21 U.S.C. 321, 351, 352, 353, 355, 360, 360i, 371, 374; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.
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.
(a)
(b)
(1)
(2)
(3)
(c)
(2) Radioactive biological products required under § 610.2 of this chapter must be sent by courier service to: Sample Custodian (ATTN: HFM-672), Food and Drug Administration, Center for Biologics Evaluation and Research, Nicholson Lane Research Center, c/o Radiation Safety Office, National Institutes of Health, 21 Wilson Dr., rm. 107, Bethesda, MD 20892-6780.
(d)
(e) Address information for submissions to CBER and CDER other than those listed in parts 600 through 680 of this chapter are included directly in the applicable regulations.
(f) Obtain updated mailing address information for biological products regulated by CBER at
As used in this subchapter:
(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h)
(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.
(2) A therapeutic serum is a product obtained from blood by removing the clot or clot components and the blood cells.
(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.
(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.
(5) A product is analogous:
(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.
(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 amino acid, derived from whole blood, plasma, or serum.
(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.
(i)
(j) A product is deemed
(k)
(l)
(m)
(n) The word
(o) The word
(p) The word
(q) The word
(r)
(s) The word
(t)
(u)
(v)
(w)
(x)
(y) A
(z)
(aa)
(bb)
(cc)
(dd)
(ee)
(ff)
(gg)
(hh)
(ii)
(jj)
(kk)
(ll)
(mm)
(a) [Reserved]
(b)
(c)
(2)
(3)
(4)
(a)
(b)
(c)
(d)
(e)
(2)
(3)
(ii) If process containment is employed in a multiproduct manufacturing area, procedures must be in place to demonstrate adequate removal of the spore-forming microorganism(s) from the manufacturing area for subsequent manufacture of other products. These procedures must provide for adequate removal or decontamination of the spore-forming microorganisms on and within manufacturing equipment, facilities, and ancillary room items as well as the removal of disposable or product dedicated items from the manufacturing area. Environmental monitoring specific for the spore-forming microorganism(s) must be conducted in adjacent areas during manufacturing operations and in the manufacturing area after completion of cleaning and decontamination.
(4)
(i)(A) Using a dedicated manufacturing area that is either in a separate
(B) Not conducting test procedures that potentially involve the presence of microorganisms other than the vaccine strains or the use of tissue culture cell lines other than primary cultures in space used for processing live vaccine; or
(ii) If manufacturing is conducted in a multiproduct manufacturing building or area, using procedural controls, and where necessary, process containment. Process containment is deemed to be necessary unless procedural controls are sufficient to prevent cross contamination of other products and other manufacturing areas within the building. Process containment is a system designed to mechanically isolate equipment or an area that involves manufacturing using live vaccine organisms. All product, equipment, and personnel movement between distinct live vaccine processing areas and between live vaccine processing areas and other manufacturing areas, up to, but not including, filling in final containers, must be conducted under conditions that will prevent cross contamination of other products and manufacturing areas within the building, including the introduction of live vaccine organisms into other areas. In addition, written procedures and effective processes must be in place to adequately remove or decontaminate live vaccine organisms from the manufacturing area and equipment for subsequent manufacture of other products. Written procedures must be in place for verification that processes to remove or decontaminate live vaccine organisms have been followed.
(5)
(f)
(2)
(ii)
(3)
(4)
(5) [Reserved]
(6)
(7)
(8)
(g)
(h)
(a)
(b)
(2)
(3)
(c)
(d)
(e)
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
(a)
(2) Exceptions:
(i) Persons who manufacture only in vitro diagnostic products that are not subject to licensing under section 351 of the Public Health Service Act do not report biological product deviations for those products under this section but must report in accordance with part 803 of this chapter;
(ii) Persons who manufacture blood and blood components, including licensed manufacturers, unlicensed registered blood establishments, and transfusion services, do not report biological product deviations for those products under this section but must report under § 606.171 of this chapter;
(iii) Persons who manufacture Source Plasma or any other blood component and use that Source Plasma or any other blood component in the further manufacture of another licensed biological product must report:
(A) Under § 606.171 of this chapter, if a biological product deviation occurs during the manufacture of that Source Plasma or any other blood component; or
(B) Under this section, if a biological product deviation occurs after the manufacture of that Source Plasma or any other blood component, and during manufacture of the licensed biological product.
(b)
(1) Either:
(i) Represents a deviation from current good manufacturing practice, applicable regulations, applicable standards, or established specifications that may affect the safety, purity, or potency of that product; or
(ii) Represents an unexpected or unforeseeable event that may affect the safety, purity, or potency of that product; and
(2) Occurs in your facility or another facility under contract with you; and
(3) Involves a distributed biological product.
(c)
(d)
(e)
(2) For biological products regulated by the Center for Drug Evaluation and Research (CDER), send the completed Form FDA-3486 to the Division of Compliance Risk Management and Surveillance (HFD-330) (see mailing addresses in § 600.2). CDER does not currently accept electronic filings.
(3) If you make a paper filing, you should identify on the envelope that a biological product deviation report (BPDR) is enclosed.
(f)
The following products shall be maintained during shipment at the specified temperatures:
(a)
(b)
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.
The inspection of an establishment for which a biologics license application is pending need not be made until the establishment is in operation and is manufacturing the complete product for which a biologics 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.
The inspector shall:
(a) Call upon the active head of the establishment, stating the object of his visit,
(b) Interrogate the proprietor or other personnel of the establishment as he may deem necessary,
(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,
(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,
(e) Obtain and cause to be sent to the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing addresses in § 600.2), adequate samples for the examination of any product or ingredient used in its manufacture,
(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,
(g) Inspect and copy, as circumstances may require, any records required to be kept pursuant to § 600.12,
(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.
(a)
(b)
(c)
(1)(i)
(ii)
(iii)
(A) A copy of all adverse biological product experience reports submitted to the licensed manufacturer of the final product;
(B) The date the report was received by the person;
(C) The date the report was submitted to the licensed manufacturer of the final product; and-
(D) The name and address of the licensed manufacturer of the final product.
(iv)
(2)
(ii) Each periodic report shall contain:
(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);
(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
(C) A history of actions taken since the last report because of adverse experiences (for example, labeling changes or studies initiated).
(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.
(d)
(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.
(e)
(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.
(f)
(2) Each completed form should refer only to an individual patient or single attached publication.
(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:
(i) The content of the alternative format is equivalent in all elements of information to those specified in the form designated by FDA; and
(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.
(4) Copies of the reporting form designated by FDA (FDA-3500A) for nonvaccine biological products may be obtained from
(g)
(h)
(i)
(j)
(k)
(1) Whole blood or components of whole blood.
(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.
(l)
The licensed manufacturer shall submit to the Center for Biologics Evaluation and Research or the Center for Drug Evaluation and Research (see mailing addresses in § 600.2), information about the quantity of the product distributed under the biologics 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.
(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:
(1) An explanation why the licensed manufacturer's compliance with the requirement is unnecessary or cannot be achieved,
(2) A description of an alternative submission that satisfies the purpose of the requirement, or
(3) Other information justifying a waiver.
(b) FDA may grant a waiver if it finds one of the following:
(1) The licensed manufacturer's compliance with the requirement is unnecessary or cannot be achieved,
(2) The licensed manufacturer's alternative submission satisfies the requirement, or
(3) The licensed manufacturer's submission otherwise justifies a waiver.
15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 355, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216, 241, 262, 263, 264; sec 122, Pub. L. 105-115, 111 Stat. 2322 (21 U.S.C. 355 note).
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.
(a)
(1) Therapeutic DNA plasmid products;
(2) Therapeutic synthetic peptide products of 40 or fewer amino acids;
(3) Monoclonal antibody products for in vivo use; and
(4) Therapeutic recombinant DNA-derived products.
(b) [Reserved]
(c)(1) To obtain marketing approval for a biological product subject to licensure which is 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 a biologics license application in accordance with paragraph (a) of this section except that 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, 610.11, 610.53, and 610.62 of this chapter.
(2) To the extent that the requirements in this paragraph (c) conflict
(d) Approval of a biologics license application or issuance of a biologics license shall constitute a determination that the establishment(s) and the product meet applicable requirements to ensure the continued safety, purity, and potency of such products. Applicable requirements for the maintenance of establishments for the manufacture of a product subject to this section shall include but not be limited to the good manufacturing practice requirements set forth in parts 210, 211, 600, 606, and 820 of this chapter.
(e) Any establishment and product license for a biological product issued under section 351 of the Public Health Service Act (42 U.S.C. 201
(a)
(1)
(2)
(3)
(b)
(1)
(2)
(c)
(2) If FDA considers an applicant's failure to take action in accordance with paragraph (c)(1) of this section to be a request to withdraw the application, the agency will notify the applicant in writing. The applicant will have 30 days from the date of the notification to explain why the application or supplement should not be withdrawn and to request an extension of time in which to resubmit the application or supplement. FDA will grant any reasonable request for an extension. If the applicant does not respond to the notification within 30 days, the application or supplement will be deemed to be withdrawn.
(a) A biologics license shall be issued upon a determination by the Director,
(b) If the Commissioner determines that the establishment or product does not meet the requirements established in this chapter, the biologics license application shall be denied and the applicant shall be informed of the grounds for, and of an opportunity for a hearing on, the 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.
(a) A biologics license shall be revoked upon application of the manufacturer giving notice of intention to discontinue the manufacture of all products manufactured under such license 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.
(b)(1) The Commissioner shall notify the licensed manufacturer of the intention to revoke the biologics license, setting forth the grounds for, and offering an opportunity for a hearing on the proposed revocation if the Commissioner finds any of the following:
(i) 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,
(ii) Manufacturing of products or of a product has been discontinued to an extent that a meaningful inspection or evaluation cannot be made,
(iii) The manufacturer has failed to report a change as required by § 601.12 of this chapter,
(iv) 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,
(v) The establishment or the manufacturing methods have been so changed as to require a new showing that the establishment or product meets the requirements established in this chapter in order to protect the public health, or
(vi) The licensed product is not safe and effective for all of its intended uses or is misbranded with respect to any such use.
(2) Except as provided in § 601.6 of this chapter, or in cases involving willfulness, the notification required in this paragraph shall provide a reasonable period for the licensed manufacturer 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 licensed manufacturer does not waive the opportunity for a hearing, the Commissioner shall issue a notice of opportunity for hearing on the matter under § 12.21(b) of this chapter.
(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, the Commissioner may notify the licensed manufacturer that the biologics license is suspended and require that the licensed manufacturer do the following:
(1) Notify the selling agents and distributors to whom such product or products have been delivered of such suspension, and
(2) Furnish to the Center for Biologics Evaluation and Research or the Center for Drug Evaluation and Research, complete records of such deliveries and notice of suspension.
(b) Upon suspension of a license, the Commissioner shall either:
(1) Proceed under the provisions of § 601.5(b) of this chapter to revoke the license, or
(2) If the licensed manufacturer agrees, hold revocation in abeyance pending resolution of the matters involved.
(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.
(b) Hearings pursuant to §§ 601.4 through 601.6 shall be governed by part 12 of this chapter.
(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.
The Commissioner, following revocation of a biologics license under 21 CFR 601.5(b), will publish a notice in the
(a)
(b)
(c)
(a)
(2) Before distributing a product made using a change, an applicant must assess the effects of the change and demonstrate through appropriate validation and/or other clinical and/or nonclinical 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.
(3) Notwithstanding the requirements of paragraphs (b), (c), and (f) of this section, an applicant must make a change provided for in those paragraphs in accordance with a regulation or guidance that provides for a less burdensome notification of the change (for example, by submission of a supplement that does not require approval prior to distribution of the product or in an annual report).
(4) The applicant must promptly revise all promotional labeling and advertising to make it consistent with any labeling change implemented in accordance with paragraphs (f)(1) and (f)(2) of this section.
(5) A supplement or annual report must include a list of all changes contained in the supplement or annual report. For supplements, this list must be provided in the cover letter.
(b)
(2) These changes include, but are not limited to:
(i) Except as provided in paragraphs (c) and (d) of this section, changes in the qualitative or quantitative formulation, including inactive ingredients, or in the specifications provided in the approved application;
(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;
(iii) Changes in the virus or adventitious agent removal or inactivation method(s);
(iv) Changes in the source material or cell line;
(v) Establishment of a new master cell bank or seed; and
(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.
(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:
(i) A detailed description of the proposed change;
(ii) The product(s) involved;
(iii) The manufacturing site(s) or area(s) affected;
(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;
(v) The data derived from such studies;
(vi) Relevant validation protocols and data; and
(vii) A reference list of relevant standard operating procedures (SOP's).
(4) An applicant may ask FDA to expedite its review of a supplement for public health reasons or if a delay in making the change described in it would impose an extraordinary hardship on the applicant. Such a supplement and its mailing cover should be plainly marked: “Prior Approval Supplement-Expedited Review Requested.
(c)
(2) These changes include, but are not limited to:
(i) [Reserved]
(ii) An increase or decrease in production scale during finishing steps that involves different equipment; and
(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.
(iv) Relaxation of an acceptance criterion or deletion of a test to comply with an official compendium that is consistent with FDA statutory and regulatory requirements.
(3) Pending approval of the supplement by FDA, and except as provided
(4) If within 30 days following FDA's receipt of the supplement, FDA informs the applicant that either:
(i) The change requires approval prior to distribution of the product in accordance with paragraph (b) of this section; or
(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.
(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.
(6) If the agency disapproves the supplemental application, it may order the manufacturer to cease distribution of the products made with the manufacturing change.
(d)
(2) These changes include, but are not limited to:
(i) Any change made to comply with a change to an official compendium, except a change described in paragraph (c)(2)(iv) of this section, that is consistent with FDA statutory and regulatory requirements.
(ii) The deletion or reduction 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;
(iii) An extension of an expiration dating period based upon full shelf life data on production batches obtained from a protocol approved in the application;
(iv) A change within the container closure system for a nonsterile product, based upon a showing of equivalency to the approved system under a protocol approved in the application or published in an official compendium;
(v) A change in the size and/or shape of a container containing the same number of dosage units for a nonsterile solid dosage form product, without a change from one container closure system to another;
(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
(vii) The addition or revision of an alternative analytical procedure that provides the same or increased assurance of the identity, strength, quality, purity, or potency of the material
(3) The following information for each change shall be contained in the annual report:
(i) A list of all products involved; and
(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.
(iii) A statement by the holder of the approved application or license that the effects of the change have been assessed.
(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.
(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.
(f)
(2)
(A) To add or strengthen a contraindication, warning, precaution, or adverse reaction for which the evidence of a causal association satisfies the standard for inclusion in the labeling under § 201.57(c) of this chapter;
(B) To add or strengthen a statement about abuse, dependence, psychological effect, or overdosage;
(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
(D) To delete false, misleading, or unsupported indications for use or claims for effectiveness.
(E) Any labeling change normally requiring a supplement submission and approval prior to distribution of the product that FDA specifically requests be submitted under this provision.
(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
(3)
(A) Editorial or similar minor changes;
(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;
(C) A change in the information specified in § 208.20(b)(8)(iii) and (b)(8)(iv) of this chapter for a Medication Guide; and
(D) A change to the information required in § 201.57(a) of this chapter as follows:
(
(
(E) A change made pursuant to an exception or alternative granted under § 201.26 or § 610.68 of this chapter.
(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.
(4)
(5) The submission and grant of a written request for an exception or alternative under § 201.26 or § 610.68 of this chapter satisfies the requirements in paragraphs (f)(1) through (f)(2) of this section.
(6) For purposes of paragraph (f)(2) of this section, information will be considered newly acquired if it consists of data, analyses, or other information not previously submitted to the agency, which may include (but are not limited to) data derived from new clinical studies, reports of adverse events, or new analyses of previously submitted data (e.g., meta-analyses) if the studies, events or analyses reveal risks of a different type or greater severity or frequency than previously included in submissions to FDA.
(g)
(h)
(a)
(b)
Random samples of each importation, obtained by the District Director of Customs and forwarded to the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing addresses in § 600.2 of this chapter) must be at least two final containers of each lot of product. A copy of the associated documents which describe and identify the shipment must accompany the shipment for forwarding with the samples to the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing addresses in § 600.2). 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 or Center for Drug Evaluation and Research accompanies each shipment.
(a)
(b)
(1) The product intended for introduction into interstate commerce is available for examination, and
(2) Such product is available for inspection during all phases of manufacture.
(c)
(d)
(e)
A biological product undergoing development, but not yet ready for a biologics 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 introduction or delivery for introduction into interstate commerce, except as provided in sections 505(i) and 520(g) of the Federal Food, Drug, and Cosmetic Act, as amended, and the regulations thereunder (21 CFR parts 312 and 812).
A biologics license issued to a manufacturer and covering all locations of manufacture shall authorize persons other than such manufacturer to conduct at places other than such locations 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 it is found upon application of such manufacturer, that 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 such manufacturer has established with respect to such persons and places such procedures, inspections, tests or other arrangements as will ensure 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 §§ 601.2 to 601.6, 601.9, 601.10, 601.20, 601.21 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.
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.
(a)
(b)
(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
(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
I. Label or labels and all other labeling (preferably mounted. Facsimile labeling is acceptable in lieu of actual container labeling), including labeling for export.
II. Representative advertising used during the past 5 years.
III. The complete quantitative composition of the biological product.
IV. Animal safety data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
C. Finished biological product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
V. Human safety data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination as to the safety of each individual active component.
5. Pertinent medical and scientific literature.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination as to the safety of combinations of the individual active components.
5. Pertinent medical and scientific literature.
C. Finished biological product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination as to the safety of the finished biological product.
5. Pertinent medical and scientific literature.
VI. Efficacy data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination on the efficacy of each individual active component.
5. Pertinent medical and scientific literature.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination as to the effectiveness of combinations of the individual active components.
5. Pertinent medical and scientific literature.
C. Finished biological product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination as to the effectiveness of the finished biological product.
5. Pertinent medical and scientific literature.
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,
VIII. If the submission is by a licensed manufacturer, a statement signed by the authorized official of the licensed manufacturer 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 licensed manufacturer, 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 available information, favorable and unfavorable available to him, pertinent to an evaluation of the safety, effectiveness, and labeling of the product.
(c)
(1) A panel may also consult any individual or group.
(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.
(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.
(d)
(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.
(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.
(3) The benefit-to-risk ratio of a biological product shall be considered in determining safety and effectiveness.
(4) A biological product may combine two or more safe and effective active components: (i) When each active component makes a contribution to the 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.
(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.
(e)
(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.
(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.
(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.
(f)
(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.
(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.
(3) A statement designating the biological products not included in either of the above two statements on the
(4) The full report or reports of the panel to the Commissioner of Food and Drugs.
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
(g)
(h) [Reserved]
(i)
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.
(a)
(b)
(c)
(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).
(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:
(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
(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.
(d)
(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);
(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.
(3) A proposal to accept or reject the findings of the advisory review panel required by § 601.26(c)(2)(i) and (ii).
(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.
(e)
(f)
(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 biologics license or licenses shall be revoked.
(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 biologics 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
(4) Labeling and promotional material for those biological products requiring additional studies shall bear a box statement in the following format:
Based on a review by the (
(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.
(g)
(h) [Reserved]
(i)
(a)
(b)
(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.
(c)
(2)
(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;
(ii) Necessary studies are impossible or highly impractical because, e.g., the number of such patients is so small or geographically dispersed; or
(iii) There is evidence strongly suggesting that the product would be ineffective or unsafe in all pediatric age groups.
(3)
(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;
(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;
(iii) There is evidence strongly suggesting that the product would be ineffective or unsafe in that age group; or
(iv) The applicant can demonstrate that reasonable attempts to produce a pediatric formulation necessary for that age group have failed.
(4)
(5)
(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 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
(ii) The product is in a class of products or for an indication for which there is a need for additional therapeutic options.
(d)
Sponsors of licensed biological products shall submit the following information each year within 60 days of the anniversary date of approval of each product under the license to the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing addresses in § 600.2 of this chapter):
(a)
(b)
(c)
(a) FDA has made available guidance documents under § 10.115 of this chapter to help you comply with certain requirements of this part.
(b) The Center for Biologics Evaluation and Research (CBER) maintains a list of guidance documents that apply to the center's regulations. The lists are maintained on the Internet and are published annually in the
This subpart applies to radiopharmaceuticals intended for in vivo administration for diagnostic and monitoring use. It does not apply to radiopharmaceuticals intended for therapeutic purposes. In situations where a particular radiopharmaceutical is proposed for both diagnostic and therapeutic uses, the radiopharmaceutical must be evaluated taking into account each intended use.
For purposes of this part,
(a) An article that is intended for use in the diagnosis or monitoring of a disease or a manifestation of a disease in humans and that exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons; or
(b) Any nonradioactive reagent kit or nuclide generator that is intended to be used in the preparation of such article as defined in paragraph (a) of this section.
FDA's determination of the safety and effectiveness of a diagnostic radiopharmaceutical includes consideration of the following:
(a) The proposed use of the diagnostic radiopharmaceutical in the practice of medicine;
(b) The pharmacological and toxicological activity of the diagnostic radiopharmaceutical (including any carrier or ligand component of the diagnostic radiopharmaceutical); and
(c) The estimated absorbed radiation dose of the diagnostic radiopharmaceutical.
(a) For diagnostic radiopharmaceuticals, the categories of proposed indications for use include, but are not limited to, the following:
(1) Structure delineation;
(2) Functional, physiological, or biochemical assessment;
(3) Disease or pathology detection or assessment; and
(4) Diagnostic or therapeutic patient management.
(b) Where a diagnostic radiopharmaceutical is not intended to provide disease-specific information, the proposed indications for use may refer to a biochemical, physiological, anatomical, or pathological process or to more than one disease or condition.
(a) The effectiveness of a diagnostic radiopharmaceutical is assessed by evaluating its ability to provide useful clinical information related to its proposed indications for use. The method of this evaluation varies depending upon the proposed indication(s) and may use one or more of the following criteria:
(1) The claim of structure delineation is established by demonstrating in a defined clinical setting the ability to locate anatomical structures and to characterize their anatomy.
(2) The claim of functional, physiological, or biochemical assessment is established by demonstrating in a defined clinical setting reliable measurement of function(s) or physiological, biochemical, or molecular process(es).
(3) The claim of disease or pathology detection or assessment is established by demonstrating in a defined clinical setting that the diagnostic radiopharmaceutical has sufficient accuracy in identifying or characterizing the disease or pathology.
(4) The claim of diagnostic or therapeutic patient management is established by demonstrating in a defined clinical setting that the test is useful in diagnostic or therapeutic patient management.
(5) For a claim that does not fall within the indication categories identified in § 601.33, the applicant or sponsor should consult FDA on how to establish the effectiveness of the diagnostic radiopharmaceutical for the claim.
(b) The accuracy and usefulness of the diagnostic information is determined by comparison with a reliable assessment of actual clinical status. A reliable assessment of actual clinical status may be provided by a diagnostic standard or standards of demonstrated accuracy. In the absence of such diagnostic standard(s), the actual clinical status must be established in another manner, e.g., patient followup.
(a) Factors considered in the safety assessment of a diagnostic radiopharmaceutical include, among others, the following:
(1) The radiation dose;
(2) The pharmacology and toxicology of the radiopharmaceutical, including any radionuclide, carrier, or ligand;
(3) The risks of an incorrect diagnostic determination;
(4) The adverse reaction profile of the drug;
(5) Results of human experience with the radiopharmaceutical for other uses; and
(6) Results of any previous human experience with the carrier or ligand of the radiopharmaceutical when the same chemical entity as the carrier or ligand has been used in a previously studied product.
(b) The assessment of the adverse reaction profile includes, but is not limited to, an evaluation of the potential of the diagnostic radiopharmaceutical, including the carrier or ligand, to elicit the following:
(1) Allergic or hypersensitivity responses,
(2) Immunologic responses,
(3) Changes in the physiologic or biochemical function of the target and nontarget tissues, and
(4) Clinically detectable signs or symptoms.
(c)(1) To establish the safety of a diagnostic radiopharmaceutical, FDA may require, among other information, the following types of data:
(A) Pharmacology data,
(B) Toxicology data,
(C) Clinical adverse event data, and
(D) Radiation safety assessment.
(2) The amount of new safety data required will depend on the characteristics of the product and available information regarding the safety of the diagnostic radiopharmaceutical, and its carrier or ligand, obtained from other studies and uses. Such information may include, but is not limited to, the dose, route of administration, frequency of use, half-life of the ligand or carrier, half-life of the radionuclide, and results of clinical and preclinical studies. FDA will establish categories of diagnostic radiopharmaceuticals based on defined characteristics relevant to risk and will specify the amount and type of safety data that are appropriate for each category (e.g., required safety data may be limited for diagnostic radiopharmaceuticals with a well established, low-risk profile). Upon reviewing the relevant product characteristics and safety information, FDA will place each diagnostic radiopharmaceutical into the appropriate safety risk category.
(d)
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).
FDA may grant marketing approval for a biological product on the basis of 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.
(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:
(1) Distribution restricted to certain facilities or physicians with special training or experience; or
(2) Distribution conditioned on the performance of specified medical procedures.
(b) The limitations imposed will be commensurate with the specific safety concerns presented by the biological product.
(a) For biological products approved under § 601.41 or § 601.42, FDA may withdraw approval, following a hearing as provided in part 15 of this chapter, as modified by this section, if:
(1) A postmarketing clinical study fails to verify clinical benefit;
(2) The applicant fails to perform the required postmarketing study with due diligence;
(3) Use after marketing demonstrates that postmarketing restrictions are inadequate to ensure safe use of the biological product;
(4) The applicant fails to adhere to the postmarketing restrictions agreed upon;
(5) The promotional materials are false or misleading; or
(6) Other evidence demonstrates that the biological product is not shown to be safe or effective under its conditions of use.
(b)
(c)
(2) If the applicant files a timely request for a hearing, the agency will publish a notice of hearing in the
(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.
(d)
(e)
(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.
(2) The presiding officer, the advisory committee members, up to three representatives of the applicant, and up to three representatives of the Center 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.
(f)
Biological products approved under this program are subject to the postmarketing recordkeeping and safety reporting applicable to all approved biological products.
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.
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.
(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.
(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.
(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.
(a) For purposes of this section the biological product file includes all data and information submitted with or incorporated by reference in any application for a biologics 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.
(b) The existence of a biological product file will not be disclosed by the Food and Drug Administration before a biologics license application has been approved unless it has previously been publicly disclosed or acknowledged. The Food and Drug Administration will maintain a list available for public disclosure of biological products for which a license application has been approved.
(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.
(d)(1) If the existence of a biological product file has been publicly disclosed or acknowledged before a license has
(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 Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852, 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.
(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:
(1) All safety and effectiveness data and information.
(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.
(3) Adverse reaction reports, product experience reports, consumer complaints, and other similar data and information, after deletion of:
(i) Names and any information that would identify the person using the product.
(ii) Names and any information that would identify any third party involved with the report, such as a physician or hospital or other institution.
(4) A list of all active ingredients and any inactive ingredients previously disclosed to the public, as defined in § 20.81 of this chapter.
(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.
(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.
(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.
(8) All records showing the testing of and action on a particular lot by the Food and Drug Administration.
(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:
(1) Manufacturing methods or processes, including quality control procedures.
(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.
(3) Quantitative or semiquantitative formulas.
(g) For purposes of this regulation, safety and effectiveness data include 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.
(a)
(1) Clinical safety;
(2) Clinical efficacy;
(3) Clinical pharmacology; and
(4) Nonclinical toxicology.
(b)
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(i)
(ii)
(iii)
(iv)
(v)
(9)
(c)
(d)
(e)
This subpart applies to certain biological products that have been studied for their safety and efficacy in ameliorating or preventing serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substances. This subpart applies only to those biological products for which: Definitive human efficacy studies cannot be conducted because it would be unethical to deliberately expose healthy human volunteers to a lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substance; and field trials to study the product's efficacy after an accidental or hostile exposure have not been feasible. This subpart does not apply to products that can be approved based on efficacy standards described elsewhere in FDA's regulations (e.g., accelerated approval based on surrogate markers or clinical endpoints other than survival or irreversible morbidity), nor does it address the safety evaluation for the products to which it does apply.
(a) FDA may grant marketing approval for a biological product for which safety has been established and for which the requirements of § 601.90 are met based on adequate and well-controlled animal studies when the results of those animal studies establish that the biological product is reasonably likely to produce clinical benefit in humans. In assessing the sufficiency of animal data, the agency may take into account other data, including human data, available to the agency. FDA will rely on the evidence from studies in animals to provide substantial evidence of the effectiveness of these products only when:
(1) There is a reasonably well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the product;
(2) The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model for predicting the response in humans;
(3) The animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity; and
(4) The data or information on the kinetics and pharmacodynamics of the product or other relevant data or information, in animals and humans, allows selection of an effective dose in humans.
(b) Approval under this subpart will be subject to three requirements:
(1)
(2)
(i) Distribution restricted to certain facilities or health care practitioners with special training or experience;
(ii) Distribution conditioned on the performance of specified medical procedures, including medical followup; and
(iii) Distribution conditioned on specified recordkeeping requirements.
(3)
(a)
(1) A postmarketing clinical study fails to verify clinical benefit;
(2) The applicant fails to perform the postmarketing study with due diligence;
(3) Use after marketing demonstrates that postmarketing restrictions are inadequate to ensure safe use of the biological product;
(4) The applicant fails to adhere to the postmarketing restrictions applied at the time of approval under this subpart;
(5) The promotional materials are false or misleading; or
(6) Other evidence demonstrates that the biological product is not shown to be safe or effective under its conditions of use.
(b)
(c)
(2) If the applicant files a timely request for a hearing, the agency will publish a notice of hearing in the
(3) An applicant who requests a hearing under this section must, within 30
(d)
(e)
(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.
(2) The presiding officer, the advisory committee members, up to three representatives of the applicant, and up to three representatives of CBER 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.
(f)
Biological products approved under this subpart are subject to the postmarketing recordkeeping and safety reporting applicable to all approved biological products.
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.
If FDA determines after approval under this subpart that the requirements established in §§ 601.91(b)(2), 601.92, and 601.93 are no longer necessary for the safe and effective use of a biological product, FDA will so notify the applicant. Ordinarily, for biological products approved under § 601.91, these requirements will no longer apply when FDA determines that the postmarketing study verifies and describes the biological product's clinical benefit. For biological products approved under § 601.91, the restrictions would no longer apply when FDA determines that safe use of the biological product can be ensured 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 of this chapter.
21 U.S.C. 321, 331, 351, 352, 355, 360, 360j, 371, 374; 42 U.S.C. 216, 262, 263a, 264.
As used in this part:
(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h)
(i)
(j)
(k)
(1) The blood or blood components have left the control of the licensed manufacturer, unlicensed registered blood establishment, or transfusion service; or
(2) The licensed manufacturer has provided Source Plasma or any other blood component for use in the manufacture of a licensed biological product.
(l)
(a) [Reserved]
(b) The personnel responsible for the collection, processing, compatibility testing, storage or distribution of blood
(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.
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:
(a) Provide adequate space for the following when applicable:
(1) Private and accurate examinations of individuals to determine their suitability as blood donors.
(2) The withdrawal of blood from donors with minimal risk of contamination, or exposure to activities and equipment unrelated to blood collection.
(3) The storage of blood or blood components pending completion of tests.
(4) The quarantine storage of blood or blood components in a designated location pending repetition of those tests that initially gave questionable serological results.
(5) The storage of finished products prior to distribution.
(6) The quarantine storage, handling and disposition of products and reagents not suitable for use.
(7) The orderly collection, processing, compatibility testing, storage and distribution of blood and blood components to prevent contamination.
(8) The adequate and proper performance of all steps in plasmapheresis, plateletpheresis and leukapheresis procedures.
(9) The orderly conduction of all packaging, labeling and other finishing operations.
(b) Provide adequate lighting, ventilation and screening of open windows and doors.
(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.
(d) Provide for safe and sanitary disposal for the following:
(1) Trash and items used during the collection, processing and compatibility testing of blood and blood components.
(2) Blood and blood components not suitable for use or distribution.
(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 so as to assure compliance with the official requirements prescribed in this chapter for blood and blood products.
(b) Equipment that shall be observed, standardized and calibrated with at least the following frequency, include but are not limited to:
(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.
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.
(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.
(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.
(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:
(d) Supplies and reagents that do not bear an expiration date shall be stored in such a manner that the oldest is used first.
(e) Supplies and reagents shall be used in a manner consistent with instructions provided by the manufacturer.
(f) Items that are required to be sterile and come into contact with blood should be disposable whenever possible.
(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.
(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 transfusion and further manufacturing purposes. Such procedures shall be available to the personnel for use in the areas where the procedures are performed. The written standard operating procedures shall include, but are not limited to, descriptions of the following, when applicable:
(1) Criteria used to determine donor suitability, including acceptable medical history criteria.
(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.
(3) Solutions and methods used to prepare the site of phlebotomy to give maximum assurance of a sterile container of blood.
(4) Method of accurately relating the product(s) to the donor.
(5) Blood collection procedure, including in-process precautions taken to measure accurately the quantity of blood removed from the donor.
(6) Methods of component preparation, including any time restrictions for specific steps in processing.
(7) All tests and repeat tests performed on blood and blood components during manufacturing.
(8) Pretransfusion testing, where applicable, including precautions to be taken to identify accurately the recipient blood samples and crossmatched donor units.
(9) Procedures for investigating adverse donor and recipient reactions.
(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.
(11) Length of expiration dates, if any, assigned for all final products as prescribed in § 610.53 of this chapter.
(12) Criteria for determining whether returned blood is suitable for reissue.
(13) Procedures used for relating a unit of blood or blood component from the donor to its final disposition.
(14) Quality control procedures for supplies and reagents employed in blood collection, processing and pretransfusion testing.
(15) Schedules and procedures for equipment maintenance and calibration.
(16) Labeling procedures, including safeguards to avoid labeling mixups.
(17) Procedures of plasmapheresis, plateletpheresis, and leukapheresis, if performed, including precautions to be taken to ensure reinfusion of a donor's own cells.
(18) Procedures for preparing recovered plasma, if performed, including details of separation, pooling, labeling, storage, and distribution.
(19) Procedures under §§ 610.46, 610.47, and 610.48 of this chapter:
(i) To identify previously donated blood and blood components from a donor who later tests reactive for evidence of human immunodeficiency virus (HIV) infection or hepatitis C virus (HCV) infection when tested under § 610.40 of this chapter, or when a blood establishment is made aware of other reliable test results or information indicating evidence of HIV or HCV infection;
(ii) To quarantine in-date blood and blood components previously donated by such a donor that are intended for use in another person or further manufacture into injectable products, except pooled components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures;
(iii) To notify consignees to quarantine in-date blood and blood components previously donated by such a donor intended for use in another person or for further manufacture into injectable products, except pooled components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures;
(iv) To determine the suitability for release, destruction, or relabeling of quarantined in-date blood and blood components;
(v) To notify consignees of the results of the HIV or HCV testing performed on the donors of such blood and blood components;
(vi) To notify the transfusion recipient, the recipient's physician of record, or the recipient's legal representative that the recipient received blood or blood components at increased risk of transmitting HIV or HCV, respectively.
(20) Procedures for donor deferral as prescribed in § 610.41 of this chapter; and procedures for donor notification and autologous donor referring physician notification, including procedures for the appropriate followup if the initial attempt at notification fails, as prescribed in § 630.6 of this chapter.
(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.
(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 organizations, as long as such specific procedures are consistent with, and at least as stringent as, the requirements contained in this part.
(1) American Association of Blood Banks.
(2) American National Red Cross.
(3) Other organizations or individual blood banks, subject to approval by the Director, Center for Biologics Evaluation and Research.
(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.
(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.
(a) Labeling operations shall be separated physically or spatially from other operations in a manner adequate to prevent mixups.
(b) The labeling operation shall include the following labeling controls:
(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.
(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.
(3) All necessary checks in labeling procedures shall be utilized to prevent errors in translating test results to container labels.
(c) All labeling shall be clear and legible.
(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.
(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.
(c) The container label shall include the following information, as well as other specialized information as required in this section for specific products:
(1) The proper name of the product in a prominent position, and modifier(s), if appropriate.
(2) The name, address, registration number, and, if a licensed product, the license number of each manufacturer.
(3) The donor, pool, or lot number relating the unit to the donor.
(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.
(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.
(i) A paid donor is a person who receives monetary payment for a blood donation.
(ii) A volunteer donor is a person who does not receive monetary payment for a blood donation.
(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.
(6) For Whole Blood, Plasma, Platelets, and partial units of Red Blood Cells, the volume of the product, accurate to within ±10 percent; or optionally for Platelets, the volume range within reasonable limits.
(7) The recommended storage temperature (in degrees Celsius).
(8) If the product is intended for transfusion, the statements:
(i) “Rx only.”
(ii) “See circular of information for indications, contraindications, cautions, and methods of infusion.”
(iii) “Properly identify intended recipient.”
(9) The statement: “This product may transmit infectious agents.”
(10) Where applicable, the name and volume of source material.
(11) The statement: “Caution: For Manufacturing Use Only”, when applicable.
(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:
(i) If the test using Anti-D Blood Grouping Reagent is positive, the product shall be labeled: “Rh positive.”
(ii) If the test using Anti-D Blood Grouping Reagent is negative but the test for D
(iii) If the test using Anti-D Blood Grouping Reagent is negative and the test for D
(13) The container label must bear encoded information in a format that is machine-readable and approved for use by the Director, Center for Biologics Evaluation and Research.
(i)
(ii)
(iii)
(A) A unique facility identifier;
(B) Lot number relating to the donor;
(C) Product code; and
(D) ABO and Rh of the donor.
(iv)
(A) Be unique to the blood or blood component;
(B) Be surrounded by sufficient blank space so that the machine-readable information can be scanned correctly; and
(C) Remain intact under normal conditions of use.
(v)
(d) Except for recovered plasma intended for manufacturing use or as otherwise approved by the Director, Center for Biologics Evaluation and Research, the paper of the container label shall be white and print shall be solid black, with the following additional exceptions:
(1) The Rh blood group shall be printed as follows:
(i) Rh positive: Use black print on white background.
(ii) Rh negative: Use white print on black background.
(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 or in solid black.
(3) The following color scheme may be used optionally for differentiating ABO Blood groups:
(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.
(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.
(e) Container label requirements for particular products or groups of products.
(1) Whole Blood labels shall include:
(i) The volume of anticoagulant.
(ii) The name of the applicable anticoagulant immediately preceding and of no less prominence than the proper name approved for use by the Director, Center for Biologics Evaluation and Research.
(iii) If tests for unexpected antibodies are positive, blood intended for transfusion shall be labeled: “Contains (
(2) Except for frozen, deglycerolized, or washed Red Blood Cell products, red blood cell labels shall include:
(i) The volume and kind of Whole Blood, including the type of anticoagulant, from which the product was prepared.
(ii) If tests for unexpected antibodies are positive and the product is intended for transfusion, the statement: “Contains (
(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.
(4) If tests for unexpected antibodies are positive, Plasma intended for
(5) Recovered plasma labels shall include:
(i) In lieu of an expiration date, the date of collection of the oldest material in the container.
(ii) The statement as applicable: “Caution: For Manufacturing Use Only”; or “Caution: For Use in Manufacturing Noninjectable Products Only.” If the recovered plasma has a reactive screening test for evidence of infection due to a communicable disease agent(s) under § 610.40 of this chapter, or is collected from a donor with a previous record of a reactive screening test for evidence of infection due to a communicable disease agent(s) under § 610.40 of this chapter, the recovered plasma must be labeled as required under § 610.40(h)(2)(ii)(E) of this chapter.
(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.”
(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.
(g) [Reserved]
(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:
(1) The statement: “FOR EMERGENCY USE ONLY BY ____.”
(2) Results of any tests prescribed under §§ 610.40, and 640.5 (a), (b), or (c) of this chapter completed before shipment.
(3) Indication of any tests prescribed under §§ 610.40, and 640.5 (a), (b), or (c) of this chapter and not completed before shipment.
(i) The following additional information shall appear on the label for Whole Blood or Red Blood Cells intended for autologous infusion:
(1) Information adequately identifying the patient, e.g., name, blood group, hospital, and identification number.
(2) Date of donation.
(3) The statement: “FOR AUTOLOGOUS USE ONLY.”
(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.”
(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.
(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.
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:
(a) Instructions to mix the product before use.
(b) Instructions to use a filter in the administration equipment.
(c) The statement “Do Not Add Medications” or an explanation concerning allowable additives.
(d) A description of the product, its source, and preparation, including the
(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).
(f) The statements: “Warning. The risk of transmitting infectious agents is present. Careful donor selection and available laboratory tests do not eliminate the hazard.”
(g) The names of cryoprotective agents and other additives that may still be present in the product.
(h) The names and results of all tests performed when necessary for safe and effective use.
(i) The use of the product, indications, contradications, side effects and hazards, dosage and administration recommendations.
(j) [Reserved]
(k) For Red Blood Cells, the instruction circular shall contain:
(1) Instructions to administer a suitable plasma volume expander if Red Blood Cells are substituted when Whole Blood is the indicated product.
(2) A warning not to add Lactated Ringer's Injection U.S.P. solution to Red Blood Cell products.
(l) For Platelets, the instruction circular shall contain:
(1) The approximate volume of plasma from which a sample unit of Platelets is prepared.
(2) Instructions to begin administration as soon as possible, but not more than 4 hours after entering the container.
(m) For Plasma, the instruction circular shall contain:
(1) A warning against further processing of the frozen product if there is evidence of breakage or thawing.
(2) Instructions to thaw the frozen product at a temperature between 30 and 37 °C.
(3) When applicable, instructions to begin administration of the product within 6 hours after thawing.
(4) Instructions to administer to ABO-group-compatible recipients.
(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.
(n) For Cryoprecipitated AHF, the instruction circular shall contain:
(1) A statement that the average potency is 80 or more International Units of antihemophilic factor.
(2) The statement: “Usually contains at least 150 milligrams of fibrinogen”; or, alternatively, the average fibrinogen level determined by assay of representative units.
(3) A warning against further processing of the product if there is evidence of breakage or thawing.
(4) Instructions to thaw the product for no more than 15 minutes at a temperature of between 30 and 37 °C.
(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.
(6) A statement that 0.9 percent Sodium Chloride Injection U.S.P. is the preferred diluent.
(7) Adequate instructions for pooling to ensure complete removal of all concentrated material from each container.
(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.”
Laboratory control procedures shall include:
(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.
(b) Adequate provisions for monitoring the reliability, accuracy, precision and performance of laboratory test procedures and instruments.
(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.
Standard operating procedures for compatibility testing shall include the following:
(a) A method of collecting and identifying the blood samples of recipients to ensure positive identification.
(b) The use of fresh recipient serum or plasma samples less than 3 days old for all pretransfusion testing if the recipient has been pregnant or transfused within the previous 3 months.
(c) Procedures to demonstrate incompatibility between the donor's cell type and the recipient's serum or plasma type.
(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.
(e) Procedures to expedite transfusion in life-threatening emergencies. Records of all such incidents shall be maintained, including complete documentation justifying the emergency action, which shall be signed by a physician.
(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.
(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.
(b) Records shall be maintained that include, but are not limited to, the following when applicable:
(1) Donor records:
(i) Donor selection, including medical interview and examination and where applicable, informed consent.
(ii) Permanent and temporary deferrals for health reasons including reason(s) for deferral.
(iii) Donor adverse reaction complaints and reports, including results of all investigations and followup.
(iv) Therapeutic bleedings, including signed requests from attending physicians, the donor's disease and disposition of units.
(v) Immunization, including informed consent, identification of the antigen, dosage and route of administration.
(vi) Blood collection, including identification of the phlebotomist.
(vii) Records to relate the donor with the unit number of each previous donation from that donor.
(viii) Records concerning the following activities performed under §§ 610.46, 610.47, and 610.48 of this chapter: Quarantine; consignee notification; testing; notification of a transfusion recipient, the recipient's physician of record, or the recipient's legal representative; and disposition.
(ix) Records of notification of donors deferred or determined not to be suitable for donation, including appropriate followup if the initial attempt at notification fails, performed under § 630.6 of this chapter.
(x) The donor's address provided at the time of donation where the donor may be contacted within 8 weeks after donation.
(xi) Records of notification of the referring physician of a deferred
(2) Processing records:
(i) Blood processing, including results and interpretation of all tests and retests.
(ii) Component preparation, including all relevant dates and times.
(iii) Separation and pooling of recovered plasma.
(iv) Centrifugation and pooling of source plasma.
(v) Labeling, including initials of the person(s) performing the procedure.
(3) Storage and distribution records:
(i) Distribution and disposition, as appropriate, of blood and blood products.
(ii) Visual inspection of whole blood and red blood cells during storage and immediately before distribution.
(iii) Storage temperature, including initialed temperature recorder charts.
(iv) Reissue, including records of proper temperature maintenance.
(v) Emergency release of blood, including signature of requesting physician obtained before or after release.
(4) Compatibility test records:
(i) Results of all compatibility tests, including crossmatching, testing of patient samples, antibody screening and identification.
(ii) Results of confirmatory testing.
(5) Quality control records:
(i) Calibration and standardization of equipment.
(ii) Performance checks of equipment and reagents.
(iii) Periodic check on sterile technique.
(iv) Periodic tests of capacity of shipping containers to maintain proper temperature in transit.
(v) Proficiency test results.
(6) Transfusion reaction reports and complaints, including records of investigations and followup.
(7) General records:
(i) Sterilization of supplies and reagents prepared within the facility, including date, time interval, temperature and mode.
(ii) Responsible personnel.
(iii) Biological product deviations.
(iv) Maintenance records for equipment and general physical plant.
(v) Supplies and reagents, including name of manufacturer or supplier, lot numbers, expiration date and date of receipt.
(vi) Disposition of rejected supplies and reagents used in the collection, processing and compatibility testing of blood and blood components.
(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.
(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. You must retain individual product records no less than 10 years after the records of processing are completed or 6 months after the latest expiration date for the individual product, whichever is the later date. When there is no expiration date, records shall be retained indefinitely.
(e) A record shall be available from which unsuitable donors may be identified so that products from such individuals will not be distributed.
(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.
(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.
(c) Receipt records shall contain the name and address of the collecting facility, date received, donor or lot number assigned by the collecting facility
(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.
(b) When a complication of blood collection or transfusion is confirmed to be fatal, the Director, Office of Compliance and Biologics Quality, Center for Biologics Evaluation and Research, shall be notified by telephone, facsimile, express mail, or electronically transmitted mail as soon as possible; a written report of the investigation shall be submitted to the Director, Office of Compliance and Biologics Quality, 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.
(a)
(b)
(1) Either:
(i) Represents a deviation from current good manufacturing practice, applicable regulations, applicable standards, or established specifications that may affect the safety, purity, or potency of that product; or
(ii) Represents an unexpected or unforeseeable event that may affect the safety, purity, or potency of that product; and
(2) Occurs in your facility or another facility under contract with you; and
(3) Involves distributed blood or blood components.
(c)
(d)
(e)
(1) If you make a paper filing, you should identify on the envelope that a BPDR (biological product deviation report) is enclosed; or
(2) If you make an electronic filing, you may submit the completed Form
(f)
21 U.S.C. 321, 331, 351, 352, 355, 360, 371, 374, 381, 393; 42 U.S.C. 262, 264, 271.
(a) The term
(b)
(c)
(d)
(e)
(f)
(g)
(h)
(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.
(j)
(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.
(b) Forms for registration of an establishment are obtainable on request from the Center for Biologics Evaluation and Research (HFM-375) (see mailing addresses in § 600.2 of this chapter), or at any of the Food and Drug Administration district offices.
(c) The completed form should be mailed to the Center for Biologics Evaluation and Research (HFM-375) (see mailing addresses in § 600.2 of this chapter).
(a) Owners or operators of all establishments, not exempt under section 510(g) of the act or subpart D of this part, that engage in the manufacture of blood products shall register and submit a list of every blood product in commercial distribution (except that registration and 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). Blood products manufactured, prepared, propagated, compounded, or processed in any State as defined in section 201(a)(1) of the act must be listed whether or not the output of such blood product establishment or any particular blood product so listed enters interstate commerce.
(b) Preparatory to engaging in the manufacture of blood products, owners or operators of establishments who are submitting a biologics license application to manufacture blood products are required to register before the biologics license application is approved.
(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.
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) of this chapter) for which a license is required, registration shall follow within 5 days after the submission of a biologics 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.
(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 Evaluation and Research (HFM-375), (see mailing addresses in § 600.2 of this chapter), 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 under § 607.35. The completed form shall be mailed to the preceding address before December 31 of that year.
(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.
(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 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).
(b) Form FD-2830 also requires furnishing blood product listing information required by the act as follows:
(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).
(2) For each blood product so listed which is subject to section 351 of the Public Health Service Act, the license
(3) For each blood product listed, the registration number of the parent establishment. An establishment not owned, operated, or controlled by another firm or establishment is its own parent establishment.
Changes in individual ownership, corporate or partnership structure, location, or blood-product handling activity shall be submitted on Form FDA-2830 (Blood Establishment Registration and Product Listing) as an 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.
(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:
(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.
(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.
(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.
(4) Any material change in any information previously submitted.
(b) When no changes have occurred since the previously submitted list, no listing information is required.
(a) In addition to the information routinely required by §§ 607.25 and 607.30, the Director of the Center for Biologics Evaluation and Research may require submission of the following information by letter or by
(1) For a particular blood product so listed, upon request made by the Director of the Center for Biologics Evaluation and Research for good cause, a copy of all advertisements.
(2) For a particular blood product so listed, upon a finding by the Director of the Center for Biologics Evaluation and Research that it is necessary to carry out the purposes of the act, a quantitative listing of all ingredients.
(3) For each registrant, upon a finding by the Director of the Center for Biologics Evaluation and Research that it is necessary to carry out the purposes of the act, a list of each listed blood product containing a particular ingredient.
(b) [Reserved]
(a) The Director of the Center for Biologics Evaluation and Research will provide to the registrant a validated
(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.
(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.
(a) A copy of the Form FD-2830 (Blood Establishment Registration and Product Listing) filed by the registrant will be available for inspection under section 510(f) of the act, at the Department of Health and Human Services, Food and Drug Administration, Office of Communication, Training and Manufacturers' Assistance (HFM-40), Center for Biologics Evaluation and Research (see mailing addresses in § 600.2 of this chapter). In addition, for domestic firms, the same information will be available for inspection at each of the Food and Drug Administration district offices 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 registered establishment will be provided. The following information submitted under the blood product listing requirements is illustrative of the type of information that will be available for public disclosure when it is compiled:
(1) A list of all blood products.
(2) A list of all blood products manufactured by each establishment.
(3) A list of blood products discontinued.
(4) All data or information that has already become a matter of public knowledge.
(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 Communication, Training and Manufacturers' Assistance (HFM-40), Center for Biologics Evaluation and Research (see mailing addresses in § 600.2 of this chapter).
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.
(a) Every foreign establishment shall comply with the establishment registration and blood product listing requirements contained in subpart B of this part, unless exempt under subpart D of this part or unless the blood product enters a foreign trade zone and is re-exported from that foreign trade zone without having entered U. S. commerce.
(b) No blood product may be imported or offered for import into the United States unless it is the subject of a blood product listing as required under subpart B of this part and is manufactured, prepared, propagated, compounded, or processed at a registered foreign establishment; however, this restriction does not apply to a blood product imported or offered for import under the investigational use provisions of part 312 of this chapter or to a blood product imported under section 801(d)(4) of the act. The establishment registration and blood product listing information shall be in the English language.
(c) Each foreign establishment required to register under paragraph (a) of this section shall, as part of the establishment registration and blood product listing, submit the name and address of the establishment and the name of the individual responsible for submitting establishment registration and blood product listing information. Any changes in this information shall be reported to the Food and Drug Administration at the intervals specified for updating establishment registration information in § 607.26 and blood product listing information in § 607.30(a).
(d) Each foreign establishment required to register under paragraph (a) of this section shall submit the name, address, and phone number of its United States agent as part of its initial and updated registration information in accordance with subpart B of this part. Each foreign establishment shall designate only one United States agent.
(1) The United States agent shall reside or maintain a place of business in the United States.
(2) Upon request from FDA, the United States agent shall assist FDA in communications with the foreign establishment, respond to questions concerning the foreign establishment's products that are imported or offered for import into the United States, and assist FDA in scheduling inspections of the foreign establishment. If the agency is unable to contact the foreign establishment directly or expeditiously, FDA may provide information or documents to the United States agent, and such an action shall be considered to be equivalent to providing the same information or documents to the foreign establishment.
(3) The foreign establishment or the United States agent shall report changes in the United States agent's name, address, or phone number to FDA within 10-business days of the change.
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), (g)(2), and (g)(3) of the act, or because the Commissioner of Food and Drugs has found, under section 510(g)(5), that such registration is not necessary for the protection of the public health. The exemptions in paragraphs (a), (b), (f), and (g) of this section are limited to those classes of persons located in any State as defined in section 201(a)(1) of the act.
(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.
(b) Practitioners who are licensed by law to prescribe or administer drugs and who manufacture blood products solely for use in the course of their professional practice.
(c) Persons who manufacture blood products which are not for sale, rather, are solely for use in research, teaching, or analysis, including laboratory samples.
(d) Carriers, by reason of their receipt, carriage, holding, or delivery of
(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.
(f) Transfusion services which are a part of a facility that is certified under the Clinical Laboratory Improvement Amendments of 1988 (42 U.S.C. 263a) and 42 CFR part 493 or has met equivalent requirements as determined by the Centers for Medicare and Medicaid Services and which are 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.
21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 360d, 360h, 360i, 371, 372, 374, 381; 42 U.S.C. 216, 262, 263, 263a, 264.
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.
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.
(a)
(b)
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:
(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
(b) Approval of the modification is received in writing from the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research.
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.
A general safety test for the detection of extraneous toxic contaminants
(a)
(b)
(c)
(1)
(2)
(3)
(d)
(1) They survive the test period.
(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.
(3) They weigh no less at the end of the test period than at the time of injection.
(e)
(2)
(f) [Reserved]
(g)
(2) For products other than those identified in paragraph (g)(1) of this section, a manufacturer may request from the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing addresses in § 600.2 of this chapter), an exemption from the general safety test. The manufacturer must submit information as part of a biologics license application submission or supplement to an approved biologics license application establishing that because of the mode of administration, the method of preparation, or the special nature of the product a test of general safety is unnecessary to assure the safety, purity, and potency of the product or cannot be performed. The request must include alternate procedures, if any, to be performed. The Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research, upon finding that the manufacturer's request justifies an exemption, may exempt the product from the general safety test subject to any condition necessary to assure the safety, purity, and potency of the product.
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.
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.
(a)
(1)
(ii)
(2)
(b)
(1)
(2)
(3)
(c)
(d)
(2)
(e)
(ii) The formula for Soybean-Casein Digest Medium is as follows:
(2)
(ii)
ATCC strains of microorganisms described in this section are available from the American Type Culture Collection, 10801 University Blvd., Manassas, VA 20110. 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
(iii)
(iv)
(v)
(
(vi)
(f)
(1) The test samples shall conform with paragraph (d) of this section; and
(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
(g)
(1)
(2)
(3) [Reserved]
(4)
(ii) Where a manufacturer submits data which the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug 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.
(5)
(6)
(7)
(8)
(9)
(h)
Products shall be free of extraneous material except that which is unavoidable in the manufacturing process described in the approved biologics license application. In addition, products shall be tested as provided in paragraphs (a) and (b) of this section.
(a)(1)
(2)
(b)
(1)
(2)
(3)
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 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.
(a)
(1) 0.85 milligrams if determined by assay;
(2) 1.14 milligrams if determined by calculation on the basis of the amount of aluminum compound added; or
(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 or the Director, Center for Drug Evaluation and Research (see mailing addresses in § 600.2 of this chapter).
(b)
(c)
Except as otherwise provided by regulation, no liquid serum or antitoxin shall contain more than 20 percent total solids.
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.
(a)
(b)
(c)
(i) Identified by history;
(ii) Described with respect to cytogenetic characteristics and tumorigenicity;
(iii) Characterized with respect to in vitro growth characteristics and life potential; and
(iv) Tested for the presence of detectable microbial agents.
(2)
(3)
(d)
Standard preparations made available by the Center for Biologics Evaluation and Research shall be applied in testing, as follows:
(a)
(b)
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.
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
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
(a)
(1) Human immunodeficiency virus, type 1;
(2) Human immunodeficiency virus, type 2;
(3) Hepatitis B virus;
(4) Hepatitis C virus;
(5) Human T-lymphotropic virus, type I; and
(6) Human T-lymphotropic virus, type II.
(b)
(c)
(ii) Each donation must be labeled as required under § 606.121 of this chapter and with a label entitled “INTENDED RECIPIENT INFORMATION LABEL” containing the name and identifying information of the recipient. Each donation must also have the following label, as appropriate:
(2)
(3)
(ii) Donations of human blood and blood components intended solely as a component of, or used to prepare, a medical device must be labeled “Caution: For Further Manufacturing Use as a Component of, or to Prepare, a Medical Device.”
(4)
(d)
(1) If you allow any autologous donation to be used for allogeneic transfusion, you must assure that all autologous donations are tested under this section.
(2) If you ship autologous donations to another establishment that allows autologous donations to be used for allogeneic transfusion, you must assure that all autologous donations shipped to that establishment are tested under this section.
(3) If you ship autologous donations to another establishment that does not allow autologous donations to be used for allogeneic transfusion, you must assure that, at a minimum, the first donation in each 30-day period is tested under this section.
(4) Each autologous donation must be labeled as required under § 606.121 of
(e)
(1) For autologous donations, you must further test under this paragraph, at a minimum, the first reactive donation in each 30-day period; or
(2) If you have a record for that donor of a positive result on a supplemental (additional, more specific) test approved for such use by FDA, you do not have to further test an autologous donation.
(f)
(g)
(1) Only in appropriately documented medical emergency situations; or
(2) For further manufacturing use as approved in writing by FDA.
(h)
(2)
(ii) You must not ship or use human blood or blood components that have a reactive screening test for evidence of infection due to a communicable disease agent(s) designated in paragraph (a) of this section or that are collected from a donor deferred under § 610.41(a) unless you meet the following conditions:
(A) Except for autologous donations, you must obtain from FDA written approval for the shipment or use;
(B) You must appropriately label such blood or blood components as required under § 606.121, or § 640.70 of this chapter, and with the “BIOHAZARD” legend;
(C) Except for autologous donations, you must label such human blood and blood components as reactive for the appropriate screening test for evidence of infection due to the identified communicable disease agent(s);
(D) If the blood or blood components are intended for further manufacturing
(E) Each blood or blood component with a reactive screening test and intended solely as a component of, or used to prepare a medical device, must be labeled with the following label, as appropriate:
(iii) The restrictions on shipment or use do not apply to samples of blood, blood components, plasma, or sera if used or distributed for clinical laboratory testing or research purposes, and not intended for administration in humans or in the manufacture of a product.
(iv) You may use human blood or blood components from a donor with a previous record of a reactive screening test(s) for evidence of infection due to a communicable disease agent(s) designated in paragraph (a) of this section, if:
(A) At the time of donation, the donor is shown or was previously shown to be suitable by a requalification method or process found acceptable for such purposes by FDA under § 610.41(b); and
(B) tests performed under paragraphs (a) and (b) of this section are nonreactive.
(v) Anti-HBc reactive donations, otherwise nonreactive when tested as required under this section, may be used for further manufacturing into plasma derivatives without prior FDA approval or a “BIOHAZARD” legend as required under paragraphs (h)(2)(ii)(A) and (h)(2)(ii)(B) of this section.
(vi) You may use human blood or blood components, excluding Source Plasma, that test reactive by a screening test for syphilis as required under paragraph (i) of this section if, consistent with § 640.5 of this chapter, the donation is further tested by an adequate and appropriate test which demonstrates that the reactive screening test is a biological false positive. You must label the blood or blood components with both test results.
(vii) You may use Source Plasma from a donor who tests reactive by a screening test for syphilis as required under § 610.40(i) of this chapter, if the donor meets the requirements of § 640.65(b)(2) of this chapter.
(i)
(a) You, an establishment that collects human blood or blood components, must defer donors testing reactive by a screening test for evidence of infection due to a communicable disease agent(s) listed in § 610.40(a) or reactive for a serological test for syphilis under § 610.40(i), from future donations of human blood and blood components, except:
(1) You are not required to defer a donor who tests reactive for anti-HBc or anti-HTLV, types I or II, on only one occasion. When a supplemental (additional, more specific) test for anti-HBc or anti-HTLV, types I and II, has been approved for use under § 610.40(e) by FDA, such a donor must be deferred;
(2) A deferred donor who tests reactive for evidence of infection due to a communicable disease agent(s) listed in § 610.40(a) may serve as a donor for blood or blood components shipped or used under § 610.40(h)(2)(ii);
(3) A deferred donor who showed evidence of infection due to hepatitis B surface antigen (HBsAg) when previously tested under § 610.40(a), (b), and (e) subsequently may donate Source Plasma for use in the preparation of Hepatitis B Immune Globulin (Human) provided the current donation tests nonreactive for HBsAg and the donor is otherwise determined to be suitable;
(4) A deferred donor, who otherwise is determined to be suitable for donation and tests reactive for anti-HBc or for evidence of infection due to HTLV, types I and II, may serve as a donor of Source Plasma;
(5) A deferred donor who tests reactive for a communicable disease agent(s) described under § 610.40(a) or reactive with a serological test for syphilis under § 610.40(i), may serve as an autologous donor under § 610.40(d).
(b) A deferred donor subsequently may be found to be suitable as a donor of blood or blood components by a requalification method or process found acceptable for such purposes by FDA. Such a donor is considered no longer deferred.
(c) You must comply with the requirements under §§ 610.46 and 610.47 when a donor tests reactive by a screening test for HIV or HCV required under § 610.40(a) and (b), or when you are aware of other reliable test results or information indicating evidence of HIV or HCV infection.
(a) In addition to labeling requirements in subchapter H of this chapter, when a medical device contains human blood or a blood component as a component of the final device, and the human blood or blood component was found to be reactive by a screening test performed under § 610.40(a) and (b) or reactive for syphilis under § 610.40(i), then you must include in the device labeling a statement of warning indicating that the product was manufactured from a donation found to be reactive by a screening test for evidence of infection due to the identified communicable disease agent(s).
(b) FDA may approve an exception or alternative to the statement of warning required in paragraph (a) of this section based on evidence that the reactivity of the human blood or blood component in the medical device presents no significant health risk through use of the medical device.
(a) When available and appropriate to verify acceptable sensitivity and specificity, you, a manufacturer of test kits, must use a reference panel you obtain from FDA or from an FDA designated source to test lots of the following products. You must test each lot of the following products, unless FDA informs you that less frequent testing is appropriate, based on your consistent prior production of products of acceptable sensitivity and specificity:
(1) A test kit approved for use in testing donations of human blood and blood components for evidence of infection due to communicable disease agents listed in § 610.40(a); and
(2) Human immunodeficiency virus (HIV) test kit approved for use in the diagnosis, prognosis, or monitoring of this communicable disease agent.
(b) You must not distribute a lot that is found to be not acceptable for sensitivity and specificity under § 610.44(a). FDA may approve an exception or alternative to this requirement. Applicants must submit such requests in writing. However, in limited circumstances, such requests may be made orally and permission may be given orally by FDA. Oral requests and approvals must be promptly followed by written requests and written approvals.
(a) If you are an establishment that collects Whole Blood or blood components, including Source Plasma and Source Leukocytes, you must establish, maintain, and follow an appropriate system for the following actions:
(1) Within 3 calendar days after a donor tests reactive for evidence of human immunodeficiency virus (HIV) infection when tested under § 610.40(a) and (b) or when you are made aware of other reliable test results or information indicating evidence of HIV infection, you must review all records required under § 606.160(d) of this chapter, to identify blood and blood components previously donated by such a donor. For those identified blood and blood components collected:
(i) Twelve months and less before the donor's most recent nonreactive screening tests, or
(ii) Twelve months and less before the donor's reactive direct viral detection test, e.g., nucleic acid test or HIV p24 antigen test, and nonreactive antibody screening test, whichever is the lesser period, you must:
(A) Quarantine all previously collected in-date blood and blood components identified under paragraph (a)(1) of this section if intended for use in another person or for further manufacture into injectable products, except pooled blood components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures; and
(B) Notify consignees to quarantine all previously collected in-date blood and blood components identified under paragraph (a)(1) of this section if intended for use in another person or for further manufacture into injectable products, except pooled blood components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures;
(2) You must perform a supplemental (additional, more specific) test for HIV as required under § 610.40(e) of this chapter on the reactive donation.
(3) You must notify consignees of the supplemental (additional, more specific) test results for HIV, or the results of the reactive screening test if there is no available supplemental test that is approved for such use by FDA, or if under an investigational new drug application (IND) or investigational device exemption (IDE), is exempted for such use by FDA, within 45 calendar days after the donor tests reactive for evidence of HIV infection under § 610.40(a) and (b) of this chapter. Notification of consignees must include the test results for blood and blood components identified under paragraph (a)(1) of this section that were previously collected from donors who later test reactive for evidence of HIV infection.
(4) You must release from quarantine, destroy, or relabel quarantined in-date blood and blood components, consistent with the results of the supplemental (additional, more specific) test performed under paragraph (a)(2) of this section or the results of the reactive screening test if there is no available supplemental test that is approved for such use by FDA, or if under an IND or IDE, exempted for such use by FDA.
(b) If you are a consignee of Whole Blood or blood components, including Source Plasma and Source Leukocytes, you must establish, maintain, and follow an appropriate system for the following actions:
(1) You must quarantine all previously collected in-date blood and blood components identified under paragraph (a)(1) of this section, except pooled blood components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures, when notified by the collecting establishment.
(2) You must release from quarantine, destroy, or relabel quarantined in-date blood and blood components consistent with the results of the supplemental (additional, more specific) test performed under paragraph (a)(2) of this section, or the results of the reactive screening test if there is no available supplemental test that is approved for such use by FDA, or if under an IND or IDE, is exempted for such use by FDA.
(3) When the supplemental (additional, more specific) test for HIV is positive or when the screening test is reactive and there is no available supplemental test that is approved for such use by FDA, or if under an IND or IDE is exempted for such use by FDA, you must notify transfusion recipients of previous collections of blood and blood components at increased risk of transmitting HIV infection, or the recipient's physician of record, of the need for recipient HIV testing and counseling. You must notify the recipient's physician of record or a legal representative or relative if the recipient is a minor, deceased, adjudged incompetent by a State court, or, if the recipient is competent but State law permits a legal representative or relative to receive information on behalf of the recipient. You must make reasonable attempts to perform the notification within 12 weeks after receiving the supplemental (additional, more specific) test results for evidence of HIV infection from the collecting establishment, or after receiving the donor's reactive
(c) Actions under this section do not constitute a recall as defined in § 7.3 of this chapter.
(a) If you are an establishment that collects Whole Blood or blood components, including Source Plasma and Source Leukocytes, you must establish, maintain, and follow an appropriate system for the following actions:
(1) Within 3 calendar days after a donor tests reactive for evidence of hepatitis C virus (HCV) infection when tested under § 610.40(a) and (b) of this chapter or when you are made aware of other reliable test results or information indicating evidence of HCV infection, you must review all records required under § 606.160(d) of this chapter, to identify blood and blood components previously donated by such a donor. For those identified blood and blood components collected:
(i) Twelve months and less before the donor's most recent nonreactive screening tests, or
(ii) Twelve months and less before the donor's reactive direct viral detection test, e.g., nucleic acid test and nonreactive antibody screening test, whichever is the lesser period, you must:
(A) Quarantine all previously collected in-date blood and blood components identified under paragraph (a)(1) of this section if intended for use in another person or for further manufacture into injectable products, except pooled blood components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures; and
(B) Notify consignees to quarantine all previously collected in-date blood and blood components identified under paragraph (a)(1) of this section if intended for use in another person or for further manufacture into injectable products, except pooled blood components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures;
(2) You must perform a supplemental (additional, more specific) test for HCV as required under § 610.40(e) on the reactive donation.
(3) You must notify consignees of the supplemental (additional, more specific) test results for HCV, or the results of the reactive screening test if there is no available supplemental test that is approved for such use by FDA, or if under an investigational new drug application (IND) or investigational device exemption (IDE), is exempted for such use by FDA, within 45 calendar days after the donor tests reactive for evidence of HCV infection under § 610.40(a) and (b). Notification of consignees must include the test results for blood and blood components identified under paragraph (a)(1) of this section that were previously collected from donors who later test reactive for evidence of HCV infection.
(4) You must release from quarantine, destroy, or relabel quarantined in-date blood and blood components consistent with the results of the supplemental (additional, more specific) test performed under paragraph (a)(2) of this section, or the results of the reactive screening test if there is no available supplemental test that is approved for such use by FDA, or if under an IND or IDE, exempted for such use by FDA.
(b) If you are a consignee of Whole Blood or blood components, including Source Plasma or Source Leukocytes, you must establish, maintain, and follow an appropriate system for the following actions:
(1) You must quarantine all previously collected in-date blood and blood components identified under paragraph (a)(1) of this section, except pooled blood components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures, when notified by the collecting establishment.
(2) You must release from quarantine, destroy, or relabel quarantined in-date blood and blood components, consistent with the results of the supplemental (additional, more specific) test performed under paragraph (a)(2)
(3) When the supplemental (additional, more specific) test for HCV is positive or when the screening test is reactive and there is no available supplemental test that is approved for such use by FDA, or if under an IND or IDE, is exempted for such use by FDA, you must notify transfusion recipients of previous collections of blood and blood components at increased risk of transmitting HCV infection, or the recipient's physician of record, of the need for recipient HCV testing and counseling. You must notify the recipient's physician of record or a legal representative or relative if the recipient is a minor, adjudged incompetent by a State court, or if the recipient is competent but State law permits a legal representative or relative to receive information on behalf of the recipient. You must make reasonable attempts to perform the notification within 12 weeks after receiving the supplemental (additional, more specific) test results for evidence of HCV infection from the collecting establishment, or after receiving the donor's reactive screening test result for HCV if there is no available supplemental test that is approved for such use by FDA, or if under an IND or IDE, is exempted for such use by FDA.
(c) Actions under this section do not constitute a recall as defined in § 7.3 of this chapter.
(a) Establishments that collect Whole Blood or blood components, including Source Plasma and Source Leukocytes, must complete the following actions by February 19, 2009.
(b) If you are an establishment that collects Whole Blood or blood components, including Source Plasma and Source Leukocytes, you must establish, maintain, and follow an appropriate system for the following actions:
(1) You must:
(i) Review all records of donor testing for hepatitis C virus (HCV) performed before February 20, 2008. The review must include records dating back indefinitely for computerized electronic records, and to January 1, 1988, for all other records. Record review, quarantine, testing, notification, and disposition performed before February 20, 2008 that otherwise satisfy the requirements under § 610.47, are exempt from this section.
(ii) Identify donors who tested reactive for evidence of HCV infection. Donors who tested reactive by a screening test and negative by an appropriate supplemental (additional, more specific) test under § 610.40(e) for evidence of HCV infection on the same donation are not subject to further action.
(iii) Identify the blood and blood components previously collected from such donors:
(A) Twelve months and less before the donor's most recent nonreactive screening tests, or
(B) Twelve months and less before the donor's reactive direct viral detection test, e.g., nucleic acid test and nonreactive antibody screening test, whichever is the lesser period.
(2) If you did not perform a supplemental (additional, more specific) test at the time of the reactive donation, you may perform a supplemental test or a licensed screening test with known greater sensitivity than the test of record using either a frozen sample from the same reactive donation or a fresh sample from the same donor, if obtainable. If neither is available, proceed with paragraphs (b)(3), (b)(4), and (b)(5) of this section.
(3) You must, within 3 calendar days after identifying the blood and blood components previously collected from donors who tested reactive for evidence of HCV infection:
(i) Quarantine all previously collected in-date blood and blood components identified under paragraph (b)(1)(iii) of this section if intended for use in another person or for further manufacture into injectable products, except pooled components solely intended for further manufacturing into products that are manufactured using validated viral clearance procedures.
(ii) Notify consignees to quarantine all previously collected in-date blood and blood components identified under paragraph (b)(1)(iii) of this section if intended for use in another person or for further manufacture into injectable products, except pooled blood components intended solely for further manufacturing into products that are manufactured using validated viral clearance procedures; and
(iii) Notify consignees of the donor's test results, including the results of a supplemental (additional, more specific) test or a licensed screening test with known greater sensitivity than the test of record, if available at that time.
(4) You must notify consignees of the results of the supplemental (additional, more specific) test or the licensed screening test with known greater sensitivity than the test of record for HCV, if performed, within 45 calendar days of completing the further testing. Notification of consignees must include the test results for blood and blood components identified under paragraph (b)(1)(iii) of this section that were previously collected from a donor who later tests reactive for evidence of HCV infection.
(5) You must release from quarantine, destroy, or relabel quarantined in-date blood and blood components consistent with the results of the further testing performed under paragraph (b)(2) of this section or the results of the reactive screening test if there is no available supplemental test that is approved for such use by FDA, or if under an investigational new drug application (IND) or investigational device exemption (IDE), is exempted for such use by FDA.
(c) If you are a consignee of Whole Blood or blood components, including Source Plasma and Source Leukocytes, you must establish, maintain, and follow an appropriate system for the following actions, which you must complete within 1 year of the date of notification by the collecting establishment:
(1) You must quarantine all previously collected in-date blood and blood components identified under paragraph (b)(1)(iii) of this section, except pooled blood components solely intended for further manufacturing into products that are manufactured using validated viral clearance procedures, when notified by the collecting establishment.
(2) You must release from quarantine, destroy, or relabel quarantined in-date blood and blood components, consistent with the results of the further testing performed under paragraph (b)(2) of this section, or the results of the reactive screening test if there is no available supplemental test that is approved for such use by FDA, or if under an IND or IDE is exempted for such use by FDA.
(3) When the supplemental (additional, more specific) test for HCV is positive; or the supplemental test is indeterminate, but the supplemental test is known to be less sensitive than the screening test; or the screening test is reactive and there is no available supplemental test that is approved for such use by FDA, or if under an IND or IDE, is exempted for such use by FDA; or if supplemental testing is not performed, you must make reasonable attempts to notify transfusion recipients of previous collections of blood and blood components at increased risk of transmitting HCV infection, or the recipient's physician of record, of the need for recipient HCV testing and counseling. You must notify the recipient's physician of record or a legal representative or relative if the recipient is a minor, adjudged incompetent by a State court, or if the recipient is competent but State law permits a legal representative or relative to receive information on behalf of the recipient.
(d) Actions under this section do not constitute a recall as defined in § 7.3 of this chapter.
(e) This section will expire on August 24, 2015.
The date of manufacture shall be determined as follows:
(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
(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.
(a)
(b)
(c)
(d)
(a)
(1) The proper name of the product;
(2) The name, address, and license number of manufacturer;
(3) The lot number or other lot identification;
(4) The expiration date;
(5) The recommended individual dose, for multiple dose containers.
(6) The statement: “ ‘Rx only’ ” for prescription biologicals.
(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 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.
(b)
(c)
(d)
(e)
The following items shall appear on the label affixed to each package containing a product:
(a) The proper name of the product;
(b) The name, address, and license number of manufacturer;
(c) The lot number or other lot identification;
(d) The expiration date;
(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”;
(f) The number of containers, if more than one;
(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;
(h) The recommended storage temperature;
(i) The words “Shake Well”, “Do not Freeze” or the equivalent, as well as other instructions, when indicated by the character of the product;
(j) The recommended individual dose if the enclosed container(s) is a multiple-dose container;
(k) The route of administration recommended, or reference to such directions in an enclosed circular;
(l) Known sensitizing substances, or reference to an enclosed circular containing appropriate information;
(m) The type and calculated amount of antibiotics added during manufacture;
(n) The inactive ingredients when a safety factor, or reference to an enclosed circular containing appropriate information;
(o) The adjuvant, if present;
(p) The source of the product when a factor in safe administration;
(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;
(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.”
(s) The statement: “ ‘Rx only’ ” for prescription biologicals.
(a)
(b)
(c)
If two or more licensed manufacturers participate in the manufacture of a biological product, the name, address,
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 _____”, “Distributed by ______”, “Manufactured by _____ for _____”, “Manufactured for _____ by ____”, “Distributor: _____”, or “Marketed by _____”. The qualifying phrases may be abbreviated.
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.
Biological products must comply with the bar code requirements at § 201.25 of this chapter. However, the bar code requirements do not apply to devices regulated by the Center for Biologics Evaluation and Research or to blood and blood components intended for transfusion. For blood and blood components intended for transfusion, the requirements at § 606.121(c)(13) of this chapter apply instead.
(a) The appropriate FDA Center Director may grant an exception or alternative to any provision listed in paragraph (f) of this section and not explicitly required by statute, for specified lots, batches, or other units of a biological product, if the Center Director determines that compliance with such labeling requirement could adversely affect the safety, effectiveness, or availability of such product that is or will be included in the Strategic National Stockpile.
(b)(1)(i) A Strategic National Stockpile official or any entity that manufactures (including labeling, packing, relabeling, or repackaging), distributes, or stores a biological product that is or will be included in the Strategic National Stockpile may submit, with written concurrence from a Strategic National Stockpile official, a written request for an exception or alternative described in paragraph (a) of this section to the Center Director.
(ii) The Center Director may grant an exception or alternative described in paragraph (a) of this section on his or her own initiative.
(2) A written request for an exception or alternative described in paragraph (a) of this section must:
(i) Identify the specified lots, batches, or other units of the biological product that would be subject to the exception or alternative;
(ii) Identify the labeling provision(s) listed in paragraph (f) of this section that are the subject of the exception or alternative request;
(iii) Explain why compliance with such labeling provision(s) could adversely affect the safety, effectiveness, or availability of the specified lots, batches, or other units of the biological product that are or will be included in the Strategic National Stockpile;
(iv) Describe any proposed safeguards or conditions that will be implemented so that the labeling of the product includes appropriate information necessary for the safe and effective use of the product, given the anticipated circumstances of use of the product;
(v) Provide a draft of the proposed labeling of the specified lots, batches, or other units of the biological product subject to the exception or alternative; and
(vi) Provide any other information requested by the Center Director in support of the request.
(c) The Center Director must respond in writing to all requests under this section.
(d) A grant of an exception or alternative under this section will include any safeguards or conditions deemed appropriate by the Center Director so that the labeling of product subject to the exception or alternative includes the information necessary for the safe and effective use of the product, given the anticipated circumstances of use.
(e) If you are a sponsor receiving a grant of a request for an exception or alternative to the labeling requirements under this section:
(1) You need not submit a supplement under § 601.12(f)(1) through (f)(2) of this chapter; however,
(2) You must report any grant of a request for an exception or alternative under this section as part of your annual report under § 601.12(f)(3) of this chapter.
(f) The Center Director may grant an exception or alternative under this section to the following provisions of this chapter, to the extent that the requirements in these provisions are not explicitly required by statute:
(1) § 610.60;
(2) § 610.61(c) and (e) through (r);
(3) § 610.62;
(4) § 610.63;
(5) § 610.64;
(6) § 610.65; and
(7) § 312.6.
21 U.S.C. 321, 331, 351, 352, 355, 360, 371; 42 U.S.C. 216, 262, 264.
(a)
(b)
(1) That the donor is deferred or determined not to be suitable for donation and the reason for that decision;
(2) Where appropriate, the types of donation of blood or blood components that the donor should not donate in the future;
(3) Where applicable, the results of tests for evidence of infection due to communicable disease agent(s) that were a basis for deferral under § 610.41 of this chapter, including results of supplemental (i.e., additional, more specific) tests as required in § 610.40(e) of this chapter; and,
(4) Where appropriate, information concerning medical followup and counseling.
(c)
(d)
(i) Information that the autologous donor is deferred based on the results of tests for evidence of infection due to
(ii) Where appropriate, the types of donation of blood or blood components that the autologous donor should not donate in the future; and
(iii) The results of tests for evidence of infection due to communicable disease agent(s), that were a basis for deferral under § 610.41 of this chapter, including results of supplemental (i.e., additional, more specific) tests as required in § 610.40(e) of this chapter.
(2) You must make reasonable attempts to notify the autologous donor's referring physician within 8 weeks after determining that the autologous donor is deferred as described in paragraph (a) of this section. You must document that you have successfully notified the autologous donor's referring physician or when you are unsuccessful that you have made reasonable attempts to notify the physician.
21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 U.S.C. 216, 262, 263, 263a, 264.
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.
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.
(a)
(b)
(c)
(1) The container has a tamper-proof seal when originally issued and this seal remains unbroken;
(2) A segment is properly attached and has not been removed, except that blood lacking a properly attached segment may be reissued in an emergency provided it is accompanied by instructions for sampling and for use within 6 hours after entering the container for sampling;
(3) The blood has been stored continuously at 1 to 6 °C and shipped between 1 and 10 °C;
(4) The blood is held for observation until a significant inspection consistent with the requirements of § 640.5(e) can be made.
(a)
(b)
(1) Normal temperature;
(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;
(3) For allogeneic donors, a blood hemoglobin level which shall be demonstrated to be no less than 12.5 grams (g) of hemoglobin per 100 milliliters (mL) of blood; or a hematocrit value of 38 percent, and for autologous donors, a blood hemoglobin level which shall be demonstrated to be no less than 11.0 g of hemoglobin per 100 mL of blood or a hematocrit value of 33 percent.
(4) Freedom from acute respiratory diseases;
(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;
(6) Freedom from any disease transmissible by blood transfusion, insofar as can be determined by history and examinations indicated above; and
(7) Freedom of the arms and forearms from skin punctures or scars indicative of addiction to self-injected narcotics.
(c)
(1) A history of viral hepatitis after the 11th birthday;
(2) A history of close contact within 12 months of donation with an individual having viral hepatitis;
(3) A history of having received within 12 months of donation, human blood or any derivative of human blood which the Food and Drug Administration has advised the blood establishment is a possible source of viral hepatitis.
(d)
(e) [Reserved]
(f)
(a)
(b)
(c)
(d)
(e)
(f)
(g)
(1) One or more segments shall be provided with each unit of blood when issued or reissued except as provided in § 640.2(c)(2) and all segments shall be from the donor who is the source of the unit of blood.
(2) All samples for laboratory tests performed by the manufacturer and all segments accompanying a unit of blood shall be collected at the time of filling the original blood container.
(3) All containers for all samples shall bear the donor's identification before collecting the samples.
(4) All segments 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.
(5) Segments for compatibility testing shall contain blood mixed with the appropriate anticoagulant.
(h)
All laboratory tests shall be made on a specimen of blood taken from the donor at the time of collecting the unit of blood, and these tests shall include the following:
(a)
(b)
(c)
(d)
(e)
(f)
Upon approval by the Director, Center for Biologics Evaluation and Research, of a supplement to the biologics 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:
(a) The antihemophilic factor shall be removed in accordance with paragraphs (a), (b), and (c) of § 640.52.
(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.
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.
(a)
(b)
The source blood for Red Blood Cells shall be obtained from a donor who meets the criteria for donor suitability prescribed in § 640.3.
(a) The source blood shall be collected as prescribed in § 640.4.
(b) Source blood may also be derived from Whole Blood manufactured in accordance with applicable provisions of this subchapter.
Blood from which Red Blood Cells are prepared shall be tested as prescribed
Segments collected in integral tubing shall meet the following standards:
(a) One or more segments shall be provided with each unit of Whole Blood or Red Blood Cells when issued or reissued.
(b) Before they are filled, all segments shall be marked or identified so as to relate them to the donor of that unit of red cells.
(c) All segments 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.
(a)
(b)
(c)
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.
(a)
(b)
(a) Whole blood donors shall meet the criteria for suitability prescribed in § 640.3.
(b) [Reserved]
(c) Plateletpheresis donors must meet the criteria for suitability as prescribed in §§ 640.3 and 640.63(c)(6) or as described in an approved biologics license application (BLA) or an approved
(a) Whole blood used as the source of Platelets shall be collected as prescribed in § 640.4.
(b) [Reserved]
(c) If plateletpheresis is used, the procedure for collection must be as prescribed in §§ 640.62, 640.64 (except paragraph (c)), and 640.65, or as described in an approved biologics license application (BLA) or an approved supplement to a BLA.
(d) The phlebotomy shall be performed by a single uninterrupted venipuncture with minimal damage to, and minimal manipulation of, the donor's tissue.
(a) Blood from which plasma is separated for the preparation of Platelets shall be tested as prescribed in § 610.40 of this chapter and § 640.5 (a), (b), and (c).
(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.
(a) Separation of plasma and platelets and resuspension of the platelets must be in a closed system. Platelets must not be pooled during processing unless the platelets are pooled as specified in the directions for use for the blood collecting, processing, and storage system approved for such use by the Director, Center for Biologics Evaluation and Research.
(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 collection center 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 or within the timeframe specified in the directions for use for the blood collecting, processing, and storage system.
(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
(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 6.2 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:
(1) 20 to 24 °C.
(2) 1 to 6 °C.
(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.
(a)
(b)
(1) Platelet count.
(2) pH of not less than 6.2 measured at the storage temperature of the unit.
(3) Measurement of actual plasma volume.
(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.
(c)
(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.
(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.
(3) The testing laboratory will participate in any proficiency testing programs undertaken by the Center for Biologics Evaluation and Research, Food and Drug Administration.
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):
(a)
(1) The fluid portion of one unit of human blood intended for intravenous use which is collected in a closed system, stabilized against clotting, and separated from the red cells; or
(2) The fluid portion of human blood intended for intravenous use which is prepared by apheresis methods as specified in the directions for use for the blood collecting, processing, and storage system including closed and open systems.
(b)
(2) Plasma may be obtained from a unit of Whole Blood collected by another licensed establishment.
(a) Whole blood donors shall meet the criteria for donor suitability prescribed in § 640.3.
(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.
(a) Whole Blood must be collected, transported, and stored as prescribed in § 640.4. When whole blood is intended for Plasma, Fresh Frozen Plasma, and Liquid Plasma, until the plasma is removed, the whole blood must be maintained at a temperature between 1 and 6 °C or as specified in the directions for use for the blood collecting, processing, and storage system approved for such use by the Director, Center for Biologics Evaluations and Research. Whole blood intended for Platelet Rich Plasma must be maintained as prescribed in § 640.24 until the plasma is removed. The red blood cells must be placed in storage at a temperature between 1 and 6 °C immediately after the plasma is separated.
(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.
(a) Blood from which plasma is separated shall be tested as prescribed in § 610.40 of this chapter and § 640.5 (a), (b), and (c).
(b) Manufacturers of Plasma collected by plasmapheresis shall have testing and recordkeeping responsibilities equivalent to those prescribed in §§ 640.71 and 640.72.
(a)
(b)
(c)
(d)
(e)
(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 within 6 hours after filling the final container or within the timeframe specified in the directions for use for the blood collecting, processing, and storage system.
(2) Cryoprecipitated AHF shall be removed as prescribed in subpart F of part 640. The remaining plasma shall be labeled “Plasma, Cryoprecipitate Reduced.”
(3) Plasma remaining after both Platelets and Cryoprecipitated AHF have been removed may be labeled “Plasma, Cryoprecipitate Reduced.”
(f)
(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.
(3) Prior to filling, the final container shall be identified by number so as to relate it to the donor.
(g)
(2) With the exception of Platelet Rich Plasma and Liquid Plasma the final product shall be inspected for evidence of thawing or breakage at the time of issuance, however, the containers need not be stored in a manner that shows evidence of thawing if records of continuous monitoring of the storage temperature establish that the temperature remained at -18 °C or colder. If continuous monitoring of the product is not available, 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.
(3) No preservative shall be added to the final product.
(a)
(b)
(a) Whole blood donors shall meet the criteria for suitability prescribed in § 640.3.
(b) Plasmapheresis 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.
(a) Whole blood used as a source of Cryoprecipitated AHF shall be collected as prescribed in § 640.4. Whole blood from which both Platelets and Cryoprecipitated AHF is derived shall be maintained as required under § 640.24 until the platelets are removed.
(b) If plasmapheresis is used, the procedure for collection shall be as prescribed in §§ 640.62, 640.64 (except that
(a) Blood from which plasma is separated for the preparation of Cryoprecipitated AHF shall be tested as prescribed in § 610.40 of this chapter and § 640.5 (a), (b), and (c).
(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.
(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.
(a)
(2) The plasma shall be placed in a freezer within 8 hours after blood collection or within the timeframe specified in the directions for use for the blood collecting, processing, and storage system. A combination of dry ice and organic solvent may be used for freezing:
(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.
(b)
(2) No diluent shall be added to the product by the manufacturer prior to freezing.
(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. 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.
A U.S. Standard Antihemophilic Factor (Factor VIII) preparation may be obtained from the Center for Biologics Evaluation and Research, (HFM-407) (see mailing addresses in § 600.2 of this chapter) for use in the preparation of a working reference to be employed in a quality control potency test of Cryoprecipitated AHF.
(a) Quality control tests for potency of antihemophilic factor shall be conducted each month on at least four representative containers of Cryoprecipitated AHF.
(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.
(c) The quality control test for potency may be performed by a clinical laboratory which meets the standards of the Clinical Laboratories Improvement Amendments of 1988 (CLIA) (42
(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.
(2) The testing laboratory will participate in any proficiency testing programs undertaken by the Center for Biologics Evaluation and Research, Food and Drug Administration.
(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.
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.
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.
A qualified licensed physician shall be on the premises when donor suitability is being determined, immunizations are being made, whole blood is being collected, and red blood cells are being returned to the donor.
(a)
(b)
(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.
(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.
(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
(c)
(1) Normal temperature;
(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;
(3) A blood hemoglobin level of no less than 12.5 grams of hemoglobin per 100 milliliters of blood or a hematocrit level of 38 percent;
(4) A normal pulse rate;
(5) A total serum or total plasma protein of no less than 6.0 grams per 100 milliliters of blood;
(6) Weight, which shall be at least 110 pounds;
(7) Freedom from acute respiratory diseases;
(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;
(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;
(10) Freedom of the arms and forearms from skin punctures or scars indicative of addiction to self-injected narcotics;
(11) Freedom from a history of viral hepatitis after the 11th birthday;
(12) Freedom from a history of close contact within 12 months of donation with an individual having viral hepatitis;
(13) Freedom from a history of having received, within 12 months, human blood or any derivative of human blood which the Food and Drug Administration has advised the blood establishment is a possible source of viral hepatitis, except for specific immunization performed in accordance with § 640.66.
(d)
(e)
(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;
(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
(3) The special characteristics of the antibody and the need for plasmapheresing the donor are documented.
(a)
(b)
(c)
(d)
(e)
(a)
(b)
(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 equivalent test to determine immunoglobulin composition of the plasma or serum shall be performed on the sample.
(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:
(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.
(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.
(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.
(iii) A donor whose serum is determined to have a biologic false-positive reaction to a serologic test for syphilis may be plasmapheresed:
(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:
(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.
(4) The amount of whole blood, not including anticoagulant, removed from a donor during a manual plasmapheresis procedure or in any 2-day 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 manual plasmapheresis procedure or in any 2-day period shall not exceed 1,200 milliliters.
(5) The amount of whole blood, not including anticoagulant, removed from a donor during a manual plasmapheresis procedure within a 7-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 a donor during a manual plasmapheresis procedure within a 7-day period shall not exceed 2,400 milliliters.
(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 of whole blood shall be removed from the donor at one time.
(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.
(8) The volume of plasma collected during an automated plasmapheresis collection procedure shall be consistent with the volumes specifically approved by the Director, Center for Biologics Evaluation and Research, and collection shall not occur less than 2 days apart or more frequently than twice in a 7-day period.
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.
Each unit of Source Plasma shall be tested for evidence of infection due to communicable disease agents as required under § 610.40 of this chapter.
(a)
(b)
(c)
(a)
(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.
(2) The pooling of plasma from two or more donors by the manufacturer of Source Plasma intended for manufacturing into noninjectable products is permitted:
(b)
(c)
(d)
(1) Prior to filling, all samples shall be marked or identified so as to relate them directly to the donor of that unit of plasma.
(2) All samples shall be filled at the time the final product is prepared by the person who prepares the final product.
(3) All samples shall be representative of the contents of the final product or be collected from the donor at the time of filling the collection container.
(4) All samples shall be collected in a manner that does not contaminate the contents of the final container.
(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:
(1) The proper name of the product.
(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”,
(3) The statement “Store at −20 °C or colder”:
(4) The total volume or weight of plasma and total quantity and type of anticoagulant used.
(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.
(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.
(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.
(8) The test for hepatitis B surface antigen used for the results, or the statement “Nonreactive for HB
(9) When plasma collected from a donor is reactive for the serologic test 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.
(10) Name, address, and license number of the manufacturer.
(11) The statement “Negative by a test for antibody to HIV”, or equivalent statement.
(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”.
(a) All steps in the manufacturing 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 and 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 Amendments of 1988 (CLIA) (42 U.S.C. 263a):
(1) The test for hepatitis B surface antigen.
(2) The total plasma or serum protein and the quantitative test for plasma or serum proteins or for immunoglobulins.
(3) The serologic test for syphilis.
(4) A test for antibody to HIV.
(b) Such testing shall not be considered divided manufacturing, which requires two biologics licenses for Source Plasma:
(1) The results of such tests are maintained by the licensed manufacturer of the Source Plasma whereby such results may be reviewed by a licensed physician as required in § 640.65(b)(2) of
(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.
(3) The testing laboratory will participate in any proficiency testing programs undertaken by the Center for Biologics Evaluation and Research, Food and Drug Administration.
(a) In addition to the recordkeeping requirements of this subchapter, the following records shall be maintained:
(1) Documentation shall be available to ensure that the shipping temperature requirements of § 600.15 of this title and of § 640.74(b)(2) are being met for Source Plasma intended for manufacture into injectable products.
(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:
(3) The original or a clear copy of the donor's written consent for participation in the plasmapheresis program or for immunization.
(4) The certification of the donor's good health as prescribed in § 640.63(b)(3).
(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.
(b) Each donor record must be directly cross-referenced to the unit(s) of Source Plasma associated with the donor.
(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.
(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.
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.
(a) Upon approval by the Director, Center for Biologics Evaluation and Research, Food and Drug Administration, of a supplement to the biologics license application 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.
(b) Source Plasma Liquid shall meet all standards of the frozen Source Plasma except:
(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
(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 licensed manufacturer of the Source Plasma Liquid or the manufacturer of the final blood derivative product who has requested the Source Plasma Liquid.
(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.
(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.
(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.
(a)
(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.
(b)
(c)
(a)
(b)
(c)
(a)
(b)
(c)
(d)
(e)
(f)
(g)
Tests shall be performed on the final product to determine that it meets the following standards:
(a)
(b)
(c)
(d)
(e)
(f)
(a)
(b)
In addition to the labeling requirements of §§ 610.60, 610.61, and 610.62 of this chapter, the container and package labels shall contain the following information:
(a) The osmotic equivalent in terms of plasma, and the sodium concentration in terms of a value or a range in milliequivalents per liter;
(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.”;
(c) The need for additional fluids when 20 percent or 25 percent albumin is administered to a patient with marked dehydration;
(d) The protein concentration, expressed as a 4 percent, 5 percent, 20 percent, or 25 percent solution.
(a)
(b)
(c)
(a)
(b)
(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.
(2) Contains less than 5 percent protein with a sedimentation coefficient greater than 7.0 S.
(3) Is safe for intravenous injection.
(c)
(d)
(e)
(f)
(g)
Tests shall be performed on the final product to determine that it meets the following standards:
(a)
(b)
(c)
(d)
(e)
(f)
(a)
(b)
In addition to the labeling requirements of §§ 610.60, 610.61, and 610.62 of this chapter, the container and package labels shall contain the following information:
(a) The osmotic equivalent in terms of plasma, and the sodium concentration in terms of a value or a range in milliequivalents per liter.
(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.”
(a)
(b)
(c)
(a)
(b)
(c)
(d)
(e)
(1) There is no prescribed potency for viral hepatitis antibodies.
(2) The product is not recommended for intravenous administration.
(a)
(b)
(c)
(d)
(e)
(a)
(b)
(a)
(b)
(1) No less than 2 units of diphtheria antitoxin per ml.
(2) A measles neutralizing antibody level that, when compared with that of a reference material designated by the Center for Biologics Evaluation and Research (CBER), Food and Drug Administration, as indicated in paragraph (c) of this section, demonstrates adequate potency. The Director, CBER, shall notify manufacturers when a new reference material will be used and will advise manufacturers of an appropriate antibody level taking into account a comparison of the new reference material to the previous reference material.
(3) A poliomyelitis Type 1, Type 2, or Type 3 neutralizing antibody level that, when compared with that of a reference material designated by the Center for Biologics Evaluation and Research, Food and Drug Administration, as indicated in paragraph (c) of this section, demonstrates adequate potency. The Director, CBER, shall notify manufacturers when a new reference material will be used and will advise manufacturers of an appropriate antibody level taking into account a comparison of the new reference material to the previous reference material.
(c)
(1) Reference Immune Globulin for correlation of measles antibody titers.
(2) Reference Immune Globulin for correlation of poliomyelitis antibody titers, Types 1, 2, and 3.
(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.
(b) FDA will publish a list of approved alternative procedures and exceptions periodically in the
21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 360d, 360h, 360i, 371, 372; 42 U.S.C. 216, 262, 263, 263a, 264.
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.
(a)
(b)
(a)
(b)
(c)
(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.
(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).
(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.
(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.
(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.
(d)
(e)
(f)
A Reference Hepatitis B Surface Antigen Panel shall be obtained from the Center for Biologics Evaluation and Research (HFM-407) (see mailing addresses in § 600.2 of this chapter) and shall be used for determining the potency and specificity of Antibody to Hepatitis B Surface Antigen.
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.
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.
(a)
(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 (see mailing addresses in § 600.2 of this chapter), within 5 working days after the manufacturer has satisfactorily completed all tests on the samples:
(i) One sample until written notification of official release is no longer required under paragraph (c)(2) of this section.
(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.
(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.
(b)
(c)
(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.
(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.
(a)
(b)
(a)
(2) Only that material that has been fully processed, thoroughly mixed in a single vessel, and filtered shall constitute a lot.
(3) A lot may be subdivided into sublots. If lots are to be subdivided, the manufacturer shall include this information in the biologics license application. The manufacturer shall describe the test specifications to verify that each sublot is identical to other sublots of the lot.
(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.
(b)
(c)
(d)
(e)
(a)
(b)
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.
(a)
(1) For Anti-K, Anti-k
(2) For Anti-S, Anti-s
(3) For Anti-U, Anti-Kp
(b)
(c)
Specificity and avidity tests shall be performed using test procedures approved by the Director, Center for Biologics Evaluation and Research.
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:
(a)
(2)
(i) Name of the antibody or antibodies present as set forth in paragraph (d) of this section.
(ii) Name, address (including ZIP code), and license number of the manufacturer.
(iii) Lot number, including sublot designations.
(iv) Expiration date.
(v) Source of product if other than human plasma or serum.
(vi) Test method(s) recommended.
(vii) Recommended storage temperature in degrees Celsius.
(viii) Volume of product if a liquid, or equivalent volume for a dried product if it is to be reconstituted.
(ix) If a dried product, to remind users to record the reconstitution date on the label, the statement “RECONSTITUTION DATE ____. EXPIRES 1 YEAR AFTER RECONSTITUTION DATE.”
(3)
(4)
(b)
(1) Proper name of the product.
(2) Name of the antibody or antibodies present as set forth in paragraph (d) of this section.
(3) Name, address (including ZIP Code), and license number of the manufacturer.
(4) Lot number, including sublot designations.
(5) Expiration date.
(6) Preservative used and its concentration.
(7) Number of containers, if more than one.
(8) Volume or equivalent volume for dried products when reconstituted, and precautions for adequate mixing when reconstituting.
(9) Recommended storage temperature in degrees Celsius.
(10) Source of the product if other than human serum or plasma.
(11) Reference to enclosed package insert.
(12) If a dried product, a statement indicating the period within which the product may be used after reconstitution.
(13) The statement: “FOR IN VITRO DIAGNOSTIC USE.”
(14) The statement: “MEETS FDA POTENCY REQUIREMENTS.”
(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.”
(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.
(c)
(d)
(a)
(b)
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.
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.
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 biologics 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
(a)
(b)
(c)
(d)
(e)
(f)
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:
(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.
(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.
(b) The container label of Group O cells shall state:
(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 ±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 ±0.5 percentage unit.
(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.
(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.
(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.
(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.
(h) The package label or package insert shall bear the cautionary statement: “The reactivity of the product may decrease during the dating period.”
(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.
(j) The package insert shall provide adequate directions for use.
(k) The package insert shall bear the statement:
(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.
(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.
(a) The following shall be submitted to the Center for Biologics Evaluation and Research Sample Custodian (ATTN: HFM-672) (see mailing addresses in § 600.2 of this chapter), within 30 days after each routine establishment inspection by FDA.
(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.
(2) A protocol which shall include the following:
(i) Complete test records of at least two donors of the samples submitted, including original and confirmation phenotyping records.
(ii) Bleeding records or receipt records which indicate collection date, volume, and HBsAg test results.
(iii) Manufacturing records which document all steps involved in the preparation of the product.
(iv) Test results which verify that the final product meets specifications.
(v) Identity test results.
(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
(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.
(a)
(b)
(a)
(b)
(c)
(d)
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.
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.
In addition to the requirements of §§ 610.60, 610.61, and 809.10 of this chapter, the labeling shall bear the following:
(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.
(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).
(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.
(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.
(a)
(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 (see mailing addresses in § 600.2 of this chapter), within 5 working days after the manufacturer has satisfactorily completed all tests on the samples:
(i) One sample until written notification of official release is no longer required under paragraph (c)(2) of this section.
(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.
(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.
(b)
(c)
(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.
(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.
(a)
(b)
(a)
(2) Anti-IgG, -C3d (polyspecific) reagents and anti-IgG products may be colored green.
(3) Only that material which has been fully processed, thoroughly mixed in a single vessel, and filtered shall constitute a lot. Each lot shall be identified by a lot number.
(4) A lot may be subdivided into sublots 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
(b)
(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.
(c)
Reference Anti-Human Globulin preparations shall be obtained from the Center for Biologics Evaluation and Research (HFM-407) (see mailing addresses in § 600.2 of this chapter), and shall be used as described in the accompanying package insert for determining the potency of Anti-Human Globulin.
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.
The following tests shall be performed using test procedures approved by the Director, Center for Biologics Evaluation and Research:
(a) Potency tests for determining anti-IgG and anti-complement activity.
(b) Specificity tests, tests for heterospecific antibodies, and additional tests for nonspecific properties.
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:
(a)
(2)
(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.
(ii) Name, address, and license number of the manufacturer.
(iii) Lot number, including any sublot designations.
(iv) Expiration date.
(v) Source of the product.
(vi) Recommended storage temperature in degrees Celsius.
(vii) Volume of product.
(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.”
(ix) If the final container is not enclosed in a package, all items required for a package label shall appear on the container label.
(3)
(4)
(b)
(1) Proper name of the product, and the name of the antibody or antibodies as listed in paragraph (d) of this section.
(2) Name, address (including zip code), and license number of the manufacturer.
(3) Lot number, including any sublot designations.
(4) Expiration date.
(5) Preservative(s) used and its concentration.
(6) Number of containers, if more than one.
(7) Recommended storage temperature in degrees Celsius.
(8) Source of the product.
(9) Reference to enclosed package insert.
(10) The statement: “For In Vitro Diagnostic Use.”
(11) The statement: “Meets FDA Potency Requirements.”
(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.
(13) Appropriate cautions.
(c)
(d)
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.
21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 U.S.C. 216, 262, 263, 263a, 264.
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.
(a)
(b)
(2)
(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.
(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 (see mailing addresses in § 600.2).
(3)
(ii)
(iii)
(iv)
(v)
(vi)
(c)
(d)
(2) Nonlicensed source material suppliers are exempt from drug registration.
(a)
(b)
(c)
(d)
(e) [Reserved]
(f)
(a)
(b)
(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
(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.
(c)
(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.
(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.
(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.
(4) Tablets and capsules need not be tested for sterility provided aseptic techniques are employed in their manufacture.
(d) [Reserved]
(e)
(f)