 0910-0227)</FP> </EXTRACT> <CITA>[41 FR 10770, Mar. 12, 1976, as amended at 50 FR 4140, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.73</SECTNO> <SUBJECT>Reporting of fatal donor reactions.</SUBJECT> <P>If a donor has a fatal reaction which, in any way, may be associated with plasmapheresis the Director of the Center for Biologics Evaluation and Research shall be notified by telephone as soon as possible. If the facility is located outside of the continental United States, notification by cable or telegram shall be acceptable.</P> <CITA>[41 FR 10770, Mar. 12, 1976, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.74</SECTNO> <SUBJECT>Modification of Source Plasma.</SUBJECT> <P>(a) Upon approval by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration, of a supplement to the product license for Source Plasma, a manufacturer may prepare Source Plasma as a liquid product for a licensed blood derivative manufacturer who has indicated a need for a liquid product.</P> <P>(b) Source Plasma Liquid shall meet all standards of the frozen Source Plasma except:</P> <P>(1) Source Plasma Liquid shall be stored in nonleachable containers so that the containers and their components will not interact with the plasma contents under conditions of storage and use so as to alter the safety, quality, purity, or potency of the plasma and shall provide adequate protection against external factors that may cause deterioration or contamination.</P> <P>(2) Source Plasma Liquid shall be shipped, stored and labeled for storage at a temperature of 10 °C or colder. An exception to the shipping or storage temperature shall be approved by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration, based upon his receipt of substantial evidence to support another temperature. Such evidence may be submitted by either the product licensee of the Source Plasma Liquid or the manufacturer of the final blood derivative product who has requested the Source Plasma Liquid.</P> <P>(3) The label for the Source Plasma Liquid shall be easily distinguished from that of the frozen product. Color coding shall not be used for this purpose.</P> <P>(4) The label affixed to each container of Source Plasma Liquid shall contain, in addition to the information required by § 640.70(a) but excluding § 640.70(a)(3), the name of the manufacturer of the final blood derivative product for whom it was prepared.</P> <P>(5) Source Plasma Liquid shall be inspected immediately prior to issuance. If the color or physical appearance is abnormal, or there is any indication or suspicion of microbial contamination, the unit of Source Plasma Liquid shall not be issued.</P> <CITA>[38 FR 32089, Nov. 20, 1973. Redesignated and amended at 41 FR 10770, Mar. 12, 1976; 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994; 63 FR 16685, Apr. 6, 1998]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.76</SECTNO> <SUBJECT>Products stored or shipped at unacceptable temperatures.</SUBJECT> <P>(a) <E T="03">Storage temperature.</E> (1) Except as provided in paragraph (a)(2) of this section, Source Plasma intended for manufacture into injectable products that is inadvertently exposed (i.e., an unforeseen occurrence in spite of compliance with good manufacturing practice) to a storage temperature warmer than −20 °C and colder than +10 °C may be issued only if labeled as “Source Plasma Salvaged.” The label shall be revised before issuance, and appropriate records shall be maintained identifying the units involved, describing their disposition, and explaining <PRTPAGE P="98"/>fully the conditions that caused the inadvertent temperature exposure.</P> <P>(2) Source Plasma intended for manufacture into injectable products that is exposed inadvertently (i.e., an unforeseen occurrence in spite of compliance with good manufacturing practice) to one episode of storage temperature fluctuation that is warmer than −20 °C and colder than −5 °C for not more than 72 hours is exempt from the labeling requirements of paragraph (a)(1) of this section, provided that the plasma has been and remains frozen solid. Appropriate records shall be maintained identifying the units involved, describing their disposition, explaining fully the conditions that caused the inadvertent temperature exposure, and documenting that the episode of temperature elevation did not exceed 72 hours, that the temperature did not rise to warmer than −5 °C in storage, and that the plasma remained frozen solid throughout the period of elevated temperature. When requested, copies of the records shall be provided to the plasma derivative manufacturer.</P> <P>(b) <E T="03">Shipping temperature.</E> If Source Plasma for manufacture into injectable products is exposed inadvertently (i.e., an unforeseen occurrence in spite of compliance with good manufacturing practice) to a shipping temperature warmer than −5 °C and colder than +10 °C, the plasma derivative manufacturer shall label it “Source Plasma Salvaged.” Appropriate records shall be maintained identifying the units involved, describing their disposition, and explaining fully the conditions that caused the inadvertent temperature exposure.</P> <P>(c) <E T="03">Relabeling.</E> If Source Plasma is required to be relabeled as “Source Plasma Salvaged” under paragraph (a)(1) or (b) of this section, the person responsible for the relabeling shall cover the original label with either (1) a complete new label containing the appropriate information or (2) a partial label affixed to the original label and containing the appropriate new information, which covers the incorrect information regarding storage temperature.</P> <CITA>[45 FR 80501, Dec. 5, 1980, as amended at 50 FR 4140, Jan. 29, 1985]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart H—Albumin (Human)</HD> <SECTION> <SECTNO>§ 640.80</SECTNO> <SUBJECT>Albumin (Human).</SUBJECT> <P>(a) <E T="03">Proper name and definition.</E> The proper name of the product shall be Albumin (Human). The product is defined as a sterile solution of the albumin component of human blood.</P> <P>(b) <E T="03">Source material.</E> The source material of Albumin (Human) shall be blood, plasma, serum or placentas from human donors determined at the time of donation to have been free from disease-causative agents that are not destroyed or removed by the processing method, as determined by the medical history of the donor and from such physical examination and clinical tests as may appear necessary for each donor at the time the blood was obtained. Where source material is a product for which additional standards are effective, the requirements of those additional standards shall determine the propriety of the source material for use in the production of Albumin (Human). Where no additional standards are effective with respect to source material for the production of Albumin (Human), such source material shall:</P> <P>(1) Be collected by a procedure which is designed to assure the integrity and to minimize the risk of contamination of the source material. The manufacturer of Albumin (Human) shall ensure that the collection procedure shall be as described in its license.</P> <P>(2) Be identified to relate it accurately to the individual donor and the dates of collection.</P> <P>(3) Not contain a preservative.</P> <P>(4) Be stored and transported in a manner designed to prevent contamination by microorganisms, pyrogens, or other impurities.</P> <P>(c) <E T="03">Additives in source material.</E> Source material shall not contain an additive unless it is shown that the processing method yields a final product free of the additive to such extent that the continued safety, purity, potency, and effectiveness of the final product will not be adversely affected.</P> <CITA>[42 FR 27582, May 31, 1977, as amended at 50 FR 4140, Jan. 29, 1985]</CITA> </SECTION> <SECTION> <PRTPAGE P="99"/> <SECTNO>§ 640.81</SECTNO> <SUBJECT>Processing.</SUBJECT> <P>(a) <E T="03">Date of manufacture.</E> The date of manufacture shall be the date of final sterile filtration of a uniform pool of bulk solution.</P> <P>(b) <E T="03">Processing method.</E> The processing method shall not affect the integrity of the product, and shall have been shown to yield consistently a product which is safe for intravenous injection.</P> <P>(c) <E T="03">Microbial contamination.</E> All processing steps shall be conducted in a manner to minimize the risk of contamination from either microorganisms or other deleterious matter. Preservatives to inhibit growth of microorganisms shall not be used during processing.</P> <P>(d) <E T="03">Storage of bulk fraction.</E> Bulk concentrate to be held more than 1 week prior to further processing shall be stored in clearly identified closed vessels at a temperature of −5 °C or colder. Any other bulk form of the product, exclusive of the sterile bulk solution, to be held more than 1 week prior to further processing shall be stored in clearly identified closed vessels at a temperature of 5 °C or colder. Any bulk fraction to be held one week or less prior to further processing shall be stored in clearly identified closed vessels at a temperature of 5 °C or colder.</P> <P>(e) <E T="03">Heat treatment.</E> Heating of the final containers of Albumin (Human) shall begin within 24 hours after completion of filling. Heat treatment shall be conducted so that the solution is heated for not less than 10 or more than 11 hours at an attained temperature of 60°<E T="21">±</E>0.5 °C.</P> <P>(f) <E T="03">Stabilizer.</E> Either 0.16 millimole sodium acetyltryptophanate, or 0.08 millimole sodium acetyltryptophanate and 0.08 millimole sodium caprylate shall be added per gram of albumin as a stabilizer.</P> <P>(g) <E T="03">Incubation.</E> All final containers of Albumin (Human) shall be incubated at 20 to 35 °C for at least 14 days following the heat treatment prescribed in paragraph (e) of this section. At the end of this incubation period, each final container shall be examined and all containers showing any indication of turbidity or microbial contamination shall not be issued. The contents of turbid final containers shall be examined microscopically and tested for sterility. If growth occurs, organisms shall be identified as to genus, and the material from such containers shall not be used for further manufacturing.</P> <CITA>[42 FR 27582, May 31, 1977, as amended at 50 FR 4140, Jan. 29, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.82</SECTNO> <SUBJECT>Tests on final product.</SUBJECT> <P>Tests shall be performed on the final product to determine that it meets the following standards:</P> <P>(a) <E T="03">Protein content.</E> Final product shall conform to one of the following concentrations: 4.0<E T="21">±</E>0.25 percent; 5.0<E T="21">±</E>0.30 percent; 20.0<E T="21">±</E>1.2 percent; and 25.0<E T="21">±</E>1.5 percent solution of protein.</P> <P>(b) <E T="03">Protein composition.</E> At least 96 percent of the total protein in the final product shall be albumin, as determined by a method that has been approved for each manufacturer by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration.</P> <P>(c) <E T="03">Hydrogen ion concentration.</E> The pH shall be 6.9<E T="21">±</E>0.5 when measured in a solution of the final product diluted to a concentration of 1 percent protein with 0.15 molar sodium chloride.</P> <P>(d) <E T="03">Sodium content.</E> The sodium content of the final product shall be 130 to 160 milliequivalents per liter.</P> <P>(e) <E T="03">Heme content.</E> The absorbance at 403 nanometers of a solution of the final product diluted to a concentration of 1 percent protein in a cell with a 1-centimeter light path shall not exceed 0.25.</P> <P>(f) <E T="03">Heat stability.</E> A final container sample of Albumin (Human) shall remain unchanged, as determined by visual inspection, after heating at 57 °C for 50 hours, when compared to its control consisting of a sample, from the same lot, which has not undergone this heating.</P> <CITA>[42 FR 27582, May 31, 1977, as amended at 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.83</SECTNO> <SUBJECT>General requirements.</SUBJECT> <P>(a) <E T="03">Preservative.</E> The final product shall not contain a preservative.</P> <P>(b) <E T="03">Storage of bulk solution.</E> After all processing steps have been completed, the sterile bulk solution shall be stored in a manner that will ensure the continued sterility of the product, and at a <PRTPAGE P="100"/>temperature that shall not exceed the recommended storage temperature of the final product prescribed in § 610.53 of this chapter.</P> <CITA>[42 FR 27582, May 31, 1977]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.84</SECTNO> <SUBJECT>Labeling.</SUBJECT> <P>In addition to the labeling requirements of §§ 610.60, 610.61, and 610.62 of this chapter,</P> <P>(a) The container and package labels shall contain the following information:</P> <P>(1) The osmotic equivalent in terms of plasma, and the sodium content in terms of a value or a range in milliequivalents per liter;</P> <P>(2) The cautionary statement placed in a prominent position on the label, “Do Not Use if Turbid. Do Not Begin Administration More Than 4 Hours After the Container Has Been Entered.”;</P> <P>(3) The need for additional fluids when 20 percent or 25 percent albumin is administered to a patient with marked dehydration;</P> <P>(4) The protein content, expressed as a 4 percent, 5 percent, 20 percent, or 25 percent solution.</P> <P>(b) The type of source material, expressed as venous plasma, placental plasma, or both, used to manufacture the final product shall appear on either the container or package label or in the package insert.</P> <CITA>[42 FR 27582, May 31, 1977, as amended at 49 FR 2244, Jan. 19, 1984]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart I—Plasma Protein Fraction (Human)</HD> <SOURCE> <HD SOURCE="HED">Source: </HD> <P>42 FR 27583, May 31, 1977, unless otherwise noted.</P> </SOURCE> <SECTION> <SECTNO>§ 640.90</SECTNO> <SUBJECT>Plasma Protein Fraction (Human).</SUBJECT> <P>(a) <E T="03">Proper name and definition.</E> The proper name of the product shall be Plasma Protein Fraction (Human). The product is defined as a sterile solution of protein composed of albumin and globulin, derived from human blood.</P> <P>(b) <E T="03">Source material.</E> The source material of Plasma Protein Fraction (Human) shall be blood, plasma, or serum from human donors determined at the time of donation to have been free from disease-causative agents that are not destroyed or removed by the processing method, as determined by the medical history of the donor and from such physical examination and clinical tests as may appear necessary for each donor at the time the blood was obtained. When source material is a product for which additional standards are effective, the requirements of those additional standards shall determine the propriety of the material for use in the production of Plasma Protein Fraction (Human). When no additional standards are effective with respect to source material for the production of Plasma Protein Fraction (Human), such source material shall:</P> <P>(1) Be collected by a procedure which is designed to assure the integrity and to minimize the risk of contamination of the source material. The manufacturer of Plasma Protein Fraction (Human) shall ensure that the collection procedure shall be as described in its license;</P> <P>(2) Be identified to relate it accurately to the individual donor and to the dates of collection;</P> <P>(3) Not contain a preservative; and</P> <P>(4) Be stored and transported in a manner designed to prevent contamination by microorganisms, pyrogens, or other impurities.</P> <P>(c) <E T="03">Additives in source material.</E> Source material shall not contain an additive unless it is shown that the processing method yields a final product free of the additive to such extent that the continued safety, purity, potency, and effectiveness of the final product will not be adversely affected.</P> </SECTION> <SECTION> <SECTNO>§ 640.91</SECTNO> <SUBJECT>Processing.</SUBJECT> <P>(a) <E T="03">Date of manufacture.</E> The date of manufacture shall be the date of final sterile filtration of a uniform pool of bulk solution.</P> <P>(b) <E T="03">Processing method.</E> The processing method shall not affect the integrity of the product, and shall have been shown to yield consistently a product which:</P> <P>(1) After the heating prescribed in paragraph (e) of this section does not show an increase in the components with electrophoretic mobility similar to that of alpha globulin that amounts to more than 5 percent of the total protein.<PRTPAGE P="101"/> </P> <P>(2) Contains less than 5 percent protein with a sedimentation coefficent greater than 7.0 S.</P> <P>(3) Is safe for intravenous injection.</P> <P>(c) <E T="03">Microbial contamination.</E> All processing steps shall be conducted in a manner to minimize the risk of contimination from either microorganisms or other deleterious matter. Preservatives to inhibit growth of microorganisms shall not be used during processing.</P> <P>(d) <E T="03">Storage of bulk fraction.</E> Bulk concentrate to be held more than 1 week prior to further processing shall be stored in clearly identified closed vessels at a temperature of −5 °C or colder. Any other bulk form of the product (exclusive of the sterile bulk solution) to be held more than 1 week prior to further processing, shall be stored in clearly identified closed vessels at a temperature of 5 °C or colder. Any bulk fraction to be held one week or less prior to further processing shall be stored in clearly identified closed vessels at a temperature of 5 °C or colder.</P> <P>(e) <E T="03">Heat treatment.</E> Heating of the final containers of Plasma Protein Fraction (Human) shall begin within 24 hours after completion of filling. Heat treatment shall be conducted so that the solution is heated for not less than 10 or more than 11 hours at an attained temperature of 60°<E T="21">±</E>0.5 °C.</P> <P>(f) <E T="03">Stabilizer.</E> Either 0.16 millimole sodium acetyltryptophanate, or 0.08 millimole sodium acetyltryptophanate and 0.08 millimole sodium caprylate shall be added per gram of protein as a stabilizer.</P> <P>(g) <E T="03">Incubation.</E> All final containers of Plasma Protein Fraction (Human) shall be incubated at 20 to 35 °C for at least 14 days following the heat treatment prescribed in paragraph (e) of this section. At the end of this incubation period, each final container shall be examined and all containers showing any indication of turbidity or microbial contamination shall not be issued. The contents of turbid final containers shall be examined microscopically and tested for sterility. If growth occurs, the types of organisms shall be identified as to genus and the material from such containers shall not be used for further manufacturing.</P> </SECTION> <SECTION> <SECTNO>§ 640.92</SECTNO> <SUBJECT>Tests on final product.</SUBJECT> <P>Tests shall be performed on the final product to determine that it meets the following standards:</P> <P>(a) <E T="03">Protein content.</E> The final product shall be a 5.0<E T="21">±</E>0.3 percent solution of protein.</P> <P>(b) <E T="03">Protein composition.</E> The total protein in the final product shall consist of at least 83 percent albumin, and no more than 17 percent globulins. No more than 1 percent of the total protein shall be gamma globulin. The protein composition shall be determined by a method that has been approved for each manufacturer by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration.</P> <P>(c) <E T="03">Hydrogen ion concentration.</E> The pH shall be 7.0<E T="21">±</E>0.3 when measured in a solution of the final product diluted to a concentration of 1 percent protein with 0.15 molar sodium chloride.</P> <P>(d) <E T="03">Sodium content.</E> The sodium content of the final product shall be 130 to 160 milliequivalents per liter.</P> <P>(e) <E T="03">Potassium content.</E> The potassium content of the final product shall not exceed 2 milliequivalents per liter.</P> <P>(f) <E T="03">Heat stability.</E> A final container sample of Plasma Protein Fraction (Human) shall remain unchanged, as determined by visual inspection, after heating at 57 °C for 50 hours, when compared to its control consisting of a sample, from the same lot, which has not undergone this heating.</P> <CITA>[42 FR 27583, May 31, 1977, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.93</SECTNO> <SUBJECT>General requirements.</SUBJECT> <P>(a) <E T="03">Preservative.</E> The final product shall not contain a preservative.</P> <P>(b) <E T="03">Storage of bulk solution.</E> After all processing steps have been completed, the sterile bulk solution shall be stored in a manner that will ensure the continued sterility of the product, and at a temperature that shall not exceed the recommended storage temperature of the final product prescribed in § 610.53 of this chapter.</P> </SECTION> <SECTION> <SECTNO>§ 640.94</SECTNO> <SUBJECT>Labeling.</SUBJECT> <P>In addition to the labeling requirements of §§ 610.60, 610.61, and 610.62 of <PRTPAGE P="102"/>this chapter, the container and package labels shall contain the following information:</P> <P>(a) The osmotic equivalent in terms of plasma, and the sodium content in terms of a value or a range in milli- equivalents per liter.</P> <P>(b) The cautionary statement placed in a prominent position on the label, “Do Not Use if Turbid. Do Not Begin Administration More than 4 Hours After the Container Has Been Entered.”</P> <CITA>[42 FR 27583, May 31, 1977, as amended at 49 FR 2244, Jan. 19, 1984]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart J—Immune Globulin (Human)</HD> <SECTION> <SECTNO>§ 640.100</SECTNO> <SUBJECT>Immune Globulin (Human).</SUBJECT> <P>(a) <E T="03">Proper name and definition.</E> The proper name of this product shall be Immune Globulin (Human). The product is defined as a sterile solution containing antibodies derived from human blood.</P> <P>(b) <E T="03">Source material.</E> The source of Immune Globulin (Human) shall be blood, plasma or serum from human donors determined at the time of donation to have been free of causative agents of diseases that are not destroyed or removed by the processing methods, as determined by the donor's history and from such physical examination and clinical tests as appear necessary for each donor at the time the blood was obtained. The source blood, plasma or serum shall not contain a preservative and shall be stored in a manner that will prevent contamination by microorganisms, pyrogens or other impurities.</P> <P>(c) <E T="03">Additives in source material.</E> Source blood, plasma or serum shall contain no additives other than citrate or acid citrate dextrose anticoagulant solution, unless it is shown that the processing method yields a product free of the additive to such an extent that the safety, purity and potency of the product will not be affected adversely.</P> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4140, Jan. 29, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.101</SECTNO> <SUBJECT>General requirements.</SUBJECT> <P>(a) <E T="03">Heat stability test.</E> Approximately 2 ml. of completely processed material of each lot shall not show any visible sign of gelation after heating in a 12 x 75 mm. stoppered glass tube at 57 °C for 4 hours.</P> <P>(b) <E T="03">Hydrogen ion concentration.</E> The pH of final container material shall be 6.8<E T="21">±</E>0.4 when measured in a solution diluted to 1 percent protein with 0.15 molar sodium chloride.</P> <P>(c) <E T="03">Turbidity.</E> The product shall be free of turbidity as determined by visual inspection of final containers.</P> <P>(d) <E T="03">Date of manufacture.</E> The date of manufacture is the date of initiating the last valid measles or poliomyelitis antibody test (§ 640.104(b) (2) and (3)) whichever date is earlier.</P> <P>(e) <E T="03">Labeling.</E> In addition to complying with all applicable labeling required in this subchapter, labeling shall indicate that:</P> <P>(1) There is no prescribed potency for viral hepatitis antibodies.</P> <P>(2) The product is not recommended for intravenous administration.</P> <P>(3) The lot is or is not suitable for use with Measles Virus Vaccine Live.</P> <P>(4) The lot is or is not recommended for poliomyelitis.</P> <P>(f) <E T="03">Samples and protocols.</E> For each lot of Immune Globulin (Human) the following material shall be submitted to the Director, Center for Biologics Evaluation and Research, Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892:</P> <P>(1) A 50 ml. sample of the final product.</P> <P>(2) All protocols relating to the history of each lot and all results of all tests prescribed in these additional standards.</P> <CITA>[38 FR 32089, Nov. 20, 1973; 48 FR 13026, Mar. 29, 1983, as amended at 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 51 FR 15611, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990; 63 FR 16685, Apr. 6, 1998]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.102</SECTNO> <SUBJECT>Manufacture of Immune Globulin (Human).</SUBJECT> <P>(a) <E T="03">Processing method.</E> The processing method shall be one that has been shown: (1) To be capable of concentrating tenfold from source material at least two different antibodies; (2) not to affect the integrity of the globulins; (3) to consistently yield a product which is safe for subcutaneous and <PRTPAGE P="103"/>intramuscular injection and (4) not to transmit viral hepatitis.</P> <P>(b) <E T="03">Microbial contamination.</E> Low temperatures or aseptic techniques shall be used to minimize contamination by microorganisms. Preservatives to inhibit growth of microorganisms shall not be used during processing.</P> <P>(c) <E T="03">Bulk storage.</E> The globulin fraction may be stored in bulk prior to further processing provided it is stored in clearly identified hermetically closed vessels. Globulin as either a liquid concentrate or a solid and containing alcohol or more than 5 percent moisture shall be stored at a temperature of −10 °C or lower. Globulin as a solid free from alcohol and containing less than 5 percent moisture, shall be stored at a temperature of 0 °C or lower.</P> <P>(d) <E T="03">Determination of the lot.</E> Each lot of Immune Globulin (Human) shall represent a pooling of approximately equal amounts of material from not less than 1,000 donors.</P> <P>(e) <E T="03">Sterilization and heating.</E> The final product shall be sterilized promptly after solution. At no time during processing shall the product be exposed to temperatures above 45 °C and after sterilization the product shall not be exposed to temperatures above 30 to 32 °C for more than 72 hours.</P> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4140, Jan. 29, 1985; 63 FR 16685, Apr. 6, 1998]</CITA> </SECTION> <SECTION> <SECTNO>§ 640.103</SECTNO> <SUBJECT>The final product.</SUBJECT> <P>(a) <E T="03">Final solution.</E> The final product shall be a 16.5<E T="21">±</E>1.5 percent solution of globulin containing 0.3 molar glycine and a preservative.</P> <P>(b) <E T="03">Protein composition.</E> At least 90 percent of the globulin shall have an electrophoretic mobility not faster than −2.8×10<E T="21">−</E> <E T="21"> 5</E> centimeters<E T="21"> 2</E> per volt per second, when measured at a 1 percent protein concentration in sodium diethylbarbiturate buffer at pH 8.6 and 0.1 ionic strength.</P> </SECTION> <SECTION> <SECTNO>§ 640.104</SECTNO> <SUBJECT>Potency.</SUBJECT> <P>(a) <E T="03">Antibody levels and tests.</E> Each lot of final product shall contain at least the minimum levels of antibodies for diphtheria, measles, and for at least one type of poliomyelitis. In the event the final bulk solution is stored at a temperature above 5 °C the antibody level tests shall be performed after such storage with a sample of the stored material.</P> <P>(b) <E T="03">Minimum levels.</E> The minimum antibody levels are as follows:</P> <P>(1) No less than 2 units of diphtheria antitoxin per ml.</P> <P>(2) A measles neutralizing antibody level of no less than 0.50 times the level of the Reference Immune Serum Globulin, except that when recommended for use with Measles Virus Vaccine Live, the measles antibody level shall be as prescribed in § 640.114.</P> <P>(3) A poliomyelitis neutralizing antibody level of no less than 1.0 for Type 1, 1.0 for Type 2, and 2.5 for Type 3, times the antibody level of the Reference Immune Serum Globulin.</P> <P>(c) <E T="03">Reference materials.</E> The following reference materials shall be obtained from the Center for Biologics Evaluation and Research:</P> <P>(1) Reference Immune Serum Globulin for correlation of measles antibody titers.</P> <P>(2) Reference Immune Serum Globulin for correlation of poliomyelitis antibody titers, Types 1, 2, and 3.</P> <CITA>[38 FR 32089, Nov. 20, 1973, as amended at 39 FR 9661, Mar. 13, 1974; 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 63 FR 16685, Apr. 6, 1998]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart K[Reserved]</HD> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart L—Alternative Procedures</HD> <SECTION> <SECTNO>§ 640.120</SECTNO> <SUBJECT>Alternative procedures.</SUBJECT> <P>(a) The Director, Center for Biologics Evaluation and Research, may approve an exception or alternative to any requirement in subchapter F of chapter I of title 21 of the Code of Federal Regulations regarding blood, blood components, or blood products. Requests for such exceptions or alternatives shall ordinarily be in writing. Licensed establishments shall submit such requests in accordance with § 601.12 of this chapter. However, in limited circumstances, such requests may be made orally and permission may be given orally by the Director. Oral requests and approvals must be promptly followed by written requests and written approvals.<PRTPAGE P="104"/> </P> <P>(b) FDA will publish a list of approved alternative procedures and exceptions periodically in the <E T="04">Federal Register</E>.</P> <CITA>[55 FR 10423, Mar. 21, 1990, as amended at 62 FR 39903, July 24, 1997]</CITA> </SECTION> </SUBPART> </PART> <PART> <EAR>Pt. 660</EAR> <HD SOURCE="HED">PART 660—ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS</HD> <CONTENTS> <SUBPART> <HD SOURCE="HED">Subpart A—Antibody to Hepatitis B Surface Antigen</HD> <SECHD>Sec.</SECHD> <SECTNO>660.1</SECTNO> <SUBJECT>Antibody to Hepatitis B Surface Antigen.</SUBJECT> <SECTNO>660.2</SECTNO> <SUBJECT>General requirements.</SUBJECT> <SECTNO>660.3</SECTNO> <SUBJECT>Reference panel.</SUBJECT> <SECTNO>660.4</SECTNO> <SUBJECT>Potency test.</SUBJECT> <SECTNO>660.5</SECTNO> <SUBJECT>Specificity.</SUBJECT> <SECTNO>660.6</SECTNO> <SUBJECT>Samples; protocols; official release.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart B[Reserved]</HD> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart C—Blood Grouping Reagent</HD> <SECTNO>660.20</SECTNO> <SUBJECT>Blood Grouping Reagent.</SUBJECT> <SECTNO>660.21</SECTNO> <SUBJECT>Processing.</SUBJECT> <SECTNO>660.22</SECTNO> <SUBJECT>Potency requirements with reference preparations.</SUBJECT> <SECTNO>660.25</SECTNO> <SUBJECT>Potency tests without reference preparations.</SUBJECT> <SECTNO>660.26</SECTNO> <SUBJECT>Specificity tests and avidity tests.</SUBJECT> <SECTNO>660.28</SECTNO> <SUBJECT>Labeling.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart D—Reagent Red Blood Cells</HD> <SECTNO>660.30</SECTNO> <SUBJECT>Reagent Red Blood Cells.</SUBJECT> <SECTNO>660.31</SECTNO> <SUBJECT>Suitability of the donor.</SUBJECT> <SECTNO>660.32</SECTNO> <SUBJECT>Collection of source material.</SUBJECT> <SECTNO>660.33</SECTNO> <SUBJECT>Testing of source material.</SUBJECT> <SECTNO>660.34</SECTNO> <SUBJECT>Processing.</SUBJECT> <SECTNO>660.35</SECTNO> <SUBJECT>Labeling.</SUBJECT> <SECTNO>660.36</SECTNO> <SUBJECT>Samples and protocols.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart E—Hepatitis B Surface Antigen</HD> <SECTNO>660.40</SECTNO> <SUBJECT>Hepatitis B Surface Antigen.</SUBJECT> <SECTNO>660.41</SECTNO> <SUBJECT>Processing.</SUBJECT> <SECTNO>660.42</SECTNO> <SUBJECT>Reference panel.</SUBJECT> <SECTNO>660.43</SECTNO> <SUBJECT>Potency test.</SUBJECT> <SECTNO>660.44</SECTNO> <SUBJECT>Specificity.</SUBJECT> <SECTNO>660.45</SECTNO> <SUBJECT>Labeling.</SUBJECT> <SECTNO>660.46</SECTNO> <SUBJECT>Samples; protocols; official release.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart F—Anti-Human Globulin</HD> <SECTNO>660.50</SECTNO> <SUBJECT>Anti-Human Globulin.</SUBJECT> <SECTNO>660.51</SECTNO> <SUBJECT>Processing.</SUBJECT> <SECTNO>660.52</SECTNO> <SUBJECT>Reference preparations.</SUBJECT> <SECTNO>660.53</SECTNO> <SUBJECT>Controls for serological procedures.</SUBJECT> <SECTNO>660.54</SECTNO> <SUBJECT>Potency tests, specificity tests, tests for heterospecific antibodies, and additional tests for nonspecific properties.</SUBJECT> <SECTNO>660.55</SECTNO> <SUBJECT>Labeling.</SUBJECT> </SUBPART> </CONTENTS> <AUTH> <HD SOURCE="HED">Authority: </HD> <P>21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 U.S.C. 216, 262, 263, 263a, 264.</P> </AUTH> <CROSSREF> <HD SOURCE="HED"> <E T="04">Cross References:</E> </HD> <P>For U.S. Customs Service regulations relating to viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal Service regulations relating to the admissibility to the United States mails see parts 124 and 125 of the Domestic Mail Manual, that is incorporated by reference in 39 CFR part 111.</P> </CROSSREF> <SUBPART> <HD SOURCE="HED">Subpart A—Antibody to Hepatitis B Surface Antigen</HD> <SECTION> <SECTNO>§ 660.1</SECTNO> <SUBJECT>Antibody to Hepatitis B Surface Antigen.</SUBJECT> <P>(a) <E T="03">Proper name and definition.</E> The proper name of this product shall be Antibody to Hepatitis B Surface Antigen. The product is defined as a preparation of serum containing antibody to hepatitis B surface antigen.</P> <P>(b) <E T="03">Source.</E> The source of this product shall be plasma or blood, obtained aseptically from animals immunized with hepatitis B surface antigen, which have met the applicable requirements of § 600.11 of this chapter, or from human donor whose blood is positive for hepatitis B surface antigen.</P> <CITA>[40 FR 29711, July 15, 1975]</CITA> </SECTION> <SECTION> <SECTNO>§ 660.2</SECTNO> <SUBJECT>General requirements.</SUBJECT> <P>(a) <E T="03">Processing.</E> The processing method shall be one that has been shown to consistently yield a specific and potent final product free of properties which would adversely affect the test results when the product is tested by the methods recommended by the manufacturer in the package enclosure.</P> <P>(b) <E T="03">Ancillary reagents and materials.</E> All ancillary reagents and materials supplied in the package with the product shall meet generally accepted standards of purity and quality and shall be effectively segregated and otherwise manufactured in a manner (such as heating at 60 °C. for 10 hours) that will reduce the risk of contaminating the product and other biological products. Ancillary reagents and materials accompanying the product which are used in the performance of the test as described by the manufacturer's recommended test procedures shall have been shown not to adversely affect the <PRTPAGE P="105"/>product within the prescribed dating period.</P> <P>(c) <E T="03">Labeling.</E> In addition to the items required by other applicable labeling provisions of this subchapter, the following shall also be included:</P> <P>(1) Indication of the source of the product immediately following the proper name on both the final container and package label, e.g., human, guinea pig.</P> <P>(2) Name of the test method(s) recommended for the product on the package label and on the final container label when capable of bearing a full label (see § 610.60(a) of this chapter).</P> <P>(3) A warning on the package label and on the final container label if capable of bearing a full label (see § 610.60(a) of this chapter) indicating that the product and antigen if supplied, shall be handled as if capable of transmitting hepatitis.</P> <P>(4) If the product is dried, the final container label shall indicate “Reconstitution date: ______” and a statement indicating the period within which the product may be used after reconstitution.</P> <P>(5) The package shall include a package enclosure providing (i) adequate instructions for use, (ii) a description of all recommended test methods, and (iii) warnings as to possible hazards, including hepatitis, in handling the product and any ancillary reagents and materials accompanying the product.</P> <P>(d) <E T="03">Final container.</E> A final container shall be sufficiently transparent to permit visual inspection of the contents for presence of particulate matter and increased turbidity. The effectiveness of the contents of a final container shall be maintained throughout its dating period.</P> <P>(e) <E T="03">Date of manufacture.</E> The date of manufacture of Antibody to Hepatitis B surface Antigen that has been iodinated with radioactive iodine (<E T="21"> 1</E> <E T="21"> 2</E> <E T="21"> 5</E>I) shall be the day of labeling the antibody with the radionuclide.</P> <P>(f) <E T="03">Retention samples.</E> Each manufacturer shall retain representative samples of the product in accordance with § 600.13 of this chapter except for that which has been iodinated with radioactive iodine. Retention samples of Antibody to Hepatitis B Surface Antigen iodinated with <E T="21">125</E>I shall consist of a minimum of two complete finished packages of each lot of the diagnostic test kit and shall be retained for a period of at least 90 days from the date of manufacture.</P> <CITA>[38 FR 32098, Nov. 20, 1973, as amended at 40 FR 29711, July 15, 1975; 46 FR 36134, July 14, 1981; 49 FR 1684, Jan. 13, 1984]</CITA> </SECTION> <SECTION> <SECTNO>§ 660.3</SECTNO> <SUBJECT>Reference panel.</SUBJECT> <P>A Reference Hepatitis B Surface Antigen Panel shall be obtained from the Center for Biologics Evaluation and Research and shall be used for determining the potency and specificity of Antibody to Hepatitis B Surface Antigen.</P> <CITA>[40 FR 29711, July 15, 1975, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 660.4</SECTNO> <SUBJECT>Potency test.</SUBJECT> <P>To be satisfactory for release, each filling of Antibody to Hepatitis B Surface Antigen shall be tested against the Reference Hepatitis B Surface Antigen Panel and shall be sufficiently potent to detect the antigen in the appropriate sera of the reference panel by all test methods recommended by the manufacturer in the package insert.</P> <CITA>[40 FR 29711, July 15, 1975]</CITA> </SECTION> <SECTION> <SECTNO>§ 660.5</SECTNO> <SUBJECT>Specificity.</SUBJECT> <P>Each filling of the product shall be specific for antibody to hepatitis B surface antigen, as determined by specificity tests found acceptable by the Director, Center for Biologics Evaluation and Research.</P> <CITA>[40 FR 29712, July 15, 1975, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 660.6</SECTNO> <SUBJECT>Samples; protocols; official release.</SUBJECT> <P>(a) <E T="03">Samples.</E> (1) For the purposes of this section, a sample of product not iodinated with <E T="21">125</E> I means a sample from each filling of each lot packaged as for distribution, including all ancillary reagents and materials; and a sample of product iodinated with <E T="21">125</E> I means a sample from each lot of diagnostic test kits in a finished package, including all ancillary reagents and materials.<PRTPAGE P="106"/> </P> <P>(2) Unless the Director, Center for Biologics Evaluation and Research, determines that the reliability and consistency of the finished product can be assured with a smaller quantity of sample or no sample and specifically reduces or eliminates the required quantity of sample, each manufacturer shall submit the following samples to the Director, Center for Biologics Evaluation and Research (HFB-1), 8800 Rockville Pike, Bethesda, MD 20892, within 5 working days after the manufacturer has satisfactorily completed all tests on the samples:</P> <P>(i) One sample until written notification of official release is no longer required under paragraph (c)(2) of this section.</P> <P>(ii) One sample at periodic intervals of 90 days, beginning after written notification of official release is no longer required under paragraph (c)(2) of this section. The sample submitted at the 90-day interval shall be from the first lot or filling, as applicable, released by manufacturer, under the requirements of § 610.1 of this chapter, after the end of the previous 90-day interval. The sample shall be identified as “surveillance sample” and shall include the date of manufacture.</P> <P>(iii) Samples may at any time be required to be submitted to the Director, Center for Biologics Evaluation and Research, if the Director finds that continued evaluation is necessary to ensure the potency, quality, and reliability of the product.</P> <P>(b) <E T="03">Protocols.</E> For each sample submitted as required in paragraph (a)(1) of this section, the manufacturer shall send a protocol that consists of a summary of the history of manufacture of the product, including all results of each test for which test results are requested by the Director, Center for Biologics Evaluation and Research. The protocols submitted with the samples at periodic intervals as provided in paragraph (a)(2)(ii) of this section shall be identified by the manufacturer as “surveillance test results.”</P> <P>(c) <E T="03">Offical release.</E> (1) The manufacturer shall not distribute the product until written notification of official release is received from the Director, Center for Biologics Evaluation and Research, except as provided in paragraph (c)(2) of this section. Official release is required for samples from at least five consecutive lots or fillings, as applicable, manufactured after licensure of the product. </P> <P>(2) After written notification of official release is received from the Director, Center for Biologics Evaluation and Research, for at least five consecutive lots or fillings, as applicable, manufactured after licensure of the product, and after the manufacturer receives from the Director, Center for Biologics Evaluation and Research, written notification that official release is no longer required, subsequent lots or fillings may be released by the manufacturer under the requirements of § 610.1 of this chapter.</P> <P>(3) The manufacturer shall not distribute lots or fillings, as applicable, of products that required sample submission under paragraph (a)(2)(iii) of this section until written notification of official release or notification that official release is no longer required is received from the Director, Center for Biologics Evaluation and Research.</P> <CITA>[48 FR 20407, May 6, 1983, as amended at 49 FR 23834, June 8, 1984; 51 FR 15611, Apr. 25, 1986; 55 FR 11013 and 11014, Mar. 26, 1990]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart B[Reserved]</HD> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart C—Blood Grouping Reagent</HD> <SOURCE> <HD SOURCE="HED">Source: </HD> <P>53 FR 12764, Apr. 19, 1988, unless otherwise noted.</P> </SOURCE> <SECTION> <SECTNO>§ 660.20</SECTNO> <SUBJECT>Blood Grouping Reagent.</SUBJECT> <P>(a) <E T="03">Proper name and definition.</E> The proper name of this product shall be Blood Grouping Reagent and it shall consist of an antibody-containing fluid prepared by a method demonstrated to yield consistently a sterile product and containing one or more of the blood grouping antibodies listed in § 660.28(d).</P> <P>(b) <E T="03">Source.</E> The source of this product shall be blood, plasma, serum, or protein-rich fluids, such as those derived from stable immunoglobulin-secreting cell lines maintained either in tissue cultures or in secondary hosts.</P> </SECTION> <SECTION> <PRTPAGE P="107"/> <SECTNO>§ 660.21</SECTNO> <SUBJECT>Processing.</SUBJECT> <P>(a) <E T="03">Processing method.</E> (1) The processing method shall be one that has been shown to yield consistently a specific, potent final product, free of properties that would affect adversely the intended use of the product throughout its dating period. Stability testing shall be performed on an adequate number of representative samples of each group of products manufactured in the same fashion.</P> <P>(2) Only that material that has been fully processed, thoroughly mixed in a single vessel, and sterile filtered shall constitute a lot.</P> <P>(3) A lot may be subdivided into clean, sterile vessels. Each subdivision shall constitute a sublot. If lots are to be subdivided, the manufacturer shall include this information in the license application. The manufacturer shall describe the test specifications to verify that each sublot is identical to other sublots of the lot.</P> <P>(4) Each lot of Blood Grouping Reagent shall be identified by a lot number. Each sublot shall be identified by that lot number to which a distinctive prefix or suffix shall be added. Final container and package labels shall bear the lot number and all distinctive prefixes and suffixes that have been applied to identify the sublot from which filling was accomplished.</P> <P>(b) <E T="03">Color coding of reagents.</E> Blood Grouping Reagents may be colored provided the added colorant does not adversely affect the safety, purity, or potency of the product and the colorant is approved by the Director, Center for Biologics Evaluation and Research (HFN-830), Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892.</P> <P>(c) <E T="03">Final containers and dropper assemblies.</E> Final containers and dropper pipettes shall be colorless and sufficiently transparent to permit observation of the contents to detect particulate matter or increased turbidity during use.</P> <P>(d) <E T="03">Volume of final product.</E> Each manufacturer shall identify the possible final container volumes in the product license application.</P> <P>(e) <E T="03">Date of manufacture.</E> The date of manufacture shall be the date the manufacturer begins the last entire group of potency tests. </P> <EXTRACT> <FP>(Information collection requirements approved by the Office of Management and Budget under control number 0910-0209)</FP> </EXTRACT> </SECTION> <SECTION> <SECTNO>§ 660.22</SECTNO> <SUBJECT>Potency requirements with reference preparations.</SUBJECT> <P>(a) <E T="03">Potency requirements.</E> Products for which reference Blood Grouping Reagents are available shall have a potency titer value at least equal to that of the reference preparation.</P> <P>(b) <E T="03">Reference preparations.</E> Reference Blood Grouping Reagents shall be obtained from the Center for Biologics Evaluation and Research (HFN-890), Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892, and shall be used as described in the accompanying package insert for determining the potency of Blood Grouping Reagents. </P> <EXTRACT> <FP>(Information collection requirements approved by the Office of Management and Budget under control number 0910-0209)</FP> </EXTRACT> </SECTION> <SECTION> <SECTNO>§ 660.25</SECTNO> <SUBJECT>Potency tests without reference preparations.</SUBJECT> <P>Products for which Reference Blood Grouping Reagents are not available shall be tested for potency by a method approved by the Director, Center for Biologics Evaluation and Research (HFN-830), Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892.</P> <P>(a) <E T="03">Potency requirements.</E> Blood Grouping Reagents recommended for the test tube methods, including the indirect antiglobulin tests, shall have the following potency titer values, unless other values are approved by the Director, Center for Biologics Evaluation and Research (HFN-830), Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892.</P> <P>(1) For Anti-K, Anti-k<AC T="8"/>, Anti-Jk <E T="51">a</E>, Anti-Fy <E T="51">a</E>, Anti-C <E T="51">w</E>, at least 1+ reaction with a 1:8 dilution of the reagent.</P> <P>(2) For Anti-S, Anti-s<AC T="8"/>, Anti-P<E T="52">1</E>, Anti-M, Anti-I, Anti-e (saline), Anti-c<AC T="8"/> (saline), and Anti-A<E T="52">1</E>, at least 1+ reaction with a 1:4 dilution of the reagent.</P> <P>(3) For Anti-U, Anti-Kp<E T="21">a</E>, Anti-Kp<E T="21">b</E>, Anti-Js<E T="21">a</E>, Anti-Js<E T="21">b</E>, Anti-Fy<E T="21">b</E>, Anti-N, Anti-Le<E T="21">a</E>, Anti-Le<E T="21">b</E>, Anti-Lu<E T="21">a</E>, Anti-Lu<E T="21">b</E>, Anti-Di<E T="21">a</E>, Anti-M<E T="21">g</E>, Anti-Jk<E T="21">b</E>, Anti-Co<E T="21">b</E>, <PRTPAGE P="108"/>Anti-Wr<E T="21">a</E>, and Anti-Xg<E T="21">a</E>, at least 2+ reaction with undiluted reagent.</P> <P>(b) <E T="03">Products recommended for slide tests or microplate techniques.</E> Blood Grouping Reagent recommended for slide test methods or microplate techniques shall produce clearly positive macroscopic results when both undiluted reagent and reagent diluted with an equal volume of diluent are tested by all methods recommended in the manufacturer's package insert using red blood cells showing heterozygous or diminished expression of the corresponding antigen. The dilution shall be made with an equal volume of compatible serum or approved diluent.</P> <P>(c) <E T="03">Products recomended for use in an automated system.</E> The manufacturer of Blood Grouping Reagent that is recommended for use in an automated system shall demonstrate that its product when used both undiluted and diluted with an equal volume of diluent satisfactorily performs when tested with cells representing heterozygous or diminished expression of the corresponding antigen. </P> <EXTRACT> <FP>(Information collection requirements approved by the Office of Management and Budget under control number 0910-0209) </FP> </EXTRACT> </SECTION> <SECTION> <SECTNO>§ 660.26</SECTNO> <SUBJECT>Specificity tests and avidity tests.</SUBJECT> <P>Specificity and avidity tests shall be performed using test procedures approved by the Director, Center for Biologics Evaluation and Research (HFN-830), Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892. </P> <EXTRACT> <FP>(Information collection requirements approved by the Office of Management and Budget under control number 0910-0209) </FP> </EXTRACT> </SECTION> <SECTION> <SECTNO>§ 660.28</SECTNO> <SUBJECT>Labeling.</SUBJECT> <P>In addition to the applicable labeling requirements of §§ 610.62 through 610.65 and § 809.10, and in lieu of the requirements in §§ 610.60 and 610.61, the following requirements shall be met:</P> <P>(a) <E T="03">Final container label</E>—(1) <E T="03">Color coding.</E> The final container label of all Blood Grouping Reagents shall be completely white, except that all or a portion of the final container label of the following Blood Grouping Reagents may be color coded with the specified color which shall be a visual match to a specific color sample designated by the Director, Center for Biologics Evaluation and Research (HFN-830), Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892. Printing on all final container labels shall be in solid black. A logo or company name may be placed on the final container label; however, the logo or company name shall be located along the bottom or end of the label, outside the main panel.</P> <GPOTABLE CDEF="s25,r25" COLS="2" OPTS="L2,p7,7/8,i1"> <BOXHD> <CHED H="1">Blood grouping reagent</CHED> <CHED H="1">Color of label paper</CHED> </BOXHD> <ROW> <ENT I="01">Anti-A</ENT> <ENT>Blue.</ENT> </ROW> <ROW> <ENT I="01">Anti-B</ENT> <ENT>Yellow.</ENT> </ROW> <ROW> <ENT I="11">Slide and rapid tube test blood grouping reagents only:</ENT> </ROW> <ROW> <ENT I="02">Anti-C</ENT> <ENT>Pink.</ENT> </ROW> <ROW> <ENT I="02">Anti-D</ENT> <ENT>Gray.</ENT> </ROW> <ROW> <ENT I="02">Anti-E</ENT> <ENT>Brown.</ENT> </ROW> <ROW> <ENT I="02">Anti-CDE</ENT> <ENT>Orange.</ENT> </ROW> <ROW> <ENT I="02">Anti-c<AC T="8"/> </ENT> <ENT>Lavender.</ENT> </ROW> <ROW> <ENT I="02">Anti-e</ENT> <ENT>Green.</ENT> </ROW> </GPOTABLE> <P>(2) <E T="03">Required information.</E> The proper name “Blood Grouping Reagent” need not appear on the final container label provided the final container is distributed in a package and the package label bears the proper name. The final container label shall bear the following information:</P> <P>(i) Name of the antibody or antibodies present as set forth in paragraph (d) of this section.</P> <P>(ii) Name, address (including ZIP code), and license number of the manufacturer.</P> <P>(iii) Lot number, including sublot designations.</P> <P>(iv) Expiration date.</P> <P>(v) Source of product if other than human plasma or serum.</P> <P>(vi) Test method(s) recommended.</P> <P>(vii) Recommended storage temperature in degrees Celsius.</P> <P>(viii) Volume of product if a liquid, or equivalent volume for a dried product if it is to be reconstituted.</P> <P>(ix) If a dried product, to remind users to record the reconstitution date on the label, the statement “RECONSTITUTION DATE <E T="72">____</E>. EXPIRES 1 YEAR AFTER RECONSTITUTION DATE.”</P> <P>(3) <E T="03">Lettering size.</E> The type size for the specificity of the antibody designation on the labels of a final container with <PRTPAGE P="109"/>a capacity of less than 5 milliliters shall be not less than 12 point. The type size for the specificity of the antibody designations on the label of a container with a capacity of 5 milliliters or more shall be not less than 18 point.</P> <P>(4) <E T="03">Visual inspection.</E> When the label has been affixed to the final container, a sufficient area of the container shall remain uncovered for its full length or no less than 5 millimeters of the lower circumference to permit inspection of the contents. The label on a final product container for antibodies Anti-c, Anti-k, or Anti-s shall display a bar immediately over the specificity letter used in the name, i.e., Anti-c<AC T="8"/>, Anti-k<AC T="8"/>, or Anti-s<AC T="8"/>.</P> <P>(b) <E T="03">Package label.</E> The following information shall appear either on the package label or on the final container label if it is visible within the package.</P> <P>(1) Proper name of the product.</P> <P>(2) Name of the antibody or antibodies present as set forth in paragraph (d) of this section.</P> <P>(3) Name, address (including ZIP Code), and license number of the manufacturer.</P> <P>(4) Lot number, including sublot designations.</P> <P>(5) Expiration date.</P> <P>(6) Preservative used and its concentration.</P> <P>(7) Number of containers, if more than one.</P> <P>(8) Volume or equivalent volume for dried products when reconstituted, and precautions for adequate mixing when reconstituting.</P> <P>(9) Recommended storage temperature in degrees Celsius.</P> <P>(10) Source of the product if other than human serum or plasma.</P> <P>(11) Reference to enclosed package insert.</P> <P>(12) If a dried product, a statement indicating the period within which the product may be used after reconstitution.</P> <P>(13) The statement: “FOR IN VITRO DIAGNOSTIC USE.”</P> <P>(14) The statement: “MEETS FDA POTENCY REQUIREMENTS.”</P> <P>(15) If human blood was used in manufacturing the product, the statement: “CAUTION: ALL BLOOD PRODUCTS SHOULD BE TREATED AS POTENTIALLY INFECTIOUS. SOURCE MATERIAL FROM WHICH THIS PRODUCT WAS DERIVED WAS FOUND NEGATIVE WHEN TESTED IN ACCORDANCE WITH CURRENT FDA REQUIRED TESTS. NO KNOWN TEST METHODS CAN OFFER ASSURANCE THAT PRODUCTS DERIVED FROM HUMAN BLOOD WILL NOT TRANSMIT INFECTIOUS AGENTS.”</P> <P>(16) A statement of an observable indication of an alteration of the product, e.g., turbidity, color change, precipitate, that may indicate possible deterioration of the product.</P> <P>(c) <E T="03">Package insert.</E> Each final container of Blood Grouping Reagent shall be accompanied by a package insert meeting the requirements of § 809.10. If two or more final containers requiring identical package inserts are placed in a single package, only one package insert per package is required.</P> <P>(d) <E T="03">Names of antibodies.</E> </P> <EXTRACT> <HD SOURCE="HD1">Blood group designation for container label</HD> <SCOL2> <LI>Anti-A</LI> <LI>Anti-A<E T="52">1</E> </LI> <LI>Anti-A, B</LI> <LI>Anti-A and B</LI> <LI>Anti-B</LI> <LI>Anti-C</LI> <LI>Anti-C<E T="51">w</E> </LI> <LI>Anti-c<AC T="8"/> </LI> <LI>Anti-CD</LI> <LI>Anti-CDE</LI> <LI>Anti-Co<E T="51">b</E> </LI> <LI>Anti-D</LI> <LI>Anti-DE</LI> <LI>Anti-Di<E T="51">a</E> </LI> <LI>Anti-E</LI> <LI>Anti-e</LI> <LI>Anti-Fy<E T="51">a</E> </LI> <LI>Anti-Fy<E T="51">b</E> </LI> <LI>Anti-I</LI> <LI>Anti-Jk<E T="51">a</E> </LI> <LI>Anti-Jk<E T="51">b</E> </LI> <LI>Anti-Js<E T="51">a</E> </LI> <LI>Anti-Js<E T="51">b</E> </LI> <LI>Anti-K</LI> <LI>Anti-k<AC T="8"/> </LI> <LI>Anti-Kp<E T="51">a</E> </LI> <LI>Anti-Kp<E T="51">b</E> </LI> <LI>Anti-Le<E T="51">a</E> </LI> <LI>Anti-Le<E T="51">b</E> </LI> <LI>Anti-Lu<E T="51">a</E> </LI> <LI>Anti-Lu<E T="51">b</E> </LI> <LI>Anti-M</LI> <LI>Anti-M<E T="51">g</E> </LI> <LI>Anti-N</LI> <LI>Anti-P<E T="52">1</E> </LI> <LI>Anti-S</LI> <LI>Anti-s<AC T="8"/> </LI> <LI>Anti-U</LI> <LI>Anti-Wr<E T="51">a</E> </LI> <LI>Anti-Xg<E T="51">a</E> </LI> </SCOL2> </EXTRACT> <CITA>[53 FR 12764, Apr. 19, 1988, as amended at 59 FR 23637, May 6, 1994] </CITA> <EXTRACT> <FP>(Information collection requirements approved by the Office of Management and Budget under control number 0910-0209) </FP> </EXTRACT> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart D—Reagent Red Blood Cells</HD> <SOURCE> <HD SOURCE="HED">Source: </HD> <P>52 FR 37450, Oct. 7, 1987, unless otherwise noted.</P> </SOURCE> <SECTION> <PRTPAGE P="110"/> <SECTNO>§ 660.30</SECTNO> <SUBJECT>Reagent Red Blood Cells.</SUBJECT> <P>(a) <E T="03">Proper name and definition.</E> The proper name of the product shall be Reagent Red Blood Cells, which shall consist of a preparation of human red blood cells used to detect or identify human blood-group antibodies.</P> <P>(b) <E T="03">Source.</E> Reagent Red Blood Cells shall be prepared from human peripheral blood meeting the criteria of §§ 660.31 and 660.32, or from umbilical cord cells which shall be collected and prepared according to the manufacturer's product license application.</P> </SECTION> <SECTION> <SECTNO>§ 660.31</SECTNO> <SUBJECT>Suitability of the donor.</SUBJECT> <P>Donors of peripheral blood for Reagent Red Blood Cells shall meet the criteria for donor suitability under § 640.3 of this chapter, except that paragraphs (b)(5) and (6), (d), and (e) of § 640.3 shall not apply.</P> </SECTION> <SECTION> <SECTNO>§ 660.32</SECTNO> <SUBJECT>Collection of source material.</SUBJECT> <P>Blood for Reagent Red Blood Cells from donors of peripheral blood shall be collected as prescribed under § 640.4 of this chapter, except that paragraphs (c), (d), (g), and (h) of § 640.4 shall not apply.</P> </SECTION> <SECTION> <SECTNO>§ 660.33</SECTNO> <SUBJECT>Testing of source material.</SUBJECT> <P>Except as provided in this section, a sample of each blood incorporated into the Reagent Red Blood Cell product shall be individually tested, with no fewer than two donor sources of each antibody specificity employed, to confirm the identification of all blood group antigens specified in the labeling as present or absent. The manufacturer shall perform at least one of the required tests for each factor. The Reagent Red Blood Cell product may be tested with a single donor source of antibody specificity if only one source of antibody is available, and the Director, Center for Biologics Evaluation and Research, has approved the use of a single donor source of antiserum. Each of these tests shall be conducted and interpreted independently, and any discrepancy between the results of these two tests shall be resolved by testing with at least one additional antiserum before concluding that the antigen is present or absent. Where fewer than three donor sources of an antibody specificity are available, test discrepancies shall be resolved in accordance with the manufacturer's product license application. Group O Reagent Red Blood Cells used in the detection or identification of unexpected antibodies shall include at least the following common antigens in each lot of the product: D, C, E, c<AC T="8"/>, e, K, k<AC T="8"/>, Fy<E T="51">a</E>, Fy<E T="51">b</E>, Jk<E T="51">a</E>, Jk<E T="51">b</E>, Le<E T="51">a</E>, Le<E T="51">b</E>, P<E T="52">1</E>, M, N, S, and s<AC T="8"/>.</P> <CITA>[52 FR 37450, Oct. 7, 1987, as amended at 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 660.34</SECTNO> <SUBJECT>Processing.</SUBJECT> <P>(a) <E T="03">Processing method.</E> The processing method shall be one that has been shown to yield consistently a product that is capable of detecting, throughout the dating period, alloantibodies corresponding to all required blood group antigens specified in the labeling as present.</P> <P>(b) <E T="03">Products prepared from pooled red blood cells.</E> If the product is recommended for the detection of unexpected antibodies, the pool shall be prepared by combining equal amounts of cells from no more than two donors. Umbilical cord cells are exempt from this requirement. Pooled cells shall not be recommended for pretransfusion tests, done in lieu of a major crossmatch, to detect unexpected antibodies in patients' samples.</P> <P>(c) <E T="03">Absence of antibodies.</E> Each lot of final product shall be free of demonstrable antibodies, including anti-A and anti-B, unless the package insert and container lable include instructions to wash the cells before use. The final product shall also be direct antiglobulin test negative when tested with polyspecific anti-human globulin.</P> <P>(d) <E T="03">Final container.</E> The final containers used for each lot of product shall be clean and shall permit observation of the contents for hemolysis or a change in color. The final container label, container cap, and dropper bulb of a Reagent Red Blood Cell product may be color-coded with a visual match to a specific color approved by the Director, Center for Biologics Evaluation and Research.</P> <P>(e) <E T="03">Date of manufacture.</E> The date of manufacture of the product shall be the date that the blood is withdrawn <PRTPAGE P="111"/>from the donor or obtained from umbilical cords. The period during which the reagent red blood cell source material is kept by the manufacturer in storage in a frozen state at −65 <E T="61">°</E>C or colder is excluded from the dating period. If the product consists of red blood cells from two or more donors, the date of manufacture of the final product shall be the date of withdrawal of blood from the donor of the oldest constituent blood. When a product consists of more than one container, e.g., cell panel, the date of manufacture of each container of the product shall be the earliest date that blood was withdrawn from a donor for any container of the product.</P> <P>(f) <E T="03">Retention samples.</E> Retention samples shall be maintained as required by § 600.13 of this chapter, except that samples must be retained only throughout the dating period of the product.</P> <APPRO>(Approved by the Office of Management and Budget under control number 0910-0073)</APPRO> <CITA>[52 FR 37450, Oct. 7, 1987, as amended at 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 660.35</SECTNO> <SUBJECT>Labeling.</SUBJECT> <P>In addition to the items required by § 809.10 of this chapter and other applicable labeling provisions of this chapter, the following information shall be included in the labeling:</P> <P>(a)(1) A logo or company name may be placed on the final container label, however, the logo or company name shall be located along the bottom or end of the label, oustide of the main panel.</P> <P>(2) If washing the cells is required by the manufacturer, the container label shall include appropriate instructions; if the cells should not be washed before use, e.g., if washing will adversely affect the product, the package insert shall explain.</P> <P>(b) The container label of Group O cells shall state: </P> <EXTRACT> <FP>“FOR USE IN DETECTION OF UNEXPECTED ANTIBODIES” or “FOR USE IN IDENTIFICATION OF UNEXPECTED ANTIBODIES” or “NOT FOR USE IN DETECTION OR IDENTIFICATION OF UNEXPECTED ANTIBODIES”.</FP> </EXTRACT> <P>(c) Except as provided in this section, the container and package labels shall state the percentage of red blood cells in the suspension either as a discrete figure with a variance of more than <E T="61">±</E>1 percentage unit or as a range the extremes of which differ by no more than 2 percentage units. If the stated red blood cell concentration is less than 2 percent, the variance shall be no more than <E T="61">±</E>0.5 percentage unit.</P> <P>(d) The words “pooled cells” shall appear on the container and package labels of products prepared from pooled cells. The package label or package insert shall state that pooled cells are not recommended for pretransfusion tests, done in lieu of a major crossmatch, to detect unexpected antibodies in patients' samples.</P> <P>(e) The package insert of a pooled product intended for detection of unexpected antibodies shall identify the number of donors contributing to the pool. Products designed exclusively for ABO Serum Grouping and umbilical cord cells need not identify the number of donors in the pool.</P> <P>(f) When the product is a multicontainer product, e.g., a cell panel, the container label and package label shall be assigned the same identifying lot number, and shall also bear a number or symbol to distinguish one container from another. Such number or symbol shall also appear on the antigenic constitution matrix.</P> <P>(g) The package label or package insert shall state the blood group antigens that have been tested for and found present or absent on the cells of each donor, or refer to such information in an accompanying antigenic constitution matrix. Cells for ABO Serum Grouping are exempt from this requirement. The package insert or antigen constitution matrix shall list each of the antigens tested with only one source of antibody.</P> <P>(h) The package label or package insert shall bear the cautionary statement: “The reactivity of the product may decrease during the dating period.”</P> <P>(i) The package insert of a product intended for the detection or identification of unexpected antibodies shall note that the rate at which antigen reactivity (e.g., agglutinability) is lost is partially dependent upon individual donor characteristics that are neither controlled nor predicted by the manufacturer.<PRTPAGE P="112"/> </P> <P>(j) The package insert shall provide adequate directions for use.</P> <P>(k) The package insert shall bear the statement: </P> <EXTRACT> <FP>“CAUTION: ALL BLOOD PRODUCTS SHOULD BE TREATED AS POTENTIALLY INFECTIOUS. SOURCE MATERIAL FROM WHICH THIS PRODUCT WAS DERIVED WAS FOUND NEGATIVE WHEN TESTED IN ACCORDANCE WITH CURRENT FDA REQUIRED TESTS. NO KNOWN TEST METHODS CAN OFFER ASSURANCE THAT PRODUCTS DERIVED FROM HUMAN BLOOD WILL NOT TRANSMIT INFECTIOUS AGENTS.”</FP> </EXTRACT> <P>(l) The package insert or the antigenic constitution matrix for each lot of product shall specify the date of manufacture or the length of the dating period.</P> <P>(m) Manufacturers shall identify with a permanent donor code in the product labeling each donor of peripheral blood used for detection or identification of unexpected antibodies.</P> <APPRO>(Approved by the Office of Management and Budget under control number 0910-0073)</APPRO> </SECTION> <SECTION> <SECTNO>§ 660.36</SECTNO> <SUBJECT>Samples and protocols.</SUBJECT> <P>(a) The following shall be submitted to the Office of Biological Product Review Sample Custodian (ATTN: HFB-215), Bldg. 29A, Rm. 1C02, Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892, within 30 days after each routine establishment inspection by FDA.</P> <P>(1) From a lot of final product, samples from a cell panel intended for identification of unexpected antibodies. The sample shall be packaged as for distribution and shall have at least 14 days remaining in the dating period when shipped to the Center for Biologics Evaluation and Research.</P> <P>(2) A protocol which shall include the following:</P> <P>(i) Complete test records of at least two donors of the samples submitted, including original and confirmation phenotyping records.</P> <P>(ii) Bleeding records or receipt records which indicate collection date, volume, and HBsAg test results.</P> <P>(iii) Manufacturing records which document all steps involved in the preparation of the product.</P> <P>(iv) Test results which verify that the final product meets specifications.</P> <P>(v) Identity test results.</P> <P>(b) A copy of the antigenic constitution matrix specifying the antigens present or absent shall be submitted to the Director, Center for Biologics Evaluation and Research, at the time of initial distribution of each lot of Reagent Red Blood Cells for detection or identification of unexpected antibodies. Products designed exclusively to identify Anti-A, Anti-A<E T="52">1</E>, and Anti-B, as well as products composed entirely of umbilical cord cells, are excluded from this requirement.</P> <P>(c) Except for umbilical cord samples, whenever a new donor is used, a sample of red blood cells from each new donor used in a cell panel intended for the identification of unexpected antibodies shall be submitted by the manufacturer to the Director, Center for Biologics Evaluation and Research. The sample should contain a minimum volume of 0.5 milliliter of red blood cells.</P> <APPRO>(Approved by the Office of Management and Budget under control number 0910-0073)</APPRO> <CITA>[52 FR 37450, Oct. 7, 1987, as amended at 55 FR 11013 and 11015, Mar. 26, 1990]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart E—Hepatitis B Surface Antigen</HD> <SOURCE> <HD SOURCE="HED">Source: </HD> <P>44 FR 36382, June 22, 1979, unless otherwise noted.</P> </SOURCE> <SECTION> <SECTNO>§ 660.40</SECTNO> <SUBJECT>Hepatitis B Surface Antigen.</SUBJECT> <P>(a) <E T="03">Proper name and definition.</E> The proper name of this product shall be Hepatitis B Surface Antigen (HBsAg), which shall consist of a serum or tissue preparation containing one or more subtypes of the Hepatitis B Surface Antigen.</P> <P>(b) <E T="03">Source.</E> The source of the product shall be blood, plasma, serum, or tissue, obtained aseptically from nonhuman primates that have met the applicable requirements of § 600.11 of this chapter, or from human donors whose blood is positive for the Hepatitis B Surface Antigen.</P> </SECTION> <SECTION> <SECTNO>§ 660.41</SECTNO> <SUBJECT>Processing.</SUBJECT> <P>(a) <E T="03">Method.</E> The processing method shall be one that has been shown to yield consistently a specific and potent final product, free of properties which <PRTPAGE P="113"/>would adversely affect the test results when the product is tested by the methods recommended by the manufacturer in the package insert. The product and all ancillary reagents and materials supplied in the package with the product shall be manufactured in a manner that will reduce the risk of transmitting type B viral hepatitis. </P> <P>(b) <E T="03">Ancillary reagents and materials.</E> All ancillary reagents and materials supplied in the package with the product shall meet generally accepted standards of purity and quality and shall be effectively segregated and otherwise manufactured in a manner that will reduce the risk of contaminating the product and other biological products. Ancillary reagents and materials accompanying the product, which are used in the performance of the test as described by the manufacturer's recommended test procedures, shall have been shown not to affect adversely the product within the prescribed dating period.</P> <P>(c) <E T="03">Final container.</E> A final container shall be sufficiently transparent to permit visual inspection of the contents for presence of particulate matter and increased turbidity. The effectiveness of the contents of a final container shall be maintained throughout its dating period.</P> <P>(d) <E T="03">Date of manufacture.</E> The date of manufacture of Hepatitis B Surface Antigen that has been iodinated with radioactive iodine (<E T="21">125</E> I) shall be the day of labeling the antibody with the radionuclide.</P> <CITA>[44 FR 36382, June 22, 1979, as amended at 49 FR 1685, Jan. 13, 1984]</CITA> </SECTION> <SECTION> <SECTNO>§ 660.42</SECTNO> <SUBJECT>Reference panel.</SUBJECT> <P>A Reference Hepatitis B Antiserum Panel shall be obtained from the Center for Biologics Evaluation and Research, 8800 Rockville Pike, Bethesda, MD 20892, and shall be used for determining the potency and specificity of Hepatitis B Surface Antigen.</P> <CITA>[44 FR 36382, June 22, 1979, as amended at 49 FR 23834, June 8, 1984; 51 FR 15611, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 660.43</SECTNO> <SUBJECT>Potency test.</SUBJECT> <P>To be satisfactory for release, each filling of Hepatitis B Surface Antigen shall be tested against the Reference Hepatitis B Antiserum Panel and shall be sufficiently potent to be able to detect the antibody in the appropriate sera of the reference panel by all test methods recommended by the manufacturer in the package insert.</P> </SECTION> <SECTION> <SECTNO>§ 660.44</SECTNO> <SUBJECT>Specificity.</SUBJECT> <P>Each filling of the product shall be specific for Hepatitis B Surface Antigen as determined by specificity tests found acceptable to the Director, Center for Biologics Evaluation and Research.</P> <CITA>[44 FR 36382, June 22, 1979, as amended at 49 FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 660.45</SECTNO> <SUBJECT>Labeling.</SUBJECT> <P>In addition to the requirements of §§ 610.60, 610.61, and 809.10 of this chapter, the labeling shall bear the following:</P> <P>(a) The “d and y” antigen subtype and the source of the product to follow immediately the proper name on both the final container label and the package label. If the product is intended to identify antibodies to the “r and w” antigen subtype, the antigen subtype designation shall include the “r and w” antigen subtype.</P> <P>(b) The name of the test method(s) recommended for use of the product on the package label and on the final container label, when capable of bearing a full label (see § 610.60(a) of this chapter).</P> <P>(c) A warning on the package label and on the final container label stating that the product is capable of transmitting hepatitis and should be handled accordingly.</P> <P>(d) The package shall include a package insert providing (1) detailed instructions for use, (2) an adequate description of all recommended test methods, and (3) warnings as to possible hazards, including hepatitis transmitted in handling the product and any ancillary reagents and materials accompanying the product.</P> </SECTION> <SECTION> <SECTNO>§ 660.46</SECTNO> <SUBJECT>Samples; protocols; official release.</SUBJECT> <P>(a) <E T="03">Samples.</E> (1) For the purposes of this section, a sample of product not iodinated with <E T="51">125</E>I means a sample <PRTPAGE P="114"/>from each filling of each lot packaged as for distribution, including all ancillary reagents and materials; and a sample of product iodinated with <E T="51">125</E>I or unlyophilized HBsAg-coated red blood cells means a sample from each lot of diagnostic test kits in a finished package, including all ancillary reagents and materials.</P> <P>(2) Unless the Director, Center for Biologics Evaluation and Research, determines that the reliability and consistency of the finished product can be assured with a smaller quantity of sample or no sample and specifically reduces or eliminates the required quantity of sample, each manufacturer shall submit the following samples to the Director, Center for Biologics Evaluation and Research (HFB-1), 8800 Rockville Pike, Bethesda, MD 20892, within 5 working days after the manufacturer has satisfactorily completed all tests on the samples:</P> <P>(i) One sample until written notification of official release is no longer required under paragraph (c)(2) of this section.</P> <P>(ii) One sample of product at periodic intervals of 90 days, beginning after written notification of official release is no longer required under paragraph (c)(2) of this section. The sample submitted at the 90-day interval shall be from the first lot or filling, as applicable, released by the manufacturer, under the requirements of § 610.1 of this chapter, after the end of the previous 90-day interval. The sample shall be identified as “surveillance sample” and shall include the date of manufacture.</P> <P>(iii) Samples may at any time be required to be submitted to the Director, Center for Biologics Evaluation and Research, if the Director finds that continued evaluation is necessary to ensure the potency, quality, and reliability of the product.</P> <P>(b) <E T="03">Protocols.</E> For each sample submitted as required in paragraph (a)(1) of this section, the manufacturer shall send a protocol that consists of a summary of the history of manufacture of the product, including all results of each test for which test results are requested by the Director, Center for Biologics Evaluation and Research. The protocols submitted with the samples at periodic intervals as provided in paragraph (a)(2)(ii) of this section shall be identified by the manufacturer as “surveillance test results.”</P> <P>(c) <E T="03">Official release.</E> (1) The manufacturer shall not distribute the product until written notification of official release is received from the Director, Center for Biologics Evaluation and Research, except as provided in paragraph (c)(2) of this section. Official release is required for at least five consecutive lots or fillings, as applicable, manufactured after licensure of the product.</P> <P>(2) After written notification of official release is received from the Director, Center for Biologics Evaluation and Research, for at least five consecutive lots or fillings manufactured after licensure of the products, and after the manufacturer receives from the Director, Center for Biologics Evaluation and Research, written notification that official release is no longer required, subsequent lots or fillings may be released by the manufacturer under the requirements of § 610.1 of this chapter.</P> <P>(3) The manufacturer shall not distribute lots or fillings, as applicable, of products that require sample submission under paragraph (a)(2)(iii) of this section until written notification of official release or notification that official release is no longer required is received from the Director, Center for Biologics Evaluation and Research.</P> <CITA>[48 FR 20407, May 6, 1983, as amended at 49 FR 23834, June 8, 1984; 51 FR 15611, Apr. 25, 1986; 55 FR 11013 and 11014, Mar. 26, 1990]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart F—Anti-Human Globulin</HD> <SECTION> <SECTNO>§ 660.50</SECTNO> <SUBJECT>Anti-Human Globulin.</SUBJECT> <P>(a) <E T="03">Proper name and definition.</E> The proper name of this product shall be Anti-Human Globulin which shall consist of one or more antiglobulin antibodies identified in § 660.55(d) and be prepared by a method demonstrated to yield consistently a sterile product.</P> <P>(b) <E T="03">Source.</E> The source of this product shall be either serum from animals immunized with one or more human serum globulins or protein-rich fluids derived from stable immunoglobulin-secreting cell lines maintained either <PRTPAGE P="115"/>in tissue cultures or in secondary hosts.</P> <CITA>[50 FR 5579, Feb. 11, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 660.51</SECTNO> <SUBJECT>Processing.</SUBJECT> <P>(a) <E T="03">Processing method.</E> (1) The processing method shall be one that has been shown to yield consistently a specific, potent final product, free of properties that would adversely affect the product for its intended use throughout its dating period.</P> <P>(2) Anti-IgG, -C3d (polyspecific) reagents and anti-IgG products may be colored green.</P> <P>(3) Only that material which has been fully processed, thoroughly mixed in a single vessel, and sterile filtered shall constitute a lot. Each lot shall be identified by a lot number.</P> <P>(4) A lot may be subdivided into clean, sterile vessels. Each subdivision shall constitute a sublot which shall be identified by the lot number to which has been added a distinctive prefix or suffix. If lots are to be subdivided, the manufacturer shall include this information in the license application and on the protocol. The manufacturer shall describe the test specifications to verify that each sublot is identical to other sublots of the lot.</P> <P>(b) <E T="03">Final containers and dropper assemblies.</E> (1) Final containers and dropper assemblies shall be clean.</P> <P>(2) Final containers and dropper pipettes shall be colorless and sufficiently transparent to permit observation of the contents for presence of particulate matter or increased turbidity.</P> <P>(c) <E T="03">Date of manufacture.</E> The date of manufacture shall be the date the manufacturer begins the last entire group of potency tests.</P> <APPRO>(Approved by the Office of Management and Budget under control number 0910-0208)</APPRO> <CITA>[50 FR 5579, Feb. 11, 1985, as amended at 50 FR 16474, Apr. 26, 1985]</CITA> </SECTION> <SECTION> <SECTNO>§ 660.52</SECTNO> <SUBJECT>Reference preparations.</SUBJECT> <P>Reference Anti-Human Globulin preparations shall be obtained from the Center for Biologics Evaluation and Research (HFB-221), Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892, and shall be used as described in the accompanying package insert for determining the potency of Anti-Human Globulin.</P> <APPRO>(Approved by the Office of Management and Budget under control number 0910-0208)</APPRO> <CITA>[50 FR 5579, Feb. 11, 1985, as amended at 50 FR 16474, Apr. 26, 1985; 51 FR 15611, Apr. 25, 1986; 55 FR 11015, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 660.53</SECTNO> <SUBJECT>Controls for serological procedures.</SUBJECT> <P>Red blood cells sensitized with complement shall be tested with appropriate positive and negative control antisera. All tests shall be performed in accordance with serological testing procedures approved by the Director, Center for Biologics Evaluation and Research (HFB-1), Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892.</P> <APPRO>(Approved by the Office of Management and Budget under control number 0910-0208)</APPRO> <CITA>[50 FR 5579, Feb. 11, 1985, as amended at 50 FR 16474, Apr. 26, 1985; 51 FR 15611, Apr. 25, 1986; 55 FR 11014, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 660.54</SECTNO> <SUBJECT>Potency tests, specificity tests, tests for heterospecific antibodies, and additional tests for nonspecific properties.</SUBJECT> <P>The following tests shall be performed using test procedures approved by the Director, Center for Biologics Evaluation and Research (HFB-1), Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892:</P> <P>(a) Potency tests for determining anti-IgG and anti-complement activity.</P> <P>(b) Specificity tests, tests for heterospecific antibodies, and additional tests for nonspecific properties.</P> <APPRO>(Approved by the Office of Management and Budget under control number 0910-0208)</APPRO> <CITA>[50 FR 5579, Feb. 11, 1985, as amended at 50 FR 16474, Apr. 26, 1985; 51 FR 15611, Apr. 25, 1986; 55 FR 11014, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 660.55</SECTNO> <SUBJECT>Labeling.</SUBJECT> <P>In addition to the applicable labeling requirements of §§ 610.62 through 610.65 and § 809.10 of this chapter, and in lieu of the requirements in §§ 610.60 and 610.61 of this chapter, the following requirements shall be met:</P> <P>(a) <E T="03">Final container label</E>—(1) <E T="03">Color coding.</E> The main panel of the final container label of all Anti-IgG, -C3d (polyspecific) reagents shall be white <PRTPAGE P="116"/>or colorless and printing shall be solid dark contrasting lettering. The main panel of the final container label of all other Anti-Human Globulin reagents shall be black with solid white lettering. A logo or company name may be placed on the final container label, however, the logo or company name shall be located along the bottom or end of the label, outside of the main panel.</P> <P>(2) <E T="03">Required information.</E> The proper name “Anti-Human Globulin” need not appear on the final container label provided the final container is distributed in a package and the package label bears the proper name. The final container label shall bear the following information:</P> <P>(i) Name of the antibody or antibodies present as set forth in paragraph (d) of this section. Anti-Human Globulin may contain one or more antibodies to either immunoglobulins or complement components but the name of each significant antibody must appear on the final container label (e.g., anti-C3b,- -C3d, -C4d). The final container labels of polyspecific Anti-Human Globulin are not required to identify antibody specificities other than anti-IgG and anti-C3d but the reactivity of the Anti-Human Globulin shall be accurately described in the package insert.</P> <P>(ii) Name, address, and license number of the manufacturer.</P> <P>(iii) Lot number, including any sublot designations.</P> <P>(iv) Expiration date.</P> <P>(v) Source of the product.</P> <P>(vi) Recommended storage temperature in degrees Celsius.</P> <P>(vii) Volume of product.</P> <P>(viii) Appropriate cautionary statement if the Anti-Human Globulin is not polyspecific. For example, “DOES NOT CONTAIN ANTIBODIES TO IMMUNOGLOBULINS” or “DOES NOT CONTAIN ANTIBODIES TO COMPLEMENT COMPONENTS.”</P> <P>(ix) If the final container is not enclosed in a package, all items required for a package label shall appear on the container label.</P> <P>(3) <E T="03">Lettering size.</E> The type size for the designation of the specific antibody on the label of a final container shall be not less than 12 point, unless otherwise approved by the Director, Center for Biologics Evaluation and Research (HFB-1). The prefix anti- and other parts of the name such as polyspecific may appear in smaller type.</P> <P>(4) <E T="03">Visual inspection.</E> When the label has been affixed to the final container, a sufficient area of the container shall remain uncovered for its full length or for no less than 5 millimeters of the lower circumference to permit inspection of the contents.</P> <P>(b) <E T="03">Package label.</E> The following items shall appear either on the package label or on the final container label if see-through packaging is used:</P> <P>(1) Proper name of the product, and the name of the antibody or antibodies as listed in paragraph (d) of this section.</P> <P>(2) Name, address (including zip code), and license number of the manufacturer.</P> <P>(3) Lot number, including any sublot designations.</P> <P>(4) Expiration date.</P> <P>(5) Preservative(s) used and its concentration.</P> <P>(6) Number of containers, if more than one.</P> <P>(7) Recommended storage temperature in degrees Celsius.</P> <P>(8) Source of the product.</P> <P>(9) Reference to enclosed package insert.</P> <P>(10) The statement: “For In Vitro Diagnostic Use.”</P> <P>(11) The statement: “Meets FDA Potency Requirements.”</P> <P>(12) A statement of an observable indication of an alteration of the product, e.g., turbidity, color change, precipitate, that may indicate possible deterioration of the product.</P> <P>(13) Appropriate cautions.</P> <P>(c) <E T="03">Package insert.</E> Each final container of Anti-Human Globulin shall be accompanied by a package insert meeting the requirements of § 809.10 of this chapter. If two or more final containers requiring identical package inserts are placed in a single package, only one package insert per package is required.</P> <P>(d) <E T="03">Names of antibodies.</E> </P> <GPOTABLE CDEF="xs60,r50" COLS="2" OPTS="L2"> <BOXHD> <CHED H="1">Antibody designation on container label</CHED> <CHED H="1">Definition</CHED> </BOXHD> <ROW> <ENT I="01">(1) Anti-IgG, -C3d; Polyspecific </ENT> <ENT>Contains anti-IgG and anti-C3d (may contain other anticomplement and anti-immunoglobulin antibodies).</ENT> </ROW> <ROW> <PRTPAGE P="117"/> <ENT I="01">(2) Anti-IgG </ENT> <ENT>Contains anti-IgG with no anti-complement activity (not necessarily gamma chain specific).</ENT> </ROW> <ROW> <ENT I="01">(3) Anti-IgG; heavy chains </ENT> <ENT>Contains only antibodies reactive against human gamma chains.</ENT> </ROW> <ROW> <ENT I="01">(4) Anti-C3b </ENT> <ENT>Contains only C3b antibodies with no anti-immunoglobulin activity. <E T="02">Note:</E> The antibody produced in response to immunization is usually directed against the antigenic determinant which is located in the C3c subunit; some persons have called this antibody “anti-C3c.” In product labeling, this antibody should be designated anti-C3b.</ENT> </ROW> <ROW> <ENT I="01">(5) Anti-C3d </ENT> <ENT>Contains only C3d antibodies with no anti-immunoglobulin activity.</ENT> </ROW> <ROW> <ENT I="01">(6) Anti-C4b </ENT> <ENT>Contains only C4b antibodies with no anti-immunoglobulin activity.</ENT> </ROW> <ROW> <ENT I="01">(7) Anti-C4d </ENT> <ENT>Contains only C4d antibodies with no anti-immunoglobulin activity.</ENT> </ROW> </GPOTABLE> <P>Anti-Human Globulin preparations may contain one or more of the antibody specificities listed in this paragraph as described in paragraph (a)(2)(i) of this section.</P> <APPRO>(Approved by the Office of Management and Budget under control number 0910-0208)</APPRO> <CITA>[50 FR 5579, Feb. 11, 1985; 50 FR 9800, Mar. 12, 1985, as amended at 50 FR 16474, Apr. 26, 1985; 55 FR 11014, Mar. 26, 1990]</CITA> </SECTION> </SUBPART> </PART> <PART> <EAR>Pt. 680</EAR> <HD SOURCE="HED">PART 680—ADDITIONAL STANDARDS FOR MISCELLANEOUS PRODUCTS</HD> <CONTENTS> <SECHD>Sec.</SECHD> <SECTNO>680.1</SECTNO> <SUBJECT>Allergenic Products.</SUBJECT> <SECTNO>680.2</SECTNO> <SUBJECT>Manufacture of Allergenic Products.</SUBJECT> <SECTNO>680.3</SECTNO> <SUBJECT>Tests.</SUBJECT> </CONTENTS> <AUTH> <HD SOURCE="HED">Authority: </HD> <P>21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 U.S.C. 216, 262, 263, 263a, 264.</P> </AUTH> <SOURCE> <HD SOURCE="HED">Source: </HD> <P>38 FR 32100, Nov. 20, 1973, unless otherwise noted.</P> </SOURCE> <CROSSREF> <HD SOURCE="HED"> <E T="04">Cross References:</E> </HD> <P>For U.S. Customs Service regulations relating to viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal Service regulations relating to the admissibility to the United States mails see parts 124 and 125 of the Domestic Mail Manual, that is incorporated by reference in 39 CFR part 111. </P> </CROSSREF> <SECTION> <SECTNO>§ 680.1</SECTNO> <SUBJECT>Allergenic Products.</SUBJECT> <P>(a) <E T="03">Definition.</E> Allergenic Products are products that are administered to man for the diagnosis, prevention or treatment of allergies.</P> <P>(b) <E T="03">Source materials—</E>(1) <E T="03">Criteria for source material.</E> Only specifically identified allergenic source materials that contain no more than a total of 1.0 percent of detectable foreign materials shall be used in the manufacture of Allergenic Products, except that this requirement shall not apply to molds and animals described under paragraphs (b) (2) and (3) of this section, respectively. Source materials such as pelts, feathers, hairs, and danders shall be collected in a manner that will minimize contamination of the source material.</P> <P>(2) <E T="03">Molds.</E> (i) Molds (excluding rusts and smuts) used as source material in the manufacture of Allergenic Products shall meet the requirements of § 610.18 of this chapter and § 680.2 (a) and (b).</P> <P>(ii) Mold cultures shall be free of contaminating materials (including microorganisms) prior to harvest, and care shall be taken to minimize contamination during harvest and subsequent processing.</P> <P>(iii) Mold manufacturers shall maintain written standard operating procedures, developed by a qualified individual, that will ensure the identity of the seed culture, prescribe adequate processing of the mold, and specify the acceptable limits and kinds of contamination. These limits shall be based on results of appropriate tests performed by the manufacturer on at least three consecutive lots of a mold that is a representative species of mold subject to the standard operating procedures. The tests shall be performed at each manufacturing step during and subsequent to harvest, as specified in the standard operating procedures. Before use of the mold as a source material for Allergenic Products, in accordance with 21 CFR 601.2, the standard operating procedures and test data from the three representative lots described above shall be submitted to and approved by the Director, Center for Biologics Evaluation and Research (HFB-1). </P> <P>(3) <E T="03">Mammals and birds</E>—(i) <E T="03">Care of animals</E>. Animals intended as a source material for Allergenic Products shall be maintained by competent personnel in facilities or designated areas that will ensure adequate care. Competent veterinary care shall be provided as needed.<PRTPAGE P="118"/> </P> <P>(ii) <E T="03">Health of animals</E>. Only animals in good health and free from detectable skin diseases shall be used as a source material for Allergenic Products. The determination of good health prior to collection of the source material shall be made by a licensed veterinarian or a competent individual under the supervision and instruction of a licensed veterinarian provided that the licensed veterinarian certifies in writing that the individual is capable of determining the good health of the animals.</P> <P>(iii) <E T="03">Immunization against tetanus</E>. Animals of the equine genus intended as a source material for Allergenic Products shall be treated to maintain immunity to tetanus.</P> <P>(iv) <E T="03">Reporting of certain diseases</E>. In cases of actual or suspected infection with foot and mouth disease, glanders, tetanus, anthrax, gas gangrene, equine infectious anemia, equine encephalomyelitis, or any of the pock diseases among animals intended for use or used as source material in the manufacture of allergenic Products, the manufacturer shall immediately notify the Director, Center for Biologics Evaluation and Research (HFB-1).</P> <P>(v) <E T="03">Dead animals</E>. Dead animals may be used as source material in the manufacture of Allergenic Products: <E T="03">Provided</E>, That (<E T="03">a</E>) the carcasses shall be frozen or kept cold until the allergen can be collected, or shall be stored under other acceptable conditions so that the postmortal decomposition processes do not adversely affect the allergen, and (<E T="03">b</E>) when alive, the animal met the applicable requirements prescribed in paragraphs (b)(3) (i), (ii), and (iii) of this section.</P> <P>(vi) <E T="03">Mammals and birds inspected by the U.S. Department of Agriculture</E>. Mammals and birds, subject to inspection by the U.S. Department of Agriculture at the time of slaughter and found suitable as food, may be used as a source material, and the requirements of paragraph (b)(3) (i) through (iv) of this section do not apply in such a case. Notwithstanding U.S. Department of Agriculture inspection, the carcasses of such inspected animals shall be frozen or kept cold until the allergen is collected, or shall be stored under other acceptable conditions so that the postmortal decomposition processes do not adversely affect the allergen.</P> <P>(c) <E T="03">Listing of source materials and suppliers</E>. Each licensed manufacturer shall initially list with the Director, Center for Biologics Evaluation and Research (HFB-1), the name and address of each of the manufacturer's source material suppliers. The listing shall identify each source material obtained from each source material supplier. The licensed manufacturers shall update the listing annually to include new source material suppliers or to delete those no longer supplying source materials.</P> <P>(d) <E T="03">Exemptions</E>. (1) Exemptions or modifications from the requirements under paragraph (b) of this section shall be made only upon written approval by the Director, Center for Biologics Evaluation and Research (HFB-1).</P> <P>(2) Nonlicensed source material suppliers are exempt from drug registration.</P> <APPRO>(Approved by the Office of Management and Budget under control number 09l0-0124 for paragraph (b)(2)(iii) and control number 0910-0161 for paragraph (c))</APPRO> <CITA>[38 FR 32100, Nov. 20, 1973, as amended at 49 FR 25432, June 21, 1984; 49 FR 31395, Aug. 7, 1984; 55 FR 11014, Mar. 26, 1990]</CITA> </SECTION> <SECTION> <SECTNO>§ 680.2</SECTNO> <SUBJECT>Manufacture of Allergenic Products.</SUBJECT> <P>(a) <E T="03">Extraneous allergenic substances.</E> All manufacturing steps shall be performed so as to insure that the product will contain only the allergenic and other substances intended to be included in the final product.</P> <P>(b) <E T="03">Cultures derived from microorganisms.</E> Culture media into which organisms are inoculated for the manufacture of Allergenic Products shall contain no allergenic substances other than those necessary as a growth requirement. Neither horse protein nor any allergenic derivative of horse protein shall be used in culture media.</P> <P>(c) <E T="03">Liquid products for oral administration.</E> Liquid products intended for oral administration that are filled in multiple dose final containers shall contain a preservative in a concentration adequate to inhibit microbial growth.<PRTPAGE P="119"/> </P> <P>(d) <E T="03">Residual pyridine.</E> Products for which pyridine is used in manufacturing shall have no more residual pyridine in the final product than 25 micrograms per milliliter.</P> <P>(e) [Reserved]</P> <P>(f) <E T="03">Records.</E> A record of the history of the manufacture or propagation of each lot of source material intended for manufacture of final Allergenic Products shall be available at the establishment of the manufacturer of the source material, as required by § 211.188 (OMB control number 0910-0139) of this chapter. A summary of the history of the manufacture or propagation of the source material shall be available at the establishment of the manufacturer of the final product.</P> <CITA>[38 FR 32100, Nov. 20, 1973, as amended at 49 FR 25433, June 21, 1984]</CITA> </SECTION> <SECTION> <SECTNO>§ 680.3</SECTNO> <SUBJECT>Tests.</SUBJECT> <P>(a) <E T="03">Identity.</E> When a specific identity test meeting the provisions of § 610.14 of this chapter cannot be performed, the manufacture of each lot shall be separated from the manufacture of other products in a manner that will preclude adulteration, and records made in the course of manufacture shall be in sufficient detail to verify the identity of the product.</P> <P>(b) <E T="03">Safety.</E> A safety test shall be performed on the contents of a final container of each lot of each product as prescribed in § 610.11 of this chapter, except for the following:</P> <P>(1) For lots consisting of no more than 20 final containers or 20 sets of individual dilutions, or where the final container contains no more than one intended human dose, the safety test need not be performed on the contents of a final container provided the safety test is performed on each lot of stock concentrate and on each lot of diluent contained in the final product. Only stock concentrates and diluents which have passed the general safety test shall be kept in the work areas used for the manufacture of Allergenic Products. A stock concentrate is an extract derived from a single allergenic source and used in the manufacture of more than one lot of product, and from which final dilutions or mixtures, are prepared directly.</P> <P>(2) For powders for scratch tests, a sample shall be suspended in a suitable diluent and injected into each animal, and the sample size shall be the single human dose recommended.</P> <P>(c) <E T="03">Sterility.</E> A sterility test shall be performed on each lot of each Allergenic Product as prescribed in § 610.12 of this chapter, with the following exceptions:</P> <P>(1) When bulk material is not prepared, the sterility test prescribed for bulk material shall be performed on each container of each stock concentrate at the time a stock concentrate is prepared, and the test sample shall be no less than 1 ml. from each stock concentrate container.</P> <P>(2) For lots consisting of no more than 5 final containers, the final container test shall be performed in accordance with § 610.12(g)(6) of this chapter using the sample therein prescribed or using a sample of no less than 0.25 ml. of product from each final container, divided in approximately equal proportions for testing in Fluid Thioglycollate and Soybean-Casein Digest Media. The test sample in the later alternative method may be an overfill in the final container.</P> <P>(3) For products prepared in sets of individual dilution series, a test sample of 0.25 ml. shall be taken from a final container of each dilution, which samples may be pooled and one half of the pooled material used for the test with Fluid Thioglycollate Medium and one half used for the test with Soybean-Casein Digest Medium.</P> <P>(4) Tablets and capsules need not be tested for sterility provided aseptic techniques are employed in their manufacture.</P> <P>(d) [Reserved]</P> <P>(e) <E T="03">Potency.</E> The potency of each lot of each Allergenic Product shall be determined as prescribed in § 610.10 of this chapter. Except as provided in this section, the potency test methods shall measure the allergenic activity of the product. Until manufacturers are notified by the Director, Center for Biologics Evaluation and Research, of the existence of a potency test that measures the allergenic activity of an allergenic product, manufacturers may continue to use unstandardized potency designations.<PRTPAGE P="120"/> </P> <P>(f) <E T="03">Records.</E> The records related to the testing requirements of this section shall be prepared and maintained as required by §§ 211.165, 211.167, 211.188, and 211.194 of this chapter. </P> <EXTRACT> <FP>(Information collection requirements in this section were approved by the Office of Management and Budget under control number 0910-0139)</FP> </EXTRACT> <CITA>[38 FR 32100, Nov. 20, 1973, as amended at 39 FR 19777, June 6, 1974; 41 FR 4015, Jan. 28, 1976; 52 FR 37607, Oct. 8, 1987; 55 FR 11013, Mar. 26, 1990]</CITA> <LRH>21 CFR Ch. I (4-1-99 Edition)</LRH> <RRH>Food and Drug Administration, HHS</RRH> </SECTION> </PART> </SUPERSED> </EFFDNOT> </SECTION> </SUBPART> </SUPERSED> </EFFDNOT> </SECTION> </SUBPART> </PART> </SUBCHAP> <SUBCHAP TYPE="P"> <PRTPAGE P="121"/> <HD SOURCE="HED">SUBCHAPTER G—COSMETICS</HD> <PART> <EAR>Pt. 700</EAR> <HD SOURCE="HED">PART 700—GENERAL</HD> <CONTENTS> <SUBPART> <HD SOURCE="HED">Subpart A—General Provisions</HD> <SECHD>Sec.</SECHD> <SECTNO>700.3</SECTNO> <SUBJECT>Definitions.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart B—Requirements for Specific Cosmetic Products</HD> <SECTNO>700.11</SECTNO> <SUBJECT>Cosmetics containing bithionol.</SUBJECT> <SECTNO>700.13</SECTNO> <SUBJECT>Use of mercury compounds in cosmetics including use as skinbleaching agents in cosmetic preparations also regarded as drugs.</SUBJECT> <SECTNO>700.14</SECTNO> <SUBJECT>Use of vinyl chloride as an ingredient, including propellant of cosmetic aerosol products.</SUBJECT> <SECTNO>700.15</SECTNO> <SUBJECT>Use of certain halogenated salicylanilides as ingredients in cosmetic products.</SUBJECT> <SECTNO>700.16</SECTNO> <SUBJECT>Use of aerosol cosmetic products containing zirconium.</SUBJECT> <SECTNO>700.18</SECTNO> <SUBJECT>Use of chloroform as an ingredient in cosmetic products.</SUBJECT> <SECTNO>700.19</SECTNO> <SUBJECT>Use of methylene chloride as an ingredient of cosmetic products.</SUBJECT> <SECTNO>700.23</SECTNO> <SUBJECT>Chlorofluorocarbon propellants.</SUBJECT> <SECTNO>700.25</SECTNO> <SUBJECT>Tamper-resistant packaging requirements for cosmetic products.</SUBJECT> </SUBPART> </CONTENTS> <AUTH> <HD SOURCE="HED">Authority: </HD> <P>21 U.S.C. 321, 331, 352, 355, 361, 362, 371, 374.</P> </AUTH> <SOURCE> <HD SOURCE="HED">Source: </HD> <P>39 FR 10054, Mar. 15, 1974, unless otherwise noted.</P> </SOURCE> <SUBPART> <HD SOURCE="HED">Subpart A—General Provisions</HD> <SECTION> <SECTNO>§ 700.3</SECTNO> <SUBJECT>Definitions.</SUBJECT> <P>As used in this subchapter:</P> <P>(a) The term <E T="03">act</E> means the Federal Food, Drug, and Cosmetic Act.</P> <P>(b) The term <E T="03">cosmetic product</E> means a finished cosmetic the manufacture of which has been completed. Any cosmetic product which is also a drug or device or component thereof is also subject to the requirements of Chapter V of the act.</P> <P>(c) The term <E T="03">flavor</E> means any natural or synthetic substance or substances used solely to impart a taste to a cosmetic product.</P> <P>(d) The term <E T="03">fragrance</E> means any natural or synthetic substance or substances used solely to impart an odor to a cosmetic product.</P> <P>(e) The term <E T="03">ingredient</E> means any single chemical entity or mixture used as a component in the manufacture of a cosmetic product.</P> <P>(f) The term <E T="03">proprietary ingredient</E> means any cosmetic product ingredient whose name, composition, or manufacturing process is protected from competition by secrecy, patent, or copyright.</P> <P>(g) The term <E T="03">chemical description</E> means a concise definition of the chemical composition using standard chemical nomenclature so that the chemical structure or structures of the components of the ingredient would be clear to a practicing chemist. When the composition cannot be described chemically, the substance shall be described in terms of its source and processing.</P> <P>(h) The term <E T="03">cosmetic raw material</E> means any ingredient, including an ingredient that is a mixture, which is used in the manufacture of a cosmetic product for commercial distribution and is supplied to a cosmetic product manufacturer, packer, or distributor by a cosmetic raw material manufacturer or supplier.</P> <P>(i) The term <E T="03">commercial distribution</E> of a cosmetic product means annual gross sales in excess of $1,000 for that product.</P> <P>(j) <E T="03">Establishment</E> means a place of business where cosmetic products are manufactured or packaged.</P> <P>(k) The term <E T="03">manufacture</E> of a cosmetic product means the making of any cosmetic product by chemical, physical, biological, or other procedures, including manipulation, sampling, testing, or control procedures applied to the product.</P> <P>(l) The term <E T="03">packaging</E> of a cosmetic product means filling or labeling the product container, including changing the immediate container or label (but excluding changing other labeling) at any point in the distribution of the cosmetic product from the original place of manufacture to the person who makes final delivery or sale to the ultimate consumer.</P> <P>(m) The term <E T="03">all business trading names used by the establishment</E> means any name which is used on a cosmetic product label and owned by the cosmetic product manufacturer or packer, <PRTPAGE P="122"/>but is different from the principal name under which the cosmetic product manufacturer or packer is registered.</P> <P>(n) The definitions and interpretations contained in sections 201, 601, and 602 of the act shall be applicable to such terms when used in the regulations in this subchapter.</P> <P>(o) <E T="03">System of commercial distribution</E> of a cosmetic product means any distribution outside the establishment manufacturing the product, whether for sale, to promote future sales (including free samples of the product), or to gage consumer acceptance through market testing, in excess of $1,000 in cost of goods.</P> <P>(p) <E T="03">Filed screening procedure</E> means a procedure that is:</P> <P>(1) On file with the Food and Drug Administration and subject to public inspection;</P> <P>(2) Designed to determine that there is a reasonable basis for concluding that an alleged injury did not occur in conjunction with the use of the cosmetic product; and</P> <P>(3) Which is subject, upon request by the Food and Drug Administration, to an audit conducted by the Food and Drug Administration at reasonable times and, where an audit is conducted, such audit shows that the procedure is consistently being applied and that the procedure is not disregarding reportable information.</P> <P>(q) <E T="03">Reportable experience</E> means an experience involving any allergic reaction, or other bodily injury, alleged to be the result of the use of a cosmetic product under the conditions of use prescribed in the labeling of the product, under such conditions of use as are customary or reasonably foreseeable for the product or under conditions of misuse, that has been reported to the manufacturer, packer, or distributor of the product by the affected person or any other person having factual knowledge of the incident, other than an alleged experience which has been determined to be unfounded or spurious when evaluated by a filed screening procedure.</P> <CITA>[39 FR 10054, Mar.15, 1974, as amended at 46 FR 38073, July 24, 1981]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart B—Requirements for Specific Cosmetic Products</HD> <SECTION> <SECTNO>§ 700.11</SECTNO> <SUBJECT>Cosmetics containing bithionol.</SUBJECT> <P>(a) Bithionol has been used to some extent as an antibacterial agent in cosmetic preparations such as detergent bars, shampoos, creams, lotions, and bases used to hide blemishes. New evidence of clinical experience and photopatch tests indicate that bithionol is capable of causing photosensitivity in man when used topically and that in some instances the photosensitization may persist for prolonged periods as severe reactions without further contact with sensitizing articles. Also, there is evidence to indicate that bithionol may produce cross-sensitization with other commonly used chemicals such as certain halogenated salicylanilides and hexachlorophene. It is, therefore, the view of the Food and Drug Administration that bithionol is a deleterious substance which may render any cosmetic product that contains it injurious to users. Accordingly, any cosmetic containing bithionol is deemed to be adulterated under section 601(a) of the Federal Food, Drug, and Cosmetic Act.</P> <P>(b) Regulatory proceedings may be initiated with respect to any cosmetic preparation containing bithionol shipped within the jurisdiction of the act after March 15, 1968.</P> </SECTION> <SECTION> <SECTNO>§ 700.13</SECTNO> <SUBJECT>Use of mercury compounds in cosmetics including use as skinbleaching agents in cosmetic preparations also regarded as drugs.</SUBJECT> <P>(a) Mercury-containing cosmetic preparations have been represented for many years as skin-bleaching agents or as preparations to remove or prevent freckles and/or brown spots (so-called age spots). Preparations intended for such use are regarded as drugs as well as cosmetics. In addition to such use as skin-bleaching agents, mercury compounds have also been widely used as preservatives in cosmetics such as hand and body creams and lotions; hair shampoos, hair sets and rinses, hair straighteners, hair coloring, and other preparations; bath oils, bubble bath, and other bath preparations; makeup; <PRTPAGE P="123"/>antiperspirants and deodorants; and eye-area cosmetics.</P> <P>(b) The toxicity of mercury compounds is extensively documented in scientific literature. It is well known that mercury compounds are readily absorbed through the unbroken skin as well as through the lungs by inhalation and by intestinal absorption after ingestion. Mercury is absorbed from topical application and is accumulated in the body, giving rise to numerous adverse effects. Mercury is a potent allergen and sensitizer, and skin irritation is common after topical application. Cosmetic preparations containing mercury compounds are often applied with regularity and frequency for prolonged periods. Such chronic use of mercury-containing skin-bleaching preparations has resulted in the accumulation of mercury in the body and the occurrence of severe reactions. Recently it has also been determined that microorganisms in the environment can convert various forms of mercury into highly toxic methyl mercury which has been found in the food supply and is now considered to be a serious environmental problem.</P> <P>(c) The effectiveness of mercury-containing preparations as skin-bleaching agents is questionable. The Food and Drug Administration has not been provided with well controlled studies to document the effectiveness of these preparations. Although mercurial preservatives are recognized as highly effective, less toxic and satisfactory substitutes are available except in the case of certain eye-area cosmetics.</P> <P>(d) Because of the known hazards of mercury, its questionable efficacy as a skin-bleaching agent, and the availability of effective and less toxic nonmercurial preservatives, there is no justification for the use of mercury in skin-bleaching preparations or its use as a preservative in cosmetics, with the exception of eye-area cosmetics for which no other effective and safe nonmercurial preservative is available. The continued use of mercurial preservatives in such eye-area cosmetics is warranted because mercury compounds are exceptionally effective in preventing <E T="03">Pseudomonas</E> contamination of cosmetics and <E T="03">Pseudomonas</E> infection of the eye can cause serious injury, including blindness. Therefore:</P> <P>(1) The Food and Drug Administration withdraws the opinion expressed in trade correspondence TC-9 (issued May 13, 1939) and concludes that any product containing mercury as a skin-bleaching agent and offered for sale as skin-bleaching, beauty, or facial preparation is misbranded within the meaning of sections 502(a), 502(f)(1) and (2), and 502(j), and may be a new drug without approval in violation of section 505 of the Federal Food, Drug, and Cosmetic Act. Any such preparation shipped within the jurisdiction of the Act after January 5, 1973 will be the subject of regulatory action.</P> <P>(2) The Food and Drug Administration withdraws the opinion expressed in trade correspondence TC-412 (issued Feb. 11, 1944) and will regard as adulterated within the meaning of section 601(a) of the Act any cosmetic containing mercury unless the cosmetic meets the conditions of paragraph (d)(2) (i) or (ii) of this section.</P> <P>(i) It is a cosmetic containing no more than a trace amount of mercury and such trace amount is unavoidable under conditions of good manufacturing practice and is less than 1 part per million (0.0001 percent), calculated as the metal; or</P> <P>(ii) It is a cosmetic intended for use only in the area of the eye, it contains no more than 65 parts per million (0.0065 percent) of mercury, calculated as the metal, as a preservative, and there is no effective and safe nonmercurial substitute preservative available for use in such cosmetic.</P> </SECTION> <SECTION> <SECTNO>§ 700.14</SECTNO> <SUBJECT>Use of vinyl chloride as an ingredient, including propellant of cosmetic aerosol products.</SUBJECT> <P>(a) Vinyl chloride has been used as an ingredient in cosmetic aerosol products including hair sprays. Where such aerosol products are used in the confines of a small room, as is often the case, the level of vinyl chloride to which the individual may be exposed could be significantly in excess of the safe level established in connection with occupational exposure. Evidence indicates that vinyl chloride inhalation can result in acute toxicity, manifested by dizziness, headache, disorientation, and <PRTPAGE P="124"/>unconsciousness where inhaled at high concentrations. Studies also demonstrate carcinogenic effects in animals as a result of inhalation exposure to vinyl chloride. Furthermore, vinyl chloride has recently been linked to liver disease, including liver cancer, in workers engaged in the polymerization of vinyl chloride. It is the view of the Commissioner that vinyl chloride is a deleterious substance which may render any cosmetic aerosol product that contains it as an ingredient injurious to users. Accordingly, any cosmetic aerosol product containing vinyl chloride as an ingredient is deemed to be adulterated under section 601(a) of the Federal Food, Drug, and Cosmetic Act.</P> <P>(b) Any cosmetic aerosol product containing vinyl chloride as an ingredient shipped within the jurisdiction of the Act is subject to regulatory action.</P> <CITA>[39 FR 30830, Aug. 26, 1974]</CITA> </SECTION> <SECTION> <SECTNO>§ 700.15</SECTNO> <SUBJECT>Use of certain halogenated salicylanilides as ingredients in cosmetic products.</SUBJECT> <P>(a) Halogenated salicylanilides (tribromsalan (TBS,3,4′,5-tribromosalicylanilide), dibromsalan (DBS,4′5-dibromosalicylanilide), metabromsalan (MBS, 3,5 - dibromosalicylanilide) and 3,3′,4,5′- tetrachlorosalicylanilide (TCSA)) have been used as antimicrobial agents for a variety of purposes in cosmetic products. These halogenated salicylanilides are potent photosensitizers and cross-sensitizers and can cause disabling skin disorders. In some instances, the photosensitization may persist for prolonged periods as a severe reaction without further exposure to these chemicals. Safer alternative antimicrobial agents are available.</P> <P>(b) These halogenated salicylanilides are deleterious substances which render any cosmetic that contains them injurious to users. Therefore, any cosmetic product that contains such a halogenated salicylanilide as an ingredient at any level for any purpose is deemed to be adulterated under section 601(a) of the Federal Food, Drug, and Cosmetic Act.</P> <P>(c) Any cosmetic product containing these halogenated salicylanilides as an ingredient that is initially introduced into interstate commerce after December 1, 1975, that is not in compliance with this section is subject to regulatory action.</P> <CITA>[40 FR 50531, Oct. 30, 1975]</CITA> </SECTION> <SECTION> <SECTNO>§ 700.16</SECTNO> <SUBJECT>Use of aerosol cosmetic products containing zirconium.</SUBJECT> <P>(a) Zirconium-containing complexes have been used as an ingredient in cosmetics and/or cosmetics that are also drugs, as, for example, aerosol antiperspirants. Evidence indicates that certain zirconium compounds have caused human skin granulomas and toxic effects in the lungs and other organs of experimental animals. When used in aerosol form, some zirconium will reach the deep portions of the lungs of users. The lung is an organ, like skin, subject to the development of granulomas. Unlike the skin, the lung will not reveal the presence of granulomatous changes until they have become advanced and, in some cases, permanent. It is the view of the Commissioner that zirconium is a deleterious substance that may render any cosmetic aerosol product that contains it injurious to users.</P> <P>(b) Any aerosol cosmetic product containing zirconium is deemed to be adulterated under section 601(a) of the Federal Food, Drug, and Cosmetic Act.</P> <P>(c) Any such cosmetic product introduced in interstate commerce after September 15, 1977 is subject to regulatory action.</P> <CITA>[42 FR 41376, Aug. 16, 1977]</CITA> </SECTION> <SECTION> <SECTNO>§ 700.18</SECTNO> <SUBJECT>Use of chloroform as an ingredient in cosmetic products.</SUBJECT> <P>(a) Chloroform has been used as an ingredient in cosmetic products. Recent information has become available associating chloroform with carcinogenic effects in animals. Studies conducted by the National Cancer Institute have demonstrated that the oral administration of chloroform to mice and rats induced hepatocellular carcinomas (liver cancer) in mice and renal tumors in male rats. Scientific literature indicates that chloroform is absorbed from the gastrointestinal tract, through the respiratory system, and through the skin. The Commissioner concludes that, on the basis of <PRTPAGE P="125"/>these findings, chloroform is a deleterious substance which may render injurious to users any cosmetic product that contains chloroform as an ingredient.</P> <P>(b) Any cosmetic product containing chloroform as an ingredient is adulterated and is subject to regulatory action under sections 301 and 601(a) of the Federal Food, Drug, and Cosmetic Act. Any cosmetic product containing chloroform in residual amounts from its use as a processing solvent during manufacture, or as a byproduct from the synthesis of an ingredient, is not, for the purpose of this section, considered to contain chloroform as an ingredient.</P> <CITA>[41 FR 26845, June 29, 1976]</CITA> </SECTION> <SECTION> <SECTNO>§ 700.19</SECTNO> <SUBJECT>Use of methylene chloride as an ingredient of cosmetic products.</SUBJECT> <P>(a) Methylene chloride has been used as an ingredient of aerosol cosmetic products, principally hair sprays, at concentrations generally ranging from 10 to 25 percent. In a 2-year animal inhalation study sponsored by the National Toxicology Program, methylene chloride produced a significant increase in benign and malignant tumors of the lung and liver of male and female mice. Based on these findings and on estimates of human exposure from the customary use of hair sprays, the Food and Drug Administration concludes that the use of methylene chloride in cosmetic products poses a significant cancer risk to consumers, and that the use of this ingredient in cosmetic products may render these products injurious to health.</P> <P>(b) Any cosmetic product that contains methylene chloride as an ingredient is deemed adulterated and is subject to regulatory action under sections 301 and 601(a) of the Federal Food, Drug, and Cosmetic Act.</P> <CITA>[54 FR 27342, June 29, 1989]</CITA> </SECTION> <SECTION> <SECTNO>§ 700.23</SECTNO> <SUBJECT>Chlorofluorocarbon propellants.</SUBJECT> <P>The use of chlorofluorocarbons in cosmetics as propellants in self-pressurized containers is prohibited as provided in § 2.125 of this chapter.</P> <CITA>[43 FR 11317, Mar. 17, 1978]</CITA> </SECTION> <SECTION> <SECTNO>§ 700.25</SECTNO> <SUBJECT>Tamper-resistant packaging requirements for cosmetic products.</SUBJECT> <P>(a) <E T="03">General.</E> Because most cosmetic liquid oral hygiene products and vaginal products are not now packaged in tamper-resistant retail packages, there is the opportunity for the malicious adulteration of those cosmetic products with health risks to individuals who unknowingly purchase adulterated products and with loss of consumer confidence in the security of cosmetic product packages. The Food and Drug Administration has the authority and responsibility under the Federal Food, Drug, and Cosmetic Act (the act) to establish a uniform national requirement for tamper-resistant packaging of cosmetic liquid oral hygiene products or products used vaginally that will improve the packaging security and help assure the safety of those products. Such a cosmetic product for retail sale that is not packaged in a tamper-resistant package or that is not properly labeled under this section is adulterated under section 601 of the act or misbranded under section 602 of the act, or both.</P> <P>(b) <E T="03">Requirement for tamper-resistant package.</E> Each manufacturer and packer who packages a cosmetic liquid oral hygiene product or vaginal product for retail sale shall package the product in a tamper-resistant package, if this product is accessible to the public while held for sale. A tamper-resistant package is one having an indicator or barrier to entry which, if breached or missing, can reasonably be expected to provide visible evidence to consumers that tampering has occurred. To reduce the likelihood of substitution of a tamper-resistant feature after tampering, the indicator or barrier to entry is required to be distinctive by design (e.g., an aerosol product container) or by the use of an identifying characteristic (e.g., a pattern, name, registered trademark, logo, or picture). For purposes of this section, the term “distinctive by design” means the packaging cannot be duplicated with commonly available materials or through commonly available processes. For purposes of this section, the term “aerosol product” means a product which depends upon the power of a liquified or compressed <PRTPAGE P="126"/>gas to expel the contents from the container. A tamper-resistant package may involve an immediate-container and closure system or secondary-container or carton system or any combination of systems intended to provide a visual indication of package integrity. The tamper-resistant feature shall be designed to and shall remain intact when handled in a reasonable manner during manufacture, distribution, and retail display.</P> <P>(c) <E T="03">Labeling.</E> Each retail package of a cosmetic product covered by this section, except aerosol products as defined in paragraph (b) of this section, is required to bear a statement that is prominently placed so that consumers are alerted to the specific tamper-resistant feature of the package. The labeling statement is also required to be so placed that it will be unaffected if the tamper-resistant feature of the package is breached or missing. If the tamper-resistant feature chosen to meet the requirement in paragraph (b) of this section is one that uses an identifying characteristic, that characteristic is required to be referred to in the labeling statement. For example, the labeling statement on a bottle with a shrink band could say “For your protection, this bottle has an imprinted seal around the neck.”</P> <P>(d) <E T="03">Requests for exemptions from packaging and labeling requirements.</E> A manufacturer or packer may request an exemption from the packaging and labeling requirements of this section. A request for an exemption is required to be submitted in the form of a citizen petition under § 10.30 of this chapter and should be clearly identified on the envelope as a “Request for Exemption from Tamper-resistant Rule.” The petition is required to contain the following:</P> <P>(1) The name of the product.</P> <P>(2) The reasons that the product's compliance with the tamper-resistant packaging or labeling requirements of this section is unnecessary or cannot be achieved.</P> <P>(3) A description of alternative steps that are available, or that the petitioner has already taken, to reduce the likelihood that the product will be the subject of malicious adulteration.</P> <P>(4) Other information justifying an exemption.</P> <FP>This information collection requirement has been approved by the Office of Management and Budget under number 0910-0149.</FP> <P>(e) <E T="03">Effective date.</E> Cosmetic products covered by this section are required to comply with the requirements of this section on the dates listed below except to the extent that a product's manufacturer or packer has obtained an exemption from a packaging or labeling requirement.</P> <P>(1) <E T="03">Initial effective date for packaging requirements.</E> (i) The packaging requirement in paragraph (b) of this section is effective on Feburary 7, 1983 for each affected cosmetic product (except vaginal tablets) packaged for retail sale on or after that date, except for the requirement in paragraph (b) of this section for a distinctive indicator or barrier to entry.</P> <P>(ii) The packaging requirement in paragraph (b) of this section is effective on May 5, 1983 for each cosmetic product that is a vaginal tablet packaged for retail sale on or after that date.</P> <P>(2) <E T="03">Initial effective date for labeling requirements.</E> The requirement in paragraph (b) of this section that the indicator or barrier to entry be distinctive by design and the requirement in paragraph (c) of this section for a labeling statement are effective on May 5, 1983 for each affected cosmetic product packaged for retail sale on or after that date, except that the requirement for a specific label reference to any identifying characteristic is effective on February 6, 1984 for each affected cosmetic product packaged for retail sale on or after that date.</P> <P>(3) <E T="03">Retail level effective date.</E> The tamper-resistant packaging requirement of paragraph (b) of this section is effective February 6, 1984 for each affected cosmetic product held for sale on or after that date that was packaged for retail sale before May 5, 1983. This does not include the requirement in paragraph (b) of this section that the indicator or barrier to entry be distinctive by design. Products packaged for retail sale after May 5, 1983, as required to be in compliance with all aspects of the <PRTPAGE P="127"/>regulations without regard to the retail level effective date.</P> <CITA>[47 FR 50451, Nov. 5, 1982; 48 FR 1707, Jan. 14, 1983; 48 FR 11427, Mar. 18, 1983, as amended at 48 FR 16664, Apr. 19, 1983; 48 FR 37624, Aug. 19, 1983]</CITA> <EFFDNOT> <HD SOURCE="HED">Effective Date Note: </HD> <P> See 48 FR 41579, Sept. 16, 1983, for a document announcing an interim stay of the effective date of certain provisions in paragraph (e)(3) of § 700.25. </P> </EFFDNOT> </SECTION> </SUBPART> </PART> <PART> <EAR>Pt. 701</EAR> <HD SOURCE="HED">PART 701—COSMETIC LABELING</HD> <CONTENTS> <SUBPART> <HD SOURCE="HED">Subpart A—General Provisions</HD> <SECHD>Sec.</SECHD> <SECTNO>701.1</SECTNO> <SUBJECT>Misbranding.</SUBJECT> <SECTNO>701.2</SECTNO> <SUBJECT>Form of stating labeling requirements.</SUBJECT> <SECTNO>701.3</SECTNO> <SUBJECT>Designation of ingredients.</SUBJECT> <SECTNO>701.9</SECTNO> <SUBJECT>Exemptions from labeling requirements.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart B—Package Form</HD> <SECTNO>701.10</SECTNO> <SUBJECT>Principal display panel.</SUBJECT> <SECTNO>701.11</SECTNO> <SUBJECT>Identity labeling.</SUBJECT> <SECTNO>701.12</SECTNO> <SUBJECT>Name and place of business of manufacturer, packer, or distributor.</SUBJECT> <SECTNO>701.13</SECTNO> <SUBJECT>Declaration of net quantity of contents.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart C—Labeling of Specific Ingredients</HD> <SECTNO>701.20</SECTNO> <SUBJECT>Detergent substances, other than soap, intended for use in cleansing the body.</SUBJECT> <SECTNO>701.30</SECTNO> <SUBJECT>Ingredient names established for cosmetic ingredient labeling.</SUBJECT> </SUBPART> </CONTENTS> <AUTH> <HD SOURCE="HED">Authority: </HD> <P>21 U.S.C. 321, 352, 361, 362, 363, 371, 374; 15 U.S.C. 1454, 1455.</P> </AUTH> <SOURCE> <HD SOURCE="HED">Source: </HD> <P>39 FR 10056, Mar. 15, 1974, unless otherwise noted.</P> </SOURCE> <SUBPART> <HD SOURCE="HED">Subpart A—General Provisions</HD> <SECTION> <SECTNO>§ 701.1</SECTNO> <SUBJECT>Misbranding.</SUBJECT> <P>(a) Among representations in labeling of a cosmetic which render such cosmetic misbranded is a false or misleading representation with respect to another cosmetic or a food, drug, or device.</P> <P>(b) The labeling of a cosmetic which contains two or more ingredients may be misleading by reason (among other reasons) of the designation of such cosmetic in such labeling by a name which includes or suggests the name of one or more but not all such ingredients, even though the names of all such ingredients are stated elsewhere in the labeling.</P> </SECTION> <SECTION> <SECTNO>§ 701.2</SECTNO> <SUBJECT>Form of stating labeling requirements.</SUBJECT> <P>(a) A word, statement, or other information required by or under authority of the Act to appear on the label may lack that prominence and conspicuousness required by section 602(c) of the Act by reason (among other reasons) of:</P> <P>(1) The failure of such word, statement, or information to appear on the part or panel of the label which is presented or displayed under customary conditions of purchase;</P> <P>(2) The failure of such word, statement, or information to appear on two or more parts or panels of the label, each of which has sufficient space therefor, and each of which is so designed as to render it likely to be, under customary conditions of purchase, the part or panel displayed;</P> <P>(3) The failure of the label to extend over the area of the container or package available for such extension, so as to provide sufficient label space for the prominent placing of such word, statement, or information;</P> <P>(4) Insufficiency of label space (for the prominent placing of such word, statement, or information) resulting from the use of label space for any word, statement, design, or device which is not required by or under authority of the Act to appear on the label;</P> <P>(5) Insufficiency of label space (for the prominent placing of such word, statement, or information) resulting from the use of label space to give materially greater conspicuousness to any other word, statement, or information, or to any design or device;</P> <P>(6) Smallness or style of type in which such word, statement, or information appears, insufficient background contrast, obscuring designs or vignettes, or crowding with other written, printed, or graphic matter.</P> <P>(b)(1) All words, statements, and other information required by or under authority of the Act to appear on the label or labeling shall appear thereon in the English language: <E T="03">Provided, however,</E> That in the case of articles distributed solely in the Commonwealth <PRTPAGE P="128"/>of Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be substituted for English.</P> <P>(2) If the label contains any representation in a foreign language, all words, statements, and other information required by or under authority of the Act to appear on the label shall appear thereon in the foreign language.</P> <P>(3) If the labeling contains any representation in a foreign language, all words, statements, and other information required by or under authority of the Act to appear on the label or labeling shall appear on the labeling in the foreign language.</P> </SECTION> <SECTION> <SECTNO>§ 701.3</SECTNO> <SUBJECT>Designation of ingredients.</SUBJECT> <P>(a) The label on each package of a cosmetic shall bear a declaration of the name of each ingredient in descending order of predominance, except that fragrance or flavor may be listed as fragrance or flavor. An ingredient which is both fragrance and flavor shall be designated by each of the functions it performs unless such ingredient is identified by name. No ingredient may be designated as fragrance or flavor unless it is within the meaning of such term as commonly understood by consumers. Where one or more ingredients is accepted by the Food and Drug Administration as exempt from public disclosure pursuant to the procedure established in § 720.8(a) of this chapter, in lieu of label declaration of identity the phrase “and other ingredients” may be used at the end of the ingredient declaration.</P> <P>(b) The declaration of ingredients shall appear with such prominence and conspicuousness as to render it likely to be read and understood by ordinary individuals under normal conditions of purchase. The declaration shall appear on any appropriate information panel in letters not less than <FR>1/16</FR> of an inch in height and without obscuring design, vignettes, or crowding. In the absence of sufficient space for such declaration on the package, or where the manufacturer or distributor wishes to use a decorative container, the declaration may appear on a firmly affixed tag, tape, or card. In those cases where there is insufficient space for such declaration on the package, and it is not practical to firmly affix a tag, tape, or card, the Commissioner may establish by regulation an acceptable alternate, e.g., a smaller type size. A petition requesting such a regulation as an amendment to this paragraph shall be submitted pursuant to part 10 of this chapter.</P> <P>(c) A cosmetic ingredient shall be identified in the declaration of ingredients by:</P> <P>(1) The name specified in § 701.30 as established by the Commissioner for that ingredient for the purpose of cosmetic ingredient labeling pursuant to paragraph (e) of this section;</P> <P>(2) In the absence of the name specified in § 701.30, the name adopted for that ingredient in the following editions and supplements of the following compendia, listed in order as the source to be utilized:</P> <P>(i) CTFA (Cosmetic, Toiletry and Fragrance Association, Inc.) Cosmetic Ingredient Dictionary, Second Ed., 1977 (available from the Cosmetic, Toiletry and Fragrance Association, Inc. 1110 Vermont Ave. NW., Suite 800, Washington, DC 20005, or available for inspection at the Office of the Federal Register, 800 North Capitol Street, NW., suite 700, Washington, DC 20408), which is incorporated by reference, except for the following deletions and revisions:</P> <P>(<E T="03">a</E>) The following names are not adopted for the purpose of cosmetic ingredient labeling: </P> <EXTRACT> <FP SOURCE="FP2-3">Acid Black 58</FP> <FP SOURCE="FP2-3">Acid Black 107</FP> <FP SOURCE="FP2-3">Acid Black 139</FP> <FP SOURCE="FP2-3">Acid Blue 168</FP> <FP SOURCE="FP2-3">Acid Blue 170</FP> <FP SOURCE="FP2-3">Acid Blue 188</FP> <FP SOURCE="FP2-3">Acid Blue 209</FP> <FP SOURCE="FP2-3">Acid Brown 19</FP> <FP SOURCE="FP2-3">Acid Brown 30</FP> <FP SOURCE="FP2-3">Acid Brown 44</FP> <FP SOURCE="FP2-3">Acid Brown 45</FP> <FP SOURCE="FP2-3">Acid Brown 46</FP> <FP SOURCE="FP2-3">Acid Brown 48</FP> <FP SOURCE="FP2-3">Acid Brown 224</FP> <FP SOURCE="FP2-3">Acid Orange 80</FP> <FP SOURCE="FP2-3">Acid Orange 85</FP> <FP SOURCE="FP2-3">Acid Orange 86</FP> <FP SOURCE="FP2-3">Acid Orange 88</FP> <FP SOURCE="FP2-3">Acid Orange 89</FP> <FP SOURCE="FP2-3">Acid Orange 116</FP> <FP SOURCE="FP2-3">Acid Red 131</FP> <FP SOURCE="FP2-3">Acid Red 213</FP> <FP SOURCE="FP2-3">Acid Red 252<PRTPAGE P="129"/> </FP> <FP SOURCE="FP2-3">Acid Red 259</FP> <FP SOURCE="FP2-3">Acid Violet 73</FP> <FP SOURCE="FP2-3">Acid Violet 76</FP> <FP SOURCE="FP2-3">Acid Violet 99</FP> <FP SOURCE="FP2-3">Acid Yellow 114</FP> <FP SOURCE="FP2-3">Acid Yellow 127</FP> <FP SOURCE="FP2-3">Direct Yellow 81</FP> <FP SOURCE="FP2-3">Solvent Black 5</FP> <FP SOURCE="FP2-3">Solvent Brown 43</FP> <FP SOURCE="FP2-3">Solvent Yellow 63</FP> <FP SOURCE="FP2-3">Solvent Yellow 90</FP> </EXTRACT> <P>(<E T="03">b</E>) The following names are adopted for the purpose of cosmetic ingredient labeling, provided the respective monographs are revised to describe their otherwise disclosed chemical compositions, or describe their chemical compositions more precisely, and such revised monographs are published in supplements to this dictionary edition by July 18, 1980. </P> <EXTRACT> <FP SOURCE="FP2-3">Acid Black 2</FP> <FP SOURCE="FP2-3">Benzophenone-11</FP> <FP SOURCE="FP2-3">Carbomer 934</FP> <FP SOURCE="FP2-3">Carbomer 934P</FP> <FP SOURCE="FP2-3">Carbomer 940</FP> <FP SOURCE="FP2-3">Carbomer 941</FP> <FP SOURCE="FP2-3">Carbomer 960</FP> <FP SOURCE="FP2-3">Carbomer 961</FP> <FP SOURCE="FP2-3">Chlorofluorocarbon 11S</FP> <FP SOURCE="FP2-3">Dimethicone Copolyol</FP> <FP SOURCE="FP2-3">Disperse Red 17</FP> <FP SOURCE="FP2-3">Pigment Green 7</FP> <FP SOURCE="FP2-3">Polyamino Sugar Condensate</FP> <FP SOURCE="FP2-3">SD Alcohol (all 27 alphanumeric designations)</FP> <FP SOURCE="FP2-3">Sodium Chondroitin Sulfate</FP> <FP SOURCE="FP2-3">Synthetic Beeswax</FP> </EXTRACT> <P>(<E T="03">c</E>) The following names are adopted for the purpose of cosmetic ingredient labeling until January 19, 1981. </P> <EXTRACT> <FP SOURCE="FP2-3">Amphoteric (all 20 numeric designations)</FP> <FP SOURCE="FP2-3">Quaternium (all 49 numeric designations)</FP> </EXTRACT> <P>(ii) United States Pharmacopeia, 19th Ed., 1975, and Second Supplement to the USP XIX and NF XIV, 1976. (Copies are available from the U.S. Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway, Rockville, MD 20852, or available for inspection at the Office of the Federal Register, 800 North Capitol Street, NW., suite 700, Washington, DC 20408.)</P> <P>(iii) National Formulary, 14th Ed., 1975, and Second Supplement to the USP XIX and NF XIV, 1976. (Copies are available from the U.S. Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway, Rockville, MD 20852, or available for inspection at the Office of the Federal Register, 800 North Capitol Street, NW., suite 700, Washington, DC 20408).</P> <P>(iv) Food Chemicals Codex, 2d Ed., 1972; First Supplement, 1974, and Second Supplement, 1975, which are incorporated by reference. Copies are available from the Center for Food Safety and Applied Nutrition, Food and Drug Administration, 200 C St. SW., Washington, DC 20204, or available for inspection at the Office of the Federal Register, 800 North Capitol Street, NW., suite 700, Washington, DC 20408.</P> <P>(v) USAN and the USP dictionary of drug names, USAN 1975, 1961-1975 cumulative list. (Copies are available from the U.S. Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway, Rockville, MD 20852, or available for inspection at the Office of the Federal Register, 800 North Capitol Street, NW., suite 700, Washington, DC 20408.)</P> <P>(3) In the absence of such a listing, the name generally recognized by consumers.</P> <P>(4) In the absence of any of the above, the chemical or other technical name or description.</P> <P>(d) Where a cosmetic product is also an over-the-counter drug product, the declaration shall declare the active drug ingredients as set forth in § 201.66(c)(2) and (d) of this chapter, and the declaration shall declare the cosmetic ingredients as set forth in § 201.66(c)(8) and (d) of this chapter.</P> <P>(e) Interested persons may submit a petition requesting the establishment of a specific name for a cosmetic ingredient pursuant to part 10 of this chapter. The Commissioner may also propose such a name on his own initiative.</P> <P>(f) As an alternative to listing all ingredients in descending order of predominance, ingredients may be grouped and the groups listed in the following manner and order:</P> <P>(1) Ingredients, other than color additives, present at a concentration greater than 1 percent, in descending order of predominance; followed by</P> <P>(2) Ingredients, other than color additives, present at a concentration of not more than 1 percent, without respect to order of predominance; followed by</P> <P>(3) Color additives, without respect to order of predominance. Ingredients <PRTPAGE P="130"/>specified in paragraph (f)(2) of this section may be included with those specified in paragraph (f)(1) of this section and listed in descending order of predominance.</P> <P>(g) A declaration of ingredients may include an ingredient not in the product if the ingredient is identified by the phrase “may contain” and:</P> <P>(1) It is a color additive added to some batches of the product for purposes of color matching; or</P> <P>(2)(i) The same declaration of ingredients is also used for other products similar in composition and intended for the same use, including products which may be assortments of products similar in composition and intended for the same use; and</P> <P>(ii) Such products are “shaded” products, i.e., those falling within the product categories identified in § 720.4 (c)(3), (7) and (8)(v) of this chapter; and</P> <P>(iii) All products sharing the common declaration of ingredients are sold by the labeler under a common trade name or brand designation, and no trade name or brand designation not common to all such products appears in the labeling of any of them; and</P> <P>(iv) The ingredient is a color additive.</P> <P>(h) As an alternative to a declaration of color additive ingredients for each product, the color additives of an assortment of cosmetic products that are sold together in the same package may be declared in a single composite list in a manner that is not misleading and that indicates that the list pertains to all the products.</P> <P>(i) As an alternative to the declaration of ingredients specified in paragraph (b) of this section, the declaration of ingredients may appear in letters not less than <FR>1/16</FR> of an inch in height in labeling accompanying the product, as for example, on padded sheets or in leaflets, if the total surface area of the package is less than 12 square inches. This paragraph is inapplicable to any packaged cosmetic product enclosed in an outer container, e.g., a folding carton. In addition, this paragraph is applicable only to cosmetic products meeting one of the following requirements:</P> <P>(1) The cosmetic products are held and displayed for sale in tightly compartmented trays or racks of a display unit. The holder of the labeling bearing the declaration of ingredients shall be attached to the display unit; or</P> <P>(2) The cosmetic products are “shaded” products, i.e., those falling within the product categories identified in § 720.4 (c)(3), (7) and (8)(v) of this chapter, and are held for sale in tightly compartmented trays or racks. The holder of the labeling bearing the declaration of ingredients shall be attached to a display chart bearing samples of the product shades, which is displayed to purchasers. Such a display chart shall be of such construction and design as to permit its continuous use as a display, such as on a counter, and shall be designed for the primary purpose of displaying samples of the shades of the products.</P> <P>(j) The holder of labeling bearing a declaration of ingredients and used in accordance with paragraph (i) of this section shall be attached to the display unit or chart and shall meet one of the following conditions:</P> <P>(1) The labeling is on the front of the display unit or chart and can be read in full by a purchaser facing the display unit or chart under customary conditions of retail sale; or</P> <P>(2) The labeling is on the front of the display unit or chart, is partially visible, and is accompanied by a conspicuous notice on the front of the display unit or chart describing the location of such labeling in letters not less than <FR>3/16</FR> of an inch in height, e.g., “Ingredient lists above”, that can be read by a purchaser facing the display unit or chart under customary conditions of retail sale, or by the notice required by provisions in paragraph (k)(3) of this section, if conspicuous at all times; or</P> <P>(3) The labeling is on a side of the display unit or chart, but not on the top, back, or bottom, and is accompanied by a conspicuous notice on the front of the display unit or chart describing the location of such labeling in letters not less than <FR>3/16</FR> of an inch in height, e.g., “Ingredient lists located on right side of display”, that can be read by a purchaser facing the display unit or chart under customary conditions of retail sale.</P> <P>(k) Any use of a display unit or chart bearing labeling under the provisions <PRTPAGE P="131"/>of paragraph (i) of this section shall meet the following requirements:</P> <P>(1) All articles of labeling bearing ingredient declarations and used in conjunction with any one display unit or chart shall be identical and shall declare the ingredients of all products sold in conjunction with the display unit or chart for which the ingredient declaration is made pursuant to paragraph (i) of this section.</P> <P>(2) Any display unit or chart intended for such use shall be shipped together with the labeling intended to be attached to it.</P> <P>(3) Every display unit or chart and/or labeling system shall be designed so that the words “Federal law requires ingredient lists to be displayed here” in letters not less than <FR>3/16</FR> of an inch in height (i) become conspicuous when no ingredient declarations are displayed and when the last list has been taken, or (ii) are conspicuous at all times adjacent to the place where ingredient declarations are to be attached.</P> <P>(4) Any labeling containing a declaration of ingredients which reflects a formulation change and not shipped accompanying a display unit or chart shall be dated. Whenever any formulation change is made, and the labeling containing the declaration of ingredients is thereby required to be used in conjunction with products of both the old and new formulations, the labeling shall declare the ingredients of both the old and new formulations separately in a way that is not misleading and in a way that permits the purchaser to identify the ingredient declaration applicable to each package, or which clearly advises the purchaser that the formulation has been changed and that either declaration may be applicable.</P> <P>(5) Sufficient copies of the declaration of ingredients shall be provided with each shipment of a cosmetic so that a purchaser may obtain a copy of the declaration with each purchase. Display units and replacement labeling for display units shall be accompanied by instructions to the retailer, which when followed will result in compliance with the requirements of this section. Copies of the declaration accompanying refills shall be attached to the specific refill items to which they pertain, or shall be packed with the specific refill items to which they pertain, in a container that does not contain other cosmetic products.</P> <P>(6) The firm whose name appears on a product pursuant to § 701.12 shall promptly mail a copy of the declaration of ingredients to any person requesting it.</P> <P>(7) The display unit or chart shall be designed and located such that the labeling is easily accessible to a purchaser facing the display unit or chart under customary conditions of retail sale.</P> <P>(l) The provisions of this section do not require the declaration of incidental ingredients that are present in a cosmetic at insignificant levels and that have no technical or functional effect in the cosmetic. For the purpose of this paragraph, incidental ingredients are:</P> <P>(1) Substances that have no technical or functional effect in the cosmetic but are present by reason of having been incorporated into the cosmetic as an ingredient of another cosmetic ingredient.</P> <P>(2) Processing aids, which are as follows:</P> <P>(i) Substances that are added to a cosmetic during the processing of such cosmetic but are removed from the cosmetic in accordance with good manufacturing practices before it is packaged in its finished form.</P> <P>(ii) Substances that are added to a cosmetic during processing for their technical or functional effect in the processing, are converted to substances the same as constituents of declared ingredients, and do not significantly increase the concentration of those constituents.</P> <P>(iii) Substances that are added to a cosmetic during the processing of such cosmetic for their technical and functional effect in the processing but are present in the finished cosmetic at insignificant levels and do not have any technical or functional effect in that cosmetic.</P> <P>(m) In the event that there is a current or anticipated shortage of a cosmetic ingredient, the declaration required by this section may specify alternatives to any ingredients that may be affected. An alternative ingredient <PRTPAGE P="132"/>shall be declared either (1) immediately following the normally used ingredient for which it substitutes, in which case it shall be identified as an alternative ingredient by the word “or” following the name of the normally used ingredient and any other alternative ingredient, or (2) following the declaration of all normally used ingredients, in which case the alternative ingredients in the group so listed shall be listed in expected descending order of predominance or in accordance with the provisions of paragraph (f) of this section and shall be identified as alternative ingredients by the phrase “may also contain”. This paragraph is inapplicable to any ingredient mentioned in advertising, or in labeling other than in the declaration of ingredients required by this section.</P> <P>(n) In the event that the shortage of a cosmetic ingredient necessitates a formulation change, packages bearing labels declaring the ingredients of the old formulation may be used if the revised ingredient declaration appears (1) on a firmly affixed tag, tape, card, or sticker or similar overlabeling attached to the package and bearing the conspicuous words “new ingredient list” in letters not less than <FR>1/16</FR> of an inch in height, or (2) on labeling inside an unsealed package and the package bears the conspicuous words, on a sticker or similar overlabeling, “new ingredient list inside” in letters not less than <FR>1/16</FR> of an inch in height.</P> <P>(o) The ingredients of products that are similar in composition and intended for the same use may be declared as follows:</P> <P>(1) The declaration of ingredients for an assortment of such products that are sold together in the same package, e.g., eyeshadows of different colors, may declare the ingredients that are common to all the products, in a single list in their cumulative order of predominance or in accordance with the provisions of paragraph (f) of this section, together with a statement, in terms that are as informative as practicable and that are not misleading, declaring the other ingredients and identifying the products in which they are present. The color additive ingredients of all the products in such an assortment, whether or not common to all the products, may be declared in a single composite list following the declaration of the other ingredients without identifying the products in which they are present.</P> <P>(2) The ingredients of an assortment of such products that are sold together in the same package, e.g., eyeshadows of different colors, may be declared in a single list in their cumulative order of predominance or in accordance with the provisions of paragraph (f) of this section, if the package is designed such that it has a total surface area available to bear labeling of less than 12 square inches. For the purpose of this paragraph, surface area is not available for labeling if physical characteristics of the package surface, e.g., decorative relief, make application of a label impractical.</P> <P>(3) The declaration of ingredients for such a product that is individually packaged and bears a label that is shared with other products pursuant to the provisions of paragraph (g)(2) of this section, e.g., one lipstick in a line of lipsticks, may declare the ingredients that are common to all such products, in a single list in their cumulative order of predominance or in accordance with the provisions of paragraph (f) of this section, together with a statement, in terms that are as informative as practicable and that are not misleading, declaring the other ingredients in such products, and identifying the products in which they are present. The color additive ingredients shall be declared in accordance with the provisions of paragraph (g) of this section.</P> <P>(4) The declaration of ingredients for an assortment of such cosmetic products that bears a label that is shared with other products pursuant to the provisions of paragraph (g)(2) of this section, e.g., one of several compacts in a line of compacts, may declare the ingredients that are common to all such products, in a single list in their cumulative order of predominance or in accordance with the provisions of paragraph (f) of this section, together with a statement, in terms that are as informative as practicable and that are not misleading, declaring the other ingredients in such products and identifying the products in which they are <PRTPAGE P="133"/>present. The color additive ingredients shall be declared in accordance with the provisions of paragraph (g) of this section.</P> <P>(p) As an alternative to the declaration of ingredients in letters not less than <FR>1/16</FR> of an inch in height, letters may be not less than <FR>1/32</FR> of an inch in height if the package is designed such that it has a total surface area available to bear labeling of less than 12 square inches. For the purpose of this paragraph, surface area is not available for labeling if physical characteristics of the package surface, e.g., decorative relief, make application of a label impractical.</P> <P>(q) The inside containers in a multiunit or multicomponent retail cosmetic package are not required to bear a declaration of ingredients when the labeling of the multiunit or multicomponent retail cosmetic package meets all the requirements of this section and the inside containers are not intended to be, and are not customarily, separated from the retail package for retail sale.</P> <P>(r) In the case of cosmetics distributed to the consumers by direct mail, as an alternative to the declaration of ingredients on an information panel, the declaration of ingredients may appear in letters not less than <FR>1/16</FR> of an inch in height in labeling that accompanies and specifically relates to the cosmetic(s) mailed, or in labeling furnished to each consumer for his personal use and from which he orders cosmetics through the mail, e.g., a direct mail sales catalog or brochure, provided all of the following additional requirements are met:</P> <P>(1) The declarations of ingredients are conspicuous and presented in a way that permits the consumer to identify the declaration of ingredients applicable to each cosmetic.</P> <P>(2) The package mailed to the consumer is accompanied by a notice located on, or affixed to, the top of the package or on top of the contents inside the package, or on the face of the package platform surrounding and holding the product(s), readily visible to the consumer on opening of the package, and provides the following information in letters not less than <FR>3/16</FR> of an inch in height:</P> <P>(i) The location of the declarations of ingredients, e.g., in an accompanying brochure, or in a sales catalog used for ordering;</P> <P>(ii) A statement that a copy of the declaration of ingredients will be mailed promptly to any person requesting it; and</P> <P>(iii) The name and place of business of the mail order distributor,</P> <P>(3) The mail order distributor promptly mails a copy of the declaration of ingredients to any person requesting it.</P> <CITA>[39 FR 10056, Mar. 15, 1974, as amended at 40 FR 8922, Mar. 3, 1975; 40 FR 18426, Apr. 28, 1975; 42 FR 4718, Jan. 25, 1977; 42 FR 15676, Mar. 22, 1977; 42 FR 24255, May 31, 1977; 42 FR 46516, Sept. 16, 1977; 42 FR 61257, Dec. 2, 1977; 45 FR 3577, Jan. 18, 1980; 47 FR 9397, Mar. 5, 1982; 54 FR 24900, June 12, 1989; 64 FR 13297, Mar. 17, 1999]</CITA> <EFFDNOT> <HD SOURCE="HED">Effective Date Note:</HD> <P> At 64 FR 13297, Mar. 17, 1999, § 701.3 was amended by revising paragraph (d), effective Apr. 16, 1999. For the convenience of the user, the superseded text follows:</P> <SUPERSED> <SECTION> <SECTNO>§ 701.3</SECTNO> <SUBJECT> Designation of ingredients.</SUBJECT> <STARS/> <P>(d) Where a cosmetic product is also a drug, the declaration shall first declare the active drug ingredients as required under section 502(e) of the Federal Food, Drug, and Cosmetic Act, and shall then declare the cosmetic ingredients.<STARS/> </P> </SECTION> <SECTION> <SECTNO>§ 701.9</SECTNO> <SUBJECT>Exemptions from labeling requirements.</SUBJECT> <P>(a) Except as provided by paragraphs (b) and (c) of this section, a shipment or other delivery of a cosmetic which is, in accordance with the practice of the trade, to be processed, labeled, or repacked in substantial quantity at an establishment other than that where originally processed or packed, shall be exempt, during the time of introduction into and movement in interstate commerce and the time of holding in such establishment, from compliance with the labeling requirements of sections 601(a) and 602(b) of the act if:</P> <P>(1) The person who introduced such shipment or delivery into interstate <PRTPAGE P="134"/>commerce is the operator of the establishment where such cosmetic is to be processed, labeled, or repacked; or</P> <P>(2) In case such person is not such operator, such shipment or delivery is made to such establishment under a written agreement, signed by and containing the post office addresses of such person and such operator, and containing such specifications for the processing, labeling, or repacking, as the case may be, of such cosmetic in such establishment as will insure, if such specifications are followed, that such cosmetic will not be adulterated or misbranded within the meaning of the act upon completion of such processing, labeling, or repacking. Such person and such operator shall each keep a copy of such agreement until 2 years after the final shipment or delivery of such cosmetic from such establishment, and shall make such copies available for inspection at any reasonable hour to any officer or employee of the Department who requests them.</P> <P>(b) An exemption of a shipment or other delivery of a cosmetic under paragraph (a)(1) of this section shall, at the beginning of the act of removing such shipment or delivery, or any part thereof, from such establishment, become void ab initio if the cosmetic comprising such shipment, delivery, or part is adulterated or misbranded within the meaning of the act when so removed.</P> <P>(c) An exemption of a shipment or other delivery of a cosmetic under paragraph (a)(2) of this section shall become void ab initio with respect to the person who introduced such shipment or delivery into interstate commerce upon refusal by such person to make available for inspection a copy of the agreement, as required by such clause.</P> <P>(d) An exemption of a shipment or other delivery of a cosmetic under paragraph (a)(2) of this section shall expire:</P> <P>(1) At the beginning of the act of removing such shipment or delivery, or any part thereof, from such establishment if the cosmetic comprising such shipment, delivery, or part is adulterated or misbranded within the meaning of the act when so removed; or</P> <P>(2) Upon refusal by the operator of the establishment where such cosmetic is to be processed, labeled, or repacked, to make available for inspection a copy of the agreement, as required by such clause.</P> </SECTION> <SUBPART> <HD SOURCE="HED">Subpart B—Package Form</HD> <SECTION> <SECTNO>§ 701.10</SECTNO> <SUBJECT>Principal display panel.</SUBJECT> <P>The term <E T="03">principal display panel</E> as it applies to cosmetics in package form and as used in this part, means the part of a label that is most likely to be displayed, presented, shown, or examined under customary conditions of display for retail sale. The principal display panel shall be large enough to accommodate all the mandatory label information required to be placed thereon by this part with clarity and conspicuousness and without obscuring designs, vignettes, or crowding. Where packages bear alternate principal display panels, information required to be placed on the principal display panel shall be duplicated on each principal display panel. For the purpose of obtaining uniform type size in declaring the quantity of contents of all packages of substantially the same size, the term “area of the principal display panel” means the area of the side or surface that bears the principal display panel, which area shall be:</P> <P>(a) In the case of a rectangular package where one entire side properly can be considered to be the principal display panel side, the product of the height times the width of that side;</P> <P>(b) In the case of a cylindrical or nearly cylindrical container, 40 percent of the product of the height of the container times the circumference; and</P> <P>(c) In the case of any other shape of container, 40 percent of the total surface of the container: <E T="03">Provided, however,</E> That where such container presents an obvious “principal display panel” such as the top of a triangular or circular package, the area shall consist of the entire top surface.</P> <FP>In determining the area of the principal display panel, exclude tops, bottoms, flanges at the tops and bottoms of cans, and shoulders and necks of bottles or jars. In the case of cylindrical or nearly cylindrical containers, information required by this part to appear <PRTPAGE P="135"/>on the principal display panel shall appear within that 40 percent of the circumference which is most likely to be displayed, presented, shown, or examined under customary conditions of display for retail sale.</FP> </SECTION> <SECTION> <SECTNO>§ 701.11</SECTNO> <SUBJECT>Identity labeling.</SUBJECT> <P>(a) The principal display panel of a cosmetic in package form shall bear as one of its principal features a statement of the identity of the commodity.</P> <P>(b) Such statement of identity shall be in terms of:</P> <P>(1) The common or usual name of the cosmetic; or</P> <P>(2) An appropriately descriptive name or, when the nature of the cosmetic is obvious, a fanciful name understood by the public to identify such cosmetic; or</P> <P>(3) An appropriate illustration or vignette representing the intended cosmetic use.</P> <P>(c) The statement of identity shall be presented in bold type on the principal display panel, shall be in a size reasonably related to the most prominent printed matter on such panel, and shall be in lines generally parallel to the base on which the package rests as it is designed to be displayed.</P> </SECTION> <SECTION> <SECTNO>§ 701.12</SECTNO> <SUBJECT>Name and place of business of manufacturer, packer, or distributor.</SUBJECT> <P>(a) The label of a cosmetic in package form shall specify conspicuously the name and place of business of the manufacturer, packer, or distributor.</P> <P>(b) The requirement for declaration of the name of the manufacturer, packer, or distributor shall be deemed to be satisfied in the case of a corporation only by the actual corporate name, which may be preceded or followed by the name of the particular division of the corporation. Abbreviations for “Company,” “Incorporated,” etc., may be used and “The” may be omitted. In the case of an individual, partnership, or association, the name under which the business is conducted shall be used.</P> <P>(c) Where the cosmetic is not manufactured by the person whose name appears on the label, the name shall be qualified by a phrase that reveals the connection such person has with such cosmetic; such as, “Manufactured for _______”, “Distributed by ________”, or any other wording that expresses the facts.</P> <P>(d) The statement of the place of business shall include the street address, city, State, and ZIP Code; however, the street address may be omitted if it is shown in a current city directory or telephone directory. The requirement for inclusion of the ZIP Code shall apply only to consumer commodity labels developed or revised after the effective date of this section. In the case of nonconsumer packages, the ZIP Code shall appear either on the label or the labeling (including the invoice).</P> <P>(e) If a person manufactures, packs, or distributes a cosmetic at a place other than his principal place of business, the label may state the principal place of business in lieu of the actual place where such cosmetic was manufactured or packed or is to be distributed, unless such statement would be misleading.</P> </SECTION> <SECTION> <SECTNO>§ 701.13</SECTNO> <SUBJECT>Declaration of net quantity of contents.</SUBJECT> <P>(a) The label of a cosmetic in package form shall bear a declaration of the net quantity of contents. This shall be expressed in terms of weight, measure, numerical count, or a combination of numerical count and weight or measure. The statement shall be in terms of fluid measure if the cosmetic is liquid or in terms of weight if the cosmetic is solid, semisolid, or viscous, or a mixture of solid and liquid. If there is a firmly established, general consumer usage and trade custom of declaring the net quantity of a cosmetic by numerical count, linear measure, or measure of area, such respective term may be used. If there is a firmly established, general consumer usage and trade custom of declaring the contents of a liquid cosmetic by weight, or a solid, semisolid, or viscous cosmetic by fluid measure, it may be used. Whenever the Commissioner determines for a specific packaged cosmetic that an existing practice of declaring net quantity of contents by weight, measure, numerical count, or a combination of these does not facilitate value comparisons by consumers, he shall by regulation designate the appropriate term or terms to be used for such cosmetic.<PRTPAGE P="136"/> </P> <P>(b) Statements of weight shall be in terms of avoirdupois pound and ounce. Statements of fluid measure shall be in terms of the U.S. gallon of 231 cubic inches and quart, pint, and fluid-ounce subdivisions thereof and shall express the volume at 68 °F. (20 °C.).</P> <P>(c) When the declaration of quantity of contents by numerical count, linear measure, or measure of area does not give accurate information as to the quantity of cosmetic in the package, it shall be augmented by such statement of weight, measure, or size of the individual units or the total weight or measure of the cosmetic as will give such information.</P> <P>(d) The declaration may contain common or decimal fractions. A common fraction shall be in terms of halves, quarters, eighths, sixteenths, or thirty-seconds; except that if there exists a firmly established, general consumer usage and trade custom of employing different common fractions in the net quantity declaration of a particular commodity they may be employed. A common fraction shall be reduced to its lowest terms; a decimal fraction shall not be carried out to more than two places. A statement that includes small fractions of an ounce shall be deemed to permit smaller variations than one which does not include such fractions.</P> <P>(e) The declaration shall be located on the principal display panel of the label; with respect to packages bearing alternate principal display panels, it shall be duplicated on each principal display panel: <E T="03">Provided,</E> That:</P> <P>(1) The principal display panel of a cosmetic marketed in a “boudoir-type” container including decorative cosmetic containers of the “cartridge,” “pill box,” “compact,” or “pencil” variety, and those with a capacity of one-fourth ounce or less, may be considered to be a tear-away tag or tape affixed to the decorative container and bearing the mandatory label information as required by this part, but the type size of the net quantity of contents statement shall be governed by the dimensions of the decorative container; and</P> <P>(2) The principal display panel of a cosmetic marketed on a display card to which the immediate container is affixed may be considered to be the display panel of the card, and the type size of the net quantity of content statement is governed by the dimensions of the display card.</P> <P>(f) The declaration shall appear as a distinct item on the principal display panel, shall be separated (by at least a space equal to the height of the lettering used in the declaration) from other printed label information appearing above or below the declaration and (by at least a space equal to twice the width of the letter “N” of the style of type used in the quantity of contents statement) from other printed label information appearing to the left or right of the declaration. It shall not include any term qualifying a unit of weight, measure, or count (such as “giant pint” and “full quart”) that tends to exaggerate the amount of the cosmetic in the container. It shall be placed on the principal display panel within the bottom 30 percent of the area of the label panel in line generally parallel to the base on which the package rests as it is designed to be displayed: <E T="03">Provided,</E> That:</P> <P>(1) On packages having a principal display panel of 5 square inches or less, the requirement for placement within the bottom 30 percent of the area of the label panel shall not apply when the declaration of net quantity of contents meets the other requirements of this part; and</P> <P>(2) In the case of a cosmetic that is marketed with both outer and inner retail containers bearing the mandatory label information required by this part, and the inner container is not intended to be sold separately, the net quantity of contents placement requirement of this section applicable to such inner containers is waived.</P> <P>(g) The declaration shall accurately reveal the quantity of cosmetic in the package exclusive of wrappers and other material packed therewith: <E T="03">Provided,</E> That:</P> <P>(1) In the case of cosmetics packed in containers designed to deliver the cosmetic under pressure, the declaration shall state the net quantity of the contents that will be expelled when the instructions for use as shown on the container are followed. The propellant is included in the net quantity declaration; and<PRTPAGE P="137"/> </P> <P>(2) In the case of a package which contains the integral components making up a complete kit, and which is designed to deliver the components in the manner of an application (for example, a home permanent wave kit), the declaration may state the net quantity of the contents in nondeceptive terms of the number of applications available in the kit when the instructions for use as shown on the container are followed.</P> <P>(h) The declaration shall appear in conspicuous and easily legible boldface print or type in distinct contrast (by typography, layout, color, embossing, or molding) to other matter on the package; except that a declaration of net quantity blown, embossed, or molded on a glass or plastic surface is permissible when all label information is so formed on the surface. Requirements of conspicuousness and legibility shall include the specifications that:</P> <P>(1) The ratio of height to width (of the letter) shall not exceed a differential of 3 units to 1 unit (no more than 3 times as high as it is wide).</P> <P>(2) Letter heights pertain to upper case or capital letters. When upper and lower case or all lower case letters are used, it is the lower case letter “o” or its equivalent that shall meet the minimum standards.</P> <P>(3) When fractions are used, each component numeral shall meet one-half the minimum height standards.</P> <P>(i) The declaration shall be in letters and numerals in a type size established in relationship to the area of the principal display panel of the package and shall be uniform for all packages of substantially the same size by complying with the following type specifications:</P> <P>(1) Not less than one-sixteenth inch in height on packages the principal display panel of which has an area of 5 square inches or less.</P> <P>(2) Not less than one-eighth inch in height on packages the principal display panel of which has an area of more than 5 but not more than 25 square inches.</P> <P>(3) Not less than three-sixteenths inch in height on packages the principal display panel of which has an area of more than 25 but not more than 100 square inches.</P> <P>(4) Not less than one-fourth inch in height on packages the principal display panel of which has an area of more than 100 square inches, except not less than one-half inch in height if the area is more than 400 square inches.</P> <FP>Where the declaration is blown, embossed, or molded on a glass or plastic surface rather than by printing, typing, or coloring, the lettering sizes specified in paragraphs (i)(1) through (4) of this section shall be increased by one-sixteenth of an inch.</FP> <P>(j) On packages containing less than 4 pounds or 1 gallon and labeled in terms of weight or fluid measure:</P> <P>(1) The declaration shall be expressed both in ounces, with identification by weight or by liquid measure and, if applicable (1 pound or 1 pint or more), followed in parentheses by a declaration in pounds for weight units, with any remainder in terms of ounces or common or decimal fractions of the pound (as set forth in paragraphs (m)(1) and (2) of this section), or in the case of liquid measure, in the largest whole units (quarts, quarts and pints, or pints, as appropriate) with any remainder in terms of fluid ounces or common or decimal fractions of the pint or quart (as set forth in paragraphs (m)(3) and (4) of this section). Net weight or fluid measure of less than 1 ounce shall be expressed in common or decimal fractions of the respective ounce and not in drams.</P> <P>(2) The declaration may appear in more than one line. The term “net weight” shall be used when stating the net quantity of contents in terms of weight. Use of the terms “net” or “net contents” in terms of fluid measure or numerical count is optional. It is sufficient to distinguish avoirdupois ounce from fluid ounce through association of terms; for example, “Net wt. 6 oz.” or “6 oz. net wt.” and “Net contents 6 fl. oz.” or “6 fl. oz.”</P> <P>(k) On packages containing 4 pounds or 1 gallon or more and labeled in terms of weight or fluid measure, the declaration shall be expressed in pounds for weight units with any remainder in terms of ounces or common or decimal fractions of the pound; in the case of fluid measure, it shall be expressed in the largest whole unit <PRTPAGE P="138"/>(gallons, followed by common or decimal fractions of a gallon or by the next smaller whole unit or units (quarts or quarts and pints)) with any remainder in terms of fluid ounces or common or decimal fractions of the pint or quart (as set forth in paragraph (m)(5) of this section).</P> <P>(l) [Reserved]</P> <P>(m) Examples: (1) A declaration of 1<FR>1/2</FR> pounds weight shall be expressed as “Net wt. 24 oz. (1 lb. 8 oz.)”, “Net wt. 24 oz. (1<FR>1/2</FR> lb.)”, or “Net wt. 24 oz. (1.5 lb.)”.</P> <P>(2) A declaration of three-fourths pound avoirdupois weight shall be expressed as “Net wt. 12 oz.”</P> <P>(3) A declaration of 1 quart liquid measure shall be expressed as “Net contents 32 fl. oz. (1 qt.)”.</P> <P>(4) A declaration of 1<FR>3/4</FR> quarts liquid measure shall be expressed as “Net contents 56 fl. oz. (1 qt. 1<FR>1/2</FR> pt.)” or “Net contents 56 fl. oz. (1 qt. 1 pt. 8 oz.)” but not in terms of quart and ounce such as “Net content 56 fl. oz. (1 qt. 24 oz.)”.</P> <P>(5) A declaration of 2<FR>1/2</FR> gallons liquid measure shall be expressed in the alternative as “Net contents 2 gal. 2 qt.” and not as “2 gal. 4 pt.”</P> <P>(n) For quantities, the following abbreviations and none other may be employed (periods and plural forms are optional): </P> <EXTRACT> <SCOL2> <LI>weight wt.</LI> <LI>square sq.</LI> <LI>fluid fl.</LI> <LI>yard yd.</LI> <LI>feet or foot ft.</LI> <LI>inch in.</LI> <LI>gallon gal.</LI> <LI>quart qt.</LI> <LI>pint pt.</LI> <LI>ounce oz.</LI> <LI>pound lb.</LI> </SCOL2> </EXTRACT> <P>(o) On packages labeled in terms of linear measure, the declaration shall be expressed both in terms of inches and, if applicable (1 foot or more), the largest whole units (yards, yards and feet, feet). The declaration in terms of the largest whole units shall be in parentheses following the declaration in terms of inches and any remainder shall be in terms of inches or common or decimal fractions of the foot or yard. Examples are “86 inches (2 yd. 1 ft. 2 inches)”, “90 inches (2<FR>1/2</FR> yd.)”, “30 inches (2.5 ft.)”, etc.</P> <P>(p) On packages labeled in terms of area measure, the declaration shall be expressed in terms of square inches and, if applicable (1 square foot or more), the largest whole square unit (square yards, square yards and square feet, square feet). The declaration in terms of the largest whole units shall be in parentheses following the declaration in terms of square inches and any remainder shall be in terms of square inches or common or decimal fractions of the square foot or square yard; for example, “158 sq. inches (1 sq. ft. 14 sq. inches)”, etc.</P> <P>(q) Nothing in this section shall prohibit supplemental statements at locations other than the principal display panel(s) describing in nondeceptive terms the net quantity of contents, provided that such supplemental statements of net quantity of contents shall not include any term qualifying a unit of weight, measure, or count that tends to exaggerate the amount of the cosmetic contained in the package; for example, “giant pint” and “full quart.” Dual or combination declarations of net quantity of contents as provided for in paragraphs (a), (c), and (j) of this section (for example, a combination of net weight plus numerical count) are not regarded as supplemental net quantity statements and shall be located on the principal display panel.</P> <P>(r) A separate statement of the net quantity of contents in terms of the metric system is not regarded as a supplemental statement and an accurate statement of the net quantity of contents in terms of the metric system of weight or measure may also appear on the principal display panel or on other panels.</P> <P>(s) The declaration of net quantity of contents shall express an accurate statement of the quantity of contents of the package. Reasonable variations caused by loss or gain of moisture during the course of good distribution practice or by unavoidable deviations in good manufacturing practice will be recognized. Variations from stated quantity of contents shall not be unreasonably large.</P> </SECTION> </SUBPART> <SUBPART> <PRTPAGE P="139"/> <HD SOURCE="HED">Subpart C—Labeling of Specific Ingredients</HD> <SECTION> <SECTNO>§ 701.20</SECTNO> <SUBJECT>Detergent substances, other than soap, intended for use in cleansing the body.</SUBJECT> <P>(a) In its definition of the term <E T="03">cosmetic,</E> the Federal Food, Drug, and Cosmetic Act specifically excludes soap. The term <E T="03">soap</E> is nowhere defined in the act. In administering the act, the Food and Drug Administration interprets the term “soap” to apply only to articles that meet the following conditions:</P> <P>(1) The bulk of the nonvolatile matter in the product consists of an alkali salt of fatty acids and the detergent properties of the article are due to the alkali-fatty acid compounds; and</P> <P>(2) The product is labeled, sold, and represented only as soap.</P> <P>(b) Products intended for cleansing the human body and which are not “soap” as set out in paragraph (a) of this section are “cosmetics,” and accordingly they are subject to the requirements of the act and the regulations thereunder. For example, such a product in bar form is subject to the requirement, among others, that it shall bear a label containing an accurate statement of the weight of the bar in avoirdupois pounds and ounces, this statement to be prominently and conspicuously displayed so as to be likely to be read under the customary conditions of purchase and use.</P> </SECTION> <SECTION> <SECTNO>§ 701.30</SECTNO> <SUBJECT>Ingredient names established for cosmetic ingredient labeling.</SUBJECT> <P>The Commissioner establishes the following names for the purpose of cosmetic ingredient labeling pursuant to paragraph (e) of § 701.3:</P> <GPOTABLE CDEF="s140,xs48,r100" COLS="3" OPTS="L2"> <BOXHD> <CHED H="1">Chemical name or description</CHED> <CHED H="1">Chemical formula</CHED> <CHED H="1">Established label name</CHED> </BOXHD> <ROW> <ENT I="01">Trichlorofluoromethane</ENT> <ENT>CCl<E T="22">3</E> <E T="31">F</E> </ENT> <ENT>Chlorofluorocarbon 11.</ENT> </ROW> <ROW> <ENT I="01">Trichlorofluoromethane and 0.3 pct nitromethane</ENT> <ENT>CCl<E T="22">3</E> <E T="31">F+CH</E> <E T="22">3</E> <E T="31">NO</E> <E T="22">2</E> </ENT> <ENT>Chlorofluorocarbon 11 S.</ENT> </ROW> <ROW> <ENT I="01">Dichlorodifluoromethane</ENT> <ENT>CCl<E T="22">2</E> <E T="31">F</E> <E T="22">2</E> </ENT> <ENT>Chlorofluorocarbon 12.</ENT> </ROW> <ROW> <ENT I="01">Chlorodifluoromethane</ENT> <ENT>CHClF<E T="22">2</E> </ENT> <ENT>Hydrochlorofluorocarbon 22.</ENT> </ROW> <ROW> <ENT I="01">1, 2-dichloro-1, 1, 2, 2-tetrafluoroethane</ENT> <ENT>CClF<E T="22">2</E> <E T="31">CClF</E> <E T="22">2</E> </ENT> <ENT>Chlorofluorocarbon 114.</ENT> </ROW> <ROW> <ENT I="01">1-Chloro-1, 1-difluoroethane</ENT> <ENT>CH<E T="22">3</E> <E T="31">CClF</E> <E T="22">2</E> </ENT> <ENT>Hydrochlorofluorocarbon 142 B.</ENT> </ROW> <ROW> <ENT I="01">1, 1-difluoroethane</ENT> <ENT>CH<E T="22">3</E> <E T="31">CHF</E> <E T="22">2</E> </ENT> <ENT>Hydrofluorocarbon 152 A.</ENT> </ROW> <ROW> <ENT I="01">Ethyl ester of hydrolyzed animal protein is the ester of ethyl alcohol and the hydrolysate of collagen or other animal protein, derived by acid, enzyme, or other form of hydrolysis</ENT> <ENT/> <ENT>Ethyl ester of hydrolyzed animal protein.</ENT> </ROW> </GPOTABLE> <CITA TYPE="W">[42 FR 24255, May 13, 1977, as amended at 45 FR 3577, Jan. 18, 1980]</CITA> </SECTION> </SUBPART> <PART> <EAR>Pt. 710</EAR> <HD SOURCE="HED">PART 710—VOLUNTARY REGISTRATION OF COSMETIC PRODUCT ESTABLISHMENTS</HD> <CONTENTS> <SECHD>Sec.</SECHD> <SECTNO>710.1</SECTNO> <SUBJECT>Who should register.</SUBJECT> <SECTNO>710.2</SECTNO> <SUBJECT>Time for registration.</SUBJECT> <SECTNO>710.3</SECTNO> <SUBJECT>How and where to register.</SUBJECT> <SECTNO>710.4</SECTNO> <SUBJECT>Information requested.</SUBJECT> <SECTNO>710.5</SECTNO> <SUBJECT>Amendments to registration.</SUBJECT> <SECTNO>710.6</SECTNO> <SUBJECT>Notification of registrant; cosmetic product establishment registration number.</SUBJECT> <SECTNO>710.7</SECTNO> <SUBJECT>Inspection of registrations.</SUBJECT> <SECTNO>710.8</SECTNO> <SUBJECT>Misbranding by reference to registration or to registration number.</SUBJECT> <SECTNO>710.9</SECTNO> <SUBJECT>Exemptions.</SUBJECT> </CONTENTS> <AUTH> <HD SOURCE="HED">Authority: </HD> <P>21 U.S.C. 321, 331, 361, 362, 371, 374.</P> </AUTH> <SOURCE> <HD SOURCE="HED">Source: </HD> <P>39 FR 10059, Mar. 15, 1974, unless otherwise noted.</P> </SOURCE> <SECTION> <SECTNO>§ 710.1</SECTNO> <SUBJECT>Who should register.</SUBJECT> <P>The owner or operator of a cosmetic product establishment which is not exempt under § 710.9 and engages in the manufacture or packaging of a cosmetic product is requested to register for each such establishment, whether or not the product enters interstate commerce. This request extends to any foreign cosmetic product establishment whose products are exported for sale in any State as defined in section 201(a)(1) of the act. No registration fee is required.</P> </SECTION> <SECTION> <SECTNO>§ 710.2</SECTNO> <SUBJECT>Time for registration.</SUBJECT> <P>The owner or operator of an establishment entering into the manufacture or packaging of a cosmetic product should register his establishment <PRTPAGE P="140"/>within 30 days after the operation begins.</P> </SECTION> <SECTION> <SECTNO>§ 710.3</SECTNO> <SUBJECT>How and where to register.</SUBJECT> <P>Form FD-2511 (“Registration of Cosmetic Product Establishment”) is obtainable on request from the Food and Drug Administration, Department of Health and Human Services, Washington, DC 20204, or at any Food and Drug Administration district office. The completed form should be mailed to Cosmetic Product Establishment Registration, Food and Drug Administration, Department of Health and Human Services, Washington, DC 20204.</P> </SECTION> <SECTION> <SECTNO>§ 710.4</SECTNO> <SUBJECT>Information requested.</SUBJECT> <P>Form FD-2511 requests information on the name and address of the cosmetic product establishment, including post office ZIP code; all business trading names used by the establishment; and the type of business (manufacturer and/or packer). The information requested should be given separately for each establishment as defined in § 700.3(j) of this chapter.</P> <CITA>[39 FR 10059, Mar. 15, 1974, as amended at 46 FR 38073, July 24, 1981; 54 FR 39640, Sept. 27, 1989]</CITA> </SECTION> <SECTION> <SECTNO>§ 710.5</SECTNO> <SUBJECT>Amendments to registration.</SUBJECT> <P>Within 30 days after a change in any of the information contained on a submitted Form FD-2511, a new Form FD-2511 should be submitted to amend the registration. This amendment is also necessary when a registration is to be canceled because an establishment has changed its name and no longer conducts business under the original name.</P> </SECTION> <SECTION> <SECTNO>§ 710.6</SECTNO> <SUBJECT>Notification of registrant; cosmetic product establishment registration number.</SUBJECT> <P>The Commissioner of Food and Drugs will provide the registrant with a validated copy of Form FD-2511 as evidence of registration. This validated copy will be sent only to the location shown for the registering establishment. A permanent registration number will be assigned to each cosmetic product establishment registered in accordance with the regulations in this part.</P> </SECTION> <SECTION> <SECTNO>§ 710.7</SECTNO> <SUBJECT>Inspection of registrations.</SUBJECT> <P>A copy of the Form FD-2511 filed by the registrant will be available for inspection at the Food and Drug Administration, Department of Health and Human Services, Washington, DC 20204.</P> </SECTION> <SECTION> <SECTNO>§ 710.8</SECTNO> <SUBJECT>Misbranding by reference to registration or to registration number.</SUBJECT> <P>Registration of a cosmetic product establishment or assignment of a registration number does not in any way denote approval of the firm or its products by the Food and Drug Administration. Any representation in labeling or advertising that creates an impression of official approval because of registration or possession of a registration number will be considered misleading.</P> </SECTION> <SECTION> <SECTNO>§ 710.9</SECTNO> <SUBJECT>Exemptions.</SUBJECT> <P>The following classes of persons are not requested to register in accordance with this part 710 because the Commissioner has found that such registration is not justified:</P> <P>(a) Beauty shops, cosmetologists, retailers, pharmacies, and other persons and organizations that compound cosmetic products at a single location and administer, dispense, or distribute them at retail from that location and who do not otherwise manufacture or package cosmetic products at that location.</P> <P>(b) Physicians, hospitals, clinics, and public health agencies.</P> <P>(c) Persons who manufacture, prepare, compound, or process cosmetic products solely for use in research, pilot plant production, teaching, or chemical analysis, and who do not sell these products.</P> </SECTION> </PART> <PART> <EAR>Pt. 720</EAR> <HD SOURCE="HED">PART 720—VOLUNTARY FILING OF COSMETIC PRODUCT INGREDIENT AND COSMETIC RAW MATERIAL COMPOSITION STATEMENTS</HD> <CONTENTS> <SECHD>Sec.</SECHD> <SECTNO>720.1</SECTNO> <SUBJECT>Who should file.</SUBJECT> <SECTNO>720.2</SECTNO> <SUBJECT>Times for filing.</SUBJECT> <SECTNO>720.3</SECTNO> <SUBJECT>How and where to file.</SUBJECT> <SECTNO>720.4</SECTNO> <SUBJECT>Information requested about cosmetic products.</SUBJECT> <SECTNO>720.5</SECTNO> <SUBJECT>[Reserved]</SUBJECT> <SECTNO>720.6</SECTNO> <SUBJECT>Amendments to statement.<PRTPAGE P="141"/> </SUBJECT> <SECTNO>720.7</SECTNO> <SUBJECT>Notification of person submitting cosmetic product ingredient statement.</SUBJECT> <SECTNO>720.8</SECTNO> <SUBJECT>Confidentiality of statements.</SUBJECT> <SECTNO>720.9</SECTNO> <SUBJECT>Misbranding by reference to filing or to statement number.</SUBJECT> </CONTENTS> <AUTH> <HD SOURCE="HED">Authority: </HD> <P>21 U.S.C. 321, 331, 361, 362, 371, 374.</P> </AUTH> <SOURCE> <HD SOURCE="HED">Source: </HD> <P>39 FR 10060, Mar. 15, 1974, unless otherwise noted.</P> </SOURCE> <SECTION> <SECTNO>§ 720.1</SECTNO> <SUBJECT>Who should file.</SUBJECT> <P>Either the manufacturer, packer, or distributor of a cosmetic product is requested to file Form FDA 2512 (“Cosmetic Product Ingredient Statement”), whether or not the cosmetic product enters interstate commerce. This request extends to any foreign manufacturer, packer, or distributor of a cosmetic product exported for sale in any State as defined in section 201(a)(1) of the Federal Food, Drug, and Cosmetic Act. No filing fee is required.</P> <CITA>[57 FR 3129, Jan. 28, 1992]</CITA> </SECTION> <SECTION> <SECTNO>§ 720.2</SECTNO> <SUBJECT>Times for filing.</SUBJECT> <P>Within 180 days after forms are made available to the industry, Form FDA 2512 should be filed for each cosmetic product being commercially distributed as of the effective date of this part. Form FDA 2512 should be filed within 60 days after the beginning of commercial distribution of any product not covered within the 180-day period.</P> <CITA>[57 FR 3129, Jan. 28, 1992]</CITA> </SECTION> <SECTION> <SECTNO>§ 720.3</SECTNO> <SUBJECT>How and where to file.</SUBJECT> <P>Forms FDA 2512 and FDA 2514 (“Discontinuance of Commercial Distribution of Cosmetic Product Formulation”) are obtainable on request from the Food and Drug Administration, Department of Health and Human Services, Washington, DC 20204, or at any Food and Drug Administration district office. The completed form should be mailed or delivered to: Cosmetic Product Statement, Food and Drug Administration, Department of Health and Human Services, Washington, DC 20204, according to the instructions provided with the forms.</P> <CITA>[57 FR 3129, Jan. 28, 1992]</CITA> </SECTION> <SECTION> <SECTNO>§ 720.4</SECTNO> <SUBJECT>Information requested about cosmetic products.</SUBJECT> <P>(a) Form FDA-2512 requests information on:</P> <P>(1) The name and address, including post office ZIP code of the person (manufacturer, packer, or distributor) designated on the label of the product.</P> <P>(2) The name and address, including post office ZIP code, of the manufacturer or packer of the product if different from the person designated on the label of the product, when the manufacturer or packer submits the information requested under this paragraph.</P> <P>(3) The brand name or names of the cosmetic product.</P> <P>(4) The cosmetic product category or categories.</P> <P>(5) The ingredients in the product.</P> <P>(b) The person filing Form FDA-2512 should:</P> <P>(1) Provide the information requested in paragraph (a) of this section.</P> <P>(2) Have the form signed by an authorized individual.</P> <P>(3) Provide poison control centers with ingredient information and/or adequate diagnostic and therapeutic procedures to permit rapid evaluation and treatment of accidental ingestion or other accidental use of the cosmetic product.</P> <P>(4) Provide ingredient information (and, when requested, ingredient samples) to a licensed physician who, in connection with the treatment of a patient, requests assistance in determining whether an ingredient in the cosmetic product is the cause of the problem for which the patient is being treated.</P> <P>(c) One or more of the following cosmetic product categories should be cited to indicate the product's intended use.</P> <P>(1) <E T="03">Baby products.</E> (i) Baby shampoos.</P> <P>(ii) Lotions, oils, powders, and creams.</P> <P>(iii) Other baby products.</P> <P>(2) <E T="03">Bath preparations.</E> (i) Bath oils, tablets, and salts.</P> <P>(ii) Bubble baths.</P> <P>(iii) Bath capsules.</P> <P>(iv) Other bath preparations.</P> <P>(3) <E T="03">Eye makeup preparations.</E> (i) Eyebrow pencil.</P> <P>(ii) Eyeliner.</P> <P>(iii) Eye shadow.<PRTPAGE P="142"/> </P> <P>(iv) Eye lotion.</P> <P>(v) Eye makeup remover.</P> <P>(vi) Mascara.</P> <P>(vii) Other eye makeup preparations.</P> <P>(4) <E T="03">Fragrance preparations.</E> (i) Colognes and toilet waters.</P> <P>(ii) Perfumes.</P> <P>(iii) Powders (dusting and talcum) (excluding aftershave talc).</P> <P>(iv) Sachets.</P> <P>(v) Other fragrance preparations.</P> <P>(5) <E T="03">Hair preparations (noncoloring).</E> </P> <P>(i) Hair conditioners.</P> <P>(ii) Hair sprays (aerosol fixatives).</P> <P>(iii) Hair straighteners.</P> <P>(iv) Permanent waves.</P> <P>(v) Rinses (noncoloring).</P> <P>(vi) Shampoos (noncoloring).</P> <P>(vii) Tonics, dressings, and other hair grooming aids.</P> <P>(viii) Wave sets.</P> <P>(ix) Other hair preparations.</P> <P>(6) <E T="03">Hair coloring preparations.</E> (i) Hair dyes and colors (all types requiring caution statement and patch test).</P> <P>(ii) Hair tints.</P> <P>(iii) Hair rinses (coloring).</P> <P>(iv) Hair shampoos (coloring).</P> <P>(v) Hair color sprays (aerosol).</P> <P>(vi) Hair lighteners with color.</P> <P>(vii) Hair bleaches.</P> <P>(viii) Other hair coloring preparations.</P> <P>(7) <E T="03">Makeup preparations (not eye).</E> (i) Blushers (all types).</P> <P>(ii) Face powders.</P> <P>(iii) Foundations.</P> <P>(iv) Leg and body paints.</P> <P>(v) Lipstick.</P> <P>(vi) Makeup bases.</P> <P>(vii) Rouges.</P> <P>(viii) Makeup fixatives.</P> <P>(ix) Other makeup preparations.</P> <P>(8) <E T="03">Manicuring preparations.</E> (i) Basecoats and undercoats.</P> <P>(ii) Cuticle softeners.</P> <P>(iii) Nail creams and lotions.</P> <P>(iv) Nail extenders.</P> <P>(v) Nail polish and enamel.</P> <P>(vi) Nail polish and enamel removers.</P> <P>(vii) Other manicuring preparations.</P> <P>(9) <E T="03">Oral hygiene products.</E> (i) Dentifrices (aerosol, liquid, pastes, and powders).</P> <P>(ii) Mouthwashes and breath fresheners (liquids and sprays).</P> <P>(iii) Other oral hygiene products.</P> <P>(10) <E T="03">Personal cleanliness.</E> (i) Bath soaps and detergents.</P> <P>(ii) Deodorants (underarm).</P> <P>(iii) Douches.</P> <P>(iv) Feminine hygiene deodorants.</P> <P>(v) Other personal cleanliness products.</P> <P>(11) <E T="03">Shaving preparations.</E> (i) Aftershave lotions.</P> <P>(ii) Beard softeners.</P> <P>(iii) Men's talcum.</P> <P>(iv) Preshave lotions (all types).</P> <P>(v) Shaving cream (aerosol, brushless, and lather).</P> <P>(vi) Shaving soap (cakes, sticks, etc.).</P> <P>(vii) Other shaving preparation products.</P> <P>(12) <E T="03">Skin care preparations, (creams, lotions, powder, and sprays).</E> (i) Cleansing (cold creams, cleansing lotions, liquids, and pads).</P> <P>(ii) Depilatories.</P> <P>(iii) Face and neck (excluding shaving preparations).</P> <P>(iv) Body and hand (excluding shaving preparations).</P> <P>(v) Foot powders and sprays.</P> <P>(vi) Moisturizing.</P> <P>(vii) Night.</P> <P>(viii) Paste masks (mud packs).</P> <P>(ix) Skin fresheners.</P> <P>(x) Other skin care preparations.</P> <P>(13) <E T="03">Suntan preparations.</E> (i) Suntan gels, creams, and liquids.</P> <P>(ii) Indoor tanning preparations.</P> <P>(iii) Other suntan preparations.</P> <P>(d) Ingredients in the product should be listed as follows:</P> <P>(1) A list of each ingredient of the cosmetic product in descending order of predominance by weight (except that the fragrance and/or flavor may be designated as such without naming each individual ingredient when the manufacturer or supplier of the fragrance and/or flavor refuses to disclose ingredient data).</P> <P>(2) An ingredient should be listed by the name adopted by the Food and Drug Administration (FDA) for the ingredient pursuant to § 701.3(c) of this chapter.</P> <P>(3) In the absence of a name adopted by FDA pursuant to § 701.3(c) of this chapter, its common or usual name, if it has one, or its chemical or technical name should be listed.</P> <P>(4) If an ingredient is a mixture, each ingredient of the mixture should be listed in accordance with paragraphs <PRTPAGE P="143"/>(d)(2) and (d)(3) of this section, unless such mixture is a formulation voluntarily registered on Form FDA 2512, in which case such mixture should be identified as “fragrance,” “flavor,” “fragrance and flavor” or “base formulation,” as appropriate, and by stating its FDA-assigned cosmetic product ingredient statement number.</P> <P>(5) When the manufacturer or supplier of a fragrance and/or flavor refuses to disclose ingredient data, the fragrance and/or flavor should be listed as such. The nonconfidential listing of the product name and/or trade name or name of the manufacturer or supplier of each proprietary fragrance and/or flavor mixture is optional.</P> <P>(e) A separate Form FDA-2512 should be filed for each different formulation of a cosmetic product. However, except for the hair coloring preparations listed in paragraph (c)(6) of this section for which a statement for each shade of such product is required, a single Form FDA-2512 may be filed for two or more shades of a cosmetic product where only the amounts of the color additive ingredient used are varied or in the case of flavors and fragrances where only the amounts of the flavors and fragrances used are varied. </P> <EXTRACT> <FP>(Information collection requirements in this section were approved by the Office of Management and Budget (OMB) and assigned OMB control number 0910-0030)</FP> </EXTRACT> <CITA>[39 FR 10060, Mar. 15, 1974, as amended at 46 FR 38073, July 24, 1981; 57 FR 3129, Jan. 28, 1992]</CITA> </SECTION> <SECTION> <SECTNO>§ 720.5</SECTNO> <RESERVED>[Reserved]</RESERVED> </SECTION> <SECTION> <SECTNO>§ 720.6</SECTNO> <SUBJECT>Amendments to statement.</SUBJECT> <P>Changes in the information requested under §§ 720.4 (a)(3) and (a)(5) on the ingredients or brand name of a cosmetic product should be submitted by filing an amended Form FDA 2512 within 60 days after the product is entered into commercial distribution. Other changes do not justify immediate amendment, but should be shown by filing an amended Form FDA 2512 within a year after such changes. Notice of discontinuance of commercial distribution of a cosmetic product formulation should be submitted by Form FDA 2514 within 180 days after discontinuance of commercial distribution becomes known to the person filing. </P> <EXTRACT> <FP>(Information collection requirements in this section were approved by the Office of Management and Budget (OMB) and assigned OMB control number 0910-0030)</FP> </EXTRACT> <CITA>[57 FR 3130, Jan. 28, 1992]</CITA> </SECTION> <SECTION> <SECTNO>§ 720.7</SECTNO> <SUBJECT>Notification of person submitting cosmetic product ingredient statement.</SUBJECT> <P>When Form FDA 2512 is received, FDA will either assign a permanent cosmetic product ingredient statement number or a Food and Drug Administration (FDA) reference number in those cases where a permanent number cannot be assigned. Receipt of the form will be acknowledged by sending the individual signing the statement an appropriate notice bearing either the FDA reference number or the permanent cosmetic product ingredient statement number. If the person submitting Form FDA 2512 has not complied with §§ 720.4 (b)(1) and (b)(2), the person will be notified as to the manner in which the statement is incomplete.</P> <CITA>[57 FR 3130, Jan. 28, 1992]</CITA> </SECTION> <SECTION> <SECTNO>§ 720.8</SECTNO> <SUBJECT>Confidentiality of statements.</SUBJECT> <P>(a) Data and information contained in, attached to, or included with Forms FDA 2512 and FDA 2514, and amendments thereto are submitted voluntarily to the Food and Drug Administration (FDA). Any request for confidentiality of a cosmetic ingredient submitted with such forms or separately will be handled in accordance with the procedure set forth in this section and in § 20.44 of this chapter. The request for confidentiality will also be subject to the provisions of § 20.111 of this chapter, as well as to the exemptions in subpart D of part 20 of this chapter and to the limitations on exemption in subpart E of part 20 of this chapter.</P> <P>(b) Any request for confidentiality of the identity of a cosmetic ingredient should contain a full statement, in a well-organized format, of the factual and legal grounds for that request, including all data and other information on which the petitioner relies, as well as representative information known <PRTPAGE P="144"/>to the petitioner that is unfavorable to the petitioner's position. The statement of the factual grounds should include, but should not be limited to, scientific or technical data, reports, tests, and other relevant information addressing the following factors that FDA will consider in determining whether the identity of an ingredient qualifies as a trade secret:</P> <P>(1) The extent to which the identity of the ingredient is known outside petitioner's business;</P> <P>(2) The extent to which the identity of the ingredient is known by employees and others involved in petitioner's business;</P> <P>(3) The extent of measures taken by the petitioner to guard the secrecy of the information;</P> <P>(4) The value of the information about the identity of the claimed trade secret ingredient to the petitioner and to its competitors;</P> <P>(5) The amount of effort or money expended by petitioner in developing the ingredient; and</P> <P>(6) The ease or difficulty with which the identity of the ingredient could be properly acquired or duplicated by others.</P> <P>(c) The request for confidentiality should also be accompanied by a statement that the identity of the ingredient for which confidentiality is requested has not previously been published or disclosed to anyone other than as provided in § 20.81(a) of this chapter.</P> <P>(d) FDA will return to the petitioner any request for confidentiality that contains insufficient data to permit a review of the merits of the request. FDA will also advise the petitioner about the additional information that is necessary to enable the agency to proceed with its review of the request.</P> <P>(e) If, after receiving all of the data that are necessary to make a determination about whether the identity of an ingredient is a trade secret, FDA tentatively decides to deny the request, the agency will inform the person requesting trade secrecy of its tentative determination in writing. FDA will set forth the grounds upon which it relied in making this tentative determination. The petitioner may withdraw the records for which FDA has tentatively denied a request for confidentiality or may submit, within 60 days from the date of receipt of the written notice of the tentative denial, additional relevant information and arguments and request that the agency reconsider its decision in light of both the additional material and the information that it originally submitted.</P> <P>(f) If the petitioner submits new data in response to FDA's tentative denial of trade secret status, the agency will consider that material together with the information that was submitted initially before making its final determination.</P> <P>(g) A final determination that an ingredient is not a trade secret within the meaning of § 20.61 of this chapter constitutes final agency action that is subject to judicial review under 5 U.S.C. Chapter 7. If suit is brought within 30 calendar days after such a determination, FDA will not disclose the records involved or require that the disputed ingredient or ingredients be disclosed in labeling until the matter is finally determined in the courts. If suit is not brought within 30 calendar days after a final determination that an ingredient is not a trade secret within the meaning of 21 CFR 20.61, and the petitioner does not withdraw the records for which a request for confidentiality has been denied, the records involved will be made a part of FDA files and will be available for public disclosure upon request.</P> <CITA>[51 FR 11444, Apr. 3, 1986, as amended at 57 FR 3130, Jan. 28, 1992]</CITA> </SECTION> <SECTION> <SECTNO>§ 720.9</SECTNO> <SUBJECT>Misbranding by reference to filing or to statement number.</SUBJECT> <P>The filing of Form FDA 2512 or assignment of a number to the statement does not in any way denote approval by the Food and Drug Administration of the firm or the product. Any representation in labeling or advertising that creates an impression of official approval because of such filing or such number will be considered misleading.</P> <CITA>[57 FR 3130, Jan. 28, 1992]</CITA> </SECTION> </PART> <PART> <PRTPAGE P="145"/> <EAR>Pt. 740</EAR> <HD SOURCE="HED">PART 740—COSMETIC PRODUCT WARNING STATEMENTS</HD> <CONTENTS> <SUBPART> <HD SOURCE="HED">Subpart A—General</HD> <SECHD>Sec.</SECHD> <SECTNO>740.1</SECTNO> <SUBJECT>Establishment of warning statements.</SUBJECT> <SECTNO>740.2</SECTNO> <SUBJECT>Conspicuousness of warning statements.</SUBJECT> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart B—Warning Statements</HD> <SECTNO>740.10</SECTNO> <SUBJECT>Labeling of cosmetic products for which adequate substantiation of safety has not been obtained.</SUBJECT> <SECTNO>740.11</SECTNO> <SUBJECT>Cosmetics in self-pressurized containers.</SUBJECT> <SECTNO>740.12</SECTNO> <SUBJECT>Feminine deodorant sprays.</SUBJECT> <SECTNO>740.17</SECTNO> <SUBJECT>Foaming detergent bath products.</SUBJECT> <SECTNO>740.18</SECTNO> <SUBJECT>Coal tar hair dyes posing a risk of cancer.</SUBJECT> </SUBPART> </CONTENTS> <AUTH> <HD SOURCE="HED">Authority: </HD> <P>21 U.S.C. 321, 331, 352, 355, 361, 362, 371, 374.</P> </AUTH> <SUBPART> <HD SOURCE="HED">Subpart A—General</HD> <SECTION> <SECTNO>§ 740.1</SECTNO> <SUBJECT>Establishment of warning statements.</SUBJECT> <P>(a) The label of a cosmetic product shall bear a warning statement whenever necessary or appropriate to prevent a health hazard that may be associated with the product.</P> <P>(b) The Commissioner of Food and Drugs, either on his own initiative or on behalf of any interested person who has submitted a petition, may publish a proposal to establish or amend, under subpart B of this part, a regulation prescribing a warning for a cosmetic. Any such petition shall include an adequate factual basis to support the petition, shall be in the form set forth in part 10 of this chapter, and will be published for comment if it contains reasonable grounds for the proposed regulation.</P> <CITA>[40 FR 8917, Mar. 3, 1975, as amended at 42 FR 15676, Mar. 22, 1977]</CITA> </SECTION> <SECTION> <SECTNO>§ 740.2</SECTNO> <SUBJECT>Conspicuousness of warning statements.</SUBJECT> <P>(a) A warning statement shall appear on the label prominently and conspicuously as compared to other words, statements, designs, or devices and in bold type on contrasting background to render it likely to be read and understood by the ordinary individual under customary conditions of purchase and use, but in no case may the letters and/or numbers be less than <FR>1/16</FR> inch in height, unless an exemption pursuant to paragraph (b) of this section is established.</P> <P>(b) If the label of any cosmetic package is too small to accommodate the information as required by this section, the Commissioner may establish by regulation an acceptable alternative method, e.g., type size smaller than <FR>1/16</FR> inch in height. A petition requesting such a regulation, as an amendment to this section, shall be submitted to the Dockets Management Branch in the form established in part 10 of this chapter.</P> <CITA>[40 FR 8917, Mar. 3, 1975, as amended at 42 FR 15676, Mar. 22, 1977]</CITA> </SECTION> </SUBPART> <SUBPART> <HD SOURCE="HED">Subpart B—Warning Statements</HD> <SECTION> <SECTNO>§ 740.10</SECTNO> <SUBJECT>Labeling of cosmetic products for which adequate substantiation of safety has not been obtained.</SUBJECT> <P>(a) Each ingredient used in a cosmetic product and each finished cosmetic product shall be adequately substantiated for safety prior to marketing. Any such ingredient or product whose safety is not adequately substantiated prior to marketing is misbranded unless it contains the following conspicuous statement on the principal display panel: </P> <EXTRACT> <P> <E T="03">Warning</E>—The safety of this product has not been determined.</P> </EXTRACT> <P>(b) An ingredient or product having a history of use in or as a cosmetic may at any time have its safety brought into question by new information that in itself is not conclusive. The warning required by paragraph (a) of this section is not required for such an ingredient or product if:</P> <P>(1) The safety of the ingredient or product had been adequately substantiated prior to development of the new information;</P> <P>(2) The new information does not demonstrate a hazard to human health; and</P> <P>(3) Adequate studies are being conducted to determine expeditiously the safety of the ingredient or product.</P> <P>(c) Paragraph (b) of this section does not constitute an exemption to the adulteration provisions of the Act or to <PRTPAGE P="146"/>any other requirement in the Act or this chapter.</P> <CITA>[40 FR 8917, Mar. 3, 1975]</CITA> </SECTION> <SECTION> <SECTNO>§ 740.11</SECTNO> <SUBJECT>Cosmetics in self-pressurized containers.</SUBJECT> <P>(a)(1) The label of a cosmetic packaged in a self-pressurized container and intended to be expelled from the package under pressure shall bear the following warning: </P> <EXTRACT> <P> <E T="03">Warning</E>—Avoid spraying in eyes. Contents under pressure. Do not puncture or incinerate. Do not store at temperature above 120° F. Keep out of reach of children. </P> </EXTRACT> <P>(2) In the case of products intended for use by children, the phrase “except under adult supervision” may be added at the end of the last sentence in the warning required by paragraph (a)(1) of this section.</P> <P>(3) In the case of products packaged in glass containers, the word “break” may be substituted for the word “puncture” in the warning required by paragraph (a)(1) of this section.</P> <P>(4) The words “Avoid spraying in eyes” may be deleted from the warning required by paragraph (a)(1) of this section in the case of a product not expelled as a spray.</P> <P>(b)(1) In addition to the warning required by paragraph (a)(1) of this section, the label of a cosmetic packaged in a self-pressurized container in which the propellant consists in whole or in part of a halocarbon or a hydrocarbon shall bear the following warning: </P> <EXTRACT> <P> <E T="03">Warning</E>—Use only as directed. Intentional misuse by deliberately concentrating and inhaling the contents can be harmful or fatal. </P> </EXTRACT> <P>(2) The warning required by paragraph (b)(1) of this section is not required for the following products:</P> <P>(i) Products expelled in the form of a foam or cream, which contain less than 10 percent propellant in the container.</P> <P>(ii) Products in a container with a physical barrier that prevents escape of the propellant at the time of use.</P> <P>(iii) Products of a net quantity of contents of less than 2 ozs. that are designed to release a measured amount of product with each valve actuation.</P> <P>(iv) Products of a net quantity of contents of less than <FR>1/2</FR> oz.</P> <P>(c) Labeling requirements for cosmetics packaged in a self- pressurized container containing or manufactured with a chlorofluorocarbon propellant or other ozone-depleting substance designated by the Environmental Protection Agency (EPA) are set forth in 40 CFR part 82.</P> <CITA>[40 FR 8917, Mar. 3, 1975, as amended at 42 FR 22033, Apr. 29, 1977; 54 FR 39640, Sept. 27, 1989; 61 FR 20101, May 3, 1996]</CITA> </SECTION> <SECTION> <SECTNO>§ 740.12</SECTNO> <SUBJECT>Feminine deodorant sprays.</SUBJECT> <P>(a) For the purpose of this section, the term “feminine deodorant spray” means any spray deodorant product whose labeling represents or suggests that the product is for use in the female genital area or for use all over the body.</P> <P>(b) The label of a feminine deodorant spray shall bear the following statement: </P> <EXTRACT> <P> <E T="03">Caution</E>—For external use only. Spray at least 8 inches from skin. Do not apply to broken, irritated, or itching skin. Persistent, unusual odor or discharge may indicate conditions for which a physician should be consulted. Discontinue use immediately if rash, irritation, or discomfort develops. </P> </EXTRACT> <FP>The sentence “Spray at least 8 inches from skin” need not be included in the cautionary statement for products whose expelled contents do not contain a liquified gas propellant such as a halocarbon or hydrocarbon propellant.</FP> <P>(c) Use of the word “hygiene” or “hygienic” or a similar word or words renders any such product misbranded under section 602(a) of the Federal Food, Drug, and Cosmetic Act. The use of any word or words which represent or suggest that such products have a medical usefulness renders such products misbranded under section 502(a) of the Act and illegal new drugs marketed in violation of section 505 of the Act.</P> <CITA>[40 FR 8929, Mar. 3, 1975]</CITA> </SECTION> <SECTION> <SECTNO>§ 740.17</SECTNO> <SUBJECT>Foaming detergent bath products.</SUBJECT> <P>(a) For the purpose of this section, a foaming detergent bath product is any product intended to be added to a bath for the purpose of producing foam that contains a surface-active agent serving as a detergent or foaming ingredient.</P> <P>(b) The label of foaming detergent bath products within the meaning of paragraph (a) of this section, except for <PRTPAGE P="147"/>those products that are labeled as intended for use exclusively by adults, shall bear adequate directions for safe use and the following caution: </P> <EXTRACT> <P> <E T="03">Caution</E>—Use only as directed. Excessive use or prolonged exposure may cause irritation to skin and urinary tract. Discontinue use if rash, redness, or itching occurs. Consult your physician if irritation persists. Keep out of reach of children.</P> </EXTRACT> <P>(c) In the case of products intended for use by children, the phrase “except under adult supervision” may be added at the end of the last sentence in the caution required by paragraph (b) of this section.</P> <CITA>[51 FR 20475, June 5, 1986]</CITA> </SECTION> <SECTION> <SECTNO>§ 740.18</SECTNO> <SUBJECT>Coal tar hair dyes posing a risk of cancer.</SUBJECT> <P>(a) The principal display panel of the label and any labeling accompanying a coal tar hair dye containing any ingredient listed in paragraph (b) of this section shall bear, in accordance with the requirements of § 740.2, the following: </P> <EXTRACT> <P> <E T="03">Warning</E>—Contains an ingredient that can penetrate your skin and has been determined to cause cancer in laboratory animals.</P> </EXTRACT> <P>(b) Hair dyes containing any of the following ingredients shall comply with the requirements of this section: (1) 4-methoxy-<E T="03">m</E>-phenylenediamine (2,4-diaminoanisole) and (2) 4-methoxy-<E T="03">m</E>-phenylenediamine sulfate (2,4-diaminoanisole sulfate).</P> <CITA>[44 FR 59522, Oct. 16, 1979]</CITA> <EFFDNOT> <HD SOURCE="HED">Effective Date Note: </HD> <P> At 47 FR 7829, Feb. 23, 1982, the effectiveness of § 740.18 was stayed until further notice. The stay was effective Sept. 18, 1980.</P> </EFFDNOT> </SECTION> </SUBPART> </PART> <PART> <RESERVED>PARTS 741—799 [RESERVED]</RESERVED> </PART> </SUPERSED> </EFFDNOT> </SECTION> </SUBPART> </PART> </SUBCHAP> </CHAPTER> FINDING AIDS

A list of CFR titles, subtitles, chapters, subchapters and parts and an alphabetical list of agencies publishing in the CFR are included in the CFR Index and Finding Aids volume to the Code of Federal Regulations which is published separately and revised annually.

Material Approved for Incorporation by Reference

Table of CFR Titles and Chapters

Alphabetical List of Agencies Appearing in the CFR

List of CFR Sections Affected

 Title 21—Food and Drugs Material Approved for Incorporation by Reference Material Approved for Incorporation by Reference (Revised as of April 1, 1999)

The Director of the Federal Register has approved under 5 U.S.C. 552(a) and 1 CFR Part 51 the incorporation by reference of the following publications. This list contains only those incorporations by reference effective as of the revision date of this volume. Incorporations by reference found within a regulation are effective upon the effective date of that regulation. For more information on incorporation by reference, see the preliminary pages of this volume.

21 CFR (PARTS 600 TO 799) FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES 21 CFR Cosmetic, Toiletry, and Fragrance Association, Inc. 1133 15th St. NW., Washington, DC 20065. Cosmetic, Toiletry, and Fragrance Association, Inc., Cosmetic Ingredient Dictionary, Second Ed., 1977 701.3(c)(2)(i). National Academy of Sciences, National Research Council 2101 Constitution Ave. NW., Washington, DC 20037. Food Chemicals Codex, 2nd Ed., 1972 720.4(d) Food Chemicals Codex, 2nd Ed., 1972, First Supplement, 1974 701.3(c) Food Chemicals Codex, 2nd Ed., 1972, Second Supplement, 1975... 701.3(c)(2)(iv) NOTE: The following materials are available through the Food and Drug Administration at the addresses indicated. Bureau of Biologics, Food and Drug Administration 8800 Rockville Pike, Bethesda, MD 20205 Standard Methods for the Examination of Water and Waste Water, 13th Ed. 630.74 United States Pharmacopeial Covention, Inc. 12601 Twinbrook Parkway, Rockville, MD 20852 United States Pharmacopeia (21st revision, 1985): Test Procedures Using Membrane Filtration, p. 1159 610.12(f) United States Pharmacopeia (23rd revision, 1995): Test Procedures Using Membrane Filtration, pp. 1689 and 1690 610.12(f) Chap. Table of CFR Titles and Chapters (Revised as of March 31, 1999) Title 1—General Provisions I Administrative Committee of the Federal Register (Parts 1—49) II Office of the Federal Register (Parts 50—299) IV Miscellaneous Agencies (Parts 400—500) Title 2—[Reserved] Title 3—The President I Executive Office of the President (Parts 100—199) Title 4—Accounts I General Accounting Office (Parts 1—99) II Federal Claims Collection Standards (General Accounting Office—Department of Justice) (Parts 100—299) Title 5—Administrative Personnel I Office of Personnel Management (Parts 1—1199) II Merit Systems Protection Board (Parts 1200—1299) III Office of Management and Budget (Parts 1300—1399) IV Advisory Committee on Federal Pay (Parts 1400—1499) V The International Organizations Employees Loyalty Board (Parts 1500—1599) VI Federal Retirement Thrift Investment Board (Parts 1600—1699) VII Advisory Commission on Intergovernmental Relations (Parts 1700—1799) VIII Office of Special Counsel (Parts 1800—1899) IX Appalachian Regional Commission (Parts 1900—1999) XI Armed Forces Retirement Home (Part 2100) XIV Federal Labor Relations Authority, General Counsel of the Federal Labor Relations Authority and Federal Service Impasses Panel (Parts 2400—2499) XV Office of Administration, Executive Office of the President (Parts 2500—2599) XVI Office of Government Ethics (Parts 2600—2699) XXI Department of the Treasury (Parts 3100—3199) XXII Federal Deposit Insurance Corporation (Part 3201) XXIII Department of Energy (Part 3301) XXIV Federal Energy Regulatory Commission (Part 3401) XXV Department of the Interior (Part 3501) XXVI Department of Defense (Part 3601) XXVIII Department of Justice (Part 3801) XXIX Federal Communications Commission (Parts 3900—3999) XXX Farm Credit System Insurance Corporation (Parts 4000—4099) XXXI Farm Credit Administration (Parts 4100—4199) XXXIII Overseas Private Investment Corporation (Part 4301) XXXV Office of Personnel Management (Part 4501) XL Interstate Commerce Commission (Part 5001) XLI Commodity Futures Trading Commission (Part 5101) XLII Department of Labor (Part 5201) XLIII National Science Foundation (Part 5301) XLV Department of Health and Human Services (Part 5501) XLVI Postal Rate Commission (Part 5601) XLVII Federal Trade Commission (Part 5701) XLVIII Nuclear Regulatory Commission (Part 5801) L Department of Transportation (Part 6001) LII Export-Import Bank of the United States (Part 6201) LIII Department of Education (Parts 6300—6399) LIV Environmental Protection Agency (Part 6401) LVII General Services Administration (Part 6701) LVIII Board of Governors of the Federal Reserve System (Part 6801) LIX National Aeronautics and Space Administration (Part 6901) LX United States Postal Service (Part 7001) LXI National Labor Relations Board (Part 7101) LXII Equal Employment Opportunity Commission (Part 7201) LXIII Inter-American Foundation (Part 7301) LXV Department of Housing and Urban Development (Part 7501) LXVI National Archives and Records Administration (Part 7601) LXIX Tennessee Valley Authority (Part 7901) LXXI Consumer Product Safety Commission (Part 8101) LXXIV Federal Mine Safety and Health Review Commission (Part 8401) LXXVI Federal Retirement Thrift Investment Board (Part 8601) LXXVII Office of Management and Budget (Part 8701) Title 6—[Reserved] Title 7—Agriculture Subtitle A—Office of the Secretary of Agriculture (Parts 0—26) Subtitle B—Regulations of the Department of Agriculture I Agricultural Marketing Service (Standards, Inspections, Marketing Practices), Department of Agriculture (Parts 27—209) II Food and Nutrition Service, Department of Agriculture (Parts 210—299) III Animal and Plant Health Inspection Service, Department of Agriculture (Parts 300—399) IV Federal Crop Insurance Corporation, Department of Agriculture (Parts 400—499) V Agricultural Research Service, Department of Agriculture (Parts 500—599) VI Natural Resources Conservation Service, Department of Agriculture (Parts 600—699) VII Farm Service Agency, Department of Agriculture (Parts 700—799) VIII Grain Inspection, Packers and Stockyards Administration (Federal Grain Inspection Service), Department of Agriculture (Parts 800—899) IX Agricultural Marketing Service (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), Department of Agriculture (Parts 900—999) X Agricultural Marketing Service (Marketing Agreements and Orders; Milk), Department of Agriculture (Parts 1000—1199) XI Agricultural Marketing Service (Marketing Agreements and Orders; Miscellaneous Commodities), Department of Agriculture (Parts 1200—1299) XIII Northeast Dairy Compact Commission (Parts 1300—1399) XIV Commodity Credit Corporation, Department of Agriculture (Parts 1400—1499) XV Foreign Agricultural Service, Department of Agriculture (Parts 1500—1599) XVI Rural Telephone Bank, Department of Agriculture (Parts 1600—1699) XVII Rural Utilities Service, Department of Agriculture (Parts 1700—1799) XVIII Rural Housing Service, Rural Business-Cooperative Service, Rural Utilities Service, and Farm Service Agency, Department of Agriculture (Parts 1800—2099) XXVI Office of Inspector General, Department of Agriculture (Parts 2600—2699) XXVII Office of Information Resources Management, Department of Agriculture (Parts 2700—2799) XXVIII Office of Operations, Department of Agriculture (Parts 2800—2899) XXIX Office of Energy, Department of Agriculture (Parts 2900—2999) XXX Office of the Chief Financial Officer, Department of Agriculture (Parts 3000—3099) XXXI Office of Environmental Quality, Department of Agriculture (Parts 3100—3199) XXXII Office of Procurement and Property Management, Department of Agriculture (Parts 3200—3299) XXXIII Office of Transportation, Department of Agriculture (Parts 3300—3399) XXXIV Cooperative State Research, Education, and Extension Service, Department of Agriculture (Parts 3400—3499) XXXV Rural Housing Service, Department of Agriculture (Parts 3500—3599) XXXVI National Agricultural Statistics Service, Department of Agriculture (Parts 3600—3699) XXXVII Economic Research Service, Department of Agriculture (Parts 3700—3799) XXXVIII World Agricultural Outlook Board, Department of Agriculture (Parts 3800—3899) XLI [Reserved] XLII Rural Business-Cooperative Service and Rural Utilities Service, Department of Agriculture (Parts 4200—4299) Title 8—Aliens and Nationality I Immigration and Naturalization Service, Department of Justice (Parts 1—499) Title 9—Animals and Animal Products I Animal and Plant Health Inspection Service, Department of Agriculture (Parts 1—199) II Grain Inspection, Packers and Stockyards Administration (Packers and Stockyards Programs), Department of Agriculture (Parts 200—299) III Food Safety and Inspection Service, Department of Agriculture (Parts 300—599) Title 10—Energy I Nuclear Regulatory Commission (Parts 0—199) II Department of Energy (Parts 200—699) III Department of Energy (Parts 700—999) X Department of Energy (General Provisions) (Parts 1000—1099) XVII Defense Nuclear Facilities Safety Board (Parts 1700—1799) Title 11—Federal Elections I Federal Election Commission (Parts 1—9099) Title 12—Banks and Banking I Comptroller of the Currency, Department of the Treasury (Parts 1—199) II Federal Reserve System (Parts 200—299) III Federal Deposit Insurance Corporation (Parts 300—399) IV Export-Import Bank of the United States (Parts 400—499) V Office of Thrift Supervision, Department of the Treasury (Parts 500—599) VI Farm Credit Administration (Parts 600—699) VII National Credit Union Administration (Parts 700—799) VIII Federal Financing Bank (Parts 800—899) IX Federal Housing Finance Board (Parts 900—999) XI Federal Financial Institutions Examination Council (Parts 1100—1199) XIV Farm Credit System Insurance Corporation (Parts 1400—1499) XV Department of the Treasury (Parts 1500—1599) XVII Office of Federal Housing Enterprise Oversight, Department of Housing and Urban Development (Parts 1700—1799) XVIII Community Development Financial Institutions Fund, Department of the Treasury (Parts 1800—1899) Title 13—Business Credit and Assistance I Small Business Administration (Parts 1—199) III Department of Commerce, Economic Development Administration, (Parts 300—399) Title 14—Aeronautics and Space I Federal Aviation Administration, Department of Transportation (Parts 1—199) II Office of the Secretary, Department of Transportation (Aviation Proceedings) (Parts 200—399) III Commercial Space Transportation, Federal Aviation Administration, Department of Transportation (Parts 400—499) V National Aeronautics and Space Administration (Parts 1200—1299) Title 15—Commerce and Foreign Trade Subtitle A—Office of the Secretary of Commerce (Parts 0—29) Subtitle B—Regulations Relating to Commerce and Foreign Trade I Bureau of the Census, Department of Commerce (Parts 30—199) II National Institute of Standards and Technology, Department of Commerce (Parts 200—299) III International Trade Administration, Department of Commerce (Parts 300—399) IV Foreign-Trade Zones Board, Department of Commerce (Parts 400—499) VII Bureau of Export Administration, Department of Commerce (Parts 700—799) VIII Bureau of Economic Analysis, Department of Commerce (Parts 800—899) IX National Oceanic and Atmospheric Administration, Department of Commerce (Parts 900—999) XI Technology Administration, Department of Commerce (Parts 1100—1199) XIII East-West Foreign Trade Board (Parts 1300—1399) XIV Minority Business Development Agency (Parts 1400—1499) Subtitle C—Regulations Relating to Foreign Trade Agreements XX Office of the United States Trade Representative (Parts 2000—2099) Subtitle D—Regulations Relating to Telecommunications and Information XXIII National Telecommunications and Information Administration, Department of Commerce (Parts 2300—2399) Title 16—Commercial Practices I Federal Trade Commission (Parts 0—999) II Consumer Product Safety Commission (Parts 1000—1799) Title 17—Commodity and Securities Exchanges I Commodity Futures Trading Commission (Parts 1—199) II Securities and Exchange Commission (Parts 200—399) IV Department of the Treasury (Parts 400—499) Title 18—Conservation of Power and Water Resources I Federal Energy Regulatory Commission, Department of Energy (Parts 1—399) III Delaware River Basin Commission (Parts 400—499) VI Water Resources Council (Parts 700—799) VIII Susquehanna River Basin Commission (Parts 800—899) XIII Tennessee Valley Authority (Parts 1300—1399) Title 19—Customs Duties I United States Customs Service, Department of the Treasury (Parts 1—199) II United States International Trade Commission (Parts 200—299) III International Trade Administration, Department of Commerce (Parts 300—399) Title 20—Employees' Benefits I Office of Workers' Compensation Programs, Department of Labor (Parts 1—199) II Railroad Retirement Board (Parts 200—399) III Social Security Administration (Parts 400—499) IV Employees' Compensation Appeals Board, Department of Labor (Parts 500—599) V Employment and Training Administration, Department of Labor (Parts 600—699) VI Employment Standards Administration, Department of Labor (Parts 700—799) VII Benefits Review Board, Department of Labor (Parts 800—899) VIII Joint Board for the Enrollment of Actuaries (Parts 900—999) IX Office of the Assistant Secretary for Veterans' Employment and Training, Department of Labor (Parts 1000—1099) Title 21—Food and Drugs I Food and Drug Administration, Department of Health and Human Services (Parts 1—1299) II Drug Enforcement Administration, Department of Justice (Parts 1300—1399) III Office of National Drug Control Policy (Parts 1400—1499) Title 22—Foreign Relations I Department of State (Parts 1—199) II Agency for International Development (Parts 200—299) III Peace Corps (Parts 300—399) IV International Joint Commission, United States and Canada (Parts 400—499) V United States Information Agency (Parts 500—599) VII Overseas Private Investment Corporation, International Development Cooperation Agency (Parts 700—799) IX Foreign Service Grievance Board Regulations (Parts 900—999) X Inter-American Foundation (Parts 1000—1099) XI International Boundary and Water Commission, United States and Mexico, United States Section (Parts 1100—1199) XII United States International Development Cooperation Agency (Parts 1200—1299) XIII Board for International Broadcasting (Parts 1300—1399) XIV Foreign Service Labor Relations Board; Federal Labor Relations Authority; General Counsel of the Federal Labor Relations Authority; and the Foreign Service Impasse Disputes Panel (Parts 1400—1499) XV African Development Foundation (Parts 1500—1599) XVI Japan-United States Friendship Commission (Parts 1600—1699) XVII United States Institute of Peace (Parts 1700—1799) Title 23—Highways I Federal Highway Administration, Department of Transportation (Parts 1—999) II National Highway Traffic Safety Administration and Federal Highway Administration, Department of Transportation (Parts 1200—1299) III National Highway Traffic Safety Administration, Department of Transportation (Parts 1300—1399) Title 24—Housing and Urban Development Subtitle A—Office of the Secretary, Department of Housing and Urban Development (Parts 0—99) Subtitle B—Regulations Relating to Housing and Urban Development I Office of Assistant Secretary for Equal Opportunity, Department of Housing and Urban Development (Parts 100—199) II Office of Assistant Secretary for Housing-Federal Housing Commissioner, Department of Housing and Urban Development (Parts 200—299) III Government National Mortgage Association, Department of Housing and Urban Development (Parts 300—399) IV Office of Multifamily Housing Assistance Restructuring, Department of Housing and Urban Development (Parts 400—499) V Office of Assistant Secretary for Community Planning and Development, Department of Housing and Urban Development (Parts 500—599) VI Office of Assistant Secretary for Community Planning and Development, Department of Housing and Urban Development (Parts 600—699) [Reserved] VII Office of the Secretary, Department of Housing and Urban Development (Housing Assistance Programs and Public and Indian Housing Programs) (Parts 700—799) VIII Office of the Assistant Secretary for Housing—Federal Housing Commissioner, Department of Housing and Urban Development (Section 8 Housing Assistance Programs, Section 202 Direct Loan Program, Section 202 Supportive Housing for the Elderly Program and Section 811 Supportive Housing for Persons With Disabilities Program) (Parts 800—899) IX Office of Assistant Secretary for Public and Indian Housing, Department of Housing and Urban Development (Parts 900—999) X Office of Assistant Secretary for Housing—Federal Housing Commissioner, Department of Housing and Urban Development (Interstate Land Sales Registration Program) (Parts 1700—1799) XII Office of Inspector General, Department of Housing and Urban Development (Parts 2000—2099) XX Office of Assistant Secretary for Housing—Federal Housing Commissioner, Department of Housing and Urban Development (Parts 3200—3899) XXV Neighborhood Reinvestment Corporation (Parts 4100—4199) Title 25—Indians I Bureau of Indian Affairs, Department of the Interior (Parts 1—299) II Indian Arts and Crafts Board, Department of the Interior (Parts 300—399) III National Indian Gaming Commission, Department of the Interior (Parts 500—599) IV Office of Navajo and Hopi Indian Relocation (Parts 700—799) V Bureau of Indian Affairs, Department of the Interior, and Indian Health Service, Department of Health and Human Services (Part 900) VI Office of the Assistant Secretary-Indian Affairs, Department of the Interior (Part 1001) VII Office of the Special Trustee for American Indians, Department of the Interior (Part 1200) Title 26—Internal Revenue I Internal Revenue Service, Department of the Treasury (Parts 1—799) Title 27—Alcohol, Tobacco Products and Firearms I Bureau of Alcohol, Tobacco and Firearms, Department of the Treasury (Parts 1—299) Title 28—Judicial Administration I Department of Justice (Parts 0—199) III Federal Prison Industries, Inc., Department of Justice (Parts 300—399) V Bureau of Prisons, Department of Justice (Parts 500—599) VI Offices of Independent Counsel, Department of Justice (Parts 600—699) VII Office of Independent Counsel (Parts 700—799) Title 29—Labor Subtitle A—Office of the Secretary of Labor (Parts 0—99) Subtitle B—Regulations Relating to Labor I National Labor Relations Board (Parts 100—199) II Office of Labor-Management Standards, Department of Labor (Parts 200—299) III National Railroad Adjustment Board (Parts 300—399) IV Office of Labor-Management Standards, Department of Labor (Parts 400—499) V Wage and Hour Division, Department of Labor (Parts 500—899) IX Construction Industry Collective Bargaining Commission (Parts 900—999) X National Mediation Board (Parts 1200—1299) XII Federal Mediation and Conciliation Service (Parts 1400—1499) XIV Equal Employment Opportunity Commission (Parts 1600—1699) XVII Occupational Safety and Health Administration, Department of Labor (Parts 1900—1999) XX Occupational Safety and Health Review Commission (Parts 2200—2499) XXV Pension and Welfare Benefits Administration, Department of Labor (Parts 2500—2599) XXVII Federal Mine Safety and Health Review Commission (Parts 2700—2799) XL Pension Benefit Guaranty Corporation (Parts 4000—4999) Title 30—Mineral Resources I Mine Safety and Health Administration, Department of Labor (Parts 1—199) II Minerals Management Service, Department of the Interior (Parts 200—299) III Board of Surface Mining and Reclamation Appeals, Department of the Interior (Parts 300—399) IV Geological Survey, Department of the Interior (Parts 400—499) VI Bureau of Mines, Department of the Interior (Parts 600—699) VII Office of Surface Mining Reclamation and Enforcement, Department of the Interior (Parts 700—999) Title 31—Money and Finance: Treasury Subtitle A—Office of the Secretary of the Treasury (Parts 0—50) Subtitle B—Regulations Relating to Money and Finance I Monetary Offices, Department of the Treasury (Parts 51—199) II Fiscal Service, Department of the Treasury (Parts 200—399) IV Secret Service, Department of the Treasury (Parts 400—499) V Office of Foreign Assets Control, Department of the Treasury (Parts 500—599) VI Bureau of Engraving and Printing, Department of the Treasury (Parts 600—699) VII Federal Law Enforcement Training Center, Department of the Treasury (Parts 700—799) VIII Office of International Investment, Department of the Treasury (Parts 800—899) Title 32—National Defense Subtitle A—Department of Defense I Office of the Secretary of Defense (Parts 1—399) V Department of the Army (Parts 400—699) VI Department of the Navy (Parts 700—799) VII Department of the Air Force (Parts 800—1099) Subtitle B—Other Regulations Relating to National Defense XII Defense Logistics Agency (Parts 1200—1299) XVI Selective Service System (Parts 1600—1699) XIX Central Intelligence Agency (Parts 1900—1999) XX Information Security Oversight Office, National Archives and Records Administration (Parts 2000—2099) XXI National Security Council (Parts 2100—2199) XXIV Office of Science and Technology Policy (Parts 2400—2499) XXVII Office for Micronesian Status Negotiations (Parts 2700—2799) XXVIII Office of the Vice President of the United States (Parts 2800—2899) XXIX Presidential Commission on the Assignment of Women in the Armed Forces (Part 2900) Title 33—Navigation and Navigable Waters I Coast Guard, Department of Transportation (Parts 1—199) II Corps of Engineers, Department of the Army (Parts 200—399) IV Saint Lawrence Seaway Development Corporation, Department of Transportation (Parts 400—499) Title 34—Education Subtitle A—Office of the Secretary, Department of Education (Parts 1—99) Subtitle B—Regulations of the Offices of the Department of Education I Office for Civil Rights, Department of Education (Parts 100—199) II Office of Elementary and Secondary Education, Department of Education (Parts 200—299) III Office of Special Education and Rehabilitative Services, Department of Education (Parts 300—399) IV Office of Vocational and Adult Education, Department of Education (Parts 400—499) V Office of Bilingual Education and Minority Languages Affairs, Department of Education (Parts 500—599) VI Office of Postsecondary Education, Department of Education (Parts 600—699) VII Office of Educational Research and Improvement, Department of Education (Parts 700—799) XI National Institute for Literacy (Parts 1100—1199) Subtitle C—Regulations Relating to Education XII National Council on Disability (Parts 1200—1299) Title 35—Panama Canal I Panama Canal Regulations (Parts 1—299) Title 36—Parks, Forests, and Public Property I National Park Service, Department of the Interior (Parts 1—199) II Forest Service, Department of Agriculture (Parts 200—299) III Corps of Engineers, Department of the Army (Parts 300—399) IV American Battle Monuments Commission (Parts 400—499) V Smithsonian Institution (Parts 500—599) VII Library of Congress (Parts 700—799) VIII Advisory Council on Historic Preservation (Parts 800—899) IX Pennsylvania Avenue Development Corporation (Parts 900—999) X Presidio Trust (Parts 1000—1099) XI Architectural and Transportation Barriers Compliance Board (Parts 1100—1199) XII National Archives and Records Administration (Parts 1200—1299) XIV Assassination Records Review Board (Parts 1400—1499) Title 37—Patents, Trademarks, and Copyrights I Patent and Trademark Office, Department of Commerce (Parts 1—199) II Copyright Office, Library of Congress (Parts 200—299) IV Assistant Secretary for Technology Policy, Department of Commerce (Parts 400—499) V Under Secretary for Technology, Department of Commerce (Parts 500—599) Title 38—Pensions, Bonuses, and Veterans' Relief I Department of Veterans Affairs (Parts 0—99) Title 39—Postal Service I United States Postal Service (Parts 1—999) III Postal Rate Commission (Parts 3000—3099) Title 40—Protection of Environment I Environmental Protection Agency (Parts 1—799) V Council on Environmental Quality (Parts 1500—1599) Title 41—Public Contracts and Property Management Subtitle B—Other Provisions Relating to Public Contracts 50 Public Contracts, Department of Labor (Parts 50-1—50-999) 51 Committee for Purchase From People Who Are Blind or Severely Disabled (Parts 51-1—51-99) 60 Office of Federal Contract Compliance Programs, Equal Employment Opportunity, Department of Labor (Parts 60-1—60-999) 61 Office of the Assistant Secretary for Veterans Employment and Training, Department of Labor (Parts 61-1—61-999) Subtitle C—Federal Property Management Regulations System 101 Federal Property Management Regulations (Parts 101-1—101-99) 105 General Services Administration (Parts 105-1—105-999) 109 Department of Energy Property Management Regulations (Parts 109-1—109-99) 114 Department of the Interior (Parts 114-1—114-99) 115 Environmental Protection Agency (Parts 115-1—115-99) 128 Department of Justice (Parts 128-1—128-99) Subtitle D—Other Provisions Relating to Property Management [Reserved] Subtitle E—Federal Information Resources Management Regulations System 201 Federal Information Resources Management Regulation (Parts 201-1—201-99) [Reserved] Subtitle F—Federal Travel Regulation System 300 General (Parts 300-1—300.99) 301 Temporary Duty (TDY) Travel Allowances (Parts 301-1—301-99) 302 Relocation Allowances (Parts 302-1—302-99) 303 Payment of Expenses Connected with the Death of Certain Employees (Parts 303-1—303-2) 304 Payment from a Non-Federal Source for Travel Expenses (Parts 304-1—304-99) Title 42—Public Health I Public Health Service, Department of Health and Human Services (Parts 1—199) IV Health Care Financing Administration, Department of Health and Human Services (Parts 400—499) V Office of Inspector General-Health Care, Department of Health and Human Services (Parts 1000—1999) Title 43—Public Lands: Interior Subtitle A—Office of the Secretary of the Interior (Parts 1—199) Subtitle B—Regulations Relating to Public Lands I Bureau of Reclamation, Department of the Interior (Parts 200—499) II Bureau of Land Management, Department of the Interior (Parts 1000—9999) III Utah Reclamation Mitigation and Conservation Commission (Parts 10000—10005) Title 44—Emergency Management and Assistance I Federal Emergency Management Agency (Parts 0—399) IV Department of Commerce and Department of Transportation (Parts 400—499) Title 45—Public Welfare Subtitle A—Department of Health and Human Services (Parts 1—199) Subtitle B—Regulations Relating to Public Welfare II Office of Family Assistance (Assistance Programs), Administration for Children and Families, Department of Health and Human Services (Parts 200—299) III Office of Child Support Enforcement (Child Support Enforcement Program), Administration for Children and Families, Department of Health and Human Services (Parts 300—399) IV Office of Refugee Resettlement, Administration for Children and Families Department of Health and Human Services (Parts 400—499) V Foreign Claims Settlement Commission of the United States, Department of Justice (Parts 500—599) VI National Science Foundation (Parts 600—699) VII Commission on Civil Rights (Parts 700—799) VIII Office of Personnel Management (Parts 800—899) X Office of Community Services, Administration for Children and Families, Department of Health and Human Services (Parts 1000—1099) XI National Foundation on the Arts and the Humanities (Parts 1100—1199) XII Corporation for National and Community Service (Parts 1200—1299) XIII Office of Human Development Services, Department of Health and Human Services (Parts 1300—1399) XVI Legal Services Corporation (Parts 1600—1699) XVII National Commission on Libraries and Information Science (Parts 1700—1799) XVIII Harry S. Truman Scholarship Foundation (Parts 1800—1899) XXI Commission on Fine Arts (Parts 2100—2199) XXII Christopher Columbus Quincentenary Jubilee Commission (Parts 2200—2299) XXIII Arctic Research Commission (Part 2301) XXIV James Madison Memorial Fellowship Foundation (Parts 2400—2499) XXV Corporation for National and Community Service (Parts 2500—2599) Title 46—Shipping I Coast Guard, Department of Transportation (Parts 1—199) II Maritime Administration, Department of Transportation (Parts 200—399) III Coast Guard (Great Lakes Pilotage), Department of Transportation (Parts 400—499) IV Federal Maritime Commission (Parts 500—599) Title 47—Telecommunication I Federal Communications Commission (Parts 0—199) II Office of Science and Technology Policy and National Security Council (Parts 200—299) III National Telecommunications and Information Administration, Department of Commerce (Parts 300—399) Title 48—Federal Acquisition Regulations System 1 Federal Acquisition Regulation (Parts 1—99) 2 Department of Defense (Parts 200—299) 3 Department of Health and Human Services (Parts 300—399) 4 Department of Agriculture (Parts 400—499) 5 General Services Administration (Parts 500—599) 6 Department of State (Parts 600—699) 7 United States Agency for International Development (Parts 700—799) 8 Department of Veterans Affairs (Parts 800—899) 9 Department of Energy (Parts 900—999) 10 Department of the Treasury (Parts 1000—1099) 12 Department of Transportation (Parts 1200—1299) 13 Department of Commerce (Parts 1300—1399) 14 Department of the Interior (Parts 1400—1499) 15 Environmental Protection Agency (Parts 1500—1599) 16 Office of Personnel Management Federal Employees Health Benefits Acquisition Regulation (Parts 1600—1699) 17 Office of Personnel Management (Parts 1700—1799) 18 National Aeronautics and Space Administration (Parts 1800—1899) 19 United States Information Agency (Parts 1900—1999) 20 Nuclear Regulatory Commission (Parts 2000—2099) 21 Office of Personnel Management, Federal Employees Group Life Insurance Federal Acquisition Regulation (Parts 2100—2199) 23 Social Security Administration (Parts 2300—2399) 24 Department of Housing and Urban Development (Parts 2400—2499) 25 National Science Foundation (Parts 2500—2599) 28 Department of Justice (Parts 2800—2899) 29 Department of Labor (Parts 2900—2999) 34 Department of Education Acquisition Regulation (Parts 3400—3499) 35 Panama Canal Commission (Parts 3500—3599) 44 Federal Emergency Management Agency (Parts 4400—4499) 51 Department of the Army Acquisition Regulations (Parts 5100—5199) 52 Department of the Navy Acquisition Regulations (Parts 5200—5299) 53 Department of the Air Force Federal Acquisition Regulation Supplement (Parts 5300—5399) 54 Defense Logistics Agency, Department of Defense (Part 5452) 57 African Development Foundation (Parts 5700—5799) 61 General Services Administration Board of Contract Appeals (Parts 6100—6199) 63 Department of Transportation Board of Contract Appeals (Parts 6300—6399) 99 Cost Accounting Standards Board, Office of Federal Procurement Policy, Office of Management and Budget (Parts 9900—9999) Title 49—Transportation Subtitle A—Office of the Secretary of Transportation (Parts 1—99) Subtitle B—Other Regulations Relating to Transportation I Research and Special Programs Administration, Department of Transportation (Parts 100—199) II Federal Railroad Administration, Department of Transportation (Parts 200—299) III Federal Highway Administration, Department of Transportation (Parts 300—399) IV Coast Guard, Department of Transportation (Parts 400—499) V National Highway Traffic Safety Administration, Department of Transportation (Parts 500—599) VI Federal Transit Administration, Department of Transportation (Parts 600—699) VII National Railroad Passenger Corporation (AMTRAK) (Parts 700—799) VIII National Transportation Safety Board (Parts 800—999) X Surface Transportation Board, Department of Transportation (Parts 1000—1399) XI Bureau of Transportation Statistics, Department of Transportation (Parts 1400—1499) Title 50—Wildlife and Fisheries I United States Fish and Wildlife Service, Department of the Interior (Parts 1—199) II National Marine Fisheries Service, National Oceanic and Atmospheric Administration, Department of Commerce (Parts 200—299) III International Fishing and Related Activities (Parts 300—399) IV Joint Regulations (United States Fish and Wildlife Service, Department of the Interior and National Marine Fisheries Service, National Oceanic and Atmospheric Administration, Department of Commerce); Endangered Species Committee Regulations (Parts 400—499) V Marine Mammal Commission (Parts 500—599) VI Fishery Conservation and Management, National Oceanic and Atmospheric Administration, Department of Commerce (Parts 600—699) CFR Index and Finding Aids Subject/Agency Index List of Agency Prepared Indexes Parallel Tables of Statutory Authorities and Rules List of CFR Titles, Chapters, Subchapters, and Parts Alphabetical List of Agencies Appearing in the CFR Alphabetical List of Agencies Appearing in the CFR (Revised as of March 31, 1999) Agency CFR Title, Subtitle or Chapter Administrative Committee of the Federal Register 1, I Advanced Research Projects Agency 32, I Advisory Commission on Intergovernmental Relations 5, VII Advisory Committee on Federal Pay 5, IV Advisory Council on Historic Preservation 36, VIII African Development Foundation 22, XV Federal Acquisition Regulation 48, 57 Agency for International Development 22, II Federal Acquisition Regulation 48, 7 Agricultural Marketing Service 7, I, IX, X, XI Agricultural Research Service 7, V Agriculture Department Agricultural Marketing Service 7, I, IX, X, XI Agricultural Research Service 7, V Animal and Plant Health Inspection Service 7, III; 9, I Chief Financial Officer, Office of 7, XXX Commodity Credit Corporation 7, XIV Cooperative State Research, Education, and Extension Service 7, XXXIV Economic Research Service 7, XXXVII Energy, Office of 7, XXIX Environmental Quality, Office of 7, XXXI Farm Service Agency 7, VII, XVIII Federal Acquisition Regulation 48, 4 Federal Crop Insurance Corporation 7, IV Food and Nutrition Service 7, II Food Safety and Inspection Service 9, III Foreign Agricultural Service 7, XV Forest Service 36, II Grain Inspection, Packers and Stockyards Administration 7, VIII; 9, II Information Resources Management, Office of 7, XXVII Inspector General, Office of 7, XXVI National Agricultural Library 7, XLI National Agricultural Statistics Service 7, XXXVI Natural Resources Conservation Service 7, VI Operations, Office of 7, XXVIII Procurement and Property Management, Office of 7, XXXII Rural Business-Cooperative Service 7, XVIII, XLII Rural Development Administration 7, XLII Rural Housing Service 7, XVIII, XXXV Rural Telephone Bank 7, XVI Rural Utilities Service 7, XVII, XVIII, XLII Secretary of Agriculture, Office of 7, Subtitle A Transportation, Office of 7, XXXIII World Agricultural Outlook Board 7, XXXVIII Air Force Department 32, VII Federal Acquisition Regulation Supplement 48, 53 Alcohol, Tobacco and Firearms, Bureau of 27, I AMTRAK 49, VII American Battle Monuments Commission 36, IV American Indians, Office of the Special Trustee 25, VII Animal and Plant Health Inspection Service 7, III; 9, I Appalachian Regional Commission 5, IX Architectural and Transportation Barriers Compliance Board 36, XI Arctic Research Commission 45, XXIII Armed Forces Retirement Home 5, XI Army Department 32, V Engineers, Corps of 33, II; 36, III Federal Acquisition Regulation 48, 51 Assassination Records Review Board 36, XIV Benefits Review Board 20, VII Bilingual Education and Minority Languages Affairs, Office of 34, V Blind or Severely Disabled, Committee for Purchase From People Who Are 41, 51 Board for International Broadcasting 22, XIII Census Bureau 15, I Central Intelligence Agency 32, XIX Chief Financial Officer, Office of 7, XXX Child Support Enforcement, Office of 45, III Children and Families, Administration for 45, II, III, IV, X Christopher Columbus Quincentenary Jubilee Commission 45, XXII Civil Rights, Commission on 45, VII Civil Rights, Office for 34, I Coast Guard 33, I; 46, I; 49, IV Coast Guard (Great Lakes Pilotage) 46, III Commerce Department 44, IV Census Bureau 15, I` Economic Affairs, Under Secretary 37, V Economic Analysis, Bureau of 15, VIII Economic Development Administration 13, III Emergency Management and Assistance 44, IV Export Administration, Bureau of 15, VII Federal Acquisition Regulation 48, 13 Fishery Conservation and Management 50, VI Foreign-Trade Zones Board 15, IV International Trade Administration 15, III; 19, III National Institute of Standards and Technology 15, II National Marine Fisheries Service 50, II, IV, VI National Oceanic and Atmospheric Administration 15, IX; 50, II, III, IV, VI National Telecommunications and Information Administration 15, XXIII; 47, III National Weather Service 15, IX Patent and Trademark Office 37, I Productivity, Technology and Innovation, Assistant Secretary for 37, IV Secretary of Commerce, Office of 15, Subtitle A Technology, Under Secretary for 37, V Technology Administration 15, XI Technology Policy, Assistant Secretary for 37, IV Commercial Space Transportation 14, III Commodity Credit Corporation 7, XIV Commodity Futures Trading Commission 5, XLI; 17, I Community Planning and Development, Office of Assistant Secretary for 24, V, VI Community Services, Office of 45, X Comptroller of the Currency 12, I Construction Industry Collective Bargaining Commission 29, IX Consumer Product Safety Commission 5, LXXI; 16, II Cooperative State Research, Education, and Extension Service 7, XXXIV Copyright Office 37, II Corporation for National and Community Service 45, XII, XXV Cost Accounting Standards Board 48, 99 Council on Environmental Quality 40, V Customs Service, United States 19, I Defense Contract Audit Agency 32, I Defense Department 5, XXVI; 32, Subtitle A Advanced Research Projects Agency 32, I Air Force Department 32, VII Army Department 32, V; 33, II; 36, III, 48, 51 Defense Intelligence Agency 32, I Defense Logistics Agency 32, I, XII; 48, 54 Engineers, Corps of 33, II; 36, III Federal Acquisition Regulation 48, 2 National Imagery and Mapping Agency 32, I Navy Department 32, VI; 48, 52 Secretary of Defense, Office of 32, I Defense Contract Audit Agency 32, I Defense Intelligence Agency 32, I Defense Logistics Agency 32, XII; 48, 54 Defense Nuclear Facilities Safety Board 10, XVII Delaware River Basin Commission 18, III Drug Enforcement Administration 21, II East-West Foreign Trade Board 15, XIII Economic Affairs, Under Secretary 37, V Economic Analysis, Bureau of 15, VIII Economic Development Administration 13, III Economic Research Service 7, XXXVII Education, Department of 5, LIII Bilingual Education and Minority Languages Affairs, Office of 34, V Civil Rights, Office for 34, I Educational Research and Improvement, Office of 34, VII Elementary and Secondary Education, Office of 34, II Federal Acquisition Regulation 48, 34 Postsecondary Education, Office of 34, VI Secretary of Education, Office of 34, Subtitle A Special Education and Rehabilitative Services, Office of 34, III Vocational and Adult Education, Office of 34, IV Educational Research and Improvement, Office of 34, VII Elementary and Secondary Education, Office of 34, II Employees' Compensation Appeals Board 20, IV Employees Loyalty Board 5, V Employment and Training Administration 20, V Employment Standards Administration 20, VI Endangered Species Committee 50, IV Energy, Department of 5, XXIII; 10, II, III, X Federal Acquisition Regulation 48, 9 Federal Energy Regulatory Commission 5, XXIV; 18, I Property Management Regulations 41, 109 Energy, Office of 7, XXIX Engineers, Corps of 33, II; 36, III Engraving and Printing, Bureau of 31, VI Environmental Protection Agency 5, LIV; 40, I Federal Acquisition Regulation 48, 15 Property Management Regulations 41, 115 Environmental Quality, Office of 7, XXXI Equal Employment Opportunity Commission 5, LXII; 29, XIV Equal Opportunity, Office of Assistant Secretary for 24, I Executive Office of the President 3, I Administration, Office of 5, XV Environmental Quality, Council on 40, V Management and Budget, Office of 25, III, LXXVII; 48, 99 National Drug Control Policy, Office of 21, III National Security Council 32, XXI; 47, 2 Presidential Documents 3 Science and Technology Policy, Office of 32, XXIV; 47, II Trade Representative, Office of the United States 15, XX Export Administration, Bureau of 15, VII Export-Import Bank of the United States 5, LII; 12, IV Family Assistance, Office of 45, II Farm Credit Administration 5, XXXI; 12, VI Farm Credit System Insurance Corporation 5, XXX; 12, XIV Farm Service Agency 7, VII, XVIII Federal Acquisition Regulation 48, 1 Federal Aviation Administration 14, I Commercial Space Transportation 14, III Federal Claims Collection Standards 4, II Federal Communications Commission 5, XXIX; 47, I Federal Contract Compliance Programs, Office of 41, 60 Federal Crop Insurance Corporation 7, IV Federal Deposit Insurance Corporation 5, XXII; 12, III Federal Election Commission 11, I Federal Emergency Management Agency 44, I Federal Acquisition Regulation 48, 44 Federal Employees Group Life Insurance Federal Acquisition Regulation 48, 21 Federal Employees Health Benefits Acquisition Regulation 48, 16 Federal Energy Regulatory Commission 5, XXIV; 18, I Federal Financial Institutions Examination Council 12, XI Federal Financing Bank 12, VIII Federal Highway Administration 23, I, II; 49, III Federal Home Loan Mortgage Corporation 1, IV Federal Housing Enterprise Oversight Office 12, XVII Federal Housing Finance Board 12, IX Federal Labor Relations Authority, and General Counsel of the Federal Labor Relations Authority 5, XIV; 22, XIV Federal Law Enforcement Training Center 31, VII Federal Maritime Commission 46, IV Federal Mediation and Conciliation Service 29, XII Federal Mine Safety and Health Review Commission 5, LXXIV; 29, XXVII Federal Pay, Advisory Committee on 5, IV Federal Prison Industries, Inc. 28, III Federal Procurement Policy Office 48, 99 Federal Property Management Regulations 41, 101 Federal Property Management Regulations System 41, Subtitle C Federal Railroad Administration 49, II Federal Register, Administrative Committee of 1, I Federal Register, Office of 1, II Federal Reserve System 12, II Board of Governors 5, LVIII Federal Retirement Thrift Investment Board 5, VI, LXXVI Federal Service Impasses Panel 5, XIV Federal Trade Commission 5, XLVII; 16, I Federal Transit Administration 49, VI Federal Travel Regulation System 41, Subtitle F Fine Arts, Commission on 45, XXI Fiscal Service 31, II Fish and Wildlife Service, United States 50, I, IV Fishery Conservation and Management 50, VI Food and Drug Administration 21, I Food and Nutrition Service 7, II Food Safety and Inspection Service 9, III Foreign Agricultural Service 7, XV Foreign Assets Control, Office of 31, V Foreign Claims Settlement Commission of the United States 45, V Foreign Service Grievance Board 22, IX Foreign Service Impasse Disputes Panel 22, XIV Foreign Service Labor Relations Board 22, XIV Foreign-Trade Zones Board 15, IV Forest Service 36, II General Accounting Office 4, I, II General Services Administration 5, LVII Contract Appeals, Board of 48, 61 Federal Acquisition Regulation 48, 5 Federal Property Management Regulations System 41, 101, 105 Federal Travel Regulation System 41, Subtitle F General 41, 300 Payment From a Non-Federal Source for Travel Expenses 41, 304 Payment of Expenses Connected With the Death of Certain Employees 41, 303 Relocation Allowances 41, 302 Temporary Duty (TDY) Travel Allowances 41, 301 Geological Survey 30, IV Government Ethics, Office of 5, XVI Government National Mortgage Association 24, III Grain Inspection, Packers and Stockyards Administration 7, VIII; 9, II Harry S. Truman Scholarship Foundation 45, XVIII Health and Human Services, Department of 5, XLV; 45, Subtitle A Child Support Enforcement, Office of 45, III Children and Families, Administration for 45, II, III, IV, X Community Services, Office of 45, X Family Assistance, Office of 45, II Federal Acquisition Regulation 48, 3 Food and Drug Administration 21, I Health Care Financing Administration 42, IV Human Development Services, Office of 45, XIII Indian Health Service 25, V Inspector General (Health Care), Office of 42, V Public Health Service 42, I Refugee Resettlement, Office of 45, IV Health Care Financing Administration 42, IV Housing and Urban Development, Department of 5, LXV; 24, Subtitle B Community Planning and Development, Office of Assistant Secretary for 24, V, VI Equal Opportunity, Office of Assistant Secretary for 24, I Federal Acquisition Regulation 48, 24 Federal Housing Enterprise Oversight, Office of 12, XVII Government National Mortgage Association 24, III Housing—Federal Housing Commissioner, Office of Assistant Secretary for 24, II, VIII, X, XX Inspector General, Office of 24, XII Multifamily Housing Assistance Restructuring, Office of 24, IV Public and Indian Housing, Office of Assistant Secretary for 24, IX Secretary, Office of 24, Subtitle A, VII Housing—Federal Housing Commissioner, Office of Assistant Secretary for 24, II, VIII, X, XX Human Development Services, Office of 45, XIII Immigration and Naturalization Service 8, I Independent Counsel, Office of 28, VII Indian Affairs, Bureau of 25, I, V Indian Affairs, Office of the Assistant Secretary 25, VI Indian Arts and Crafts Board 25, II Indian Health Service 25, V Information Agency, United States 22, V Federal Acquisition Regulation 48, 19 Information Resources Management, Office of 7, XXVII Information Security Oversight Office, National Archives and Records Administration 32, XX Inspector General Agriculture Department 7, XXVI Health and Human Services Department 42, V Housing and Urban Development Department 24, XII Institute of Peace, United States 22, XVII Inter-American Foundation 5, LXIII; 22, X Intergovernmental Relations, Advisory Commission on 5, VII Interior Department American Indians, Office of the Special Trustee 25, VII Endangered Species Committee 50, IV Federal Acquisition Regulation 48, 14 Federal Property Management Regulations System 41, 114 Fish and Wildlife Service, United States 50, I, IV Geological Survey 30, IV Indian Affairs, Bureau of 25, I, V Indian Affairs, Office of the Assistant Secretary 25, VI Indian Arts and Crafts Board 25, II Land Management, Bureau of 43, II Minerals Management Service 30, II Mines, Bureau of 30, VI National Indian Gaming Commission 25, III National Park Service 36, I Reclamation, Bureau of 43, I Secretary of the Interior, Office of 43, Subtitle A Surface Mining and Reclamation Appeals, Board of 30, III Surface Mining Reclamation and Enforcement, Office of 30, VII Internal Revenue Service 26, I International Boundary and Water Commission, United States and Mexico, United States Section 22, XI International Development, Agency for 22, II Federal Acquisition Regulation 48, 7 International Development Cooperation Agency, United States 22, XII International Development, Agency for 22, II; 48, 7 Overseas Private Investment Corporation 5, XXXIII; 22, VII International Fishing and Related Activities 50, III International Investment, Office of 31, VIII International Joint Commission, United States and Canada 22, IV International Organizations Employees Loyalty Board 5, V International Trade Administration 15, III; 19, III International Trade Commission, United States 19, II Interstate Commerce Commission 5, XL James Madison Memorial Fellowship Foundation 45, XXIV Japan-United States Friendship Commission 22, XVI Joint Board for the Enrollment of Actuaries 20, VIII Justice Department 5, XXVIII; 28, I Drug Enforcement Administration 21, II Federal Acquisition Regulation 48, 28 Federal Claims Collection Standards 4, II Federal Prison Industries, Inc. 28, III Foreign Claims Settlement Commission of the United States 45, V Immigration and Naturalization Service 8, I Offices of Independent Counsel 28, VI Prisons, Bureau of 28, V Property Management Regulations 41, 128 Labor Department 5, XLII Benefits Review Board 20, VII Employees' Compensation Appeals Board 20, IV Employment and Training Administration 20, V Employment Standards Administration 20, VI Federal Acquisition Regulation 48, 29 Federal Contract Compliance Programs, Office of 41, 60 Federal Procurement Regulations System 41, 50 Labor-Management Standards, Office of 29, II, IV Mine Safety and Health Administration 30, I Occupational Safety and Health Administration 29, XVII Pension and Welfare Benefits Administration 29, XXV Public Contracts 41, 50 Secretary of Labor, Office of 29, Subtitle A Veterans' Employment and Training, Office of the Assistant Secretary for 41, 61; 20, IX Wage and Hour Division 29, V Workers' Compensation Programs, Office of 20, I Labor-Management Standards, Office of 29, II, IV Land Management, Bureau of 43, II Legal Services Corporation 45, XVI Library of Congress 36, VII Copyright Office 37, II Management and Budget, Office of 5, III, LXXVII; 48, 99 Marine Mammal Commission 50, V Maritime Administration 46, II Merit Systems Protection Board 5, II Micronesian Status Negotiations, Office for 32, XXVII Mine Safety and Health Administration 30, I Minerals Management Service 30, II Mines, Bureau of 30, VI Minority Business Development Agency 15, XIV Miscellaneous Agencies 1, IV Monetary Offices 31, I Multifamily Housing Assistance Restructuring, Office of 24, IV National Aeronautics and Space Administration 5, LIX; 14, V Federal Acquisition Regulation 48, 18 National Agricultural Library 7, XLI National Agricultural Statistics Service 7, XXXVI National Archives and Records Administration 5, LXVI; 36, XII Information Security Oversight Office 32, XX National Bureau of Standards 15, II National Capital Planning Commission 1, IV National Commission for Employment Policy 1, IV National Commission on Libraries and Information Science 45, XVII National and Community Service, Corporation for 45, XII, XXV National Council on Disability 34, XII National Credit Union Administration 12, VII National Drug Control Policy, Office of 21, III National Foundation on the Arts and the Humanities 45, XI National Highway Traffic Safety Administration 23, II, III; 49, V National Imagery and Mapping Agency 32, I National Indian Gaming Commission 25, III National Institute for Literacy 34, XI National Institute of Standards and Technology 15, II National Labor Relations Board 5, LXI; 29, I National Marine Fisheries Service 50, II, IV, VI National Mediation Board 29, X National Oceanic and Atmospheric Administration 15, IX; 50, II, III, IV, VI National Park Service 36, I National Railroad Adjustment Board 29, III National Railroad Passenger Corporation (AMTRAK) 49, VII National Science Foundation 5, XLIII; 45, VI Federal Acquisition Regulation 48, 25 National Security Council 32, XXI National Security Council and Office of Science and Technology Policy 47, II National Telecommunications and Information Administration 15, XXIII; 47, III National Transportation Safety Board 49, VIII National Weather Service 15, IX Natural Resources Conservation Service 7, VI Navajo and Hopi Indian Relocation, Office of 25, IV Navy Department 32, VI Federal Acquisition Regulation 48, 52 Neighborhood Reinvestment Corporation 24, XXV Northeast Dairy Compact Commission 7, XIII Nuclear Regulatory Commission 5, XLVIII; 10, I Federal Acquisition Regulation 48, 20 Occupational Safety and Health Administration 29, XVII Occupational Safety and Health Review Commission 29, XX Offices of Independent Counsel 28, VI Operations Office 7, XXVIII Overseas Private Investment Corporation 5, XXXIII; 22, VII Panama Canal Commission 48, 35 Panama Canal Regulations 35, I Patent and Trademark Office 37, I Payment From a Non-Federal Source for Travel Expenses 41, 304 Payment of Expenses Connected With the Death of Certain Employees 41, 303 Peace Corps 22, III Pennsylvania Avenue Development Corporation 36, IX Pension and Welfare Benefits Administration 29, XXV Pension Benefit Guaranty Corporation 29, XL Personnel Management, Office of 5, I, XXXV; 45, VIII Federal Acquisition Regulation 48, 17 Federal Employees Group Life Insurance Federal Acquisition Regulation 48, 21 Federal Employees Health Benefits Acquisition Regulation 48, 16 Postal Rate Commission 5, XLVI; 39, III Postal Service, United States 5, LX; 39, I Postsecondary Education, Office of 34, VI President's Commission on White House Fellowships 1, IV Presidential Commission on the Assignment of Women in the Armed Forces 32, XXIX Presidential Documents 3 Presidio Trust 36, X Prisons, Bureau of 28, V Procurement and Property Management, Office of 7, XXXII Productivity, Technology and Innovation, Assistant Secretary 37, IV Public Contracts, Department of Labor 41, 50 Public and Indian Housing, Office of Assistant Secretary for 24, IX Public Health Service 42, I Railroad Retirement Board 20, II Reclamation, Bureau of 43, I Refugee Resettlement, Office of 45, IV Regional Action Planning Commissions 13, V Relocation Allowances 41, 302 Research and Special Programs Administration 49, I Rural Business-Cooperative Service 7, XVIII, XLII Rural Development Administration 7, XLII Rural Housing Service 7, XVIII, XXXV Rural Telephone Bank 7, XVI Rural Utilities Service 7, XVII, XVIII, XLII Saint Lawrence Seaway Development Corporation 33, IV Science and Technology Policy, Office of 32, XXIV Science and Technology Policy, Office of, and National Security Council 47, II Secret Service 31, IV Securities and Exchange Commission 17, II Selective Service System 32, XVI Small Business Administration 13, I Smithsonian Institution 36, V Social Security Administration 20, III; 48, 23 Soldiers' and Airmen's Home, United States 5, XI Special Counsel, Office of 5, VIII Special Education and Rehabilitative Services, Office of 34, III State Department 22, I Federal Acquisition Regulation 48, 6 Surface Mining and Reclamation Appeals, Board of 30, III Surface Mining Reclamation and Enforcement, Office of 30, VII Surface Transportation Board 49, X Susquehanna River Basin Commission 18, VIII Technology Administration 15, XI Technology Policy, Assistant Secretary for 37, IV Technology, Under Secretary for 37, V Tennessee Valley Authority 5, LXIX; 18, XIII Thrift Supervision Office, Department of the Treasury 12, V Trade Representative, United States, Office of 15, XX Transportation, Department of 5, L Coast Guard 33, I; 46, I; 49, IV Coast Guard (Great Lakes Pilotage) 46, III Commercial Space Transportation 14, III Contract Appeals, Board of 48, 63 Emergency Management and Assistance 44, IV Federal Acquisition Regulation 48, 12 Federal Aviation Administration 14, I Federal Highway Administration 23, I, II; 49, III Federal Railroad Administration 49, II Federal Transit Administration 49, VI Maritime Administration 46, II National Highway Traffic Safety Administration 23, II, III; 49, V Research and Special Programs Administration 49, I Saint Lawrence Seaway Development Corporation 33, IV Secretary of Transportation, Office of 14, II; 49, Subtitle A Surface Transportation Board 49, X Transportation Statistics Bureau 49, XI Transportation, Office of 7, XXXIII Transportation Statistics Brureau 49, XI Travel Allowances, Temporary Duty (TDY) 41, 301 Treasury Department 5, XXI; 12, XV; 17, IV Alcohol, Tobacco and Firearms, Bureau of 27, I Community Development Financial Institutions Fund 12, XVIII Comptroller of the Currency 12, I Customs Service, United States 19, I Engraving and Printing, Bureau of 31, VI Federal Acquisition Regulation 48, 10 Federal Law Enforcement Training Center 31, VII Fiscal Service 31, II Foreign Assets Control, Office of 31, V Internal Revenue Service 26, I International Investment, Office of 31, VIII Monetary Offices 31, I Secret Service 31, IV Secretary of the Treasury, Office of 31, Subtitle A Thrift Supervision, Office of 12, V Truman, Harry S. Scholarship Foundation 45, XVIII United States and Canada, International Joint Commission 22, IV United States and Mexico, International Boundary and Water Commission, United States Section 22, XI Utah Reclamation Mitigation and Conservation Commission 43, III Veterans Affairs Department 38, I Federal Acquisition Regulation 48, 8 Veterans' Employment and Training, Office of the Assistant Secretary for 41, 61; 20, IX Vice President of the United States, Office of 32, XXVIII Vocational and Adult Education, Office of 34, IV Wage and Hour Division 29, V Water Resources Council 18, VI Workers' Compensation Programs, Office of 20, I World Agricultural Outlook Board 7, XXXVIII 21 CFR (4-1-99 Edition) List of CFR Sections Affected List of CFR Sections Affected

All changes in this volume of the Code of Federal Regulations which were made by documents published in the Federal Register since January 1, 1986, are enumerated in the following list. Entries indicate the nature of the changes effected. Page numbers refer to Federal Register pages. The user should consult the entries for chapters and parts as well as sections for revisions.

For the period before January 1, 1986, see the “List of CFR Sections Affected, 1943-1963, 1964-1972, and 1973-1985” published in seven separate volumes.

1986 21 CFR 51 FR Page Chapter I Mandatory compliance date 1-1-89 34085 601Authority citation revised 15607 601.25(d)(2) amended 15607 610Authority citation revised 15607, 37450, 44453, 44906 610.9(b) amended 15607 610.11Introductory text, (c) introductory text, (2), and (3) amended 15607 610.12(a)(1)(i), (e)(2), (f), and (g) (2) and (8) revised; (h) added 44906 610.15(a) introductory text amended 15607 610.18(c) and (d) added; OMB number 44453 610.40(b)(4), (d)(1)(v) and (2)(iv) amended 15607 610.53(c) table revised 15607 (c) table corrected 19750 (c) table amended 37450 620Authority citation revised 15610 620.6(h) amended 15610 620.12Introductory text amended 15610 620.14(c) introductory text amended 15610 620.24(c) introductory text amended 15610 620.35(e) introductory text amended 15610 620.43Amended 15610 620.48(a) introductory text and (2) amended 15610 630Authority citation revised 15610 630.5(c) introductory text amended 15610 (c) introductory text corrected 18580 630.10(a) revised 44454 630.12(b) revised 44454 630.13(b)(1) revised; (c) removed 44454 630.16(a)(6) amended 15610 630.17(e) introductory text amended 15610 630.36(h) introductory text amended 15610 630.56(f) introductory text amended 15610 630.66(e) introductory text amended 15610 630.75(d) introductory text amended 15610 630.86(e) introductory text amended 15611 640.1Amendments at 50 FR 4138 effective date deferred to 9-2-86 3773 640.3(b) introductory text, (c) introductory text, (d), and (e) amended 15611 640.10Amendments at 50 FR 4138 effective date deferred to 9-2-86 3773 640.20Amendments at 50 FR 4139 effective date deferred to 9-2-86 3773 640.30Amendments at 50 FR 4139 effective date deferred to 9-2-86 3773 640.50Amendments at 50 FR 4139 effective date deferred to 9-2-86 3773 640.101(f) introductory text amended 15611 640.111(g) introductory text amended 15611 650Authority citation revised 15611 650.11(c) introductory text amended 15611 660Authority citation revised 15611 660.6(a)(2) amended 15611 660.22Amended 15611 660.29(a) introductory text amended 15611 660.30—660.36 (Subpart D)Revised; effective in part 10-7-88 37450 660.36(a) introductory text amended 15611 660.42Amended 15611 660.46(a)(2) amended 15611 660.52Amended 15611 660.53Amended 15611 660.54Introductory text amended 15611 660.101Introductory text amended 15611 660.102Introductory text amended 39637 660.103(f)(1) revised 39637 660.105(a) introductory text amended 15611 (a)(1) revised 39637 680Authority citation revised 15611 680.3(e) and (f) added; OMB number 37607 680.4(c)(1) introductory text amended 15611 Removed 37607 680.21Amended 15611 680.26Amended 15611 720Authority citation revised 11444 720.8Revised 11444 730Authority citation revised; section authority citations removed 25687 730.2Revised 25687 730.3Revised 25687 730.4(a)(1) revised 25687 740Authority citation revised 20475 740.17Revised; eff. 6-5-87 20475 1987 21 CFR 52 FR Page Chapter I 610Authority citation revised 37450 610.53(c) table amended 37450 660.30-660.36 (Subpart D) Revised; eff. in part 10-7-88 37450 660.102Introductory text amended 39637 660.103(f)(1) revised 39637 660.105(a)(1) revised 39637 680.3(e) and (f) added; OMB number 37607 680.4Removed 37607 1988 21 CFR 53 FR Page Chapter I Uniform compliance date 1-1-91 44861 606Authority citation revised 116 606.121(h) revised 116 606.122(e) revised 116 610Authority citation revised 116 610.12(g)(4)(i) revised 12764 610.45Added 116 610.53(c) table amended 12764 640Authority citation revised 116 640.2(f) revised; OMB number 116 640.5(f) added 117 (b) and (c) amended 12764 640.14Revised 117 640.23(a) revised 117 640.33(a) revised 117 640.53(a) revised 117 640.67Revised 117 640.70(a)(11) added 117 640.71(a)(4) added 117 640.72(a)(2) revised; OMB number 117 660.20—660.28 (Subpart C)Revised; eff. in part 4-19-89 12764 660.29Removed 12764 1989 21 CFR 54 FR Page Chapter I 600Authority citation revised; sectional authority citations removed 39639 601Authority citation revised; sectional and subpart authority citations removed 39639 606Authority citation revised 24707, 39639 607Authority citation revised 39639 610Authority citation revised; sectional authority citations removed 39639 620Authority citation revised; sectional authority citations removed 39639 630Authority citation revised; sectional authority citations removed 39639 640Authority citation revised; sectional authority citations removed 39639 650Authority citation revised; sectional authority citations removed 39640 660Authority citation revised; sectional and subpart authority citations removed 39640 680Authority citation revised; sectional authority citations removed 39640 700Authority citation revised 27342 Authority citation revised; sectional authority citations removed 39640 700.19Added 27342 701Authority citation revised; sectional authority citations removed 39640 701.3(c)(2)(iv) amended 24900 710Authority citation revised 39640 710.4Authority citation removed 39640 720Authority citation revised 39640 730Authority citation revised 39640 740Authority citation revised 39640 740.11Authority citation removed 39640 1990 21 CFR 55 FR Page Chapter I Uniform compliance date 1-1-93 276 600.3(d) revised 11014 600.10(a) nomenclature change 11014 600.11(f)(6) nomenclature change 11013 600.12(b)(2) and (3) nomenclature change 11013 600.13Nomenclature change 11013 600.14(a) amended 11014 600.15(b) nomenclature change 11013 600.22(e) nomenclature change 11013 601.2(a) nomenclature change 11013 (b) amended 11014 601.3(a) introductory text and (b) introductory text nomenclature change 11013 601.4(a) nomenclature change 11013 601.6(a)(2) nomenclature change 11013 601.9(a) nomenclature change 11013 601.12(a) and (b) nomenclature change 11013 601.21Amended 11014 601.25(b)(2) amended 11014 601.31Nomenclature change 11013 601.33Nomenclature change 11013 601.51(b) nomenclature change 11013 606.20(a) nomenclature change 11014 606.100(a) and (d)(3) nomenclature change 11013 606.110(b) nomenclature change 11013 606.121(c)(13), (d) introductory text, (4), and (5) nomenclature change 11014 606.170(b) nomenclature change 11014 607.3(e) nomenclature change 11014 607.7(b) and (c) nomenclature change 11014 607.22(a) and (b) nomenclature change 11014 607.25(b)(2) nomenclature change 11013 607.37(a) introductory text and (b) amended 11014 607.40(b) nomenclature change 11014 610.2(a) nomenclature change 11013 (b) amended 11014 610.9(b) nomenclature change 11014 610.11(c)(2) and (3) nomenclature change 11013 610.12(e)(2)(i) and (g)(4)(ii) nomenclature change 11013 610.13(a) revised; OMB control number 28381 610.15(a)(3) nomenclature change 11013 610.18(c)(2) nomenclature change 11013 610.20Introductory text nomenclature change 11013 610.40(a) and (e)(2) nomenclature change 11013 (b)(4), (d)(1)(v) and (2)(iv) amended 11014 610.53(d) nomenclature change 11014 610.61(s) removed; (t) redesignated as (s) 10423 Technical correction 14037 620.6(h) introductory text nomenclature change 11013 620.12Introductory text amended 11015 620.13(h) nomenclature change 11013 620.14(c)(2) and (3) nomenclature change 11013 (c) introductory text amended 11015 620.21(b) nomenclature change 11013 620.22Nomenclature change 11013 620.24(c) introductory text, (1), and (3) nomenclature change 11013 620.31(a)(1) nomenclature change 11013 620.32Introductory text nomenclature change 11013 620.35(e) introductory text, (2), and (3) nomenclature change 11013 620.43Nomenclature change 11013 620.44(c) nomenclature change 11013 620.45(b) introductory text, (1), (4), and (5) nomenclature change 11013 620.48(a) introductory text, (a)(2) and (b) nomenclature change 11013 630Authority citation revised 47875 Technical correction 50279 630.1(b) and (c) nomenclature change 11013 630.2(c) nomenclature change 11013 630.3Introductory text and (a) nomenclature change 11013 630.4(e)(1) and (3) nomenclature change 11013 630.5(c) introductory text and (4) nomenclature change 11013 630.10(a), (b)(2), (4), (5), and (6) nomenclature change 11013 630.12(a)(1) and (b) nomenclature change 11013 630.14Nomenclature change 11013 630.17(e) introductory text and (1) nomenclature change 11013 630.30(c)(1)(iii) nomenclature change 11013 (c)(1) introductory text revised 47875 630.31Revised 47875 630.33Nomenclature change 11013 630.36(h) introductory text and (1)(i) nomenclature change 11013 630.50(c)(1)(ii) nomenclature change 11013 (c)(1) introductory text revised 47875 630.53Nomenclature change 11013 630.55(a)(4) revised 47876 630.56(f) introductory text and (1) nomenclature change 11013 630.60(d)(3) and (e)(1)(ii) nomenclature change 11013 (e)(1) introductory text revised 47876 630.62(a) revised 47876 630.63Nomenclature change 11013 630.66(e) introductory text, (1)(i), and (3) nomenclature change 11013 630.70(b) nomenclature change 11013 630.72Nomenclature change 11013 630.74(c) nomenclature change 11013 630.75(d)(1), (i) and (2) nomenclature change 11013 630.80—630.86 (Subpart I)Removed 47876 630.81Nomenclature change 11013 630.83Nomenclature change 11013 630.86(e) introductory text, (1)(i), and (3) nomenclature change 11013 640.2(a) nomenclature change 11013 640.3(a)(1) nomenclature change 11013 640.4(a)(1) nomenclature change 11013 640.6Introductory text nomenclature change 11013 640.17Nomenclature change 11013 640.21(c) nomenclature change 11013 640.22(c) nomenclature change 11013 640.25(c) introductory text and (3) nomenclature change 11013 640.55Nomenclature change 11013 640.56(c) introductory text and (2) nomenclature change 11013 640.64(c) introductory text nomenclature change 11013 640.66Nomenclature change 11013 640.71(b)(3) nomenclature change 11013 640.73Nomenclature change 11013 640.74(a) and (b)(2) nomenclature change 11013 640.75Removed 10423 Technical correction 14037 640.82(b) nomenclature change 11013 640.92(b) nomenclature change 11013 640.101(f) introductory text nomenclature change 11013 640.104(c) introductory text nomenclature change 11013 640.111(g) introductory text nomenclature change 11013 640.112(b) nomenclature change 11013 640.120 (Subpart L)Added 10423 Technical correction 14037 650.6Introductory text, (a), and (c) nomenclature change 11013 650.11(c) introductory text, (1), and (5) nomenclature change 11013 660.3Nomenclature change 11013 660.5Nomenclature change 11013 660.6(a)(2) introductory text and (iii), (b), (c)(1), (2), and (3) nomenclature change 11013 660.33Nomenclature change 11013 660.34(d) nomenclature change 11013 660.36(a)(1), (b), and (c) nomenclature change 11013 (a) introductory text amended 11015 660.42Nomenclature change 11013 660.44Nomenclature change 11013 660.46(a)(2) introductory text and (iii), (b), (c)(1), (2), and (3) nomenclature change 11013 (a)(2)Introductory text amended 11014 660.52Amended 11015 660.53Nomenclature change 11014 660.54Introductory text nomenclature change 11014 660.55(a)(3) nomenclature change 11014 660.101Introductory text nomenclature change 11013 660.102(b)(1) and (c)(7) nomenclature change 11013 660.103(d) and (g)(2)(ii) nomenclature change 11013 660.105(a) introductory and (b) nomenclature change 11013 680Nomenclature change 11014 680.1(b)(2)(iii), (3)(iv), (c), and (d)(1) nomenclature change 11014 680.3(e) nomenclature change 11013 680.11Nomenclature change 11013 Heading revised 11015 680.12Nomenclature change 11013 680.21Nomenclature change 11013 680.24(e) nomenclature change 11013 680.26Introductory text and (c) nomenclature change 11013 1991 21 CFR 56 FR Page Chapter I 620.1Revised 63410 630.10—630.19 (Subpart B)Revised 21432 Regulation at 56 FR 21432 effective date delayed in part 23505 630.12(a)(3) corrected 27787 630.18(a)(3) and (5) corrected 27787 1992 21 CFR 57 FR Page Chapter I 601.40—601.46 (Subpart E)Added 58959 Technical correction 61489 606.60(c) amended 11263 (c) corrected 12862 606.121(a) amended 10814 610.41Amended 10814 620.1Technical correction 2135 630.4(e)(3) amended 10814 640.67(a) amended 10814 720.1Revised 3129 720.2Revised 3129 720.3Revised 3129 720.4(a) introductory text, (b) introductory text, (c)(13) introductory text and (e) amended; (b)(5), (c)(12)(xi) and (xii) removed; (c)(12)(iii), (iv), (v), (ix), (x) and (d) revised; OMB number 3129 720.5Removed 3130 Technical correction 5210 720.6Revised; OMB number 3130 720.7Revised 3130 720.8(a) amended 3130 720.9Revised 3130 1993 21 CFR 57 FR Page Chapter I 601Technical correction 4078 630.13(b)(4) amended 19609 1994 21 CFR 59 FR Page Chapter I 600Authority citation revised 54042 600.15(b) amended 49351 600.80—600.90 (Subpart D)Added 54042 606.65(c) table amended 23636 606.121(c)(12)(i), (ii) and (iii) amended 23636 610.9(a) amended 49351 610.11Introductory text amended 49351 610.53(d) amended 49351 630.10(c)(3) amended 49351 640.6Introductory text amended 49351 640.21(c) amended 49351 640.22(c) amended 49351 640.64(c) amended 49351 640.74(a) amended 49351 660.28(a)(1) table and (4) amended 23637 1995 (No regulations published) 1996 21 CFR 61 FR Page Chapter I 600.3(t) revised 24232 601.2(a) existing text designated as (a) introductory text; new (a) introductory text amended; (a)(1) through (4) and (c) added 24232 601.22Amended 24233 601.30Removed 40154 601.31Removed 40154 601.32Removed 40154 601.51(d) redesignated as (d)(1); (d)(2) added 51530 606.100(b)(19) added 47422 Regulation at 61 FR 47422 eff. date corrected to 2-7-97 66919 606.160(b)(1)(vii) and (viii) added 47422 Regulation at 61 FR 47422 eff. date corrected to 2-7-97 66919 610.45(d) added 47423 Regulation at 61 FR 47423 eff. date corrected to 2-7-97 66919 610.46Added 47423 Regulation at 61 FR 47423 eff. date corrected to 2-7-97 66919 610.47Added 47423 Regulation at 61 FR 47423 eff. date corrected to 2-7-97 66919 610.64Revised 57330 620Removed 40154 630Removed 40155 640.110—640.114 (Subpart K)Removed 40155 650Removed 40155 660.100—660.105 (Subpart K)Removed 40155 680.1—680.3 (Subpart A)Heading removed 40155 680.10—680.16 (Subpart B)Removed 40155 680.20—680.26 (Subpart C)Removed 40155 700.10Removed 27779 730.3Amended 14481 740.11(c) revised; interim 20101 1997 21 CFR 62 FR Page Chapter I 600Meeting 44891 Authority citation revised 51519 600.3(ff) and (gg) added 39901 600.10(a) removed; (b) heading revised 53538 600.80(c)(1)(ii) removed; (c)(1)(iii) and (iv) redesignated as (c)(1)(ii) and (iii); (a), new (c)(1)(ii) introductory text, (d)(1) and (m) amended; (f)(1) revised 34168 (a), (c)(1) and (f)(1) revised; (b) and (g) amended; (j) removed; (k), (l) and (m) redesignated as (j), (k) and (l); eff. 4-6-98 52252 601Meeting 44891, 46198 Technical correction 47760 Authority citation revised 51519 601.2(c)(3) corrected 11769 (a) and (c)(2) amended 40600 (a) introductory text amended; (c)(6) added 53538 601.12Revised 39901 601.25(b)(3) amended 53538 606Authority citation revised 51519 606.20(a) removed 53538 607Authority citation revised 51519 610Meeting 44891 Authority citation revised 51519 610.9Revised 39903 610.12(f) revised 48175 610.53(c) table amended 15110 640Meeting 44891 Authority citation revised 51519 640.120(a) revised 39903 660Authority citation revised 51519 680Authority citation revised 51519 700Authority citation revised 51519 701Authority citation revised 51519 710Authority citation revised 51519 720Authority citation revised 51519 730Removed 43074 Authority citation revised 51519 740Authority citation revised 51519 1998 21 CFR 63 FR Page Chapter I 600.80(l) correctly revised; eff. 4-6-98 14612 601Authority citation revised 66671 601.2(a) introductory text amended; eff. 2-2-99 5253 (a) introductory text amended; (c)(1)(viii) revised; eff. 6-1-99 66399 601.12(f)(1) amended; (f)(3)(i) revised; eff. 6-1-99 66399 601.27Added 66671 601.37Added 66671 606.121(e)(1)(ii) amended 16685 610.11(g) revised 19403 Regulation at 63 FR 19403 withdrawn in part 41718 610.30Amended 16685 610.60(a)(7) added; eff. 6-1-99 66400 640.2(e)(3) amended 16685 640.17Amended 16685 640.24(b) amended 16685 640.64(c)(2) amended 16685 640.69(b) amended 16685 640.70(a)(3) amended 16685 640.74(b)(2) amended 16685 640.101(a) amended 16685 640.102(c) and (e) amended 16685 640.104(a) amended 16685 1999 (Regulations published from January 1, 1999, through April 1, 1999) 21 CFR 64 FR Page Chapter I 701.3(d) revised; eff. 4-16-99 13297 ○>