[Title 21 CFR ]
[Code of Federal Regulations (annual edition) - April 1, 1999 Edition]
[From the U.S. Government Printing Office]
21
Food and Drugs
[[Page i]]
PARTS 200 TO 299
Revised as of April 1, 1999
CONTAINING
A CODIFICATION OF DOCUMENTS
OF GENERAL APPLICABILITY
AND FUTURE EFFECT
AS OF APRIL 1, 1999
With Ancillaries
Published by
the Office of the Federal Register
National Archives and Records
Administration
as a Special Edition of
the Federal Register
[[Page ii]]
U.S. GOVERNMENT PRINTING OFFICE
WASHINGTON : 1999
For sale by U.S. Government Printing Office
Superintendent of Documents, Mail Stop: SSOP, Washington, DC 20402-9328
[[Page iii]]
Table of Contents
Page
Explanation................................................. v
Title 21:
Chapter I--Food and Drug Administration, Department
of Health and Human Services (Continued)............ 3
Finding Aids:
Material Approved for Incorporation by Reference........ 173
Table of CFR Titles and Chapters........................ 175
Alphabetical List of Agencies Appearing in the CFR...... 193
List of CFR Sections Affected........................... 203
[[Page iv]]
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Cite this Code: CFR
To cite the regulations in
this volume use title,
part and section number.
Thus, 21 CFR 200.5 refers
to title 21, part 200,
section 5.
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[[Page v]]
EXPLANATION
The Code of Federal Regulations is a codification of the general and
permanent rules published in the Federal Register by the Executive
departments and agencies of the Federal Government. The Code is divided
into 50 titles which represent broad areas subject to Federal
regulation. Each title is divided into chapters which usually bear the
name of the issuing agency. Each chapter is further subdivided into
parts covering specific regulatory areas.
Each volume of the Code is revised at least once each calendar year
and issued on a quarterly basis approximately as follows:
Title 1 through Title 16.................................as of January 1
Title 17 through Title 27..................................as of April 1
Title 28 through Title 41...................................as of July 1
Title 42 through Title 50................................as of October 1
The appropriate revision date is printed on the cover of each
volume.
LEGAL STATUS
The contents of the Federal Register are required to be judicially
noticed (44 U.S.C. 1507). The Code of Federal Regulations is prima facie
evidence of the text of the original documents (44 U.S.C. 1510).
HOW TO USE THE CODE OF FEDERAL REGULATIONS
The Code of Federal Regulations is kept up to date by the individual
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To determine whether a Code volume has been amended since its
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Sections Affected (LSA),'' which is issued monthly, and the ``Cumulative
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EFFECTIVE AND EXPIRATION DATES
Each volume of the Code contains amendments published in the Federal
Register since the last revision of that volume of the Code. Source
citations for the regulations are referred to by volume number and page
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OMB CONTROL NUMBERS
The Paperwork Reduction Act of 1980 (Pub. L. 96-511) requires
Federal agencies to display an OMB control number with their information
collection request.
[[Page vi]]
Many agencies have begun publishing numerous OMB control numbers as
amendments to existing regulations in the CFR. These OMB numbers are
placed as close as possible to the applicable recordkeeping or reporting
requirements.
OBSOLETE PROVISIONS
Provisions that become obsolete before the revision date stated on
the cover of each volume are not carried. Code users may find the text
of provisions in effect on a given date in the past by using the
appropriate numerical list of sections affected. For the period before
January 1, 1986, consult either the List of CFR Sections Affected, 1949-
1963, 1964-1972, or 1973-1985, published in seven separate volumes. For
the period beginning January 1, 1986, a ``List of CFR Sections
Affected'' is published at the end of each CFR volume.
INCORPORATION BY REFERENCE
What is incorporation by reference? Incorporation by reference was
established by statute and allows Federal agencies to meet the
requirement to publish regulations in the Federal Register by referring
to materials already published elsewhere. For an incorporation to be
valid, the Director of the Federal Register must approve it. The legal
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if it were published in full in the Federal Register (5 U.S.C. 552(a)).
This material, like any other properly issued regulation, has the force
of law.
What is a proper incorporation by reference? The Director of the
Federal Register will approve an incorporation by reference only when
the requirements of 1 CFR part 51 are met. Some of the elements on which
approval is based are:
(a) The incorporation will substantially reduce the volume of
material published in the Federal Register.
(b) The matter incorporated is in fact available to the extent
necessary to afford fairness and uniformity in the administrative
process.
(c) The incorporating document is drafted and submitted for
publication in accordance with 1 CFR part 51.
Properly approved incorporations by reference in this volume are
listed in the Finding Aids at the end of this volume.
What if the material incorporated by reference cannot be found? If
you have any problem locating or obtaining a copy of material listed in
the Finding Aids of this volume as an approved incorporation by
reference, please contact the agency that issued the regulation
containing that incorporation. If, after contacting the agency, you find
the material is not available, please notify the Director of the Federal
Register, National Archives and Records Administration, Washington DC
20408, or call (202) 523-4534.
CFR INDEXES AND TABULAR GUIDES
A subject index to the Code of Federal Regulations is contained in a
separate volume, revised annually as of January 1, entitled CFR Index
and Finding Aids. This volume contains the Parallel Table of Statutory
Authorities and Agency Rules (Table I), and Acts Requiring Publication
in the Federal Register (Table II). A list of CFR titles, chapters, and
parts and an alphabetical list of agencies publishing in the CFR are
also included in this volume.
An index to the text of ``Title 3--The President'' is carried within
that volume.
The Federal Register Index is issued monthly in cumulative form.
This index is based on a consolidation of the ``Contents'' entries in
the daily Federal Register.
[[Page vii]]
A List of CFR Sections Affected (LSA) is published monthly, keyed to
the revision dates of the 50 CFR titles.
REPUBLICATION OF MATERIAL
There are no restrictions on the republication of material appearing
in the Code of Federal Regulations.
INQUIRIES
For a legal interpretation or explanation of any regulation in this
volume, contact the issuing agency. The issuing agency's name appears at
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For inquiries concerning CFR reference assistance, call 202-523-5227
or write to the Director, Office of the Federal Register, National
Archives and Records Administration, Washington, DC 20408.
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Raymond A. Mosley,
Director,
Office of the Federal Register.
April 1, 1999.
[[Page ix]]
THIS TITLE
Title 21--Food and Drugs is composed of nine volumes. The parts in
these volumes are arranged in the following order: Parts 1-99, 100-169,
170-199, 200-299, 300-499, 500-599, 600-799, 800-1299 and 1300-end. The
first eight volumes, containing parts 1-1299, comprise Chapter I--Food
and Drug Administration, Department of Health and Human Services. The
ninth volume, containing part 1300 to end, includes Chapter II--Drug
Enforcement Administration, Department of Justice, and Chapter III--
Office of National Drug Control Policy. The contents of these volumes
represent all current regulations codified under this title of the CFR
as of April 1, 1999.
Redesignation tables for Chapter I--Food and Drug Administration
appear in the Finding Aids section for the volumes containing parts 170-
199 and 500-599.
For this volume, Kenneth R. Payne was Chief Editor. The Code of
Federal Regulations publication program is under the direction of
Frances D. McDonald, assisted by Alomha S. Morris.
[[Page x]]
[[Page 1]]
TITLE 21--FOOD AND DRUGS
(This book contains parts 200 to 299)
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Part
Chapter I--Food and Drug Administration, Department of
Health and Human Services (Continued)..................... 200
Cross References: Food Safety and Inspection Service, Department of
Agriculture: See Meat and Poultry Inspection, 9 CFR chapter III.
Federal Trade Commission: See Commercial Practices, 16 CFR chapter I.
U.S. Customs Service, Department of the Treasury: See Customs Duties,
19 CFR chapter I.
Internal Revenue Service, Department of the Treasury: See Internal
Revenue, 26 CFR chapter I.
Bureau of Alcohol, Tobacco, and Firearms, Department of the Treasury:
See Alcohol, Tobacco Products and Firearms, 27 CFR chapter I.
[[Page 3]]
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES
(Parts 200 to 299)
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SUBCHAPTER C--DRUGS: GENERAL
Part Page
200 General..................................... 5
201 Labeling.................................... 8
202 Prescription drug advertising............... 74
205 Guidelines for State licensing of wholesale
prescription drug distributors.......... 83
206 Imprinting of solid oral dosage form drug
products for human use.................. 87
207 Registration of producers of drugs and
listing of drugs in commercial
distribution............................ 89
208 Medication Guides for prescription drug
products (eff. 6-1-99).................. 98
210 Current good manufacturing practice in
manufacturing, processing, packing, or
holding of drugs; general............... 102
211 Current good manufacturing practice for
finished pharmaceuticals................ 104
216 Pharmacy compounding........................ 124
225 Current good manufacturing practice for
medicated feeds......................... 126
226 Current good manufacturing practice for Type
A medicated articles.................... 133
250 Special requirements for specific human
drugs................................... 137
290 Controlled drugs............................ 145
291 Drugs used for treatment of narcotic addicts 146
299 Drugs; official names and established names. 168
[[Page 5]]
SUBCHAPTER C--DRUGS: GENERAL
PART 200--GENERAL--Table of Contents
Subpart A--General Provisions
Sec.
200.5 Mailing of important information about drugs.
200.7 Supplying pharmacists with indications and dosage information.
200.10 Contract facilities (including consulting laboratories) utilized
as extramural facilities by pharmaceutical manufacturers.
200.11 Use of octadecylamine in steam lines of drug establishments.
200.15 Definition of term ``insulin''.
Subpart B [Reserved]
Subpart C--Requirements for Specific Classes of Drugs
200.50 Ophthalmic preparations and dispensers.
Subpart D [Reserved]
Subpart E--Prescription Drug Consumer Price Listing
200.200 Prescription drugs; reminder advertisements and reminder
labeling to provide price information to consumers.
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360e, 371,
374, 375.
Source: 40 FR 13996, Mar. 27, 1975, unless otherwise noted.
Subpart A--General Provisions
Sec. 200.5 Mailing of important information about drugs.
Manufacturers and distributors of drugs and the Food and Drug
Administration occasionally are required to mail important information
about drugs to physicians and others responsible for patient care. In
the public interest, such mail should be distinctive in appearance so
that it will be promptly recognized and read. The Food and Drug
Administration will make such mailings in accordance with the
specifications set forth in this section. Manufacturers and distributors
of drugs are asked to make such mailings as prescribed by this section
and not to use the distinctive envelopes for ordinary mail.
(a) Use first class mail and No. 10 white envelopes.
(b) The name and address of the agency or the drug manufacturer or
distributor is to appear in the upper left corner of the envelope.
(c) The following statements are to appear in the far left third of
the envelope front, in the type and size indicated, centered in a
rectangular space approximately 3 inches wide and 2\1/4\ inches high
with an approximately \3/8\ inch-wide border in the color indicated:
(1) When the information concerns a significant hazard to health,
the statement:
IMPORTANT
DRUG
WARNING
The statement shall be in three lines, all capitals, and centered.
``Important'' shall be in 36 point Gothic Bold type. ``Drug'' and
``Warning'' shall be in 36 point Gothic Condensed type. The rectangle's
border and the statement therein shall be red.
(2) When the information concerns important changes in drug package
labeling, the statement:
IMPORTANT
PRESCRIBING
INFORMATION
The statement shall be in three lines, all capitals, and centered.
``Important'' shall be in 36 point Gothic Bold type. ``Prescribing'' and
``Information'' shall be in 36 point Gothic Condensed type. The
rectangle's border and the statement therein shall be blue.
(3) When the information concerns a correction of prescription drug
advertising or labeling, the statement:
[[Page 6]]
IMPORTANT
CORRECTION
OF DRUG
INFORMATION
The statement shall be in four lines, all capitals, and centered.
``Important'' shall be in 36 point Gothic Bold type. ``Correction,''
``Of Drug,'' and ``Information'' shall be in 36 point Gothic Condensed
type. The rectangle's border and the statement therein shall be brown.
Sec. 200.7 Supplying pharmacists with indications and dosage information.
There are presently no regulations under the Federal Food, Drug, and
Cosmetic Act that prevent a manufacturer of prescription drugs from
sending the pharmacist data he needs on indications and dosage in
exercising his important professional function of checking against
possible mistakes in a prescription. The Food and Drug Administration
believes manufacturers should be encouraged to supply such printed
matter to the pharmacist for his professional information. Obviously,
such printed matter should not be displayed to prospective purchasers to
promote over-the-counter sale of prescription drugs.
Sec. 200.10 Contract facilities (including consulting laboratories) utilized as extramural facilities by pharmaceutical manufacturers.
(a) Section 704(a) of the Federal Food, Drug, and Cosmetic Act
specifically authorizes inspection of consulting laboratories as well as
any factory, warehouse, or establishment in which prescription drugs are
manufactured, processed, packed, or held.
(b) The Food and Drug Administration is aware that many
manufacturers of pharmaceutical products utilize extramural independent
contract facilities, such as testing laboratories, contract packers or
labelers, and custom grinders, and regards extramural facilities as an
extension of the manufacturer's own facility.
(c) The Food and Drug Administration reserves the right to disclose
to the pharmaceutical manufacturer, or to the applicant of a new drug
application (NDA) or to the sponsor of an Investigational New Drug (IND)
Application, any information obtained during the inspection of an
extramural facility having a specific bearing on the compliance of the
manufacturer's, applicant's, or sponsor's product with the Federal Food,
Drug, and Cosmetic Act. The Food and Drug Administration's position is
that by the acceptance of such contract work, the extramural facility
authorizes such disclosures.
(d) The Food and Drug Administration does not consider results of
validation studies of analytical and assay methods and control
procedures to be trade secrets that may be withheld from the drug
manufacturer by the contracted extramural facility.
[40 FR 13996, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990]
Sec. 200.11 Use of octadecylamine in steam lines of drug establishments.
The Food and Drug Administration will not object to the use of
octadecylamine in steam lines where the steam may be used for
autoclaving surgical instruments and gauze if the octadecylamine in the
steam is not more than 2.4 parts per million.
Sec. 200.15 Definition of term ``insulin.''
For purposes of sections 801 and 802 of the act and this title, the
term insulin means the active principle of the pancreas that affects the
metabolism of carbohydrates in the animal body and which is of value in
the treatment of diabetes mellitus. The term includes synthetic and
biotechnologically derived products that are the same as, or similar to,
naturally occurring insulins in structure, use, and intended effect and
are of value in the treatment of diabetes mellitus.
[63 FR 26698, May 13, 1998]
Subpart B [Reserved]
Subpart C--Requirements for Specific Classes of Drugs
Sec. 200.50 Ophthalmic preparations and dispensers.
(a)(1) Informed medical opinion is in agreement that all
preparations offered
[[Page 7]]
or intended for ophthalmic use, including preparations for cleansing the
eyes, should be sterile. It is further evident that such preparations
purport to be of such purity and quality as to be suitable for safe use
in the eye.
(2) The Food and Drug Administration concludes that all such
preparations, if they are not sterile, fall below their professed
standard of purity or quality and may be unsafe. In a statement of
policy issued on September 1, 1964, the Food and Drug Administration
ruled that liquid preparations offered or intended for ophthalmic use
that are not sterile may be regarded as adulterated within the meaning
of section 501(c) of the Federal Food, Drug, and Cosmetic Act (the act),
and, further, may be deemed misbranded within the meaning of section
502(j) of the act. This ruling is extended to affect all preparations
for ophthalmic use. By this regulation, this ruling is applicable to
ophthalmic preparations that are regulated as drugs. By the regulation
in Sec. 800.10 of this chapter, this ruling is applicable to ophthalmic
preparations that are regulated as medical devices.
(3) The containers of ophthalmic preparations shall be sterile at
the time of filling and closing, and the container or individual carton
shall be so sealed that the contents cannot be used without destroying
the seal. The packaging and labeling of ophthalmic preparations that are
over-the-counter drugs shall also comply with Sec. 211.132 of this
chapter on tamper-resistant packaging requirements.
(b) Liquid ophthalmic preparations packed in multiple-dose
containers should:
(1) Contain one or more suitable and harmless substances that will
inhibit the growth of microorganisms; or
(2) Be so packaged as to volume and type of container and so labeled
as to duration of use and with such necessary warnings as to afford
adequate protection and minimize the hazard of injury resulting from
contamination during use.
(c) Eye cups, eye droppers, and other dispensers intended for
ophthalmic use should be sterile, and may be regarded as falling below
their professed standard of purity or quality if they are not sterile.
These articles, which are regulated as drugs if packaged with the drugs
with which they are to be used, should be packaged so as to maintain
sterility until the package is opened and be labeled, on or within the
retail package, so as to afford adequate directions and necessary
warnings to minimize the hazard of injury resulting from contamination
during use.
[40 FR 13996, Mar. 27, 1975, as amended at 47 FR 50455, Nov. 5, 1982]
Subpart D [Reserved]
Subpart E--Prescription Drug Consumer Price Listing
Sec. 200.200 Prescription drugs; reminder advertisements and reminder labeling to provide price information to consumers.
(a) Prescription drug reminder advertisements and reminder labeling
intended to provide price information to consumers are exempt from the
requirements of Secs. 201 .100 and 202.1 of this chapter if all of the
following conditions are met:
(1) The only purpose of the reminder advertisement or reminder
labeling is to provide consumers with information concerning the price
charged for a prescription for a particular drug product, and the
reminder advertisement or reminder labeling contains no representation
or suggestion concerning the drug product's safety, effectiveness, or
indications for use.
(2) The reminder advertisement or reminder labeling contains the
proprietary name of the drug product, if any; the established (generic)
name of the drug product, if any; the drug product's strength if the
product contains a single active ingredient or if the product contains
more than one active ingredient and a relevant strength can be
associated with the product without indicating each active ingredient
(the established name and quantity of each active ingredient are not
required); the dosage form; and the price charged for a prescription for
a specific quantity of the drug product.
(3) The reminder advertisement or reminder labeling may also include
other written, printed, or graphic matter,
[[Page 8]]
e.g., identification of professional or convenience services provided by
the pharmacy: Provided, That such information is neither false nor
misleading and contains no representation or suggestion concerning the
drug product's safety, effectiveness, or indications for use.
(4) The price stated in the reminder advertisement or reminder
labeling as that charged for a prescription shall include all charges to
the consumer including, but not limited to, the cost of the drug
product, professional fees, and handling fees, if any. Mailing fees and
delivery fees, if any, may be stated separately and without repetition.
(b) This exemption from Secs. 201.100 and 202.1 of this chapter is
applicable to all prescription drug reminder labeling and reminder
advertisements solely intended to provide consumers with information
regarding the price charged for prescriptions including price lists,
catalogs, and other promotional material, whether mailed, posted in a
pharmacy, placed in a newspaper, or aired on radio or television.
(c) Any reminder advertisement or reminder labeling intended to
provide consumers with prescription price information which is not in
compliance with this section shall be the subject of appropriate
regulatory action. Such action may be taken against the product and/or
the responsible person.
[40 FR 58799, Dec. 18, 1975]
PART 201--LABELING--Table of Contents
Subpart A--General Labeling Provisions
Sec.
201.1 Drugs; name and place of business of manufacturer, packer, or
distributor.
201.2 Drugs and devices; National Drug Code numbers.
201.5 Drugs; adequate directions for use.
201.6 Drugs; misleading statements.
201.10 Drugs; statement of ingredients.
201.15 Drugs; prominence of required label statements.
201.16 Drugs; Spanish-language version of certain required statements.
201.17 Drugs; location of expiration date.
201.18 Drugs; significance of control numbers.
201.19 Drugs; use of term ``infant''.
201.20 Declaration of presence of FD&C Yellow No. 5 and/or FD&C Yellow
No. 6 in certain drugs for human use.
201.21 Declaration of presence of phenylalanine as a component of
aspartame in over-the-counter and prescription drugs for human
use.
201.22 Prescription drugs containing sulfites; required warning
statements.
201.23 Required pediatric studies.
Subpart B--Labeling Requirements for Prescription Drugs and/or Insulin
201.50 Statement of identity.
201.51 Declaration of net quantity of contents.
201.55 Statement of dosage.
201.56 General requirements on content and format of labeling for human
prescription drugs.
201.57 Specific requirements on content and format of labeling for
human prescription drugs.
201.58 Requests for waiver of requirement for adequate and well-
controlled studies to substantiate certain labeling
statements.
201.59 Effective date of Secs. 201.56, 201.57, 201.100(d)(3), and
201.100(e).
Subpart C--Labeling Requirements for Over-the-Counter Drugs
201.60 Principal display panel.
201.61 Statement of identity.
201.62 Declaration of net quantity of contents.
201.63 Pregnancy/breast-feeding warning.
201.64 Sodium labeling.
201.66 Format and content requirements for over-the-counter (OTC) drug
product labeling.
Subpart D--Exemptions From Adequate Directions for Use
201.100 Prescription drugs for human use.
201.105 Veterinary drugs.
201.115 New drugs or new animal drugs.
201.116 Drugs having commonly known directions.
201.117 Inactive ingredients.
201.119 In vitro diagnostic products.
201.120 Prescription chemicals and other prescription components.
201.122 Drugs for processing, repacking, or manufacturing.
201.125 Drugs for use in teaching, law enforcement, research, and
analysis.
201.127 Drugs; expiration of exemptions.
201.128 Meaning of ``intended uses''.
201.129 Drugs; exemption for radioactive drugs for research use.
Subpart E--Other Exemptions
201.150 Drugs; processing, labeling, or repacking.
201.161 Carbon dioxide and certain other gases.
[[Page 9]]
Subpart F--Labeling Claims for Drugs in Drug Efficacy Study
201.200 Disclosure of drug efficacy study evaluations in labeling and
advertising.
Subpart G--Specific Labeling Requirements for Specific Drug Products
201.300 Notice to manufacturers, packers, and distributors of glandular
preparations.
201.301 Notice to manufacturers, packers, and distributors of
estrogenic hormone preparations.
201.302 Notice to manufacturers, packers, and distributors of drugs for
internal use which contain mineral oil.
201.303 Labeling of drug preparations containing significant
proportions of wintergreen oil.
201.304 Tannic acid and barium enema preparations.
201.305 Isoproterenol inhalation preparations (pressurized aerosols,
nebulizers, powders) for human use; warnings.
201.306 Potassium salt preparations intended for oral ingestion by man.
201.307 Sodium phosphates; package size limitation, warnings, and
directions for over-the-counter sale.
201.308 Ipecac syrup; warnings and directions for use for over-the-
counter sale.
201.309 Acetophenetidin (phenacetin)-containing preparations; necessary
warning statement.
201.310 Phenindione; labeling of drug preparations intended for use by
man.
201.311 [Reserved]
201.312 Magnesium sulfate heptahydrate; label declaration on drug
products.
201.313 Estradiol labeling.
201.314 Labeling of drug preparations containing salicylates.
201.315 Over-the-counter drugs for minor sore throats; suggested
warning.
201.316 Drugs with thyroid hormone activity for human use; required
warning.
201.317 Digitalis and related cardiotonic drugs for human use in oral
dosage forms; required warning.
201.319 Water-soluble gums, hydrophilic gums, and hydrophilic
mucilloids (including, but not limited to agar, alginic acid,
calcium polycarbophil, carboxymethylcellulose sodium,
carrageenan, chondrus, glucomannan ((B-1,4 linked) polymannose
acetate), guar gum, karaya gum, kelp, methylcellulose,
plantago seed (psyllium), polycarbophil tragacanth, and
xanthan gum) as active ingredients; required warnings and
directions.
201.320 Warning statements for drug products containing or manufactured
with chlorofluorocarbons or other ozone-depleting substances.
201.322 Over-the-counter drug products containing internal analgesic/
antipyretic active ingredients; required alcohol warning.
Appendix A to Part 201--Examples of Graphic Enhancements Used by FDA
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360, 360b,
360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.
Source: 40 FR 13998, Mar. 27, 1975, unless otherwise noted.
Subpart A--General Labeling Provisions
Sec. 201.1 Drugs; name and place of business of manufacturer, packer, or distributor.
(a) A drug or drug product (as defined in Sec. 320.1 of this
chapter) in finished package form is misbranded under section 502 (a)
and (b)(1) of the act if its label does not bear conspicuously the name
and place of business of the manufacturer, packer, or distributor. This
paragraph does not apply to any drug or drug product dispensed in
accordance with section 503(b)(1) of the act.
(b) As used in this section, and for purposes of section 502 (a) and
(b)(1) of the act, the manufacturer of a drug product is the person who
performs all of the following operations that are required to produce
the product: (1) Mixing, (2) granulating, (3) milling, (4) molding, (5)
lyophilizing, (6) tableting, (7) encapsulating, (8) coating, (9)
sterilizing, and (10) filling sterile, aerosol, or gaseous drugs into
dispensing containers.
(c) If no person performs all of the applicable operations listed in
paragraph (b) of this section, no person may be represented as
manufacturer except as follows:
(1) If the person performs more than one half of the applicable
operations listed in paragraph (b) of this section and acknowledges the
contribution of other persons who have performed the remaining
applicable operations by stating on the product label that ``Certain
manufacturing operations have been performed by other firms.''; or
(2) If the person performs at least one applicable operation listed
in paragraph (b) of this section and identifies by appropriate
designation all other
[[Page 10]]
persons who have performed the remaining applicable operations, e.g.,
``Made by (Person A), Filled by (Person B), Sterilized by (Person C)'';
or
(3) If the person performs at least one applicable operation listed
in paragraph (b) of this section and the person is listed along with all
other persons who have performed the remaining applicable operations as
``joint manufacturers.'' A list of joint manufacturers shall be
qualified by the phrase ``Jointly Manufactured By ____________,'' and
the names of all of the manufacturers shall be printed together in the
same type size and style; or
(4) If the person performs all applicable operations listed in
paragraph (b) of this section except for those operations listed in
paragraph (d) of this section. For purposes of this paragraph, person,
when it identifies a corporation, includes a parent, subsidiary, or
affiliate company where the related companies are under common ownership
and control.
(d) The Food and Drug Administration finds that it is the common
practice in the drug industry to contract out the performance of certain
manufacturing operations listed in paragraph (b) of this section. These
operations include: (1) Soft-gelatin encapsulating, (2) aerosol filling,
(3) sterilizing by irradiation, (4) lyophilizing, and (5) ethylene oxide
sterilization.
(e) A person performs an operation listed in paragraph (b) of this
section only if the operation is performed, including the performance of
the appropriate in-process quality control operations, except laboratory
testing of samples taken during processing, as follows:
(1) By individuals, a majority of whom are employees of the person
and, throughout the performance of the operation, are subject to the
person's direction and control;
(2) On premises that are continuously owned or leased by the person
and subject to the person's direction and control; and
(3) On equipment that is continuously owned or leased by the person.
As used in this paragraph, person, when it identifies a corporation,
includes a parent, subsidiary, or affiliate company where the related
companies are under common ownership and control.
(f) The name of the person represented as manufacturer under
paragraph (b) or (c) of this section must be the same as either (1) the
name of the establishment (as defined in Sec. 207.3(b) of this chapter)
under which that person is registered at the time the labeled product is
produced or (2) the registered establishment name of a parent,
subsidiary, or affiliate company where the related companies are under
common ownership and control. In addition, the name shall meet the
requirements of paragraph (g) of this section.
(g) The requirement for declaration of the name of the manufacturer,
packer, or distributor shall be deemed to be satisfied, in the case of a
corporate person, only by the actual corporate name, except that the
corporate name may be the name of a parent, subsidiary, or affiliate
company where the related companies are under common ownership and
control. The corporate name may be preceded or followed by the name of
the particular division of the corporation. ``Company,''
``Incorporated,'' etc., may be abbreviated or omitted and ``The'' may be
omitted. In the case of an individual, partnership, or association, the
name under which the business is conducted shall be used.
(h)(1) Except as provided in this section, no person other than the
manufacturer, packer, or distributor may be identified on the label of a
drug or drug product.
(2) The appearance on a drug product label of a person's name
without qualification is a representation that the named person is the
sole manufacturer of the product. That representation is false and
misleading, and the drug product is misbranded under section 502(a) of
the act, if the person is not the manufacturer of the product in
accordance with this section.
(3) If the names of two or more persons appear on the label of a
drug or drug product, the label may identify which of the persons is to
be contacted for further information about the product.
(4) If a trademark appears on the drug or drug product label or
appears as a mark directly on the drug product
[[Page 11]]
(e.g., tablet or capsule), the label may identify the holder or licensee
of the trademark. The label may also state whether the person identified
holds the trademark or is licensee of the trademark.
(5) If the distributor is named on the label, the name shall be
qualified by one of the following phrases: ``Manufactured for
____________'', ``Distributed by ____________'', ``Manufactured by
____________ for ____________'', ``Manufactured for __________by
__________'', ``Distributor: ____________'', ``Marketed by
____________''. The qualifying phrases may be abbreviated.
(6) If the packer is identified on the label, the name shall be
qualified by the phrase ``Packed by ____________'' or ``Packaged by
____________''. The qualifying phrases may be abbreviated.
(i) The statement of the place of business shall include the street
address, city, State, and ZIP Code. For a foreign manufacturer, the
statement of the place of business shall include the street address,
city, country, and any applicable mailing code. The street address may
be omitted if it is shown in a current city directory or telephone
directory. The requirement for inclusion of the ZIP Code shall apply to
consumer commodity labels developed or revised after July 1, 1969. In
the case of nonconsumer packages, the ZIP Code shall appear either on
the label or the labeling (including the invoice).
(j) If a person manufactures, packs, or distributes a drug or drug
product at a place other than the person's principal place of business,
the label may state the principal place of business in lieu of the
actual place where such drug or drug product was manufactured or packed
or is to be distributed, unless such statement would be misleading.
(k) Paragraphs (b), (c), (d), (e), and (f) of this section, do not
apply to the labeling of drug components.
(l) A drug product is misbranded under section 502(a) of the act if
its labeling identifies a person as manufacturer, packer, or
distributor, and that identification does not meet the requirements of
this section.
(m) This section does not apply to biological drug products that are
subject to the requirements of section 351 of the Public Health Service
Act, 42 U.S.C. 262.
[45 FR 25775, Apr. 15, 1980; 45 FR 72118, Oct. 31, 1980, as amended at
48 FR 37620, Aug. 19, 1983]
Sec. 201.2 Drugs and devices; National Drug Code numbers.
The National Drug Code (NDC) number is requested but not required to
appear on all drug labels and in all drug labeling, including the label
of any prescription drug container furnished to a consumer. If the NDC
number is shown on a drug label, it shall be displayed as required in
Sec. 207.35(b)(3) of this chapter.
[40 FR 52002, Nov. 7, 1975]
Sec. 201.5 Drugs; adequate directions for use.
Adequate directions for use means directions under which the layman
can use a drug safely and for the purposes for which it is intended.
(Section 201.128 defines ``intended use.'') Directions for use may be
inadequate because, among other reasons, of omission, in whole or in
part, or incorrect specification of:
(a) Statements of all conditions, purposes, or uses for which such
drug is intended, including conditions, purposes, or uses for which it
is prescribed, recommended, or suggested in its oral, written, printed,
or graphic advertising, and conditions, purposes, or uses for which the
drug is commonly used; except that such statements shall not refer to
conditions, uses, or purposes for which the drug can be safely used only
under the supervision of a practitioner licensed by law and for which it
is advertised solely to such practitioner.
(b) Quantity of dose, including usual quantities for each of the
uses for which it is intended and usual quantities for persons of
different ages and different physical conditions.
(c) Frequency of administration or application.
(d) Duration of administration or application.
(e) Time of administration or application (in relation to time of
meals, time of onset of symptoms, or other time factors).
(f) Route or method of administration or application.
[[Page 12]]
(g) Preparation for use, i.e., shaking, dilution, adjustment of
temperature, or, other manipulation or process.
[41 FR 6908, Feb. 13, 1976]
Sec. 201.6 Drugs; misleading statements.
(a) Among representations in the labeling of a drug which render
such drug misbranded is a false or misleading representation with
respect to another drug or a device or a food or cosmetic.
(b) The labeling of a drug which contains two or more ingredients
may be misleading by reason, among other reasons, of the designation of
such drug in such labeling by a name which includes or suggests the name
of one or more but not all such ingredients, even though the names of
all such ingredients are stated elsewhere in the labeling.
[41 FR 6908, Feb. 13, 1976]
Sec. 201.10 Drugs; statement of ingredients.
(a) The ingredient information required by section 502(e) of the
Federal Food, Drug, and Cosmetic Act shall appear together, without any
intervening written, printed, or graphic matter, except the proprietary
names of ingredients, which may be included with the listing of
established names, and such statements as ``Warning--May be habit
forming'' that are specifically required for certain ingredients by the
act or regulations in this chapter.
(b) The term ingredient applies to any substance in the drug,
whether added to the formulation as a single substance or in admixture
with other substances.
(c) The labeling of a drug may be misleading by reason (among other
reasons) of:
(1) The order in which the names of the ingredients present in the
drug appear in the labeling, or the relative prominence otherwise given
such names.
(2) Failure to reveal the proportion of, or other fact with respect
to, an ingredient present in such drug, when such proportion or other
fact is material in the light of the representation that such ingredient
is present in such drug.
(3) The employment of a fanciful proprietary name for a drug or
ingredient in such a manner as to imply that the drug or ingredient has
some unique effectiveness or composition when, in fact, the drug or
ingredient is a common substance, the limitations of which are readily
recognized when the drug or ingredient is listed by its established
name.
(4) The featuring in the labeling of inert or inactive ingredients
in a manner that creates an impression of value greater than their true
functional role in the formulation.
(5) Designation of a drug or ingredient by a proprietary name that,
because of similarity in spelling or pronunciation, may be confused with
the proprietary name or the established name of a different drug or
ingredient.
(d)(1) If the drug is in tablet or capsule form or other unit dosage
form, any statement of the quantity of an ingredient contained therein
shall express the quantity of such ingredient in each such unit. If the
drug is not in unit dosage form, any statement of the quantity of an
ingredient contained therein shall express the amount of such ingredient
in a specified unit of weight or measure of the drug, or the percentage
of such ingredient in such drug. Such statements shall be in terms that
are informative to licensed practitioners, in the case of a prescription
drug, and to the layman, in the case of a nonprescription drug.
(2) A statement of the percentage of an ingredient in a drug shall,
if the term percent is used without qualification, mean percent weight-
in-weight, if the ingredient and the drug are both solids, or if the
ingredient is a liquid and the drug is a solid; percent weight in volume
at 68 deg.F. (20 deg.C.), if the ingredient is a solid and the drug is
a liquid; and percent volume in volume at 68 deg.F. (20 deg.C.), if
both the ingredient and the drug are liquids, except that alcohol shall
be stated in terms of percent volume of absolute alcohol at 60 deg.F.
(15.56 deg.C.).
(e) A derivative or preparation of a substance named in section
502(e) of the act is an article derived or prepared from such substance
by any method, including actual or theoretical chemical action.
[[Page 13]]
(f) If an ingredient is a derivative or preparation of a substance
specifically named in section 502(e) of the act and the established name
of such ingredient does not indicate that it is a derivative or
preparation of the parent substance named in section 502(e) of the act,
the labeling shall, in conjunction with the listing of the established
name of such ingredient, declare that such article is a derivative or
preparation of such parent substance.
(g)(1) If the label or labeling of a prescription drug bears a
proprietary name or designation for the drug or any ingredient thereof,
the established name, if such there be, corresponding to such
proprietary name or designation shall accompany such proprietary name or
designation each time it is featured on the label or in the labeling for
the drug; but, except as provided in this subparagraph, the established
name need not be used with the proprietary name or designation in the
running text of the label or labeling. On any label or page of labeling
in which the proprietary name or designation is not featured but is used
in the running text, the established name shall be used at least once in
the running text in association with such proprietary name or
designation and in the same type size used in such running text:
Provided, however, That if the proprietary name or designation is used
in the running text in larger size type, the established name shall be
used at least once in association with, and in type at least half as
large as the type used for, the most prominent presentation of the
proprietary name or designation in such running text. If any labeling
includes a column with running text containing detailed information as
to composition, prescribing, side effects, or contraindications and the
proprietary name or designation is used in such column but is not
featured above or below the column, the established name shall be used
at least once in such column of running text in association with such
proprietary name or designation and in the same type size used in such
column of running text: Provided, however, That if the proprietary name
or designation is used in such column of running text in larger size
type, the established name shall be used at least once in association
with, and in type at least half as large as the type used for, the most
prominent presentation of the proprietary name or designation in such
column of running text. Where the established name is required to
accompany or to be used in association with the proprietary name or
designation, the established name shall be placed in direct conjunction
with the proprietary name or designation, and the relationship between
the proprietary name or designation and the established name shall be
made clear by use of a phrase such as ``brand of'' preceding the
established name, by brackets surrounding the established name, or by
other suitable means.
(2) The established name shall be printed in letters that are at
least half as large as the letters comprising the proprietary name or
designation with which it is joined, and the established name shall have
a prominence commensurate with the prominence with which such
proprietary name or designation appears, taking into account all
pertinent factors, including typography, layout, contrast, and other
printing features.
(h)(1) In the case of a prescription drug containing two or more
active ingredients, if the label bears a proprietary name or designation
for such mixture and there is no established name corresponding to such
proprietary name or designation, the quantitative ingredient information
required on the label by section 502(e) of the act shall be placed in
direct conjunction with the most prominent display of the proprietary
name or designation. The prominence of the quantitative ingredient
information shall bear a reasonable relationship to the prominence of
the proprietary name.
(2) If the drug is packaged in a container too small to bear the
quantitative ingredient information on the main display panel, the
quantitative ingredient information required by section 502(e) of the
act may appear elsewhere on the label, even though the proprietary name
or designation appears on the main display panel of the label; but side-
or back-panel placement shall in this case be so arranged and printed as
to provide size and
[[Page 14]]
prominence of display reasonably related to the size and prominence of
the front-panel display.
(i) A drug packaged in a container too small or otherwise unable to
accommodate a label with sufficient space to bear the information
required for compliance with section 502(e)(1) (A)(ii) and (B) of the
act shall be exempt from compliance with those clauses: Provided, That:
(1) The label bears:
(i) The proprietary name of the drug;
(ii) The established name, if such there be, of the drug;
(iii) An identifying lot or control number; and
(iv) The name of the manufacturer, packer, or distributor of the
drug; and
(2) All the information required to appear on the label by the act
and the regulations in this chapter appears on the carton or other outer
container or wrapper if such carton, outer container, or wrapper has
sufficient space to bear such information, or such complete label
information appears on a leaflet with the package.
Sec. 201.15 Drugs; prominence of required label statements.
(a) A word, statement, or other information required by or under
authority of the act to appear on the label may lack that prominence and
conspicuousness required by section 502(c) of the act by reason, among
other reasons, of:
(1) The failure of such word, statement, or information to appear on
the part or panel of the label which is presented or displayed under
customary conditions of purchase;
(2) The failure of such word, statement, or information to appear on
two or more parts or panels of the label, each of which has sufficient
space therefor, and each of which is so designed as to render it likely
to be, under customary conditions of purchase, the part or panel
displayed;
(3) The failure of the label to extend over the area of the
container or package available for such extension, so as to provide
sufficient label space for the prominent placing of such word,
statement, or information;
(4) Insufficiency of label space for the prominent placing of such
word, statement, or information, resulting from the use of label space
for any word, statement, design, or device which is not required by or
under authority of the act to appear on the label;
(5) Insufficiency of label space for the prominent placing of such
word, statement, or information, resulting from the use of label space
to give materially greater conspicuousness to any other word, statement,
or information, or to any design or device; or
(6) Smallness or style of type in which such word, statement, or
information appears, insufficient background contrast, obscuring designs
or vignettes, or crowding with other written, printed, or graphic
matter.
(b) No exemption depending on insufficiency of label space, as
prescribed in regulations promulgated under section 502 (b) or (e) of
the act, shall apply if such insufficiency is caused by:
(1) The use of label space for any word, statement, design, or
device which is not required by or under authority of the act to appear
on the label;
(2) The use of label space to give greater conspicuousness to any
word, statement, or other information than is required by section 502(c)
of the act; or
(3) The use of label space for any representation in a foreign
language.
(c)(1) All words, statements, and other information required by or
under authority of the act to appear on the label or labeling shall
appear thereon in the English language: Provided, however, That in the
case of articles distributed solely in the Commonwealth of Puerto Rico
or in a Territory where the predominant language is one other than
English, the predominant language may be substituted for English.
(2) If the label contains any representation in a foreign language,
all words, statements, and other information required by or under
authority of the act to appear on the label shall appear thereon in the
foreign language.
(3) If the labeling contains any representation in a foreign
language, all words, statements, and other information required by or
under authority of the act to appear on the label or labeling shall
appear on the labeling in the foreign language.
[41 FR 6908, Feb. 13, 1976]
[[Page 15]]
Sec. 201.16 Drugs; Spanish-language version of certain required statements.
An increasing number of medications restricted to prescription use
only are being labeled solely in Spanish for distribution in the
Commonwealth of Puerto Rico where Spanish is the predominant language.
Such labeling is authorized under Sec. 201.15(c). Two required warnings,
the wording of which is fixed by law in the English language, are
presently being translated in various ways, from literal translation to
loose interpretation. The statutory nature of these two statements
requires that the translation must convey the meaning properly, in order
to avoid confusion and dilution of the purposes of the warnings. The
Commissioner of Food and Drugs hereby adopts the following Spanish-
language versions as the accepted equivalents of the English wording of
the following:
(a) Section 503(b)(4) of the Federal Food, Drug, and Cosmetic Act
requires the statement ``Caution: Federal law prohibits dispensing
without prescription.'' The Spanish version of this shall be:
``Precaucion: La ley Federal prohibe su despacho sin prescripcion
facultativa.''
(b) Section 502(d) of the Federal Food, Drug, and Cosmetic Act
requires the statement ``Warning--May be habit forming'' on habit-
forming drugs. The Spanish version of this shall be: ``Aviso--Puede
formar habito o vicio.''
[41 FR 6908, Feb. 13, 1976]
Sec. 201.17 Drugs; location of expiration date.
When an expiration date of a drug is required, e.g., expiration
dating of drug products required by Sec. 211.137 of this chapter, it
shall appear on the immediate container and also the outer package, if
any, unless it is easily legible through such outer package. However,
when single-dose containers are packed in individual cartons, the
expiration date may properly appear on the individual carton instead of
the immediate product container.
[43 FR 45076, Sept. 29, 1978]
Sec. 201.18 Drugs; significance of control numbers.
The lot number on the label of a drug should be capable of yielding
the complete manufacturing history of the package. An incorrect lot
number may be regarded as causing the article to be misbranded.
Sec. 201.19 Drugs; use of term ``infant''.
The regulations affecting special dietary foods (Sec. 105.3(e) of
this chapter) define an infant as a child not more than 12 months old.
Apart from this, the Food and Drug Administration has not established
any definition of the term infant. Some question has arisen whether, for
the purposes of drug labeling, an infant means a child up to 1 year of
age or a child up to 2 years of age. Until the term is more precisely
defined by legislation or formal regulation, where the exact meaning of
the term is significant, manufacturers should qualify any reference to
``infant'' to indicate whether it refers to a child who is not more than
1 year of age, or a child not more than 2 years of age.
[40 FR 13998, Mar. 27, 1975, as amended at 42 FR 14091, Mar. 15, 1977;
44 FR 16006, Mar. 16, 1979]
Sec. 201.20 Declaration of presence of FD&C Yellow No. 5 and/or FD&C Yellow No. 6 in certain drugs for human use.
(a) The label for over-the-counter and prescription drug products
intended for human use administered orally, nasally, rectally, or
vaginally, or for use in the area of the eye, containing FD&C Yellow No.
5 as a color additive using the names FD&C Yellow No. 5 and tartrazine.
The labeling for over-the-counter and prescription drug products shall
bear a statement such as ``Contains FD&C Yellow No. 5 (tartrazine) as a
color additive'' or ``Contains color additives including FD&C Yellow No.
5 (tartrazine)''. The labels of certain drug products subject to this
labeling requirement that are also cosmetics, such as antibacterial
mouthwashes and fluoride toothpastes, need not comply with this
requirement provided they comply with the requirements of Sec. 701.3 of
this chapter.
[[Page 16]]
(b) For prescription drugs for human use containing FD&C Yellow No.
5 that are administered orally, nasally, vaginally, or rectally, or for
use in the area of the eye, the labeling required by Sec. 201.100(d)
shall bear the warning statement ``This product contains FD&C Yellow No.
5 (tartrazine) which may cause allergic-type reactions (including
bronchial asthma) in certain susceptible persons. Although the overall
incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general
population is low, it is frequently seen in patients who also have
aspirin hypersensitivity.'' This warning statement shall appear in the
``Precautions'' section of the labeling.
(c) The label for over-the-counter drug products intended for human
use administered orally, nasally, rectally, or vaginally containing FD&C
Yellow No. 6 shall specifically declare the presence of FD&C Yellow No.
6 by listing the color additive using the name FD&C Yellow No. 6. The
labeling for over-the-counter and prescription drug products containing
FD&C Yellow No. 6 shall declare the presence of FD&C Yellow No. 6. The
labels of certain drug products subject to this labeling requirement
that are also cosmetics, such as antibacterial mouthwashes and fluoride
toothpastes, need not comply with this requirement provided they comply
with the requirements of Sec. 701.3 of this chapter.
[45 FR 60422, Sept. 12, 1980, as amended at 51 FR 41783, Nov. 19, 1986;
52 FR 21509, June 8, 1987; 59 FR 60898, Nov. 29, 1994]
Effective Date Note: At 53 FR 49138, Dec. 6, 1988, Sec. 201.20(c)
was suspended pending further agency action.
Sec. 201.21 Declaration of presence of phenylalanine as a component of aspartame in over-the-counter and prescription drugs for human use.
(a) Aspartame is the methylester of a dipeptide composed of two
amino acids, phenylalanine and aspartic acid. When these two amino acids
are so combined to form aspartame (1-methyl N-L--aspartyl-L-
phenylalanine), they produce an intensely sweet-tasting substance,
approximately 180 times as sweet as sucrose. The Food and Drug
Administration has determined that aspartame when used at a level no
higher than reasonably required to perform its intended technical
function is safe for use as an inactive ingredient in human drug
products, provided persons with phenylketonuria, who must restrict
carefully their phenylalanine intake, are alerted to the presence of
phenylalanine in the drug product and the amount of the ingredient in
each dosage unit.
(b) The label and labeling of all over-the-counter human drug
products containing aspartame as an inactive ingredient shall bear a
statement to the following effect: Phenylketonurics: Contains
Phenylalanine (__)mg Per (Dosage Unit).
(c) The package labeling and other labeling providing professional
use information concerning prescription drugs for human use containing
aspartame as an inactive ingredient shall bear a statement to the
following effect under the ``Precautions'' section of the labeling, as
required in Sec. 201.57(f)(2): Phenylketonurics: Contains Phenylalanine
(__)mg Per (Dosage Unit).
(d) Holders of approved new drug applications who reformulate their
drug products under the provisions of this section shall submit
supplements under Sec. 314.70 of this chapter to provide for the new
composition and the labeling changes.
(Approved by the Office of Management and Budget under control number
0910-0242)
[52 FR 2111, Jan. 20, 1987; 52 FR 12152, April 15, 1987; 53 FR 4135,
Feb. 12, 1988]
Sec. 201.22 Prescription drugs containing sulfites; required warning statements.
(a) Sulfites are chemical substances that are added to certain drug
products to inhibit the oxidation of the active drug ingredient.
Oxidation of the active drug ingredient may result in instability and a
loss of potency of the drug product. Examples of specific sulfites used
to inhibit this oxidation process include sodium bisulfite, sodium
metabisulfite, sodium sulfite, potassium bisulfite, and potassium
metabisulfite. Recent studies have demonstrated that sulfites may cause
allergic-type reactions in certain susceptible persons, especially
asthmatics. The labeling for any prescription drug
[[Page 17]]
product to which sulfites have been added as an inactive ingredient,
regardless of the amount added, must bear the warning specified in
paragraph (b) or (c) of this section.
(b) The labeling required by Secs. 201.57 and 201.100(d) for
prescription drugs for human use containing a sulfite, except
epinephrine for injection when intended for use in allergic or other
emergency situations, shall bear the warning statement ``Contains
(insert the name of the sulfite, e.g., sodium metabisulfite), a sulfite
that may cause allergic-type reactions including anaphylactic symptoms
and life-threatening or less severe asthmatic episodes in certain
susceptible people. The overall prevalence of sulfite sensitivity in the
general population is unknown and probably low. Sulfite sensitivity is
seen more frequently in asthmatic than in nonasthmatic people.'' This
statement shall appear in the ``Warnings'' section of the labeling.
(c) The labeling required by Secs. 201.57 and 201.100(d) for
sulfite-containing epinephrine for injection for use in allergic
emergency situations shall bear the warning statement ``Epinephrine is
the preferred treatment for serious allergic or other emergency
situations even though this product contains (insert the name of the
sulfite, e.g., sodium metabisulfite), a sulfite that may in other
products cause allergic-type reactions including anaphylactic symptoms
or life-threatening or less severe asthmatic episodes in certain
susceptible persons. The alternatives to using epinephrine in a life-
threatening situation may not be satisfactory. The presence of a
sulfite(s) in this product should not deter administration of the drug
for treatment of serious allergic or other emergency situations.'' This
statement shall appear in the ``Warnings'' section of the labeling.
[51 FR 43904, Dec. 5, 1986]
Sec. 201.23 Required pediatric studies.
(a) A manufacturer of a marketed drug product, including a
biological drug product, that is used in a substantial number of
pediatric patients, or that provides a meaningful therapeutic benefit
over existing treatments for pediatric patients, as defined in
Secs. 314.55(c)(5) and 601.27(c)(5) of this chapter, but whose label
does not provide adequate information to support its safe and effective
use in pediatric populations for the approved indications may be
required to submit an application containing data adequate to assess
whether the drug product is safe and effective in pediatric populations.
The application may be required to contain adequate evidence to support
dosage and administration in some or all pediatric subpopulations,
including neonates, infants, children, and adolescents, depending upon
the known or appropriate use of the drug product in such subpopulations.
The applicant may also be required to develop a pediatric formulation
for a drug product that represents a meaningful therapeutic benefit over
existing therapies for pediatric populations for whom a pediatric
formulation is necessary, unless the manufacturer demonstrates that
reasonable attempts to produce a pediatric formulation have failed.
(b) The Food and Drug Administration (FDA) may by order, in the form
of a letter, after notifying the manufacturer of its intent to require
an assessment of pediatric safety and effectiveness of a pediatric
formulation, and after offering an opportunity for a written response
and a meeting, which may include an advisory committee meeting, require
a manufacturer to submit an application containing the information or
request for approval of a pediatric formulation described in paragraph
(a) of this section within a time specified in the order, if FDA finds
that:
(1) The drug product is used in a substantial number of pediatric
patients for the labeled indications and the absence of adequate
labeling could pose significant risks to pediatric patients; or
(2) There is reason to believe that the drug product would represent
a meaningful therapeutic benefit over existing treatments for pediatric
patients for one or more of the claimed indications, and the absence of
adequate labeling could pose significant risks to pediatric patients.
(c)(1) An applicant may request a full waiver of the requirements of
paragraph (a) of this section if the applicant certifies that:
[[Page 18]]
(i) Necessary studies are impossible or highly impractical because,
e.g., the number of such patients is so small or geographically
dispersed, or
(ii) There is evidence strongly suggesting that the product would be
ineffective or unsafe in all pediatric age groups.
(2) An applicant may request a partial waiver of the requirements of
paragraph (a) of this section with respect to a specified pediatric age
group, if the applicant certifies that:
(i) The product:
(A) Does not represent a meaningful therapeutic benefit over
existing therapies for pediatric patients in that age group, and
(B) Is not likely to be used in a substantial number of patients in
that age group, and
(C) The absence of adequate labeling could not pose significant
risks to pediatric patients; or
(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, or
(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.
(3) FDA shall grant a full or partial waiver, as appropriate, if the
agency finds that there is a reasonable basis on which to conclude that
one or more of the grounds for waiver specified in paragraphs (c)(2) or
(c)(3) of this section have been met. If a waiver is granted on the
ground that it is not possible to develop a pediatric formulation, the
waiver will cover only those pediatric age groups requiring that
formulation. If a waiver is granted because there is evidence that the
product would be ineffective or unsafe in pediatric populations, this
information will be included in the product's labeling.
(d) If a manufacturer fails to submit a supplemental application
containing the information or request for approval of a pediatric
formulation described in paragraph (a) of this section within the time
specified by FDA, the drug product may be considered misbranded or an
unapproved new drug or unlicensed biologic.
[63 FR 66668, Dec. 2, 1998]
Subpart B--Labeling Requirements for Prescription Drugs and/or Insulin
Sec. 201.50 Statement of identity.
(a) The label of prescription and insulin-containing drugs in
package form shall bear as one of its principal features a statement of
the identity of the drug.
(b) Such statement of identity shall be in terms of the established
name of the drug. In the case of a prescription drug that is a mixture
and that has no established name, the requirement for statement of
identity shall be deemed to be satisfied by a listing of the
quantitative ingredient information as prescribed by Sec. 201.10.
(c) The statement of identity of a prescription drug shall also
comply with the placement, size and prominence requirements of
Sec. 201.10.
[40 FR 13998, Mar. 27, 1975, as amended at 63 FR 26698, May 13, 1998]
Sec. 201.51 Declaration of net quantity of contents.
(a) The label of a prescription or insulin-containing drug in
package form shall bear a declaration of the net quantity of contents.
This shall be expressed in the terms of weight, measure, numerical
count, or a combination of numerical count and weight or measure. The
statement of quantity of drugs in tablet, capsule, ampule, or other unit
dosage form shall be expressed in terms of numerical count; the
statement of quantity for drugs in other dosage forms shall be in terms
of weight if the drug is solid, semi-solid, or viscous, or in terms of
fluid measure if the drug is liquid. When the drug quantity statement is
in terms of the numerical count of the drug units, it shall be augmented
to give the weight or measure of the drug units or the quantity of each
active ingredient in each drug unit or, when quantity does not
accurately reflect drug potency, a statement of the drug potency.
(b) Statements of weight of the contents shall in the case of
prescription
[[Page 19]]
drugs be expressed in terms of avoirdupois pound, ounce, and grain or of
kilogram, gram, and subdivisions thereof. A statement of liquid measure
of the contents shall in the case of prescription drugs be expressed in
terms of the U.S. gallon of 231 cubic inches and quart, pint, fluid-
ounce, and fluid-dram subdivisions thereof, or of the liter and
milliliter, or cubic centimeter, and shall express the volume at 68
deg.F. (20 deg.C.). A statement of the liquid measure of the contents
in the case of insulin-containing drugs shall be expressed in terms of
the liter and milliliter, or cubic centimeter, and shall express the
volume at 68 deg.F. (20 deg.C.).
(c) The declaration shall contain only such fractions as are
generally used in expressing the quantity of the drug. A common fraction
shall be reduced to its lowest terms; a decimal fraction shall not be
carried out to more than three places, except in the case of a statement
of the quantity of an active ingredient in a unit of a drug.
(d) The declaration shall appear as a distinct item on the label
and, in the case of large volume parenterals, may be embossed on the
glass.
(e) The declaration shall accurately reveal the quantity of drug in
the package exclusive of wrappers and other material packed therewith.
(f) A statement of the quantity of a prescription or insulin-
containing drug in terms of weight or measure applicable to such drug,
under the provisions of paragraph (a) of this section, shall express
with prominence and conspicuousness the number of the largest whole
unit, as specified in paragraph (b) of this section, that are contained
in the package. Any remainder shall be expressed in terms of common or
decimal fractions of such unit or in terms of the next smaller whole
unit and common or decimal fractions thereof.
(g) The declaration of net quantity of contents shall express an
accurate statement of the quantity of contents of the package.
Reasonable variations caused by loss or gain of moisture during the
course of good distribution practice or by unavoidable deviations in
good manufacturing practice will be recognized. Variations from stated
quantity of contents shall not be unreasonably large. In the case of a
liquid drug in ampules or vials, intended for injection, the declaration
shall be considered to express the minimum quantity and the variation
above the stated measure shall comply with the excess volume prescribed
by the National Formulary or the U.S. Pharmacopeia for filling of
ampules. In the case of a solid drug in ampules or vials, the
declaration shall be considered to express the accurate net weight.
Variations shall comply with the limitations provided in the U.S.
Pharmacopeia or the National Formulary.
(h) A drug shall be exempt from compliance with the net quantity
declaration required by this section if it is an ointment labeled
``sample'', ``physician's sample'', or a substantially similar statement
and the contents of the package do not exceed 8 grams.
Sec. 201.55 Statement of dosage.
Section 201.100(b)(2) requires that labels for prescription drugs
bear a statement of the recommended or usual dosage. Since the dosage
for some prescription drugs varies within extremely wide limits,
depending upon the conditions being treated, it may not be possible in
all cases to present an informative or useful statement of the
recommended or usual dosage in the space available on the label or
carton of the package. It is the view of the Food and Drug
Administration that when such a situation prevails, compliance with this
requirement would be met by a statement such as ``See package insert for
dosage information'', where the detailed information is contained in
such insert. However, if an informative, realistic, recommended or usual
dosage can readily be set forth on the label, it should appear thereon.
Sec. 201.56 General requirements on content and format of labeling for human prescription drugs.
Prescription drug labeling described in Sec. 201.100(d) shall
contain the information in the format required by Sec. 201.57 and shall
meet the following general requirements:
(a) The labeling shall contain a summary of the essential scientific
information needed for the safe and effective use of the drug.
[[Page 20]]
(b) The labeling shall be informative and accurate and neither
promotional in tone nor false or misleading in any particular.
(c) The labeling shall be based whenever possible on data derived
from human experience. No implied claims or suggestions of drug use may
be made if there is inadequate evidence of safety or a lack of
substantial evidence of effectiveness. Conclusions based on animal data
but necessary for safe and effective use of the drug in humans shall be
identified as such and included with human data in the appropriate
section of the labeling, headings for which are listed in paragraph (d)
of this section.
(d)(1) The labeling shall contain specific information required
under Sec. 201.57 under the following section headings and in the
following order:
Description.
Clinical Pharmacology.
Indications and Usage.
Contraindications.
Warnings.
Precautions.
Adverse Reactions.
Drug Abuse and Dependence.
Overdosage.
Dosage and Administration.
How Supplied.
(2) The labeling may contain the following additional section
headings if appropriate and if in compliance with Sec. 201.57 (l) and
(m):
Animal Pharmacology and/or Animal Toxicology.
Clinical Studies.
References.
(3) The labeling may omit any section or subsection of the labeling
format if clearly inapplicable.
(4) The labeling may contain a ``Product Title'' section preceding
the ``Description'' section and containing only the information required
by Sec. 201.57(a)(1)(i), (ii), (iii), and (iv) and Sec. 201.100(e). The
information required by Sec. 201.57(a)(1)(i), (ii), (iii), and (iv)
shall appear in the ``Description'' section of the labeling, whether or
not it also appears in a ``Product Title.''
(e) The labeling shall contain the date of the most recent revision
of the labeling, identified as such, placed prominently immediately
after the last section of the labeling.
[44 FR 37462, June 26, 1979]
Sec. 201.57 Specific requirements on content and format of labeling for human prescription drugs.
Each section heading listed in Sec. 201.56(d), if not omitted under
Sec. 201.56(d)(3), shall contain the following information in the
following order:
(a) Description. (1) Under this section heading, the labeling shall
contain:
(i) The proprietary name and the established name, if any, as
defined in section 502(e)(2) of the act, of the drug;
(ii) The type of dosage form and the route of administration to
which the labeling applies;
(iii) The same qualitative and/or quantitative ingredient
information as required under Sec. 201.100(b) for labels;
(iv) If the product is sterile, a statement of that fact;
(v) The pharmacological or therapeutic class of the drug;
(vi) The chemical name and structural formula of the drug;
(vii) If the product is radioactive, a statement of the important
nuclear physical characteristics, such as the principal radiation
emission data, external radiation, and physical decay characteristics.
(2) If appropriate, other important chemical or physical
information, such as physical constants, or pH, shall be stated.
(b) Clinical Pharmacology. (1) Under this section heading, the
labeling shall contain a concise factual summary of the clinical
pharmacology and actions of the drug in humans. The summary may include
information based on in vitro and/or animal data if the information is
essential to a description of the biochemical and/or physiological mode
of action of the drug or is otherwise pertinent to human therapeutics.
Pharmacokinetic information that is important to safe and effective use
of the drug is required, if known, e.g., degree and rate of absorption,
pathways of biotransformation, percentage of dose as unchanged drug and
metabolites, rate or half-time of elimination, concentration in body
fluids associated with therapeutic and/or toxic effects,
[[Page 21]]
degree of binding to plasma proteins, degree of uptake by a particular
organ or in the fetus, and passage across the blood brain barrier.
Inclusion of pharmacokinetic information is restricted to that which
relates to clinical use of the drug. If the pharmacological mode of
action of the drug is unknown or if important metabolic or
pharmacokinetic data in humans are unavailable, the labeling shall
contain a statement about the lack of information.
(2) Data that demonstrate activity or effectiveness in in vitro or
animal tests and that have not been shown by adequate and well-
controlled clinical studies to be pertinent to clinical use may be
included under this section of the labeling only under the following
circumstances:
(i) In vitro data for anti-infective drugs may be included if the
data are immediately preceded by the statement ``The following in vitro
data are available but their clinical significance is unknown.''
(ii) For other classes of drugs, in vitro and animal data that have
not been shown by adequate and well-controlled clinical studies, as
defined in Sec. 314.126(b) of this chapter, to be pertinent to clinical
use may be used only if a waiver is granted under Sec. 201.58 or
Sec. 314.126(b) of this chapter.
(c) Indications and Usage. (1) Under this section heading, the
labeling shall state that:
(i) The drug is indicated in the treatment, prevention, or diagnosis
of a recognized disease or condition, e.g., penicillin is indicated for
the treatment of pneumonia due to susceptible pneumococci; and/or
(ii) The drug is indicated for the treatment, prevention, or
diagnosis of an important manifestation of a disease or condition, e.g.,
chlorothiazide is indicated for the treatment of edema in patients with
congestive heart failure; and/or
(iii) The drug is indicated for the relief of symptoms associated
with a disease or syndrome, e.g., chlorpheniramine is indicated for the
symptomatic relief of nasal congestion in patients with vasomotor
rhinitis; and/or
(iv) The drug, if used for a particular indication only in
conjuction with a primary mode of therapy, e.g., diet, surgery, or some
other drug, is an adjunct to the mode of therapy.
(2) All indications shall be supported by substantial evidence of
effectiveness based on adequate and well-controlled studies as defined
in Sec. 314.126(b) of this chapter unless the requirement is waived
under Sec. 201.58 or Sec. 314.126(b) of this chapter.
(3) This section of the labeling shall also contain the following
additional information:
(i) If evidence is available to support the safety and effectiveness
of the drug only in selected subgroups of the larger population with a
disease, syndrome, or symptom under consideration, e.g., patients with
mild disease or patients in a special age group, the labeling shall
describe the available evidence and state the limitations of usefulness
of the drug. The labeling shall also identify specific tests needed for
selection or monitoring of the patients who need the drug, e.g., microbe
susceptibility tests. Information on the approximate kind, degree, and
duration of improvement to be anticipated shall be stated if available
and shall be based on substantial evidence derived from adequate and
well-controlled studies as defined in Sec. 314.126(b) of this chapter
unless the requirement is waived under Sec. 201.58 or Sec. 314.126(b) of
this chapter. If the information is relevant to the recommended
intervals between doses, the usual duration of treatment, or any
modification of dosage, it shall be stated in the ``Dosage and
Administration'' section of the labeling and referenced in this section.
(ii) If safety considerations are such that the drug should be
reserved for certain situations, e.g., cases refractory to other drugs,
this information shall be stated in this section.
(iii) If there are specific conditions that should be met before the
drug is used on a long-term basis, e.g., demonstration of responsiveness
to the drug in a short-term trial, the labeling shall identify the
conditions; or, if the indications for long-term use are different from
those for short-term use, the labeling shall identify the specific
indications for each use.
(iv) If there is a common belief that the drug may be effective for
a certain
[[Page 22]]
use or if there is a common use of the drug for a condition, but the
preponderance of evidence related to the use or condition shows that the
drug is ineffective, the Food and Drug Administration may require that
the labeling state that there is a lack of evidence that the drug is
effective for that use or condition.
(v) Any statements comparing the safety or effectiveness, either
greater or less, of the drug with other agents for the same indication
shall be supported by adequate and well-controlled studies as defined in
Sec. 314.126(b) of this chapter unless this requirement is waived under
Sec. 201.58 or Sec. 314.126(b) of this chapter.
(d) Contraindications. Under this section heading, the labeling
shall describe those situations in which the drug should not be used
because the risk of use clearly outweighs any possible benefit. These
situations include administration of the drug to patients known to have
a hypersensitivity to it; use of the drug in patients who, because of
their particular age, sex, concomitant therapy, disease state, or other
condition, have a substantial risk of being harmed by it; or continued
use of the drug in the face of an unacceptably hazardous adverse
reaction. Known hazards and not theoretical possibilities shall be
listed, e.g., if hypersensitivity to the drug has not been demonstrated,
it should not be listed as a contraindication. If no contraindications
are known, this section of the labeling shall state ``None known.''
(e) Warnings. Under this section heading, the labeling shall
describe serious adverse reactions and potential safety hazards,
limitations in use imposed by them, and steps that should be taken if
they occur. The labeling shall be revised to include a warning as soon
as there is reasonable evidence of an association of a serious hazard
with a drug; a causal relationship need not have been proved. A specific
warning relating to a use not provided for under the ``Indications and
Usage'' section of the labeling may be required by the Food and Drug
Administration if the drug is commonly prescribed for a disease or
condition, and there is lack of substantial evidence of effectivenes for
that disease or condition, and such usage is associated with serious
risk or hazard. Special problems, particularly those that may lead to
death or serious injury, may be required by the Food and Drug
Administration to be placed in a prominently displayed box. The boxed
warning ordinarily shall be based on clinical data, but serious animal
toxicity may also be the basis of a boxed warning in the absence of
clinical data. If a boxed warning is required, its location will be
specified by the Food and Drug Administration. The frequency of these
serious adverse reactions and, if known, the approximate mortality and
morbidity rates for patients sustaining the reaction, which are
important to safe and effective use of the drug, shall be expressed as
provided under the ``Adverse Reactions'' section of the labeling.
(f) Precautions. Under this section heading, the labeling shall
contain the following subsections as appropriate for the drug:
(1) General. This subsection of the labeling shall contain
information regarding any special care to be exercised by the
practitioner for safe and effective use of the drug, e.g., precautions
not required under any other specific section or subsection of the
labeling.
(2) Information for patients. This subsection of the labeling shall
contain information to be given to patients for safe and effective use
of the drug, e.g., precautions concerning driving or the concomitant use
of other substances that may have harmful additive effects. Any printed
patient information or Medication Guide required under this chapter to
be distributed to the patient shall be referred to under the
``Precautions'' section of the labeling and the full text of such
patient information or Medication Guide shall be reprinted at the end of
the labeling. The print size requirements for the Medication Guide set
forth in Sec. 208.20 of this chapter, however, do not apply to the
Medication Guide that is reprinted in the professional labeling.
(3) Laboratory tests. This subsection of the labeling shall identify
any laboratory tests that may be helpful in following the patient's
response or in identifying possible adverse reactions. If appropriate,
information shall be
[[Page 23]]
provided on such factors as the range of normal and abnormal values
expected in the particular situation and the recommended frequency with
which tests should be done before, during, and after therapy.
(4)(i) Drug interactions. This subsection of the labeling shall
contain specific practical guidance for the physician on preventing
clinically significant drug/drug and drug/food interactions that may
occur in vivo in patients taking the drug. Specific drugs or classes of
drugs with which the drug to which the labeling applies may interact in
vivo shall be identified, and the mechanism(s) of the interaction shall
be briefly described. Information in this subsection of the labeling
shall be limited to that pertaining to clinical use of the drug in
patients. Drug interactions supported only by animal or in vitro
experiments may not ordinarily be included, but animal or in vitro data
may be used if shown to be clinically relevant. Drug incompatibilities,
i.e., drug interactions that may occur when drugs are mixed in vitro, as
in a solution for intravenous administration, shall be discussed under
the ``Dosage and Administration'' section of the labeling rather than
under this subsection of the labeling.
(ii) Drug/laboratory test interactions. This subsection of the
labeling shall contain practical guidance on known interference of the
drug with laboratory tests.
(5) Carcinogenesis, mutagenesis, impairment of fertility. This
subsection of the labeling shall state whether long-term studies in
animals have been performed to evaluate carcinogenic potential and, if
so, the species and results. If reproduction studies or other data in
animals reveal a problem or potential problem concerning mutagenesis or
impairment of fertility in either males or females, the information
shall be described. Any precautionary statement on these topics shall
include practical, relevant advice to the physician on the significance
of these animal findings. If there is evidence from human data that the
drug may be carcinogenic or mutagenic or that it impairs fertility, this
information shall be included under the ``Warnings'' section of the
labeling. Also, under ``Precautions,'' the labeling shall state: ``See
`Warnings' section for information on carcinogenesis, mutagenesis, and
impairment of fertility.''
(6) Pregnancy. This subsection of the labeling may be omitted only
if the drug is not absorbed systemically and the drug is not known to
have a potential for indirect harm to the fetus. For all other drugs,
this subsection of the labeling shall contain the following information:
(i) Teratogenic effects. Under this heading the labeling shall
identify one of the following categories that applies to the drug, and
the labeling shall bear the statement required under the category:
(a) Pregnancy category A. If adequate and well-controlled studies in
pregnant women have failed to demonstrate a risk to the fetus in the
first trimester of pregnancy (and there is no evidence of a risk in
later trimesters), the labeling shall state: ``Pregnancy Category A.
Studies in pregnant women have not shown that (name of drug) increases
the risk of fetal abnormalities if administered during the first
(second, third, or all) trimester(s) of pregnancy. If this drug is used
during pregnancy, the possibility of fetal harm appears remote. Because
studies cannot rule out the possibility of harm, however, (name of drug)
should be used during pregnancy only if clearly needed.'' The labeling
shall also contain a description of the human studies. If animal
reproduction studies are available and they fail to demonstrate a risk
to the fetus, the labeling shall also state: ``Reproduction studies have
been performed in (kinds of animal(s)) at doses up to (x) times the
human dose and have revealed no evidence of impaired fertility or harm
to the fetus due to (name of drug).'' The labeling shall also contain a
description of available data on the effect of the drug on the later
growth, development, and functional maturation of the child.
(b) Pregnancy category B. If animal reproduction studies have failed
to demonstrate a risk to the fetus and there are no adequate and well-
controlled studies in pregnant women, the labeling shall state:
``Pregnancy Category
[[Page 24]]
B. Reproduction studies have been performed in (kind(s) of animal(s)) at
doses up to (x) times the human dose and have revealed no evidence of
impaired fertility or harm to the fetus due to (name of drug). There
are, however, no adequate and well-controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human
response, this drug should be used during pregnancy only if clearly
needed.'' If animal reproduction studies have shown an adverse effect
(other than decrease in fertility), but adequate and well-controlled
studies in pregnant women have failed to demonstrate a risk to the fetus
during the first trimester of pregnancy (and there is no evidence of a
risk in later trimesters), the labeling shall state: ``Pregnancy
Category B. Reproduction studies in (kind(s) of animal(s)) have shown
(describe findings) at (x) times the human dose. Studies in pregnant
women, however, have not shown that (name of drug) increases the risk of
abnormalities when administered during the first (second, third, or all)
trimester(s) of pregnancy. Despite the animal findings, it would appear
that the possibility of fetal harm is remote, if the drug is used during
pregnancy. Nevertheless, because the studies in humans cannot rule out
the possibility of harm, (name of drug) should be used during pregnancy
only if clearly needed.'' The labeling shall also contain a description
of the human studies and a description of available data on the effect
of the drug on the later growth, development, and functional maturation
of the child.
(c) Pregnancy category C. If animal reproduction studies have shown
an adverse effect on the fetus, if there are no adequate and well-
controlled studies in humans, and if the benefits from the use of the
drug in pregnant women may be acceptable despite its potential risks,
the labeling shall state: ``Pregnancy Category C. (Name of drug) has
been shown to be teratogenic (or to have an embryocidal effect or other
adverse effect) in (name(s) of species) when given in doses (x) times
the human dose. There are no adequate and well-controlled studies in
pregnant women. (Name of drug) should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus.'' The
labeling shall contain a description of the animal studies. If there are
no animal reproduction studies and no adequate and well-controlled
studies in humans, the labeling shall state: ``Pregnancy Category C.
Animal reproduction studies have not been conducted with (name of drug).
It is also not known whether (name of drug) can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity.
(Name of drug) should be given to a pregnant woman only if clearly
needed.'' The labeling shall contain a description of any available data
on the effect of the drug on the later growth, development, and
functional maturation of the child.
(d) Pregnancy category D. If there is positive evidence of human
fetal risk based on adverse reaction data from investigational or
marketing experience or studies in humans, but the potential benefits
from the use of the drug in pregnant women may be acceptable despite its
potential risks (for example, if the drug is needed in a life-
threatening situation or serious disease for which safer drugs cannot be
used or are ineffective), the labeling shall state: ``Pregnancy Category
D. See `Warnings' section.'' Under the ``Warnings'' section, the
labeling states: ``(Name of drug) can cause fetal harm when administered
to a pregnant woman. (Describe the human data and any pertinent animal
data.) If this drug is used during pregnancy, or if the patient becomes
pregnant while taking this drug, the patient should be apprised of the
potential hazard to the fetus.''
(e) Pregnancy category X. If studies in animals or humans have
demonstrated fetal abnormalities or if there is positive evidence of
fetal risk based on adverse reaction reports from investigational or
marketing experience, or both, and the risk of the use of the drug in a
pregnant woman clearly outweighs any possible benefit (for example,
safer drugs or other forms of therapy are available), the labeling shall
state: ``Pregnancy Category X. See `Contraindications' section.'' Under
``Contraindications,'' the labeling shall state: ``(Name of drug) may
(can) cause fetal harm when administered to a pregnant woman. (Describe
the human
[[Page 25]]
data and any pertinant animal data.) (Name of drug) is contraindicated
in women who are or may become pregnant. If this drug is used during
pregnancy, or if the patient becomes pregnant while taking this drug,
the patient should be apprised of the potential hazard to the fetus.''
(ii) Nonteratogenic effects. Under this heading the labeling shall
contain other information on the drug's effects on reproduction and the
drug's use during pregnancy that is not required specifically by one of
the pregnancy categories, if the information is relevant to the safe and
effective use of the drug. Information required under this heading shall
include nonteratogenic effects in the fetus or newborn infant (for
example, withdrawal symptoms or hypoglycemia) that may occur because of
a pregnant woman's chronic use of the drug for a preexisting condition
or disease.
(7) Labor and delivery. If the drug has a recognized use during
labor or delivery (vaginal or abdominal delivery), whether or not the
use is stated in the indications section of the labeling, this
subsection of the labeling shall describe the available information
about the effect of the drug on the mother and the fetus, on the
duration of labor or delivery, on the possibility that forceps delivery
or other intervention or resuscitation of the newborn will be necessary,
and the effect of the drug on the later growth, development, and
functional maturation of the child. If any information required under
this subsection is unknown, this subsection of the labeling shall state
that the information is unknown.
(8) Nursing mothers. (i) If a drug is absorbed systemically, this
subsection of the labeling shall contain, if known, information about
excretion of the drug in human milk and effects on the nursing infant.
Pertinent adverse effects observed in animal offspring shall be
described.
(ii) If a drug is absorbed systemically and is known to be excreted
in human milk, this subsection of the labeling shall contain one of the
following statements, as appropriate. If the drug is associated with
serious adverse reactions or if the drug has a known tumorigenic
potential, the labeling shall state: ``Because of the potential for
serious adverse reactions in nursing infants from (name of drug) (or,
``Because of the potential for tumorigenicity shown for (name of drug)
in (animal or human) studies), a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.'' If the drug is not associated
with serious adverse reactions and does not have a known tumorigenic
potential, the labeling shall state: ``Caution should be exercised when
(name of drug) is administered to a nursing woman.''
(iii) If a drug is absorbed systemically and information on
excretion in human milk is unknown, this subsection of the labeling
shall contain one of the following statements, as appropriate. If the
drug is associated with serious adverse reactions or has a known
tumorigenic potential, the labeling shall state: ``It is not known
whether this drug is excreted in human milk. Because many drugs are
excreted in human milk and because of the potential for serious adverse
reactions in nursing infants from (name of drug) (or, ``Because of the
potential for tumorigenicity shown for (name of drug) in (animal or
human) studies), a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance
of the drug to the mother.'' If the drug is not associated with serious
adverse reactions and does not have a known tumorigenic potential, the
labeling shall state: ``It is not known whether this drug is excreted in
human milk. Because many drugs are excreted in human milk, caution
should be exercised when (name of drug) is administered to a nursing
woman.''
(9) Pediatric use. (i) Pediatric population(s)/pediatric patient(s):
For the purposes of paragraphs (f)(9)(ii) through (f)(9)(viii) of this
setion, the terms pediatric population(s) and pediatric patient(s) are
defined as the pediatric age group, from birth to 16 years, including
age groups often called neonates, infants, children, and adolescents.
(ii) If there is a specific pediatric indication (i.e., an
indication different from those approved for adults) that is
[[Page 26]]
supported by adequate and well-controlled studies in the pediatric
population, it shall be described under the ``Indications and Usage''
section of the labeling, and appropriate pediatric dosage information
shall be given under the ``Dosage and Administration'' section of the
labeling. The ``Pediatric use'' subsection shall cite any limitations on
the pediatric indication, need for specific monitoring, specific hazards
associated with use of the drug in any subsets of the pediatric
population (e.g., neonates), differences between pediatric and adult
responses to the drug, and other information related to the safe and
effective pediatric use of the drug. Data summarized in this subsection
of the labeling should be discussed in more detail, if appropriate,
under the ``Clinical Pharmacology'' or ``Clinical Studies'' section. As
appropriate, this information shall also be contained in the
``Contraindications,'' ``Warnings,'' and elsewhere in the
``Precautions'' sections.
(iii) If there are specific statements on pediatric use of the drug
for an indication also approved for adults that are based on adequate
and well-controlled studies in the pediatric population, they shall be
summarized in the ``Pediatric use'' subsection of the labeling and
discussed in more detail, if appropriate, under the ``Clinical
Pharmacology'' and ``Clinical Studies'' sections. Appropriate pediatric
dosage shall be given under the ``Dosage and Administration'' section of
the labeling. The ``Pediatric use'' subsection of the labeling shall
also cite any limitations on the pediatric use statement, need for
specific monitoring, specific hazards associated with use of the drug in
any subsets of the pediatric population (e.g., neonates), differences
between pediatric and adult responses to the drug, and other information
related to the safe and effective pediatric use of the drug. As
appropriate, this information shall also be contained in the
``Contraindications,'' ``Warnings,'' and elsewhere in the
``Precautions'' sections.
(iv) FDA may approve a drug for pediatric use based on adequate and
well-controlled studies in adults, with other information supporting
pediatric use. In such cases, the agency will have concluded that the
course of the disease and the effects of the drug, both beneficial and
adverse, are sufficiently similar in the pediatric and adult populations
to permit extrapolation from the adult efficacy data to pediatric
patients. The additional information supporting pediatric use must
ordinarily include data on the pharmacokinetics of the drug in the
pediatric population for determination of appropriate dosage. Other
information, such as data from pharmacodynamic studies of the drug in
the pediatric population, data from other studies supporting the safety
or effectiveness of the drug in pediatric patients, pertinent
premarketing or postmarketing studies or experience, may be necessary to
show that the drug can be used safely and effectively in pediatric
patients. When a drug is approved for pediatric use based on adequate
and well-controlled studies in adults with other information supporting
pediatric use, the ``Pediatric use'' subsection of the labeling shall
contain either the following statement, or a reasonable alternative:
``The safety and effectiveness of (drug name) have been established in
the age groups __ to __ (note any limitations, e.g., no data for
pediatric patients under 2, or only applicable to certain indications
approved in adults). Use of (drug name) in these age groups is supported
by evidence from adequate and well-controlled studies of (drug name) in
adults with additional data (insert wording that accurately describes
the data submitted to support a finding of substantial evidence of
effectiveness in the pediatric population).'' Data summarized in the
preceding prescribed statement in this subsection of the labeling shall
be discussed in more detail, if appropriate, under the ``Clinical
Pharmacology'' or the ``Clinical Studies'' section. For example,
pediatric pharmacokinetic or pharmacodynamic studies and dose-response
information should be described in the ``Clinical Pharmacology''
section. Pediatric dosing instructions shall be included in the ``Dosage
and Administration'' section of the labeling. Any differences between
pediatric and adult responses, need for specific monitoring, dosing
adjustments, and any other information related to safe and effective use
of the
[[Page 27]]
drug in pediatric patients shall be cited briefly in the ``Pediatric
use'' subsection and, as appropriate, in the ``Contraindications,''
``Warnings,'' ``Precautions,'' and ``Dosage and Administration''
sections.
(v) If the requirements for a finding of substantial evidence to
support a pediatric indication or a pediatric use statement have not
been met for a particular pediatric population, the ``Pediatric use''
subsection of the labeling shall contain an appropriate statement such
as ``Safety and effectiveness in pediatric patients below the age of
(__) have not been established.'' If use of the drug in this pediatric
population is associated with a specific hazard, the hazard shall be
described in this subsection of the labeling, or, if appropriate, the
hazard shall be stated in the ``Contraindications'' or ``Warnings''
section of the labeling and this subsection shall refer to it.
(vi) If the requirements for a finding of substantial evidence to
support a pediatric indication or a pediatric use statement have not
been met for any pediatric population, this subsection of the labeling
shall contain the following statement: ``Safety and effectiveness in
pediatric patients have not been established.'' If use of the drug in
premature or neonatal infants, or other pediatric subgroups, is
associated with a specific hazard, the hazard shall be described in this
subsection of the labeling, or, if appropriate, the hazard shall be
stated in the ``Contraindications'' or ``Warnings'' section of the
labeling and this subsection shall refer to it.
(vii) If the sponsor believes that none of the statements described
in paragraphs (f)(9)(ii) through (f)(9)(vi) of this section is
appropriate or relevant to the labeling of a particular drug, the
sponsor shall provide reasons for omission of the statements and may
propose alternative statement(s). FDA may permit use of an alternative
statement if FDA determines that no statement described in those
paragraphs is appropriate or relevant to the drug's labeling and that
the alternative statement is accurate and appropriate.
(viii) If the drug product contains one or more inactive ingredients
that present an increased risk of toxic effects to neonates or other
pediatric subgroups, a special note of this risk shall be made,
generally in the ``Contraindications,'' ``Warnings,'' or ``Precautions''
section.
(10) Geriatric use. (i) A specific geriatric indication, if any,
that is supported by adequate and well-controlled studies in the
geriatric population shall be described under the ``Indications and
Usage'' section of the labeling, and appropriate geriatric dosage shall
be stated under the ``Dosage and Administration'' section of the
labeling. The ``Geriatric use'' subsection shall cite any limitations on
the geriatric indication, need for specific monitoring, specific hazards
associated with the geriatric indication, and other information related
to the safe and effective use of the drug in the geriatric population.
Unless otherwise noted, information contained in the ``Geriatric use''
subsection of the labeling shall pertain to use of the drug in persons
65 years of age and older. Data summarized in this subsection of the
labeling shall be discussed in more detail, if appropriate, under
``Clinical Pharmacology'' or the ``Clinical Studies'' section. As
appropriate, this information shall also be contained in
``Contraindications,'' ``Warnings,'' and elsewhere in ``Precautions.''
(ii) Specific statements on geriatric use of the drug for an
indication approved for adults generally, as distinguished from a
specific geriatric indication, shall be contained in the ``Geriatric
use'' subsection and shall reflect all information available to the
sponsor that is relevant to the appropriate use of the drug in elderly
patients. This information includes detailed results from controlled
studies that are available to the sponsor and pertinent information from
well-documented studies obtained from a literature search. Controlled
studies include those that are part of the marketing application and
other relevant studies available to the sponsor that have not been
previously submitted in the investigational new drug application, new
drug application, biological license application, or a supplement or
amendment to one of these applications (e.g., postmarketing studies or
adverse drug reaction reports). The ``Geriatric use'' subsection shall
contain the following statement(s) or
[[Page 28]]
reasonable alternative, as applicable, taking into account available
information:
(A) If clinical studies did not include sufficient numbers of
subjects aged 65 and over to determine whether elderly subjects respond
differently from younger subjects, and other reported clinical
experience has not identified such differences, the ``Geriatric use''
subsection shall include the following statement:
``Clinical studies of (name of drug) did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience
has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.''
(B) If clinical studies (including studies that are part of
marketing applications and other relevant studies available to the
sponsor that have not been submitted in the sponsor's applications)
included enough elderly subjects to make it likely that differences in
safety or effectiveness between elderly and younger subjects would have
been detected, but no such differences (in safety or effectiveness) were
observed, and other reported clinical experience has not identified such
differences, the ``Geriatric use'' subsection shall contain the
following statement:
Of the total number of subjects in clinical studies of (name of
drug), __ percent were 65 and over, while __ percent were 75 and over.
(Alternatively, the labeling may state the total number of subjects
included in the studies who were 65 and over and 75 and over.) No
overall differences in safety or effectiveness were observed between
these subjects and younger subjects, and other reported clinical
experience has not identified differences in responses between the
elderly and younger patients, but greater sensitivity of some older
individuals cannot be ruled out.
(C) If evidence from clinical studies and other reported clinical
experience available to the sponsor indicates that use of the drug in
elderly patients is associated with differences in safety or
effectiveness, or requires specific monitoring or dosage adjustment, the
``Geriatric use'' subsection of the labeling shall contain a brief
description of observed differences or specific monitoring or dosage
requirements and, as appropriate, shall refer to more detailed
discussions in the ``Contraindications,'' ``Warnings,'' ``Dosage and
Administration,'' or other sections of the labeling.
(iii)(A) If specific pharmacokinetic or pharmacodynamic studies have
been carried out in the elderly, they shall be described briefly in the
``Geriatric use'' subsection of the labeling and in detail under the
``Clinical Pharmacology'' section. The ``Clinical Pharmacology'' section
and ``Drug interactions'' subsection of the ``Precautions'' section
ordinarily contain information on drug-disease and drug-drug
interactions that is particularly relevant to the elderly, who are more
likely to have concomitant illness and to utilize concomitant drugs.
(B) If a drug is known to be substantially excreted by the kidney,
the ``Geriatric use'' subsection shall include the statement:
``This drug is known to be substantially excreted by the kidney, and
the risk of toxic reactions to this drug may be greater in patients with
impaired renal function. Because elderly patients are more likely to
have decreased renal function, care should be taken in dose selection,
and it may be useful to monitor renal function.''
(iv) If use of the drug in the elderly appears to cause a specific
hazard, the hazard shall be described in the ``Geriatric use''
subsection of the labeling, or, if appropriate, the hazard shall be
stated in the ``Contraindications,'' ``Warnings,'' or ``Precautions''
section of the labeling, and the ``Geriatric use'' subsection shall
refer to those sections.
(v) Labeling under paragraphs (f)(10)(i) through (f)(10)(iii) of
this section may include statements, if they would be useful in
enhancing safe use of the drug, that reflect good clinical practice or
past experience in a particular situation, e.g., for a sedating drug, it
could be stated that:
``Sedating drugs may cause confusion and over-sedation in the
elderly; elderly patients generally should be started on low doses of
(name of drug) and observed closely.''
[[Page 29]]
(vi) If the sponsor believes that none of the requirements described
in paragraphs (f)(10)(i) through (f)(10)(v) of this section is
appropriate or relevant to the labeling of a particular drug, the
sponsor shall provide reasons for omission of the statements and may
propose an alternative statement. FDA may permit omission of the
statements if FDA determines that no statement described in those
paragraphs is appropriate or relevant to the drug's labeling. FDA may
permit use of an alternative statement if the agency determines that
such statement is accurate and appropriate.
(g) Adverse Reactions. An adverse reaction is an undesirable effect,
reasonably associated with the use of the drug, that may occur as part
of the pharmacological action of the drug or may be unpredictable in its
occurrence.
(1) This section of the labeling shall list the adverse reactions
that occur with the drug and with drugs in the same pharmacologically
active and chemically related class, if applicable.
(2) In this listing, adverse reactions may be categorized by organ
system, by severity of the reaction, by frequency, or by toxicological
mechanism, or by a combination of these, as appropriate. If frequency
information from adequate clinical studies is available, the categories
and the adverse reactions within each category shall be listed in
decreasing order of frequency. An adverse reaction that is significantly
more severe than the other reactions listed in a category, however,
shall be listed before those reactions, regardless of its frequency. If
frequency information from adequate clinical studies is not available,
the categories and adverse reactions within each category shall be
listed in decreasing order of severity. The approximate frequency of
each adverse reaction shall be expressed in rough estimates or orders of
magnitude essentially as follows: ``The most frequent adverse
reaction(s) to (name of drug) is (are) (list reactions). This (these)
occur(s) in about (e.g., one-third of patients; one in 30 patients; less
than one-tenth of patients). Less frequent adverse reactions are (list
reactions), which occur in approximately (e.g., one in 100 patients).
Other adverse reactions, which occur rarely, in approximately (e.g., one
in 1,000 patients), are (list reactions).'' Percent figures may not
ordinarily be used unless they are documented by adequate and well-
controlled studies as defined in Sec. 314.126(b) of this chapter, they
are shown to reflect general experience, and they do not falsely imply a
greater degree of accuracy than actually exists.
(3) The ``Warnings'' section of the labeling or, if appropriate, the
``Contraindications'' section of the labeling shall identify any
potentially fatal adverse reaction.
(4) Any claim comparing the drug to which the labeling applies with
other drugs in terms of frequency, severity, or character of adverse
reactions shall be based on adequate and well-controlled studies as
defined in Sec. 314.126(b) of this chapter unless this requirement is
waived under Sec. 201.58 or Sec. 314.126(b) of this chapter.
(h) Drug Abuse and Dependence. Under this section heading, the
labeling shall contain the following subsections, as appropriate for the
drug:
(1) Controlled Substance. If the drug is controlled by the Drug
Enforcement Administration, the schedule in which it is controlled shall
be stated.
(2) Abuse. This subsection of the labeling shall be based primarily
on human data and human experience, but pertinent animal data may also
be used. This subsection shall state the types of abuse that can occur
with the drug and the adverse reactions pertinent to them. Particularly
susceptible patient populations shall be identified.
(3) Dependence. This subsection of the labeling shall describe
characteristic effects resulting from both psychological and physical
dependence that occur with the drug and shall identify the quantity of
the drug over a period of time that may lead to tolerance or dependence,
or both. Details shall be provided on the adverse effects of chronic
abuse and the effects of abrupt withdrawal. Procedures necessary to
diagnose the dependent state shall be provided, and the principles of
treating the effects of abrupt withdrawal shall be described.
(i) Overdosage. Under this section heading, the labeling shall
describe the
[[Page 30]]
signs, symptoms, and laboratory findings of acute overdosage and the
general principles of treatment. This section shall be based on human
data, when available. If human data are unavailable, appropriate animal
and in vitro data may be used. Specific information shall be provided
about the following:
(1) Signs, symptoms, and laboratory findings associated with an
overdosage of the drug.
(2) Complications that can occur with the drug (for example, organ
toxicity or delayed acidosis).
(3) Oral LD50 of the drug in animals; concentrations of
the drug in biologic fluids associated with toxicity and/or death;
physiologic variables influencing excretion of the drug, such as urine
pH; and factors that influence the dose response relationship of the
drug, such as tolerance. The pharmacokinetic data given in the
``Clinical Pharmacology'' section also may be referenced here, if
applicable to overdoses.
(4) The amount of the drug in a single dose that is ordinarily
associated with symptoms of overdosage and the amount of the drug in a
single dose that is likely to be life-threatening.
(5) Whether the drug is dialyzable.
(6) Recommended general treatment procedures and specific measures
for support of vital functions, such as proven antidotes, induced
emesis, gastric lavage, and forced diuresis. Unqualified recommendations
for which data are lacking with the specific drug or class of drugs,
especially treatment using another drug (for example, central nervous
system stimulants, respiratory stimulants) may not be stated unless
specific data or scientific rationale exists to support safe and
effective use.
(j) Dosage and Administration. This section of the labeling shall
state the recommended usual dose, the usual dosage range, and, if
appropriate, an upper limit beyond which safety and effectiveness have
not been established; dosages shall be stated for each indication when
appropriate. This section shall also state the intervals recommended
between doses, the optimal method of titrating dosage, the usual
duration of treatment, and any modification of dosage needed in special
patient populations, e.g., in children, in geriatric age groups, or in
patients with renal or hepatic disease. Specific tables or monographs
may be included to clarify dosage schedules. Radiation dosimetry
information shall be stated for both the patient receiving a radioactive
drug and the person administering it. This section shall also contain
specific direction on dilution, preparation (including the strength of
the final dosage solution, when prepared according to instructions, in
terms of milligrams active ingredient per milliliter of reconstituted
solution, unless another measure of the strength is more appropriate),
and administration of the dosage form, if needed, e.g., the rate of
administration of parenteral drug in milligrams per minute; storage
conditions for stability of the drug or reconstituted drug, when
important; essential information on drug incompatibilities if the drug
is mixed in vitro with other drugs; and the following statement for
parenterals: ``Parenteral drug products should be inspected visually for
particulate matter and discoloration prior to administration, whenever
solution and container permit.''
(k) How Supplied. This section of the labeling shall contain
information on the available dosage forms to which the labeling applies
and for which the manufacturer or distributor is responsible. The
information shall ordinarily include:
(1) The strength of the dosage form, e.g., 10-milligram tablets, in
metric system and, if the apothecary system is used, a statement of the
strength is placed in parentheses after the metric designation;
(2) The units in which the dosage form is ordinarily available for
prescribing by practitioners, e.g., bottles of 100;
(3) Appropriate information to facilitate identification of the
dosage forms, such as shape, color, coating, scoring, and National Drug
Code; and
(4) Special handling and storage conditions.
(l) Animal Pharmacology and/or Animal Toxicology. In most cases, the
labeling need not include this section. Significant animal data
necessary for safe and
[[Page 31]]
effective use of the drug in humans shall ordinarily be included in one
or more of the other sections of the labeling, as appropriate. Commonly
for a drug that has been marketed for a long time, and in rare cases for
a new drug, chronic animal toxicity studies have not been performed or
completed for a drug that is administered over prolonged periods or is
implanted in the body. The unavailability of such data shall be stated
in the appropriate section of the labeling for the drug. If the
pertinent animal data cannot be appropriately incorporated into other
sections of the labeling, this section may be used.
(m) ``Clinical Studies'' and ``References''. These sections may
appear in labeling in the place of a detailed discussion of a subject
that is of limited interest but nonetheless important. A reference to a
specific important clinical study may be made in any section of the
format required under Secs. 201.56 and 201.57 if the study is essential
to an understandable presentation of the available information.
References may appear in sections of the labeling format, other than the
``Clinical Studies'' or ``References'' section, in rare circumstances
only. A clinical study or reference may be cited in prescription drug
labeling only under the following conditions:
(1) If the clinical study or reference is cited in the labeling in
the place of a detailed discussion of data and information concerning an
indication for use of the drug, the reference shall be based upon, or
the clinical study shall constitute, an adequate and well-controlled
clinical investigation under Sec. 314.126(b) of this chapter.
(2) If the clinical study or reference is cited in the labeling in
the place of a detailed discussion of data and information concerning a
risk or risks from the use of the drug, the risk or risks shall also be
identified or discussed in the appropriate section of the labeling for
the drug.
[44 FR 37462, June 26, 1979, as amended at 55 FR 11576, Mar. 29, 1990;
59 FR 64249, Dec. 13, 1994; 62 FR 45325, Aug. 27, 1997; 63 FR 66396,
Dec. 1, 1998]
Effective Date Note: At 63 FR 66396, Dec. 1, 1998, Sec. 201.57 was
amended by revising paragraph (f)(2), effective June 1, 1999. For the
convenience of the user, the superseded text is set forth as follows:
Sec. 201.57 Specific requirements on content and format of labeling for
human prescription drugs.
* * * * *
(f) * * *
(2) Information for patients. This subsection of the labeling shall
contain information to be given to patients for safe and effective use
of the drug, e.g., precautions concerning driving or the concomitant use
of other substances that may have harmful additive effects. Any printed
patient information required under this chapter to be distributed to the
patient shall be referenced under the ``Precautions'' section of the
labeling and the full text of such patient information shall be
reprinted at the end of the labeling.
* * * * *
Sec. 201.58 Requests for waiver of requirement for adequate and well-controlled studies to substantiate certain labeling statements.
A request under Sec. 201.57(b)(2)(ii), (c)(2), (c)(3)(i), (c)(3)(v),
(f)(9), and (g)(4) for a waiver of the requirements of Sec. 314.126(b)
of this chapter shall be submitted in writing as provided in
Sec. 314.126(b) to the Director, Center for Drug Evaluation and
Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD
20587, or, if applicable, the Director, Center for Biologics Evaluation
and Research, 8800 Rockville Pike, Bethesda, MD 20892. The waiver shall
be granted or denied in writing by such Director or the Director's
designee.
[55 FR 11576, Mar. 29, 1990]
Sec. 201.59 Effective date of Secs. 201.56, 201.57, 201.100(d)(3), and 201.100(e).
(a) On and after December 26, 1979, no person may initially
introduce or initially deliver for introduction into interstate commerce
any drug to which Secs. 201.56, 201.57, 201.100(d)(3) apply unless the
drug's labeling complies with the requirements set forth in the
regulations, with the following exceptions:
(1) If the drug is a prescription drug that is not a biologic and
not subject to section 505 of the act (21 U.S.C. 355), and was not
subject to former section 507 of the act (21 U.S.C. 357, repealed
[[Page 32]]
1997), Secs. 201.56, 201.57, and 201.100(d)(3) are effective on April
10, 1981.
(2) If the drug is a prescription drug that on December 26, 1979 is
(i) a licensed biologic, (ii) a new drug subject to an approved new drug
application or abbreviated new drug application under section 505 of the
act or (iii) an antibiotic drug subject to an approved antibiotic form,
Secs. 201.56, 201.57, and 201.100(d)(3) are effective on the date listed
below for the class of drugs to which the drug belongs. Dates are also
listed below for the submission of supplemental applications,
amendments, and license changes.
(3) If the drug is approved after December 26, 1979 but is a
duplicate of a drug approved on or before that date (for example, a drug
approved under an abbreviated new drug application or an antibiotic
form), Secs. 201.56, 201.57, and 201.100(d)(3) are effective on the date
listed below for the class of drugs to which the drug belongs. Dates are
also listed below for the submission of supplemental applications,
amendments, and license changes.
----------------------------------------------------------------------------------------------------------------
Effective Revised labeling due Drug class Mail routing code
----------------------------------------------------------------------------------------------------------------
Biologics
----------------------------------------------------------------------------------------------------------------
Nov. 1, 1982.......... Nov. 1, 1980.......... Bacterial vaccines and HFB-240
antigens with no U.S.
standard of potency.
Do................ ......do.............. Skin test antigens.......... HFB-240
Nov. 1, 1982 \1\...... Nov. 1,1980 \2\....... Bacteral vaccines and HFB-240
toxoids with standards of
potency..
Do................ ......do.............. Viral and rickettsial HFB-240
vaccines.
Do................ ......do.............. Allergenic extracts......... HFB-240
Do................ ......do.............. Blood and blood derivatives. HFB-240
----------------------------------------------------------------------------------------------------------------
New Drugs and Antibiotic Drugs
----------------------------------------------------------------------------------------------------------------
Nov. 1, 1982.......... Nov. 1, 1980.......... Antiarrhythmics............. HFD-110
Do................ ......do.............. Replenishers and regulators HFD-110, HFD-510, and HFD-160
of electrolytes and water
balance.
Do................ ......do.............. Anticonvulsants............. HFD-120
Do................ ......do.............. Adrenal corticosteroids..... HFD-510 and HFD-150
Do................ ......do.............. Aminoglycosides............. HFD-520
Do................ ......do.............. Scabicides.................. Do.
Do................ ......do.............. Pediculicides............... Do.
Do................ ......do.............. General anesthetics......... HFD-160
Dec. 1, 1982.......... Dec. 1, 1980.......... Antivirals.................. HFD-520
Do................ ......do.............. Dermatologics............... Do.
Jan. 1, 1983.......... Jan. 1, 1981.......... Glaucoma ophthalmics........ HFD-520
Do................ ......do.............. Topical otics............... Do.
Feb. 1, 1983.......... Feb. 1, 1981.......... Antispasmodics.............. HFD-110
Do................ ......do.............. Anticholinergics............ Do.
Do................ ......do.............. Diuretics................... Do.
Do................ ......do.............. Narcotic antagonists........ HFD-120
Do................ ......do.............. Alcohol antagonists......... Do.
Do................ ......do.............. Antipsychotics/antimanics... Do.
Do................ ......do.............. Androgens................... HFD-510
Do................ ......do.............. Anabolic steroids........... Do.
Do................ ......do.............. Hyperlipidemia.............. Do.
Do................ ......do.............. Anthelmintics............... HFD-520
Do................ ......do.............. Antigout.................... HFD-150
Mar. 1, 1983.......... Mar. 1, 1981.......... Vaginal antibiotics......... HFD-520
Apr. 1, 1983.......... Apr. 1, 1981.......... Cephalosporins.............. HFD-520
May 1, 1983........... May 1, 1981........... General analgesics.......... HFD-120
Do................ ......do.............. Anterior pituitary hormones. HFD-510
Do................ ......do.............. Hypothalamic hormones....... Do.
Do................ ......do.............. Progestins.................. Do.
Do................ ......do.............. Mydriatic ophthalmics....... HFD-520
Do................ ......do.............. Cycloplegic ophthalmics..... Do.
Do................ ......do.............. Radiopharmaceuticals, HFD-150
diagnostic.
Do................ ......do.............. Radiopharmaceuticals, Do.
therapeutic.
Do................ ......do.............. Contrast agents diagnostic Do.
radiopaque.
Do................ ......do.............. Local anesthetics........... HFD-160
Do................ ......do.............. Antihistamines.............. Do.
June 1, 1983.......... June 1, 1981.......... Antifungals................. HFD-520
July 1, 1983.......... July 1, 1981.......... Antidiarrheals.............. HFD-110
Do................ ......do.............. Cardiac glycosides.......... Do.
Do................ ......do.............. Sedatives................... HFD-120
Do................ ......do.............. Hypnotics................... Do.
Do................ ......do.............. Tetracyclines............... HFD-520
[[Page 33]]
Aug. 1, 1983.......... Aug. 1, 1981.......... Calcium metabolism.......... HFD-510
Do................ ......do.............. Vitamins and minerals....... Do.
Do................ ......do.............. Antiinfective ophthalmics... HFD-520
Do................ ......do.............. Antiinflammatory ophthalmics Do.
Sept. 1, 1983......... Sept. 1, 1981......... Antihypertensives........... HFD-110
Do................ ......do.............. Drugs indicated for HFD-120
extrapyramidal movement
disorders.
Do................ ......do.............. Antiprotozoals.............. HFD-520
Oct. 1, 1983.......... Oct. 1, 1981.......... Penicillins................. HFD-520
Nov. 1, 1983.......... Nov. 1, 1981.......... Blood glucose regulators HFD-510
(except sulfonylureas).
Oct. 9, 1984.......... July 10, 1984......... Sulfonylurea blood glucose HFN-130
regulators.
Nov. 1, 1983.......... Nov. 1, 1981.......... Drugs indicated for HFD-510 and HFD-160
parenteral nutrition.
Do................ ......do.............. Drugs indicated for enteral Do.
nutrition.
Do................ ......do.............. Miscellaneous ophthalmics... HFD-520
Do................ ......do.............. Immunomodulators............ HFD-150
Dec. 1, 1983.......... Dec. 1, 1981.......... Anticoagulants.............. HFD-110
Do................ ......do.............. Thrombolytics............... Do.
Do................ ......do.............. Drugs indicated for acid Do.
peptic disorders.
Do................ ......do.............. Antidepressants............. HFD-120
Do................ ......do.............. Drugs indicated for skeletal Do.
muscle hyperactivity.
Do................ ......do.............. Sulfonamides and related HFD-520
sulfa compounds.
Do................ ......do.............. Dental preparations......... HFD-160
Jan. 1, 1984.......... Jan. 1, 1982.......... Miscellaneous antibacterials HFD-520
Feb. 1, 1984.......... Feb. 1, 1982.......... Drugs indicated for HFD-510
infertility.
Do................ ......do.............. Thyroids.................... Do.
Do................ ......do.............. Antithyroids................ Do.
Do................ ......do.............. Polymyxins.................. HFD-520
Do................ ......do.............. Antineoplastics............. HFD-150
Mar. 1, 1984.......... Mar. 1, 1982.......... Urinary tract stimulants.... HFD-110
Do................ ......do.............. Urinary tract relaxants..... Do.
Do................ ......do.............. Antimigraine................ HFD-120
Antimycobacterials HFD-520
(including antileprosy).
Do................ ......do.............. Adjuncts to anethesia....... HFD-160
Apr. 1, 1984.......... Apr. 1, 1982.......... Antianginals................ HFD-110
Do................ ......do.............. Laxatives................... Do.
Do................ ......do.............. CNS stimulants.............. HFD-120
Do................ ......do.............. Anorexiants................. Do.
Do................ ......do.............. Chloramphenicol and HFD-520
derivatives.
May 1, 1984........... May 1, 1982........... Drugs indicated for vertigo/ HFD-120
motion sickness/vomiting.
Do................ ......do.............. Antidiuretics............... HFD-510
Do................ ......do.............. Contraceptives.............. Do.
Do................ ......do.............. Macrolides.................. HFD-520
Do................ ......do.............. Lincosamides................ Do.
Do................ ......do.............. Antiarthritics.............. HFD-150
Do................ ......do.............. Antitussives................ HFD-160
Do................ ......do.............. Expectorants................ Do.
Do................ ......do.............. Inhalants................... Do.
June 1, 1984.......... June 1, 1982.......... Urinary tract antiseptics... HFD-520
July 1, 1984.......... July 1, 1982.......... Chelating agents/heavy metal HFD-110
antagonists.
Do................ ......do.............. All other gastrointestinal HFD-110
drugs.
Do................ ......do.............. Antianxiety................. HFD-120
Do................ ......do.............. Drugs indicated for HFD-120
myasthenia gravis.
Do................ ......do.............. All other antiinfective HFD-520
drugs.
Do................ ......do.............. Bronchodilators/ HFD-160
antiasthmatics.
Aug. 1, 1984.......... Aug. 1, 1982.......... Estrogens................... HFD-510
Do................ ......do.............. Uterine stimulants.......... HFD-510
Do................ ......do.............. Uterine relaxants........... Do.
Sept. 1, 1984......... Sept. 1, 1982......... Drugs indicated for HFD-110
hypotension and shock.
Oct. 1, 1984.......... Oct. 1, 1982.......... All other cardiac drugs..... HFD-110
Do................ ......do.............. Nasal decongestants......... HFD-160
Nov. 1, 1984.......... Nov. 1, 1982.......... All other prescription drugs
----------------------------------------------------------------------------------------------------------------
\1\ Except the effective date for all biological products reviewed generically by the advisory panel is 30
months after a final order is published under 21 CFR 601.25(g).
\2\ Except the due date for all biological products reviewed generically by the advisory panel is 6 months after
a final order is published under 21 CFR 601.25(g).
[45 FR 32552, May 16, 1980, as amended at 46 FR 7272, Jan. 23, 1981; 49
FR 14331, Apr. 11, 1984; 50 FR 8995, Mar. 6, 1985; 55 FR 11576, Mar. 29,
1990; 64 FR 400, Jan. 5, 1999]
[[Page 34]]
Effective Date Note: At 64 FR 400, Jan. 5, 1999, Sec. 201.59 was
amended by revising paragraph (a)(1), effective May 20, 1999. For the
convenience of the user, the superseded text is set forth as follows:
Sec. 201.59 Effective date of Secs. 201.56, 201.57, 201.100(d)(3), and
201.100(e).
(a) * * *
(1) If the drug is a prescription drug that is not a biologic, not
subject to section 505 of the act (21 U.S.C. 355), and not subject to
section 507 of the act (21 U.S.C. 357), Secs. 201.56, 201.57, and
201.100(d)(3) are effective on April 10, 1981.
* * * * *
Subpart C--Labeling Requirements for Over-the-Counter Drugs
Source: 41 FR 6908, Feb. 13, 1976, unless otherwise noted.
Sec. 201.60 Principal display panel.
The term principal display panel, as it applies to over-the-counter
drugs in package form and as used in this part, means the part of a
label that is most likely to be displayed, presented, shown, or examined
under customary conditions of display for retail sale. The principal
display panel shall be large enough to accommodate all the mandatory
label information required to be placed thereon by this part with
clarity and conspicuousness and without obscuring designs, vignettes, or
crowding. Where packages bear alternate principal display panels,
information required to be placed on the principal display panel shall
be duplicated on each principal display panel. For the purpose of
obtaining uniform type size in declaring the quantity of contents for
all packages of substantially the same size, the term area of the
principal display panel means the area of the side or surface that bears
the principal display panel, which area shall be:
(a) In the case of a rectangular package where one entire side
properly can be considered to be the principal display panel side, the
product of the height times the width of that side;
(b) In the case of a cylindrical or nearly cylindrical container, 40
percent of the product of the height of the container times the
circumference; and
(c) In the case of any other shape of container, 40 percent of the
total surface of the container: Provided, however, That where such
container presents an obvious ``principal display panel'' such as the
top of a triangular or circular package, the area shall consist of the
entire top surface.
In determining the area of the principal display panel, exclude tops,
bottoms, flanges at the tops and bottoms of cans, and shoulders and
necks of bottles or jars. In the case of cylindrical or nearly
cylindrical containers, information required by this part to appear on
the principal display panel shall appear within that 40 percent of the
circumference which is most likely to be displayed, presented, shown, or
examined under customary conditions of display for retail sale.
Sec. 201.61 Statement of identity.
(a) The principal display panel of an over-the-counter drug in
package form shall bear as one of its principal features a statement of
the identity of the commodity.
(b) Such statement of identity shall be in terms of the established
name of the drug, if any there be, followed by an accurate statement of
the general pharmacological category(ies) of the drug or the principal
intended action(s) of the drug. In the case of an over-the-counter drug
that is a mixture and that has no established name, this requirement
shall be deemed to be satisfied by a prominent and conspicuous statement
of the general pharmacological action(s) of the mixture or of its
principal intended action(s) in terms that are meaningful to the layman.
Such statements shall be placed in direct conjunction with the most
prominent display of the proprietary name or designation and shall
employ terms descriptive of general pharmacological
[[Page 35]]
category(ies) or principal intended action(s); for example, ``antacid,''
``analgesic,'' ``decongestant,'' ``antihistaminic,'' etc. The
indications for use shall be included in the directions for use of the
drug, as required by section 502(f)(1) of the act and by the regulations
in this part.
(c) The statement of identity shall be presented in bold face type
on the principal display panel, shall be in a size reasonably related to
the most prominent printed matter on such panel, and shall be in lines
generally parallel to the base on which the package rests as it is
designed to be displayed.
Sec. 201.62 Declaration of net quantity of contents.
(a) The label of an over-the-counter drug in package form shall bear
a declaration of the net quantity of contents. This shall be expressed
in the terms of weight, measure, numerical count, or a combination or
numerical count and weight, measure, or size. The statement of quantity
of drugs in tablet, capsule, ampule, or other unit form and the quantity
of devices shall be expressed in terms of numerical count; the statement
of quantity for drugs in other dosage forms shall be in terms of weight
if the drug is solid, semisolid, or viscous, or in terms of fluid
measure if the drug is liquid. The drug quantity statement shall be
augmented when necessary to give accurate information as to the strength
of such drug in the package; for example, to differentiate between
several strengths of the same drug ``100 tablets, 5 grains each'' or
``100 capsules, 125 milligrams each'' or ``100 capsules, 250 milligrams
each'': Provided, That:
(1) In the case of a firmly established, general consumer usage and
trade custom of declaring the quantity of a drug in terms of linear
measure or measure of area, such respective term may be used. Such term
shall be augmented when necessary for accuracy of information by a
statement of the weight, measure, or size of the individual units or of
the entire drug; for example, the net quantity of adhesive tape in
package form shall be expressed in terms of linear measure augmented by
a statement of its width.
(2) Whenever the Commissioner determines for a specific packaged
drug that an existing practice of declaring net quantity of contents by
weight, measure, numerical count, or a combination of these does not
facilitate value comparisons by consumers, he shall by regulation
designate the appropriate term or terms to be used for such article.
(b) Statements of weight of the contents shall be expressed in terms
of avoirdupois pound and ounce. A statement of liquid measure of the
contents shall be expressed in terms of the U.S. gallon of 231 cubic
inches and quart, pint, and fluid-ounce subdivisions thereof, and shall
express the volume at 68 deg.F (20 deg.C). See also paragraph (p) of
this section.
(c) The declaration may contain common or decimal fractions. A
common fraction shall be in terms of halves, quarters, eights,
sixteenths, or thirty-seconds; except that if there exists a firmly
established, general consumer usage and trade custom of employing
different common fractions in the net quantity declaration of a
particular commodity, they may be employed. A common fraction shall be
reduced to its lowest terms; a decimal fraction shall not be carried out
to more than two places. A statement that includes small fractions of an
ounce shall be deemed to permit smaller variations than one which does
not include such fractions.
(d) The declaration shall be located on the principal display panel
of the label, and with respect to packages bearing alternate principal
panels it shall be duplicated on each principal display panel.
(e) The declaration shall appear as a distinct item on the principal
display panel, shall be separated, by at least a space equal to the
height of the lettering used in the declaration, from other printed
label information appearing above or below the declaration and, by at
least a space equal to twice the width of the letter ``N'' of the style
of type used in the quantity of contents statement, from other printed
label information appearing to the left or right of the declaration. It
shall not include any term qualifying a unit of weight, measure, or
count, such as ``giant pint''
[[Page 36]]
and ``full quart'', that tends to exaggerate the amount of the drug in
the container. It shall be placed on the principal display panel within
the bottom 30 percent of the area of the label panel in lines generally
parallel to the base on which the package rests as it is designed to be
displayed: Provided, That:
(1) On packages having a principal display panel of 5 square inches
or less the requirement for placement within the bottom 30 percent of
the area of the label panel shall not apply when the declaration of net
quantity of contents meets the other requirements of this part; and
(2) In the case of a drug that is marketed with both outer and inner
retail containers bearing the mandatory label information required by
this part and the inner container is not intended to be sold separately,
the net quantity of contents placement requirement of this section
applicable to such inner container is waived.
(3) The principal display panel of a drug marketed on a display card
to which the immediate container is affixed may be considered to be the
display panel of the card, and the type size of the net quantity of
contents statement is governed by the dimensions of the display card.
(f) The declaration shall accurately reveal the quantity of drug or
device in the package exclusive of wrappers and other material packed
therewith: Provided, That in the case of drugs packed in containers
designed to deliver the drug under pressure, the declaration shall state
the net quantity of the contents that will be expelled when the
instructions for use as shown on the container are followed. The
propellant is included in the net quantity declaration.
(g) The declaration shall appear in conspicuous and easily legible
boldface print or type in distinct contrast (by typography, layout,
color, embossing, or molding) to other matter on the package; except
that a declaration of net quantity blown, embossed, or molded on a glass
or plastic surface is permissible when all label information is so
formed on the surface. Requirements of conspicuousness and legibility
shall include the specifications that:
(1) The ratio of height to width of the letter shall not exceed a
differential of 3 units to 1 unit, i.e., no more than 3 times as high as
it is wide.
(2) Letter heights pertain to upper case or capital letters. When
upper and lower case or all lower case letters are used, it is the lower
case letter ``o'' or its equivalent that shall meet the minimum
standards.
(3) When fractions are used, each component numeral shall meet one-
half the minimum height standards.
(h) The declaration shall be in letters and numerals in a type size
established in relationship to the area of the principal display panel
of the package and shall be uniform for all packages of substantially
the same size by complying with the following type specifications:
(1) Not less than one-sixteenth inch in height on packages the
principal display panel of which has an area of 5 square inches or less.
(2) Not less than one-eighth inch in height on packages the
principal display panel of which has an area of more than five but not
more than 25 square inches.
(3) Not less than three-sixteenths inch in height on packages the
principal display panel of which has an area of more than 25 but not
more than 100 square inches.
(4) Not less than one-fourth inch in height on packages the
principal display panel of which has an area of more than 100 square
inches, except not less than one-half inch in height if the area is more
than 400 square inches.
Where the declaration is blown, embossed, or molded on a glass or
plastic surface rather than by printing, typing, or coloring, the
lettering sizes specified in paragraphs (h) (1) through (4) of this
section shall be increased by one-sixteenth of an inch.
(i) On packages containing less than 4 pounds or 1 gallon and
labeled in terms of weight or fluid measure:
(1) The declaration shall be expressed both in ounces, with
identification by weight or by liquid measure and, if applicable (1
pound or 1 pint or more) followed in parentheses by a declaration in
pounds for weight units, with any remainder in terms of ounces or common
or decimal fractions of the pound (see
[[Page 37]]
examples set forth in paragraphs (k) (1) and (2) of this section), or in
the case of liquid measure, in the largest whole units (quarts, quarts
and pints, or pints, as appropriate) with any remainder in terms of
fluid ounces or common or decimal fractions of the pint or quart (see
examples set forth in paragraphs (k) (3) and (4) of this section). If
the net weight of the package is less than 1 ounce avoirdupois or the
net fluid measure is less than 1 fluid ounce, the declaration shall be
in terms of common or decimal fractions of the respective ounce and not
in terms of drams.
(2) The declaration may appear in more than one line. The term net
weight shall be used when stating the net quantity of contents in terms
of weight. Use of the terms net or net contents in terms of fluid
measure or numerical count is optional. It is sufficient to distinguish
avoirdupois ounce from fluid ounce through association of terms; for
example, ``Net wt. 6 oz'' or ``6 oz net wt.,'' and ``6 fl oz'' or ``net
contents 6 fl oz''.
(j) On packages containing 4 pounds or 1 gallon or more and labeled
in terms of weight or fluid measure, the declaration shall be expressed
in pounds for weight units with any remainder in terms of ounces or
common or decimal fractions of the pound; in the case of fluid measure,
it shall be expressed in the largest whole unit (gallons, followed by
common or decimal fractions of a gallon or by the next smaller whole
unit or units (quarts or quarts and pints)) with any remainder in terms
of fluid ounces or common or decimal fractions of the pint or quart; see
paragraph (k)(5) of this section.
(k) Examples:
(1) A declaration of 1\1/2\ pounds weight shall be expressed as
``Net wt. 24 oz (1 lb 8 oz),'' or ``Net wt. 24 oz (1\1/2\ lb)'' or ``Net
wt. 24 oz (1.5 lb)''.
(2) A declaration of three-fourths pound avoirdupois weight shall be
expressed as ``Net wt. 12 oz''.
(3) A declaration of 1 quart liquid measure shall be expressed as
``Net contents 32 fl oz (1 qt)'' or ``32 fl oz (1 qt)''.
(4) A declaration of 1\3/4\ quarts liquid measure shall be expressed
as ``Net contents 56 fl oz (1 qt 1 pt 8 oz)'' or ``Net contents 56 fl oz
(1 qt 1.5 pt),'' but not in terms of quart and ounce such as ``Net 56 fl
oz (1 qt 24 oz).''
(5) A declaration of 2\1/2\ gallons liquid measure shall be
expressed as ``Net contents 2 gal 2 qt,'' ``Net contents 2.5 gallons,''
or ``Net contents 2\1/2\ gal'' but not as ``2 gal 4 pt''.
(l) For quantities, the following abbreviations and none other may
be employed. Periods and plural forms are optional:
Gallon gal
quart qt
pint pt
ounce oz
pound lb
grain gr
kilogram kg
gram g
milligram mg
microgram mcg
liter l
milliliter ml
cubic centimeter cc
yard yd
feet or foot ft
inch in
meter m
centimeter cm
millimeter mm
fluid fl
square sq
weight wt
(m) On packages labeled in terms of linear measure, the declaration
shall be expressed both in terms of inches and, if applicable (1 foot or
more), the largest whole units (yards, yards and feet, feet). The
declaration in terms of the largest whole units shall be in parentheses
following the declaration in terms of inches and any remainder shall be
in terms of inches or common or decimal fractions of the foot or yard;
if applicable, as in the case of adhesive tape, the initial declaration
in linear inches shall be preceded by a statement of the width. Examples
of linear measure are ``86 inches (2 yd 1 ft 2 in),'' ``90 inches (2\1/
2\ yd),'' ``30 inches (2.5 ft),'' `` \3/4\ inch by 36 in (1 yd),'' etc.
(n) On packages labeled in terms of area measure, the declaration
shall be expressed both in terms of square inches and, if applicable (1
square foot or more), the largest whole square unit (square yards,
square yards and square feet, square feet). The declaration in terms of
the largest whole units shall be in parentheses following the
declaration in terms of square inches and any remainder shall be in
terms of square inches or common or decimal fractions of the square foot
or square yard; for example, ``158 sq inches (1 sq ft 14 sq in).''
[[Page 38]]
(o) Nothing in this section shall prohibit supplemental statements
at locations other than the principal display panel(s) describing in
nondeceptive terms the net quantity of contents, provided that such
supplemental statements of net quantity of contents shall not include
any term qualifying a unit of weight, measure, or count that tends to
exaggerate the amount of the drug contained in the package; for example,
``giant pint'' and ``full quart.'' Dual or combination declarations of
net quantity of contents as provided for in paragraphs (a) and (i) of
this section are not regarded as supplemental net quantity statements
and shall be located on the principal display panel.
(p) A separate statement of net quantity of contents in terms of the
metric system of weight or measure is not regarded as a supplemental
statement and an accurate statement of the net quantity of contents in
terms of the metric system of weight or measure may also appear on the
principal display panel or on other panels.
(q) The declaration of net quantity of contents shall express an
accurate statement of the quantity of contents of the package.
Reasonable variations caused by loss or gain of moisture during the
course of good distribution practice or by unavoidable deviations in
good manufacturing practice will be recognized. Variations from stated
quantity of contents shall not be unreasonably large.
(r) A drug shall be exempt from compliance with the net quantity
declaration required by this section if it is an ointment labeled
``sample,'' ``physician's sample,'' or a substantially similar statement
and the contents of the package do not exceed 8 grams.
Sec. 201.63 Pregnancy/breast-feeding warning.
(a) The labeling for all over-the-counter (OTC) drug products that
are intended for systemic absorption, unless specifically exempted,
shall contain a general warning under the heading ``Warning'' (or
``Warnings'' if it appears with additional warning statements) as
follows: ``If pregnant or breast-feeding, ask a health professional
before use.'' [first four words of this statement in bold type] In
addition to the written warning, a symbol that conveys the intent of the
warning may be used in labeling.
(b) Where a specific warning relating to use during pregnancy or
while nursing has been established for a particular drug product in a
new drug application (NDA) or for a product covered by an OTC drug final
monograph in part 330 of this chapter, the specific warning shall be
used in place of the warning in paragraph (a) of this section, unless
otherwise stated in the NDA or in the final OTC drug monograph.
(c) The following OTC drugs are exempt from the provisions of
paragraph (a) of this section:
(1) Drugs that are intended to benefit the fetus or nursing infant
during the period of pregnancy or nursing.
(2) Drugs that are labeled exclusively for pediatric use.
(d) The Food and Drug Administration will grant an exemption from
paragraph (a) of this section where appropriate upon petition under the
provisions of Sec. 10.30 of this chapter. Decisions with respect to
requests for exemptions shall be maintained in a permanent file for
public review by the Dockets Management Branch (HFA-305), Food and Drug
Administration, rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857.
(e) The labeling of orally or rectally administered OTC aspirin and
aspirin-containing drug products must bear a warning that immediately
follows the general warning identified in paragraph (a) of this section.
The warning shall be as follows:
``It is especially important not to use'' (select ``aspirin'' or
``carbaspirin calcium,'' as appropriate) ``during the last 3 months of
pregnancy unless definitely directed to do so by a doctor because it may
cause problems in the unborn child or complications during delivery.''
[47 FR 54757, Dec. 3, 1982, as amended at 55 FR 27784, July 5, 1990; 59
FR 14364, Mar. 28, 1994; 64 FR 13286, Mar. 17, 1999]
Effective Date Note: At 64 FR 13286, Mar. 17, 1999, Sec. 201.63 was
amended by revising the section heading, the first sentence in paragraph
(a), and paragraph (e), effective Apr. 16, 1999. For the convenience of
the user the superseded text is set forth as follows:
[[Page 39]]
Sec. 201.63 Pregnancy-nursing warning.
(a) The labeling for all over-the-counter (OTC) drugs that are
intended for systemic absorption, unless specifically exempted, shall
contain a general warning under the heading ``Warning'' (or ``Warnings''
if it appears with additional warning statements) as follows: ``As with
any drug, if you are pregnant or nursing a baby, seek the advice of a
health professional before using this product.'' * * *
* * * * *
(e) The labeling of orally or rectally administered OTC aspirin and
aspirin-containing drug products must bear a warning that immediately
follows the general warning identified in paragraph (a) of this section.
The warning shall be as follows:
``IT IS ESPECIALLY IMPORTANT NOT TO USE'' (select ``ASPIRIN'' or
``CARBASPIRIN CALCIUM,'' as appropriate) ``DURING THE LAST 3 MONTHS OF
PREGNANCY UNLESS SPECIFICALLY DIRECTED TO DO SO BY A DOCTOR BECAUSE IT
MAY CAUSE PROBLEMS IN THE UNBORN CHILD OR COMPLICATIONS DURING
DELIVERY.''
Sec. 201.64 Sodium labeling.
(a) The labeling of over-the-counter (OTC) drug products intended
for oral ingestion shall contain the sodium content per dosage unit
(e.g., tablet, teaspoonful) if the sodium content of a single
recommended dose of the product (which may be one or more dosage units)
is 5 milligrams or more. OTC drug products intended for oral ingestion
include gum and lozenge dosage forms, but do not include dentifrices,
mouthwashes, or mouth rinses.
(b) The sodium content shall be expressed in milligrams per dosage
unit and shall include the total amount of sodium regardless of the
source, i.e., from both active and inactive ingredients. The sodium
content shall be rounded-off to the nearest whole number. The sodium
content per dosage unit shall follow the heading ``Other information''
as stated in Sec. 201.66(c)(7).
(c) The labeling of OTC drug products intended for oral ingestion
shall contain the following warning under the heading ``Warning'' (or
``Warnings'' if it appears with additional warning statements) if the
amount of sodium present in the labeled maximum daily dose of the
product is more than 140 milligrams: ``Do not use this product if you
are on a sodium-restricted diet unless directed by a doctor.''
(d) The term sodium free may be used in the labeling of OTC drug
products intended for oral ingestion if the amount of sodium in the
labeled maximum daily dose is 0 milligram. For example, a product
containing 0.4 (rounded-off to zero (0)) milligram sodium per tablet
with directions to take one tablet daily may use the term ``sodium
free'' in its labeling. However, when the recommended dose provides for
taking more than one dosage unit per day, e.g., take one or two tablets,
or take two tablets, the same product containing 0.4 milligram sodium
per tablet shall not use the term ``sodium free'' because the labeled
maximum daily dose contains 0.8 milligram sodium.
(e) The term very low sodium may be used in the labeling of OTC drug
products intended for oral ingestion if the amount of sodium in the
labeled maximum daily dose is 35 milligrams or less.
(f) The term low sodium may be used in the labeling of OTC drug
products intended for oral ingestion if the amount of sodium in the
labeled maximum daily dose is 140 milligrams or less.
(g) The term salt is not synonymous with the term sodium and shall
not be used interchangeably or substituted for the term sodium.
(h) The terms sodium free, very low sodium, and low sodium shall be
in print size and style no larger than the product's statement of
identity and shall not be unduly prominent in print size or style
compared to the statement of identity.
(i) Any product subject to this paragraph that contains sodium
bicarbonate, sodium phosphate, or sodium biphosphate as an active
ingredient for oral ingestion and that is not labeled as required by
this paragraph and that is initially introduced or initially delivered
for introduction into interstate commerce after April 22, 1997, is
misbranded under sections 201(n) and 502 (a) and (f) of the Federal
Food, Drug, and Cosmetic Act (the act).
[61 FR 17806, Apr. 22, 1996, as amended at 62 FR 19925, Apr. 24, 1997;
64 FR 13286, Mar. 17, 1999]
[[Page 40]]
Effective Date Note 1: At 62 FR 19925, Apr. 24, 1997, the effective
date for Sec. 201.64 (a) through (h) was delayed until further notice.
Effective Date Note 2: At 64 FR 13286, Mar. 17, 1999, Sec. 201.64
was amended by revising the last sentence in paragraph (b), effective
Apr. 16, 1999. For the convenience of the user the superseded text is
set forth as follows:
Sec. 201.64 Sodium labeling.
* * * * *
(b) * * * The sodium content per dosage unit shall be listed on a
separate line after the heading ``Sodium Content'' as the last statement
in the ingredients section.
* * * * *
Sec. 201.66 Format and content requirements for over-the-counter (OTC) drug product labeling.
(a) Scope. This section sets forth the content and format
requirements for the labeling of all OTC drug products. Where an OTC
drug product is the subject of an applicable monograph or regulation
that contains content and format requirements that conflict with this
section, the content and format requirements in this section must be
followed unless otherwise specifically provided in the applicable
monograph or regulation.
(b) Definitions. The following definitions apply to this section:
(1) Act means the Federal Food, Drug, and Cosmetic Act (secs. 201 et
seq. (21 U.S.C. 321 et seq.)).
(2) Active ingredient means any component that is intended to
furnish pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment, or prevention of disease, or to
affect the structure or any function of the body of humans. The term
includes those components that may undergo chemical change in the
manufacture of the drug product and be present in the drug product in a
modified form intended to furnish the specified activity or effect.
(3) Approved drug application means a new drug (NDA) or abbreviated
new drug (ANDA) application approved under section 505 of the act (21
U.S.C. 355).
(4) Bullet means a geometric symbol that precedes each statement in
a list of statements. For purposes of this section, the bullet style is
limited to solid squares or solid circles, in the format set forth in
paragraph (d)(4) of this section.
(5) Established name of a drug or ingredient thereof means the
applicable official name designated under section 508 of the act (21
U.S.C. 358), or, if there is no designated official name and the drug or
ingredient is recognized in an official compendium, the official title
of the drug or ingredient in such compendium, or, if there is no
designated official name and the drug or ingredient is not recognized in
an official compendium, the common or usual name of the drug or
ingredient.
(6) FDA means the Food and Drug Administration.
(7) Heading means the required statements in quotation marks listed
in paragraphs (c)(2) through (c)(9) of this section, excluding
subheadings (as defined in paragraph (a)(9) of this section).
(8) Inactive ingredient means any component other than an active
ingredient.
(9) Subheading means the required statements in quotation marks
listed in paragraphs (c)(5)(ii) through (c)(5)(vii) of this section.
(10) Drug facts labeling means the title, headings, subheadings, and
information required under or otherwise described in paragraph (c) of
this section.
(11) Title means the heading listed at the top of the required OTC
drug product labeling, as set forth in paragraph (c)(1) of this section.
(12) Total surface area available to bear labeling means all
surfaces of the outside container of the retail package or, if there is
no such outside container, all surfaces of the immediate container or
container wrapper except for the flanges at the tops and bottoms of cans
and the shoulders and necks of bottles and jars.
(c) Content requirements. The outside container or wrapper of the
retail package, or the immediate container label if there is no outside
container or wrapper, shall contain the title, headings, subheadings,
and information set forth in paragraphs (c)(1) through (c)(8) of this
section, and may contain the information under the heading in paragraph
(c)(9) of this section, in the order listed.
[[Page 41]]
(1) (Title) ``Drug Facts''. If the drug facts labeling appears on
more than one panel, the title ``Drug Facts (continued)'' shall appear
at the top of each subsequent panel containing such information.
(2) ``Active ingredient'' or ``Active ingredients'' ``(in each
[insert the dosage unit stated in the directions for use (e.g., tablet,
5 mL teaspoonful) or in each gram as stated in Secs. 333.110 and 333.120
of this chapter])'', followed by the established name of each active
ingredient and the quantity of each active ingredient per dosage unit.
Unless otherwise provided in an applicable OTC drug monograph or
approved drug application, products marketed without discrete dosage
units (e.g., topicals) shall state the proportion (rather than the
quantity) of each active ingredient.
(3) ``Purpose'' or ``Purposes'', followed by the general
pharmacological category(ies) or the principal intended action(s) of the
drug or, where the drug consists of more than one ingredient, the
general pharmacological categories or the principal intended actions of
each active ingredient. When an OTC drug monograph contains a statement
of identity, the pharmacological action described in the statement of
identity shall also be stated as the purpose of the active ingredient.
(4) ``Use'' or ``Uses'', followed by the indication(s) for the
specific drug product.
(5) ``Warning'' or ``Warnings'', followed by one or more of the
following, if applicable:
(i) ``For external use only'' [in bold type] for topical drug
products not intended for ingestion, or ``For'' (select one of the
following, as appropriate: ``rectal'' or ``vaginal'') ``use only'' [in
bold type].
(ii) All applicable warnings listed in paragraphs (c)(5)(ii)(A)
through (c)(5)(ii)(G) of this section with the appropriate subheadings
highlighted in bold type:
(A) Allergic reaction warnings set forth in any applicable OTC drug
monograph or approved drug application for any product that requires a
separate allergy warning. This warning shall follow the subheading
``Allergy alert:''
(B) Reye's syndrome warning for drug products containing salicylates
set forth in Sec. 201.314(h)(1). This warning shall follow the
subheading ``Reye's syndrome:''
(C) Flammability warning, with appropriate flammability signal word
(e.g., Secs. 358.150(c) and 358.550(c) of this chapter). This warning
shall follow a subheading containing the appropriate flammability signal
word described in an applicable OTC drug monograph or approved drug
application.
(D) Water soluble gums warning set forth in Sec. 201.319. This
warning shall follow the subheading ``Choking:''
(E) Alcohol warning set forth in Sec. 201.322. This warning shall
follow the subheading ``Alcohol warning:''
(F) Sore throat warning set forth in Sec. 201.315. This warning
shall follow the subheading ``Sore throat warning:''
(G) Warning for drug products containing sodium phosphates set forth
in Sec. 201.307(b)(2)(i) or (b)(2)(ii). This warning shall follow the
subheading ``Dosage warning:''
(iii) ``Do not use'' [in bold type], followed by all
contraindications for use with the product. These contraindications are
absolute and are intended for situations in which consumers should not
use the product unless a prior diagnosis has been established by a
doctor or for situations in which certain consumers should not use the
product under any circumstances regardless of whether a doctor or health
professional is consulted.
(iv) ``Ask a doctor before use if you have'' [in bold type] or, for
products labeled only for use in children under 12 years of age, ``Ask a
doctor before use if the child has'' [in bold type], followed by all
warnings for persons with certain preexisting conditions (excluding
pregnancy) and all warnings for persons experiencing certain symptoms.
The warnings under this heading are those intended only for situations
in which consumers should not use the product until a doctor is
consulted.
(v) ``Ask a doctor or pharmacist before use if you are'' [in bold
type] or, for products labeled only for use in children under 12 years
of age, ``Ask a doctor or pharmacist before use if the child is'' [in
bold type], followed by all
[[Page 42]]
drug-drug and drug-food interaction warnings.
(vi) ``When using this product'' [in bold type], followed by the
side effects that the consumer may experience, and the substances (e.g.,
alcohol) or activities (e.g., operating machinery, driving a car,
warnings set forth in Sec. 369.21 of this chapter for drugs in
dispensers pressurized by gaseous propellants) to avoid while using the
product.
(vii) ``Stop use and ask a doctor if'' [in bold type], followed by
any signs of toxicity or other reactions that would necessitate
immediately discontinuing use of the product.
(viii) Any required warnings in an applicable OTC drug monograph,
other OTC drug regulations, or approved drug application that do not fit
within one of the categories listed in paragraphs (c)(5)(i) through
(c)(5)(vii), (c)(5)(ix), and (c)(5)(x) of this section.
(ix) The pregnancy/breast-feeding warning set forth in
Sec. 201.63(a); the third trimester warning set forth in Sec. 201.63(e)
for products containing aspirin or carbaspirin calcium; the third
trimester warning set forth in approved drug applications for products
containing ketoprofen, naproxen sodium, and ibuprofen (not intended
exclusively for use in children).
(x) The ``Keep out of reach of children'' warning and the accidental
overdose/ingestion warning set forth in Sec. 330.1(g) of this chapter.
(6) ``Directions'', followed by the directions for use described in
an applicable OTC drug monograph or approved drug application.
(7) ``Other information'', followed by additional information that
is not included under paragraphs (c)(2) through (c)(6), (c)(8), and
(c)(9) of this section, but which is required by or is made optional
under an applicable OTC drug monograph, other OTC drug regulation, or is
included in the labeling of an approved drug application.
(i) Required information about certain ingredients in OTC drug
products (e.g., sodium in Sec. 201.64(c)) shall appear as follows:
``each (insert appropriate dosage unit) contains:'' [in bold type]
(insert name(s) of ingredient(s) and the quantity of each ingredient).
This information shall be the first statement under this heading.
(ii) The phenylalanine/aspartame content required by Sec. 201.21(b),
if applicable, shall appear as the next item of information.
(iii) Additional information that is authorized to appear under this
heading shall appear as the next item(s) of information. There is no
required order for this subsequent information.
(8) ``Inactive ingredients'', followed by a listing of the
established name of each inactive ingredient. If the product is an OTC
drug product that is not also a cosmetic product, then the inactive
ingredients shall be listed in alphabetical order. If the product is an
OTC drug product that is also a cosmetic product, then the inactive
ingredients shall be listed as set forth in Sec. 701.3(a) or (f) of this
chapter, the names of cosmetic ingredients shall be determined in
accordance with Sec. 701.3(c) of this chapter, and the provisions in
Sec. 701.3(e), (g), (h), (l), (m), (n), and (o) of this chapter and
Sec. 720.8 of this chapter may also apply, as appropriate. If there is a
difference in the labeling provisions in this Sec. 201.66 and
Secs. 701.3 and 720.8 of this chapter, the labeling provisions in this
Sec. 201.66 shall be used.
(9) ``Questions?'' or ``Questions or comments?'', followed by the
telephone number of a source to answer questions about the product. It
is recommended that the days of the week and times of the day when a
person is available to respond to questions also be included. A graphic
of a telephone or telephone receiver may appear before the heading. The
telephone number must appear in a minimum 6-point bold type.
(d) Format requirements. The title, headings, subheadings, and
information set forth in paragraphs (c)(1) through (c)(9) of this
section shall be presented on OTC drug products in accordance with the
following specifications. In the interest of uniformity of presentation,
FDA strongly reccommends that the Drug Facts labeling be presented using
the graphic specifications set forth in appendix A to part 201.
(1) The title ``Drug Facts'' or ``Drug Facts (continued)'' shall use
uppercase letters for the first letter of the words ``Drug'' and
``Facts.'' All headings and subheadings in paragraphs (c)(2) through
(c)(9) of this section shall use an uppercase letter for the first
letter
[[Page 43]]
in the first word and lowercase letters for all other words. The title,
headings, and subheadings in paragraphs (c)(1), (c)(2), and (c)(4)
through (c)(9) of this section shall be left justified.
(2) The letter height or type size for the title ``Drug Facts''
shall appear in a type size larger than the largest type size used in
the Drug Facts labeling. The letter height or type size for the title
``Drug Facts (continued)'' shall be no smaller than 8-point type. The
letter height or type size for the headings in paragraphs (c)(2) through
(c)(9) of this section shall be the larger of either 8-point or greater
type, or 2-point sizes greater than the point size of the text. The
letter height or type size for the subheadings and all other information
described in paragraphs (c)(2) through (c)(9) of this section shall be
no smaller than 6-point type.
(3) The title, headings, subheadings, and information in paragraphs
(c)(1) through (c)(9) of this section shall be legible and clearly
presented, shall not appear in reverse type, shall have at least 0.5-
point leading (i.e., space between two lines of text), and shall not
have letters that touch. The type style for the title, headings,
subheadings, and all other required information described in paragraphs
(c)(2) through (c)(9) of this section shall be any single, clear, easy-
to-read type style, with no more than 39 characters per inch. The title
and headings shall be in bold italic, and the subheadings shall be in
bold type, except that the word ``(continued)'' in the title ``Drug
Facts (continued)'' shall be regular type. The type shall be all black
or one dark color, printed on a white or other light, neutral color,
contrasting background, except that the title and the headings may be
presented in a single, alternative, contrasting dark color unless
otherwise provided in an approved drug application, OTC drug monograph
(e.g., current requirements for bold print in Secs. 341.76 and 341.80 of
this chapter), or other OTC drug regulation (e.g., the requirement for a
box and red letters in Sec. 201.308(c)(1)).
(4) When there is more than one statement, each individual statement
listed under the headings and subheadings in paragraphs (c)(4) through
(c)(7) of this section shall be preceded by a solid square or solid
circle bullet of 5-point type size. Bullets shall be presented in the
same shape and color throughout the labeling. The first bulleted
statement on each horizontal line of text shall be either left justified
or separated from an appropriate heading or subheading by at least two
square ``ems'' (i.e., two squares of the size of the letter ``M''). If
more than one bulleted statement is placed on the same horizontal line,
the end of one bulleted statement shall be separated from the beginning
of the next bulleted statement by at least two square ``ems'' and the
complete additional bulleted statement(s) shall not continue to the next
line of text. Additional bulleted statements appearing on each
subsequent horizontal line of text under a heading or subheading shall
be vertically aligned with the bulleted statements appearing on the
previous line.
(5) The title, headings, subheadings, and information set forth in
paragraphs (c)(1) through (c)(9) of this section may appear on more than
one panel on the outside container of the retail package, or the
immediate container label if there is no outside container or wrapper.
The continuation of the required content and format onto multiple panels
must retain the required order and flow of headings, subheadings, and
information. A visual graphic (e.g., an arrow) shall be used to signal
the continuation of the Drug Facts labeling to the next adjacent panel.
(6) The heading and information required under paragraph (c)(2) of
this section shall appear immediately adjacent and to the left of the
heading and information required under paragraph (c)(3) of this section.
The active ingredients and purposes shall be aligned under the
appropriate headings such that the heading and information required
under paragraph (c)(2) of this section shall be left justified and the
heading and information required under paragraph (c)(3) of this section
shall be right justified. If the OTC drug product contains more than one
active ingredient, the active ingredients shall be listed in
alphabetical order. If more than one active ingredient has the same
purpose, the purpose need not be
[[Page 44]]
repeated for each active ingredient, provided the information is
presented in a manner that readily associates each active ingredient
with its purpose (i.e., through the use of brackets, dot leaders, or
other graphical features). The information described in paragraphs
(c)(4) and (c)(6) through (c)(9) of this section may start on the same
line as the required headings. None of the information described in
paragraph (c)(5) of this section shall appear on the same line as the
``Warning'' or ``Warnings'' heading.
(7) Graphical images (e.g., the UPC symbol) and information not
described in paragraphs (c)(1) through (c)(9) of this section shall not
appear in or in any way interrupt the required title, headings,
subheadings, and information in paragraphs (c)(1) through (c)(9) of this
section. Hyphens shall not be used except to punctuate compound words.
(8) The information described in paragraphs (c)(1) through (c)(9) of
this section shall be set off in a box or similar enclosure by the use
of a barline. A distinctive horizontal barline extending to each end of
the ``Drug Facts'' box or similar enclosure shall provide separation
between each of the headings listed in paragraphs (c)(2) through (c)(9)
of this section. When a heading listed in paragraphs (c)(2) through
(c)(9) of this section appears on a subsequent panel immediately after
the ``Drug Facts (continued)'' title, a horizontal hairline shall follow
the title and immediately precede the heading. A horizontal hairline
extending within two spaces on either side of the ``Drug Facts'' box or
similar enclosure shall immediately follow the title and shall
immediately precede each of the subheadings set forth in paragraph
(c)(5) of this section, except the subheadings in paragraphs
(c)(5)(ii)(A) through (c)(5)(ii)(G) of this section.
(9) The information set forth in paragraph (c)(6) of this section
under the heading ``Directions'' shall appear in a table format when
dosage directions are provided for three or more age groups or
populations. The last line of the table may be the horizontal barline
immediately preceding the heading of the next section of the labeling.
(10) If the title, headings, subheadings, and information in
paragraphs (c)(1) through (c)(9) of this section, printed in accordance
with the specifications in paragraphs (d)(1) through (d)(9) of this
section, and any other FDA required information for drug products, and,
as appropriate, cosmetic products, other than information required to
appear on a principle display panel, requires more than 60 percent of
the total surface area available to bear labeling, then the Drug Facts
labeling shall be printed in accordance with the specifications set
forth in paragraphs (d)(10)(i) through (d)(10)(v) of this section. In
determining whether more than 60 percent of the total surface area
available to bear labeling is required, the indications for use listed
under the ``Use(s)'' heading, as set forth in paragraph (c)(4) of this
section, shall be limited to the minimum required uses reflected in the
applicable monograph, as provided in Sec. 330.1(c)(2) of this chapter.
(i) Paragraphs (d)(1), (d)(5), (d)(6), and (d)(7) of this section
shall apply.
(ii) Paragraph (d)(2) of this section shall apply except that the
letter height or type size for the title ``Drug Facts (continued)''
shall be no smaller than 7-point type and the headings in paragraphs
(c)(2) through (c)(9) of this section shall be the larger of either 7-
point or greater type, or 1-point size greater than the point size of
the text.
(iii) Paragraph (d)(3) of this section shall apply except that less
than 0.5-point leading may be used, provided the ascenders and
descenders do not touch.
(iv) Paragraph (d)(4) of this section shall apply except that if
more than one bulleted statement is placed on the same horizontal line,
the additional bulleted statements may continue to the next line of
text, and except that the bullets under each heading or subheading need
not be vertically aligned.
(v) Paragraph (d)(8) of this section shall apply except that the box
or similar enclosure required in paragraph (d)(8) of this section may be
omitted if the Drug Facts labeling is set off from the rest of the
labeling by use of color contrast.
(11)(i) The following labeling outlines the various provisions in
paragraphs (c) and (d) of this section:
[[Page 45]]
[GRAPHIC] [TIFF OMITTED] TR17MR99.003
(ii) The following sample label illustrates the provisions in
paragraphs (c) and (d) of this section:
[[Page 46]]
[GRAPHIC] [TIFF OMITTED] TR17MR99.004
(iii) The following sample label illustrates the provisions in
paragraphs (c) and (d) of this section, including paragraph (d)(10) of
this section, which permits modifications for small packages:
[[Page 47]]
[GRAPHIC] [TIFF OMITTED] TR17MR99.005
(iv) The following sample label illustrates the provisions in
paragraphs (c) and (d) of this section for a drug product marketed with
cosmetic claims:
[[Page 48]]
[GRAPHIC] [TIFF OMITTED] TR17MR99.006
(e) Exemptions and deferrals. FDA on its own initiative or in
response to a written request from any manufacturer, packer, or
distributor, may exempt or defer, based on the circumstances presented,
one or more specific requirements set forth in this section on the basis
that the requirement is inapplicable, impracticable, or contrary to
public health or safety. Requests for exemptions shall be submitted in
three copies in the form of an ``Application for Exemption'' to the Food
and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD
20852. The request shall be clearly identified on the envelope as a
``Request for Exemption from 21 CFR 201.66 (OTC Labeling Format)'' and
shall be directed to Docket No. 98N-0337. A separate request shall be
submitted for each OTC drug product. Sponsors of a product marketed
under an approved drug application shall also submit a single copy of
the exemption request to their application. Decisions on exemptions and
deferrals will be maintained in a permanent file in this docket for
public review. Exemption and deferral requests shall:
(1) Document why a particular requirement is inapplicable,
impracticable, or is contrary to public health or safety; and
(2) Include a representation of the proposed labeling, including any
outserts, panel extensions, or other graphical or packaging techniques
intended to be used with the product.
(f) Interchangeable terms and connecting terms. The terms listed in
Sec. 330.1(i) of this chapter may be used
[[Page 49]]
interchangeably in the labeling of OTC drug products, provided such use
does not alter the meaning of the labeling that has been established and
identified in an applicable OTC drug monograph or by regulation. The
terms listed in Sec. 330.1(j) of this chapter may be deleted from the
labeling of OTC drug products when the labeling is revised to comply
with this section, provided such deletion does not alter the meaning of
the labeling that has been established and identified in an applicable
OTC drug monograph or by regulation. The terms listed in Sec. 330.1(i)
and (j) of this chapter shall not be used to change in any way the
specific title, headings, and subheadings required under paragraphs
(c)(1) through (c)(9) of this section.
(g) Regulatory action. An OTC drug product that is not in compliance
with the format and content requirements in this section is subject to
regulatory action.
[64 FR 13286, Mar. 17, 1999]
Effective Date Note: At 64 FR 13286, Mar. 17, 1999, Sec. 201.66 was
added, effective Apr. 16, 1999.
Subpart D--Exemptions From Adequate Directions for Use
Sec. 201.100 Prescription drugs for human use.
A drug subject to the requirements of section 503(b)(1) of the act
shall be exempt from section 502(f)(1) if all the following conditions
are met:
(a) The drug is:
(1)(i) In the possession of a person (or his agents or employees)
regularly and lawfully engaged in the manufacture, transportation,
storage, or wholesale distribution of prescription drugs; or
(ii) In the possession of a retail, hospital, or clinic pharmacy, or
a public health agency, regularly and lawfully engaged in dispensing
prescription drugs; or
(iii) In the possession of a practitioner licensed by law to
administer or prescribe such drugs; and
(2) It is to be dispensed in accordance with section 503(b)
(b) The label of the drug bears:
(1) The statement ``Caution: Federal law prohibits dispensing
without prescription'' and
(2) The recommended or usual dosage and
(3) The route of administration, if it is not for oral use; and
(4) The quantity or proportion of each active ingredient, as well as
the information required by section 502 (d) and (e); and
(5) If it is for other than oral use, the names of all inactive
ingredients, except that:
(i) Flavorings and perfumes may be designated as such without naming
their components.
(ii) Color additives may be designated as coloring without naming
specific color components unless the naming of such components is
required by a color additive regulation prescribed in subchapter A of
this chapter.
(iii) Trace amounts of harmless substances added solely for
individual product identification need not be named. If it is intended
for administration by parenteral injection, the quantity or proportion
of all inactive ingredients, except that ingredients added to adjust the
pH or to make the drug isotonic may be declared by name and a statement
of their effect; and if the vehicle is water for injection it need not
be named.
(6) An identifying lot or control number from which it is possible
to determine the complete manufacturing history of the package of the
drug.
(7) A statement directed to the pharmacist specifying the type of
container to be used in dispensing the drug product to maintain its
identity, strength, quality, and purity. Where there are standards and
test procedures for determining that the container meets the
requirements for specified types of containers as defined in an official
compendium, such terms may be used. For example, ``Dispense in tight,
light-resistant container as defined in the National Formulary''. Where
standards and test procedures for determining the types of containers to
be used in dispensing the drug product are not included in an official
compendium, the specific container or types of containers known to be
adequate to maintain the identity, strength, quality,
[[Page 50]]
and purity of the drug products shall be described. For example,
``Dispense in containers which (statement of specifications which
clearly enable the dispensing pharmacist to select an adequate
container)'': Provided, however, That in the case of containers too
small or otherwise unable to accommodate a label with sufficient space
to bear all such information, but which are packaged within an outer
container from which they are removed for dispensing or use, the
information required by paragraph (b) (2), (3), (5), and (7) of this
section may be contained in other labeling on or within the package from
which it is to be dispensed; the information referred to in paragraph
(b)(1) of this section may be placed on such outer container only; and
the information required by paragraph (b)(6) of this section may be on
the crimp of the dispensing tube. The information required by this
paragraph (b)(7) is not required for prescription drug products packaged
in unit-dose, unit-of-use, on other packaging format in which the
manufacturer's original package is designed and intended to be dispensed
to patients without repackaging.
(c)(1) Labeling on or within the package from which the drug is to
be dispensed bears adequate information for its use, including
indications, effects, dosages, routes, methods, and frequency and
duration of administration, and any relevant hazards, contraindications,
side effects, and precautions under which practitioners licensed by law
to administer the drug can use the drug safely and for the purposes for
which it is intended, including all purposes for which it is advertised
or represented; and
(2) If the article is subject to section 505 of the act, the
labeling bearing such information is the labeling authorized by the
approved new drug application or required as a condition for the
certification or the exemption from certification requirements
applicable to preparations of insulin or antibiotic drugs.
(d) Any labeling, as defined in section 201(m) of the act, whether
or not it is on or within a package from which the drug is to be
dispensed, distributed by or on behalf of the manufacturer, packer, or
distributor of the drug, that furnishes or purports to furnish
information for use or which prescribes, recommends, or suggests a
dosage for the use of the drug (other than dose information required by
paragraph (b)(2) of this section and Sec. 201.105(b)(2) contains:
(1) Adequate information for such use, including indications,
effects, dosages, routes, methods, and frequency and duration of
administration and any relevant warnings, hazards, contraindications,
side effects, and precautions, under which practitioners licensed by law
to administer the drug can use the drug safely and for the purposes for
which it is intended, including all conditions for which it is
advertised or represented; and if the article is subject to section 505
of the act, the parts of the labeling providing such information are the
same in language and emphasis as labeling approved or permitted, under
the provisions of section 505, and any other parts of the labeling are
consistent with and not contrary to such approved or permitted labeling;
and
(2) The same information concerning the ingredients of the drug as
appears on the label and labeling on or within the package from which
the drug is to be dispensed.
(3) The information required, and in the format specified, by
Secs. 201.56 and 201.57.
(e) All labeling described in paragraph (d) of this section bears
conspicuously the name and place of business of the manufacturer,
packer, or distributor, as required for the label of the drug under
Sec. 201.1.
(f) Reminder labeling which calls attention to the name of the drug
product but does not include indications or dosage recommendations for
use of the drug product is exempted from the provisions of paragraph (d)
of this section. This reminder labeling shall contain only the
proprietary name of the drug product, if any; the established name of
the drug product, if any; the established name of each active ingredient
in the drug product; and, optionally, information relating to
quantitative ingredient statements, dosage form, quantity of package
contents, price, the name and address of the manufacturer, packer, or
distributor or other written, printed, or graphic matter
[[Page 51]]
containing no representation or suggestion relating to the drug product.
If the Commissioner finds that there is evidence of significant
incidence of fatalities or serious injury associated with the use of a
particular prescription drug, he may withdraw this exemption by so
notifying the manufacturer, packer, or distributor of the drug by
letter. Reminder labeling, other than price lists and catalogs solely
intended to convey price information including, but not limited to,
those subject to the requirements of Sec. 200.200 of this chapter, is
not permitted for a prescription drug product whose labeling contains a
boxed warning relating to a serious hazard associated with the use of
the drug product. Reminder labeling which is intended to provide
consumers with information concerning the price charged for a
prescription for a particular drug product shall meet all of the
conditions contained in Sec. 200.200 of this chapter. Reminder labeling,
other than that subject to the requirements of Sec. 200.200 of this
chapter, is not permitted for a drug for which an announcement has been
published pursuant to a review of the labeling claims for the drug by
the National Academy of Sciences/National Research Council (NAS/NRC),
Drug Efficacy Study Group, and for which no claim has been evaluated as
higher than ``possibly effective.'' If the Commissioner finds the
circumstances are such that reminder labeling may be misleading to
prescribers of drugs subject to NAS/NRC evaluation, such reminder
labeling will not be allowed and the manufacturer, packer, or
distributor will be notified either in the publication of the
conclusions on the effectiveness of the drug or by letter.
[40 FR 13998, Mar. 27, 1975, as amended at 40 FR 58799, Dec. 18, 1975;
42 FR 15674, Mar. 22, 1977; 43 FR 37989, Aug. 25, 1978; 44 FR 20659,
Apr. 6, 1979; 44 FR 37467, June 26, 1979; 45 FR 25777, Apr. 15, 1980; 63
FR 26698, May 13, 1998; 64 FR 400, Jan. 5, 1999]
Effective Date Note: At 64 FR 400, Jan. 5, 1999, Sec. 201.100 was
amended by removing ``or 507'' from paragraph (c)(2), and by removing
``or 507'' and ``or 507, respectively'' from paragraph (d)(1), effective
May 20, 1999.
Sec. 201.105 Veterinary drugs.
A drug subject to the requirements of section 503(f)(1) of the act
shall be exempt from section 502(f)(1) of the act if all the following
conditions are met:
(a) The drug is:
(1)(i) In the possession of a person (or his agents or employees)
regularly and lawfully engaged in the manufacture, transportation,
storage, or wholesale distribution of drugs that are to be used only by
or on the prescription or other order of a licensed veterinarian; or
(ii) In the possession of a retail, hospital, or clinic pharmacy, or
other person authorized under State law to dispense veterinary
prescription drugs, who is regularly and lawfully engaged in dispensing
drugs that are to be used only by or on the prescription or other order
of a licensed veterinarian; or
(iii) In the possession of a licensed veterinarian for use in the
course of his professional practice; and
(2) To be dispensed in accordance with section 503(f) of the act.
(b) The label of the drug bears:
(1) The statement ``Caution: Federal law restricts this drug to use
by or on the order of a licensed veterinarian''; and
(2) The recommended or usual dosage; and
(3) The route of administration, if it is not for oral use; and
(4) The quantity or proportion of each active ingredient as well as
the information required by section 502(e) of the act; and
(5) If it is for other than oral use, the names of all inactive
ingredients, except that:
(i) Flavorings and perfumes may be designated as such without naming
their components.
(ii) Color additives may be designated as coloring without naming
specific color components unless the naming of such components is
required by a color additive regulation prescribed in subchapter A of
this chapter.
(iii) Trace amounts of harmless substances added solely for
individual product identification need not be named.
If it is intended for administration by parenteral injection, the
quantity or proportion of all inactive ingredients,
[[Page 52]]
except that ingredients added to adjust the pH or to make the drug
isotonic may be declared by name and a statement of their effect; and if
the vehicle is water for injection, it need not be named.
(6) An identifying lot or control number from which it is possible
to determine the complete manufacturing history of the package of the
drug;
Provided, however, That in the case of containers too small or otherwise
unable to accommodate a label with sufficient space to bear all such
information, but which are packaged within an outer container from which
they are removed for dispensing or use, the information required by
paragraphs (b) (2), (3), and (5) of this section may be contained in
other labeling on or within the package from which it is to be so
dispensed, and the information referred to in paragraph (b)(1) of this
section may be placed on such outer container only, and the information
required by paragraph (b)(6) of this section may be on the crimp of the
dispensing tube.
(c)(1) Labeling on or within the package from which the drug is to
be dispensed bears adequate information for its use, including
indications, effects, dosages, routes, methods, and frequency and
duration of administration, and any relevant hazards, contraindications,
side effects, and precautions under which veterinarians licensed by law
to administer the drug can use the drug safely and for the purposes for
which it is intended, including all purposes for which it is advertised
or represented; and
(2) If the article is subject to section 512 of the act, the
labeling bearing such information is the labeling authorized by the
approved new animal drug application or required as a condition for the
certification or the exemption from certification requirements
applicable to preparations of antibiotic drugs: Provided, however, That
the information required by paragraph (c)(1) of this section may be
omitted from the dispensing package if, but only if, the article is a
drug for which directions, hazards, warnings, and use information are
commonly known to veterinarians licensed by law to administer the drug.
Upon written request, stating reasonable grounds therefore, the
Commissioner will offer an opinion on a proposal to omit such
information from the dispensing package under this proviso.
(d) Any labeling, as defined in section 201(m) of the act, whether
or not it is on or within a package from which the drug is to be
dispensed, distributed by or on behalf of the manufacturer, packer, or
distributor of the drug, that furnishes or purports to furnish
information for use or which prescribes, recommends, or suggests a
dosage for the use of the drug (other than dose information required by
paragraph (b)(2) of this section and Sec. 201.100(b)(2)) contains:
(1) Adequate information for such use, including indications,
effects, dosages, routes, methods, and frequency and duration of
administration, and any relevant warnings, hazards, contraindications,
side effects, and precautions, and including information relevant to
compliance with the new animal drug provisions of the act, under which
veterinarians licensed by law to administer the drug can use the drug
safely and for the purposes for which it is intended, including all
conditions for which it is advertised or represented; and if the article
is subject to section 512 of the act, the parts of the labeling
providing such information are the same in language and emphasis as
labeling approved or permitted under the provisions of section 512, and
any other parts of the labeling are consistent with and not contrary to
such approved or permitted labeling; and
(2) The same information concerning the ingredients of the drug as
appears on the label and labeling on or within the package from which
the drug is to be dispensed;
Provided, however, That the information required by paragraphs (d) (1)
and (2) of this section is not required on the so-called reminder-piece
labeling which calls attention to the name of the drug but does not
include indications or dosage recommendations for use of the drug.
(e) All labeling, except labels and cartons, bearing information for
use of the drug also bears the date of the issuance or the date of the
latest revision of such labeling.
[[Page 53]]
(f) A prescription drug intended for both human and veterinary use
shall comply with paragraphs (e) and (f) of this section and
Sec. 201.100.
[40 FR 13998, Mar. 27, 1975, as amended at 42 FR 15674, Mar. 22, 1977;
57 FR 54300, Nov. 18, 1992]
Sec. 201.115 New drugs or new animal drugs.
A new drug shall be exempt from section 502(f)(1) of the act:
(a) To the extent to which such exemption is claimed in an approved
application with respect to such drug under section 505 or 512 of the
act; or
(b) If no application under section 505 of the act is approved with
respect to such drug but it complies with section 505(i) or 512 of the
act and regulations thereunder.
No exemption shall apply to any other drug which would be a new drug if
its labeling bore representations for its intended uses.
Sec. 201.116 Drugs having commonly known directions.
A drug shall be exempt from section 502(f)(1) of the act insofar as
adequate directions for common uses thereof are known to the ordinary
individual.
[41 FR 6910, Feb. 13, 1976]
Sec. 201.117 Inactive ingredients.
A harmless drug that is ordinarily used as an inactive ingredient,
such as a coloring, emulsifier, excipient, flavoring, lubricant,
preservative, or solvent, in the preparation of other drugs shall be
exempt from section 502(f)(1) of the act. This exemption shall not apply
to any substance intended for a use which results in the preparation of
a new drug, unless an approved new-drug application provides for such
use.
Sec. 201.119 In vitro diagnostic products.
(a) ``In vitro diagnostic products'' are those reagents, instruments
and systems intended for use in the diagnosis of disease or in the
determination of the state of health in order to cure, mitigate, treat,
or prevent disease or its sequelae. Such products are intended for use
in the collection, preparation and examination of specimens taken from
the human body. These products are drugs or devices as defined in
section 201(g) and 201(h), respectively, of the Federal Food, Drug, and
Cosmetic Act (the act) or are a combination of drugs and devices, and
may also be a biological product subject to section 351 of the Public
Health Service Act.
(b) A product intended for use in the diagnosis of disease and which
is an in vitro diagnostic product as defined in paragraph (a) of this
section shall be deemed to be in compliance with the requirements of
this section and section 502(f)(1) of the act if it meets the
requirements of Sec. 809.10 of this chapter.
[41 FR 6910, Feb. 13, 1976]
Sec. 201.120 Prescription chemicals and other prescription components.
A drug prepared, packaged, and primarily sold as a prescription
chemical or other component for use by registered pharmacists in
compounding prescriptions or for dispensing in dosage unit form upon
prescriptions shall be exempt from section 502(f)(1) of the act if all
the following conditions are met:
(a) The drug is an official liquid acid or official liquid alkali,
or is not a liquid solution, emulsion, suspension, tablet, capsule, or
other dosage unit form; and
(b) The label of the drug bears:
(1) The statement ``For prescription compounding''; and
(2) If in substantially all dosage forms in which it may be
dispensed it is subject to section 503(b)(1) of the act, the statement
``Caution: Federal law prohibits dispensing without prescription''; or
(3) If it is not subject to section 503(b)(1) of the act and is by
custom among retail pharmacists sold in or from the interstate package
for use by consumers, ``adequate directions for use'' in the conditions
for which it is so sold.
Provided, however, That the information referred to in paragraph (b)(3)
of this section may be contained in the labeling on or within the
package from which it is to be dispensed.
(c) This exemption shall not apply to any substance intended for use
in compounding which results in a new
[[Page 54]]
drug, unless an approved new-drug application covers such use of the
drug in compounding prescriptions.
Sec. 201.122 Drugs for processing, repacking, or manufacturing.
A drug in a bulk package, except tablets, capsules, or other dosage
unit forms, intended for processing, repacking, or use in the
manufacture of another drug shall be exempt from section 502(f)(1) of
the act if its label bears the statement ``Caution: For manufacturing,
processing, or repacking''; and if in substantially all dosage forms in
which it may be dispensed it is subject to section 503(b)(1) of the act,
the statement ``Caution: Federal law prohibits dispensing without
prescription'', or if in substantially all dosage forms in which it may
be dispensed it is subject to section 503(f)(1) of the act, the
statement ``Caution: Federal law restricts this drug to use by or on the
order of a licensed veterinarian''. This exemption and the exemption
under Sec. 201.120 may be claimed for the same article. However, the
exemption shall not apply to a substance intended for a use in
manufacture, processing, or repacking which causes the finished article
to be a new drug or new animal drug, unless:
(a) An approved new drug application or new animal drug application
covers the production and delivery of the drug substance to the
application holder by persons named in the application, and, for a new
drug substance, the export of it by such persons under Sec. 314.410 of
this chapter; or
(b) If no application is approved with respect to such new drug or
new animal drug, the label statement ``Caution: For manufacturing,
processing, or repacking'' is immediately supplemented by the words ``in
the preparation of a new drug or new animal drug limited by Federal law
to investigational use'', and the delivery is made for use only in the
manufacture of such new drug or new animal drug limited to
investigational use as provided in part 312 or Sec. 511.1 of this
chapter; or
(c) A new drug application or new animal drug application covering
the use of the drug substance in the production and marketing of a
finished drug product has been submitted but not yet approved or
disapproved, the bulk drug is not exported, and the finished drug
product is not further distributed after it is manufactured until after
the new drug application or new animal drug application is approved.
[41 FR 6911, Feb. 13, 1976, as amended at 41 FR 15844, Apr. 15, 1976; 50
FR 7492, Feb. 22, 1985; 55 FR 11576, Mar. 29, 1990; 57 FR 54301, Nov.
18, 1992]
Sec. 201.125 Drugs for use in teaching, law enforcement, research, and analysis.
A drug subject to Sec. 201.100 or Sec. 201.105, shall be exempt from
section 502(f)(1) of the act if shipped or sold to, or in the possession
of, persons regularly and lawfully engaged in instruction in pharmacy,
chemistry, or medicine not involving clinical use, or engaged in law
enforcement, or in research not involving clinical use, or in chemical
analysis, or physical testing, and is to be used only for such
instruction, law enforcement, research, analysis, or testing.
[41 FR 6911, Feb. 13, 1976]
Sec. 201.127 Drugs; expiration of exemptions.
(a) If a shipment or delivery, or any part thereof, of a drug which
is exempt under the regulations in this section is made to a person in
whose possession the article is not exempt, or is made for any purpose
other than those specified, such exemption shall expire, with respect to
such shipment or delivery or part thereof, at the beginning of that
shipment or delivery. The causing of an exemption to expire shall be
considered an act which results in such drug being misbranded unless it
is disposed of under circumstances in which it ceases to be a drug or
device.
(b) The exemptions conferred by Secs. 201.117, 201.119, 201.120,
201.122, and 201.125 shall continue until the drugs are used for the
purposes for which they are exempted, or until they are relabeled to
comply with section 502(f)(1) of the act. If, however, the drug is
converted, compounded, or manufactured into a dosage form limited to
prescription dispensing, no exemption shall thereafter apply to the
[[Page 55]]
article unless the dosage form is labeled as required by section 503(b)
and Secs. 201.100 or 201.105.
[41 FR 6911, Feb. 13, 1976]
Sec. 201.128 Meaning of ``intended uses''.
The words intended uses or words of similar import in Secs. 201.5,
201.115, 201.117, 201.119, 201.120, and 201.122 refer to the objective
intent of the persons legally responsible for the labeling of drugs. The
intent is determined by such persons' expressions or may be shown by the
circumstances surrounding the distribution of the article. This
objective intent may, for example, be shown by labeling claims,
advertising matter, or oral or written statements by such persons or
their representatives. It may be shown by the circumstances that the
article is, with the knowledge of such persons or their representatives,
offered and used for a purpose for which it is neither labeled nor
advertised. The intended uses of an article may change after it has been
introduced into interstate commerce by its manufacturer. If, for
example, a packer, distributor, or seller intends an article for
different uses than those intended by the person from whom he received
the drug, such packer, distributor, or seller is required to supply
adequate labeling in accordance with the new intended uses. But if a
manufacturer knows, or has knowledge of facts that would give him
notice, that a drug introduced into interstate commerce by him is to be
used for conditions, purposes, or uses other than the ones for which he
offers it, he is required to provide adequate labeling for such a drug
which accords with such other uses to which the article is to be put.
[41 FR 6911, Feb. 13, 1976]
Sec. 201.129 Drugs; exemption for radioactive drugs for research use.
A radioactive drug intended for administration to human research
subjects during the course of a research project intended to obtain
basic research information regarding metabolism (including kinetics,
distribution, and localization) of a radioactively labeled drug or
regarding human physiology, pathophysiology, or biochemistry (but not
intended for immediate therapeutic, diagnostic, or similar purposes),
under the conditions set forth in Sec. 361.1 of this chapter, shall be
exempt from section 502(f)(1) of the act if the packaging, label, and
labeling are in compliance with Sec. 361.1(f) of this chapter.
[41 FR 6911, Feb. 13, 1976]
Subpart E--Other Exemptions
Sec. 201.150 Drugs; processing, labeling, or repacking.
(a) Except as provided by paragraphs (b) and (c) of this section, a
shipment or other delivery of a drug which is, in accordance with the
practice of the trade, to be processed, labeled, or repacked in
substantial quantity at an establishment other than that where
originally processed or packed, shall be exempt, during the time of
introduction into and movement in interstate commerce and the time of
holding in such establishment, from compliance with the labeling and
packaging requirements of sections 501(b) and 502 (b), (d), (e), (f),
and (g) of the act if:
(1) The person who introduced such shipment or delivery into
interstate commerce is the operator of the establishment where such drug
is to be processed, labeled, or repacked; or
(2) In case such person is not such operator, such shipment or
delivery is made to such establishment under a written agreement, signed
by and containing the post-office addresses of such person and such
operator, and containing such specifications for the processing,
labeling, or repacking, as the case may be, of such drug in such
establishment as will insure, if such specifications are followed, that
such drug will not be adulterated or misbranded within the meaning of
the act upon completion of such processing, labeling, or repacking. Such
person and such operator shall each keep a copy of such agreement until
2 years after the final shipment or delivery of such drug from such
establishment, and shall make such copies available for inspection at
any reasonable hour to any officer or employee of the Department who
requests them.
[[Page 56]]
(b) An exemption of a shipment or other delivery of a drug under
paragraph (a)(1) of this section shall, at the beginning of the act of
removing such shipment or delivery, or any part thereof, from such
establishment, become void ab initio if the drug comprising such
shipment, delivery, or part is adulterated or misbranded within the
meaning of the act when so removed.
(c) An exemption of a shipment or other delivery of a drug under
paragraph (a)(2) of this section shall become void ab initio with
respect to the person who introduced such shipment or delivery into
interstate commerce upon refusal by such person to make available for
inspection a copy of the agreement, as required by such paragraph (a)(2)
of this section.
(d) An exemption of a shipment or other delivery of a drug under
paragraph (a)(2) of this section shall expire:
(1) At the beginning of the act of removing such shipment or
delivery, or any part thereof, from such establishment if the drug
comprising such shipment, delivery, or part is adulterated or misbranded
within the meaning of the act when so removed; or
(2) Upon refusal by the operator of the establishment where such
drug is to be processed, labeled, or repacked, to make available for
inspection a copy of the agreement, as required by such clause.
[41 FR 6911, Feb. 13, 1976, as amended at 64 FR 400, Jan. 5, 1999]
Effective Date Note: At 64 FR 400, Jan. 5, 1999, Sec. 201.150 was
amended by removing paragraphs (e) through (h), effective May 20, 1999.
For the convenience of the user, the superseded text is set forth as
follows:
Sec. 201.150 Drugs; processing, labeling, or repacking.
* * * * *
(e) Except as provided in paragraphs (g) and (h) of this section, a
shipment or other delivery of a drug which is subject to section 507 of
the act and which is, in accordance with the practice of the trade, to
be processed or repacked in a substantial quantity at an establishment
other than that where originally processed or packed shall be exempt
from compliance with the labeling requirements of section 502(f) of the
act during the time such drug is also exempt from the requirements of
section 502(l) of the act or, in the case of a new animal drug, is
exempt from certification under section 512(n) of the act under the
provisions of Sec. 433.15 or Sec. 433.16 of this chapter.
(f) Except as provided by paragraphs (g) and (h) of this section, a
shipment or other delivery of a drug which is subject to section 507 of
the act and which is, in accordance with the practice of the trade, to
be labeled in substantial quantity at an establishment other than that
where originally processed or packed shall be exempt from compliance
with the labeling requirements of section 502 (b), (e) and (f) of the
act during the time such drug is also exempt from the requirements of
section 502(l) of the act or, in the case of a new animal drug, is
exempt from certification under section 512(n) of the act under
Sec. 433.12 of this chapter, if the words, statements, and other
information required by section 502 (b) and (e) of the act appear on
each shipping container of such drug.
(g) In case the person who introduced such shipment or other
delivery into interstate commerce is the operator of the establishment
where such drug is to be processed, labeled, or repacked, an exemption
of such shipment or delivery under paragraph (e) or (f) of this section
shall become void at the beginning of the act of removing such shipment
or delivery or any part thereof from such establishment if the drug
comprising such shipment, delivery, or part is adulterated or misbranded
within the meaning of the act when so removed.
(h) In case the person who introduced such shipment or delivery into
interstate commerce is not the operator of the establishment where such
drug is to be processed, labeled, or repacked, an exemption of a
shipment or other delivery of such drug under paragraph (e) or (f) of
this section shall expire at the beginning of the act of removing such
shipment or delivery or any part thereof from such establishment if the
drug comprising such shipment, delivery, or part is adulterated or
misbranded within the meaning of the act when so removed.
* * * * *
Sec. 201.161 Carbon dioxide and certain other gases.
(a) Carbon dioxide, cyclopropane, ethylene, helium, and nitrous
oxide gases intended for drug use are exempted from the requirements of
Sec. 201.100(b) (2), (3), and (c)(1) provided the labeling bears, in
addition to any other information required by the Federal Food, Drug,
and Cosmetic Act, the following:
(1) The warning statement ``Warning--Administration of (name of gas)
[[Page 57]]
may be hazardous or contraindicated. For use only by or under the
supervision of a licensed practitioner who is experienced in the use and
administration of (name of gas) and is familiar with the indications,
effects, dosages, methods, and frequency and duration of administration,
and with the hazards, contraindications, and side effects and the
precautions to be taken''; and
(2) Any needed directions concerning the conditions for storage and
warnings against the inherent dangers in the handling of the specific
compressed gas.
(b) This labeling exemption does not apply to mixtures of any one or
more of these gases with oxygen or with each other.
(c) Regulatory action may be initiated with respect to any article
shipped within the jurisdiction of the Act contrary to the provisions of
this section after 60 days following publication of this section in the
Federal Register.
Subpart F--Labeling Claims for Drugs in Drug Efficacy Study
Sec. 201.200 Disclosure of drug efficacy study evaluations in labeling and advertising.
(a)(1) The National Academy of Sciences--National Research Council,
Drug Efficacy Study Group, has completed an exhaustive review of
labeling claims made for drugs marketed under new-drug and antibiotic
drug procedures between 1938 and 1962. The results are compiled in
``Drug Efficacy Study, A Report to the Commissioner of Food and Drugs
from the National Academy of Sciences (1969).'' As the report notes,
this review has made ``an audit of the state of the art of drug usage
that has been uniquely extensive in scope and uniquely intensive in
time'' and is applicable to more than 80 percent of the currently
marketed drugs. The report further notes that the quality of the
evidence of efficacy, as well as the quality of the labeling claims, is
poor. Labeling and other promotional claims have been evaluated as
``effective,'' ``probably effective,'' ``possibly effective,''
``ineffective,'' ``ineffective as a fixed combination,'' and ``effective
but,'' and a report for each drug in the study has been submitted to the
Commissioner.
(2) The Food and Drug Administration is processing the reports,
seeking voluntary action on the part of the drug manufacturers and
distributors in the elimination or modification of unsupported
promotional claims, and initiating administrative actions as necessary
to require product and labeling changes.
(3) Delays have been encountered in bringing to the attention of the
prescribers of prescription items the conclusions of the expert panels
that reviewed the promotional claims.
(b) The Commissioner of Food and Drugs concludes that:
(1) The failure to disclose in the labeling of a drug and in other
promotional material the conclusions of the Academy experts that a claim
is ``ineffective,'' ``possibly effective,'' ``probably effective,'' or
``ineffective as a fixed combination,'' while labeling and promotional
material bearing any such claim are being used, is a failure to disclose
facts that are material in light of the representations made and causes
the drug to be misbranded.
(2) The Academy classification of a drug as other than ``effective''
for a claim for which such drug is recommended establishes that there is
a material weight of opinion among qualified experts contrary to the
representation made or suggested in the labeling, and failure to reveal
this fact causes such labeling to be misleading.
(c) Therefore, after publication in the Federal Register of a Drug
Efficacy Study Implementation notice on a prescription drug, unless
exempted or otherwise provided for in the notice, all package labeling
(other than the immediate container or carton label, unless such
labeling contains information required by Sec. 201.100(c)(1) in lieu of
a package insert), promotional labeling, and advertisements shall
include, as part of the information for practitioners under which the
drug can be safely and effectively used, an appropriate qualification of
all claims evaluated as other than ``effective'' by a panel of the
National Academy of Sciences--National Research Council, Drug Efficacy
Study Group, if such
[[Page 58]]
claims continue to be included in either the labeling or advertisements.
However, this qualifying information will be required in advertisements
only if promotional material is included therein for claims evaluated as
less than ``effective'' or if such claims are included in the
indications section of the portion of the advertisement containing the
information required in brief summary by Sec. 202.1(e)(1) of this
chapter. When, however, the Food and Drug Administration classification
of such claim is ``effective'' (for example, on the basis of revision of
the language of the claim or submission or existence of adequate data),
such qualification is not necessary. When the Food and Drug
Administration classification of the claim, as stated in the
implementation notice, differs from that of the Academy but is other
than ``effective,'' the qualifying statement shall refer to this
classification in lieu of the Academy's classification.
(d) For new drugs and antibiotics, supplements to provide for
revised labeling in accord with paragraph (c) of this section shall be
submitted under the provisions of Sec. 314.70 and Sec. 514.8 of this
chapter within 90 days after publication of the implementation notice in
the Federal Register or by May 15, 1972, for those drugs for which
notices have been published and such labeling shall be put into use as
soon as possible but not later than the end of the time period allowed
for submitting supplements to provide for revised labeling.
(e) Qualifying information required in drug labeling by paragraph
(c) of this section in order to advise prescribers of a drug of the
findings made by a panel of the Academy in evaluating a claim as other
than ``effective'' shall be at least of the same size and color and
degree of prominence as other printing in the labeling and shall be
presented in a prominent box using one of the following formats and
procedures:
(1) In drug labeling the box statement may entirely replace the
indications section and be in the following format:
------------------------------------------------------------------
Indications
Based on a review of this drug by the National Academy of
Sciences--National Research Council and/or other
information, FDA has classified the indication(s) as
follows:
Effective: (list or state in paragraph form).
``Probably'' effective: (list or state in paragraph
form).
``Possibly'' effective: (list or state in paragraph
form).
Final classification of the less-than-effective
indications requires further investigation.
------------------------------------------------------------------
(2) Or the indication(s) for which the drug has been found effective
may appear outside the boxed statement and be followed immediately by
the following boxed statement:
------------------------------------------------------------------
Based on a review of this drug by the National Academy of
Sciences--National Research Council and/or other
information, FDA has classified the other indication(s) as
follows:
``Probably'' effective: (list or state in paragraph
form).
``Possibly'' effective: (list or state in paragraph
form).
Final classification of the less-than-effective
indications requires further investigation.
------------------------------------------------------------------
(3) In drug labeling (other than that which is required by
Sec. 201.100(c)(1)) which may contain a promotional message, the
promotional message shall be keyed to the boxed statement by the same
means as those provided for advertisements in paragraph (f)(2) of this
section.
(f) Qualifying information required in prescription drug advertising
by paragraph (c) of this section shall contain a prominent boxed
statement of the advertised indication(s) and of the limitations of
effectiveness using the same format, language, and emphasis as that
required in labeling by paragraph (e) of this section.
(1) The boxed statement shall appear in (or next to) the information
required in brief summary by Sec. 202.1(e)(1) of this chapter and shall
have prominence at least equal to that provided for other
[[Page 59]]
information presented in the brief summary and shall have type size,
captions, color, and other physical characteristics comparable to the
information required in the brief summary.
(2) Less-than-effective indication(s) in the promotional message of
an advertisement which is a single page or less shall be keyed to the
boxed statement by asterisk, by an appropriate statement, or by other
suitable means providing adequate emphasis on the boxed statement. On
each page where less-than-effective indication(s) appear in a mutiple
page advertisement, an asterisk shall be placed after the most prominent
mention of the indi- cation(s); if the degree of prominence does not
vary, an asterisk shall be placed after the first mention of the
indication. The asterisk shall refer to a notation at the bottom of the
page which shall state ``This drug has been evaluated as probably
effective (or possibly effective whichever is appropriate) for this
indication'' and ``See Brief Summary'' or ``See Prescribing
Information,'' the latter legend to be used only if the advertisement
carries the required information for professional use as set forth in
Sec. 201.100(c)(1).
(3) For less-than-effective indications which are included in the
advertisement only as a part of the information required in brief
summary, the disclosure information shall appear in this portion of the
advertisement in the same manner as is specified for labeling in
paragraph (e) of this section.
(g) The Commissioner may find circumstances are such that, while the
elimination of claims evaluated as other than effective will generally
eliminate the need for disclosure about such claims, there will be
instances in which the change in the prescribing or promotional profile
of the drug is so substantial as to require a disclosure of the reason
for the change so that the purchaser or prescriber is not misled by
being left unaware through the sponsor's silence that a basic change has
taken place. The Food and Drug Administration will identify these
situations in direct correspondence with the drug promoters, after which
the failure to make the disclosure will be regarded as misleading and
appropriate action will be taken.
[40 FR 13998, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990]
Subpart G--Specific Labeling Requirements for Specific Drug Products
Sec. 201.300 Notice to manufacturers, packers, and distributors of glandular preparations.
(a) Under date of December 4, 1941, in a notice to manufacturers of
glandular preparations, the Food and Drug Administration expressed the
opinion that preparations of inert glandular materials intended for
medicinal use should, in view of the requirement of section 201(n) of
the Federal Food, Drug, and Cosmetic Act (52 Stat. 1041; 21 U.S.C.
321(n) ), be labeled with a statement of the material fact that there is
no scientific evidence that the articles contain any therapeutic or
physiologically active constituents. Numerous preparations of such inert
glandular materials were subsequently marketed with disclaimers of the
type suggested. The term inert glandular materials means preparations
incapable of exerting an action or effect of some significant or
measurable benefit in one way or another, i.e., in the diagnosis, cure,
mitigation, treatment, or prevention of disease, or in affecting the
structure or any function of the body.
(b) Manufacturers have heretofore taken advantage of Sec. 201.100
permitting omission of directions for use when the label bears the
prescription legend. Section 201.100(c) requires that the labeling of
the drug, which may include brochures readily available to licensed
practitioners, bear information as to the use of the drug by
practitioners licensed by law to administer it. Obviously, information
adequate for the use of an inert glandular preparation is not available
to practitioners licensed by law.
(c) The Department of Health and Human Services is of the opinion
that inert glandular materials may not be exempted from the requirements
of section 502(f)(1) of the act that they bear adequate directions for
use; and, accordingly, that their labeling must
[[Page 60]]
include among other things, representations as to the conditions for
which such articles are intended to be used or as to the structure or
function of the human body that they are intended to affect. Since any
such representations offering these articles for use as drugs would be
false or misleading, such articles will be considered to be misbranded
if they are distributed for use as drugs.
(d) The amended regulations provide also that in the case of drugs
intended for parenteral administration there shall be no exemption from
the requirement that their labelings bear adequate directions for use.
Such inert glandular materials for parenteral use are therefore subject
to the same comment as applies to those intended for oral
administration.
Sec. 201.301 Notice to manufacturers, packers, and distributors of estrogenic hormone preparations.
Some drug preparations fabricated wholly or in part from estradiol
and labeled as to potency in terms of international units or in terms of
international units of estrone activity have been marketed. The
international unit of the estrus-producing hormone was established by
the International Conference on the Standardization of Sex Hormones at
London, England, on August 1, 1932. This unit was defined as ``the
specific estrus-producing activity contained in 0.1 gamma (=0.0001 mg.)
of the standard'' hydroxyketonic hormone found in urine (estrone). The
International Conference declared that it did not recommend the
determination of the activity of nonhydroxyketonic forms of estrogenic
hormones in units of estrone because of the varying ratios between the
activity of such nonhydroxyketonic estrogenic hormones and estrone, when
measured by different methods on test animals. There is no international
unit for measuring the activity of estradiol and no accepted
relationship between its activity and that of estrone, either in test
animals or in humans. The declaration of potency of estradiol in terms
of international units or in terms of international units of estrone
activity is therefore considered misleading, within the meaning of 21
U.S.C. 352(a). The declaration of the estradiol content of an estrogenic
hormone preparation in terms of weight is considered appropriate.
Sec. 201.302 Notice to manufacturers, packers, and distributors of drugs for internal use which contain mineral oil.
(a) In the past few years research studies have altered medical
opinion as to the usefulness and harmfulness of mineral oil in the human
body. These studies have indicated that when mineral oil is used orally
near mealtime it interferes with absorption from the digestive tract of
provitamin A and the fat-soluble vitamins A, D, and K, and consequently
interferes with the utilization of calcium and phosphorus, with the
result that the user is left liable to deficiency diseases. When so used
in pregnancy it predisposes to hemorrhagic disease of the newborn.
(b) There is accumulated evidence that the indiscriminate
administration of mineral oil to infants may be followed by aspiration
of the mineral oil and subsequent ``lipoid pneumonia.''
(c) In view of these facts, the Department of Health and Human
Services will regard as misbranded under the provisions of the Federal
Food, Drug, and Cosmetic Act a drug for oral administration consisting
in whole or in part of mineral oil, the labeling of which encourages its
use in pregnancy or indicates or implies that such drug is for
administration to infants.
(d) It is also this Department's view that the act requires the
labelings of such drugs to bear a warning against consumption other than
at bedtime and against administration to infants. The following form of
warning is suggested: ``Caution: To be taken only at bedtime. Do not use
at any other time or administer to infants, except upon the advice of a
physician.''
(e) This statement of interpretation does not in any way exempt
mineral oil or preparations containing mineral oil from complying in all
other respects with the requirements of the Federal Food, Drug, and
Cosmetic Act.
[[Page 61]]
Sec. 201.303 Labeling of drug preparations containing significant proportions of wintergreen oil.
(a) Because methyl salicylate (wintergreen oil) manifests no
toxicity in the minute amounts in which it is used as a flavoring, it is
mistakenly regarded by the public as harmless even when taken in
substantially larger amounts. Actually, it is quite toxic when taken in
quantities of a teaspoonful or more. Wintergreen oil and preparations
containing it have caused a number of deaths through accidental misuse
by both adults and children. Children are particularly attracted by the
odor and are likely to swallow these products when left within reach.
(b) To safeguard against fatalities from this cause, the Department
of Health and Human Services will regard as misbranded under the
provisions of the Federal Food, Drug, and Cosmetic Act any drug
containing more than 5 percent methyl salicylate (wintergreen oil), the
labeling of which fails to warn that use otherwise than as directed
therein may be dangerous and that the article should be kept out of
reach of children to prevent accidental poisoning.
(c) This statement of interpretation in no way exempts methyl
salicylate (wintergreen oil) or its preparations from complying in all
other respects with the requirements of the Federal Food, Drug, and
Cosmetic Act.
Sec. 201.304 Tannic acid and barium enema preparations.
(a) It has become a widespread practice for tannic acid to be added
to barium enemas to improve X-ray pictures. Tannic acid is capable of
causing diminished liver function and severe liver necrosis when
absorbed in sufficient amounts. The medical literature reports a number
of deaths associated with the addition of tannic acid to barium enemas.
There is a lack of scientific evidence to establish the conditions, if
any, under which tannic acid is safe and effective for use in enemas.
Tannic acid for rectal use to enhance X-ray visualization is regarded as
a new drug within the meaning of section 201(p) of the Federal Food,
Drug, and Cosmetic Act.
(b) In view of the hazards involved when tannic acid is used in
barium enemas, any shipments of tannic acid labeled to come within the
exemptions under 502(f) of the Act containing such phrases as:
``Caution: For manufacturing, processing, or repackaging,'' ``For
prescription compounding,'' or ``Diagnostic reagent--For professional
use only'' will be regarded by the Commissioner of Food and Drugs as
misbranded within the meaning of section 502(f) of the Federal Food,
Drug, and Cosmetic Act unless the label and the labeling bear
conspicuously a warning to the effect: ``Warning-- Not for use in
enemas.''
(c) Any tannic acid intended for use by man and found within the
jurisdiction of the Federal Food, Drug, and Cosmetic Act labeled
contrary to this section after 60 days from the date of its publication
in the Federal Register may be made the subject of regulatory
proceedings.
Sec. 201.305 Isoproterenol inhalation preparations (pressurized aerosols, nebulizers, powders) for human use; warnings.
(a) Accumulating reports have been received by the Food and Drug
Administration and have appeared in the medical literature of severe
paradoxical bronchoconstriction associated with repeated, excessive use
of isoproterenol inhalation preparations in the treatment of bronchial
asthma and other chronic bronchopulmonary disorders. The cause of this
paradoxical reaction is unknown; it has been observed, however, that
patients have not responded completely to other forms of therapy until
use of the isoproterenol inhalation preparation was discontinued. In
addition, sudden unexpected deaths have been associated with the
excessive use of isoproterenol inhalation preparations. The mechanism of
these deaths and their relationship, if any, to the cases of severe
paradoxical bronchospasm are not clear. Cardiac arrest was noted in
several of these cases of sudden death.
(b) On the basis of the above information and after discussion with
and concurrence of the Respiratory and Anesthetic Drugs Advisory
Committee for Food and Drug Administration, the
[[Page 62]]
Commissioner of Food and Drugs concludes that in order for the labeling
of such drugs to bear adequate information for their safe use, as
required by Sec. 201.100, such labeling must include the following:
Warning: Occasional patients have been reported to develop severe
paradoxical airway resistance with repeated, excessive use of
isoproterenol inhalation preparations. The cause of this refractory
state is unknown. It is advisable that in such instances the use of this
preparation be discontinued immediately and alternative therapy
instituted, since in the reported cases the patients did not respond to
other forms of therapy until the drug was withdrawn.
Deaths have been reported following excessive use of isoproterenol
inhalation preparations and the exact cause is unknown. Cardiac arrest
was noted in several instances.
(c)(1) The Commissioner also concludes that in view of the manner in
which these preparations are self-administered for relief of attacks of
bronchial asthma and other chronic bronchopulmonary disorders, it is
necessary for the protection of users that warning information to
patients be included as a part of the label and as part of any
instructions to patients included in the package dispensed to the
patient as follows:
Warning: Do not exceed the dose prescribed by your physician. If
difficulty in breathing persists, contact your physician immediately.
(2) The warning on the label may be accomplished (i) by including it
on the immediate container label with a statement directed to
pharmacists not to remove the label or (ii) by including in the package
a printed warning with instructions to pharmacists to place the warning
on the container prior to dispensing.
(d) The marketing of isoproterenol inhalation preparations may be
continued if all the following conditions are met:
(1) Within 30 days following the date of publication of this section
in the Federal Register:
(i) The label and labeling of such preparations shipped within the
jurisdiction of the act are in accordance with paragraphs (b) and (c) of
this section.
(ii) The holder of an approved new-drug application for such
preparation submits a supplement to his new-drug application to provide
for appropriate labeling changes as described in paragraphs (b) and (c)
of this section.
(2) Within 90 days following the date of publication of this section
in the Federal Register, the manufacturer, packer, or distributor of any
drug containing isoproterenol intended for inhalation for which a new-
drug approval is not in effect submits a new-drug application containing
satisfactory information of the kinds required by Sec. 314.50 of this
chapter, including appropriate labeling as described in paragraphs (b)
and (c) of this section.
(3) The applicant submits additional information required for the
approval of the application as may be specified in a written
communication from the Food and Drug Administration.
(e) After 270 days following expiration of said 90 days, regulatory
proceedings based on section 505(a) of the Federal Food, Drug, and
Cosmetic Act may be initiated with regard to any such drug shipped
within the jurisdiction of the act for which an approved new-drug
application is not in effect.
[40 FR 13998, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990]
Sec. 201.306 Potassium salt preparations intended for oral ingestion by man.
(a) The Food and Drug Administration will initiate no regulatory
action with respect to the continued marketing of coated tablets
containing potassium chloride or other potassium salts which supply 100
milligrams or more of potassium per tablet provided all the following
conditions are met:
(1) Within 30 days from the date of publication of this statement of
policy in the Federal Register:
(i) The labeling of the drug bears the prescription caution
statement quoted in section 503(b)(4) of the Federal Food, Drug, and
Cosmetic Act;
(ii) The labeling on or within the package from which the drug is to
be dispensed bears adequate information for its use by practitioners in
accord with the ``full disclosure'' labeling requirements of
Sec. 201.100 of this chapter, including the following warning statement:
[[Page 63]]
Warning--There have been several reports, published and unpublished,
concerning nonspecific small-bowel lesions consisting of stenosis, with
or without ulceration, associated with the administration of enteric-
coated thiazides with potassium salts. These lesions may occur with
enteric-coated potassium tablets alone or when they are used with
nonenteric-coated thiazides, or certain other oral diuretics. These
small-bowel lesions have caused obstruction, hemorrhage, and
perforation. Surgery was frequently required and deaths have occurred.
Based on a large survey of physicians and hospitals, both United States
and foreign, the incidence of these lesions is low, and a causal
relationship in man has not been definitely established. Available
information tends to implicate enteric-coated potassium salts, although
lesions of this type also occur spontaneously. Therefore, coated
potassium-containing formulations should be administered only when
indicated, and should be discontinued immediately if abdominal pain,
distention, nausea, vomiting, or gastrointestinal bleeding occur. Coated
potassium tablets should be used only when adequate dietary
supplementation is not practicable.
(Although the warning statement includes references to enteric-coated
potassium salt preparations, it applies to any capsule or coated tablet
of a potassium salt intended for oral ingestion without prior dilution
with an adequate volume of liquid to preclude gastrointestinal injury.)
(iii) Any other labeling or additional advertising for the drug
conforms to the labeling described in paragraph (a)(1)(ii) of this
section, in accordance with Secs. 202.1 and 201.100 of this chapter.
(2) Within 90 days from the date of publication of this statement of
policy in the Federal Register, the manufacturer, packer, or distributor
of the drug shall submit a new-drug application containing satisfactory
information of the kind required by Sec. 314.50 of this chapter, with
appropriate labeling as described in this paragraph.
(b) The Food and Drug Administration may initiate regulatory
proceedings after 30 days from the date of publication of this section,
with respect to the marketing of uncoated tablets containing potassium
chloride or other potassium salts which supply 100 milligrams or more of
potassium per tablet or with respect to liquid preparations containing
potassium chloride or other potassium salts which supply 20 milligrams
or more of potassium per milliliter, labeled or intended for human use,
unless all the following conditions are met:
(1) The labeling of the drug bears the prescription caution
statement quoted in section 503(b)(4) of the Federal Food, Drug, and
Cosmetic Act; and
(2) The labeling on or within the package from which the drug is to
be dispensed bears adequate information for its use by practitioners in
accord with the ``full disclosure'' labeling requirements of
Sec. 201.100 of this chapter, including a recommendation that patients
be directed to dissolve any such tablets in an appropriate amount of
liquid and to dilute any such liquid preparations adequately to assure
against gastrointestinal injury associated with the oral ingestion of
concentrated potassium salt preparations.
[40 FR 13998, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990]
Sec. 201.307 Sodium phosphates; package size limitation, warnings, and directions for over-the-counter sale.
(a) Reports in the medical literature and data accumulated by the
Food and Drug Administration indicate that multiple container sizes of
sodium phosphates oral solution available in the marketplace have caused
consumer confusion and appear to have been involved in several consumer
deaths. Sodium phosphates oral solution has been marketed in 45-
milliliter (mL), 90-mL, and 240-mL container sizes. The 45-mL and 90-mL
container sizes of sodium phosphates oral solution are often recommended
and prescribed by physicians for bowel cleansing prior to surgery and
diagnostic procedures of the colon. Sodium phosphates oral solution
(adult dose 20 mL to 45 mL) is also used as an over-the-counter (OTC)
laxative for the relief of occasional constipation. Accidental
overdosing and deaths have occurred because the 240-mL container was
mistakenly used instead of the 45-mL or 90-mL container. The Food and
Drug Administration is limiting the amount of sodium phosphates oral
solution to not more than 90 mL (3 ounces (oz)) per OTC container
because of the serious health risks associated with the ingestion of
larger than intended doses of this product. Further, because an overdose
of either oral or
[[Page 64]]
rectal enema sodium phosphates can cause an electrolyte imbalance,
additional warning and direction statements are required for the safe
use of any OTC laxative drug product containing sodium phosphates.
(b) Any OTC drug product for laxative or bowel cleansing use
containing sodium phosphates as an active ingredient when marketed as
described in paragraph (a) of this section is misbranded within the
meaning of section 502 of the Federal Food, Drug, and Cosmetic Act
unless packaged and labeled as follows:
(1) Package size limitation for sodium phosphates oral solution:
Container shall not contain more than 90 mL (3 oz).
(2) Warnings. The following sentences shall appear in boldface type
as the first statement under the heading ``Warnings.''
(i) Oral dosage forms. ``Taking more than the recommended dose in 24
hours can be harmful.''
(ii) Rectal enema dosage forms. ``Using more than one enema in 24
hours can be harmful.''
(3) Directions--(i) The labeling of all orally or rectally
administered OTC drug products containing sodium phosphates shall
contain the following directions in boldface type immediately preceding
the dosage information: ``Do not'' (``take'' or ``use'') ``more unless
directed by a doctor. See Warnings.''
(ii) For products containing dibasic sodium phosphate/monobasic
sodium phosphate identified in Sec. 334.16(d) marketed as a solution.
Adults and children 12 years of age and over: Oral dosage is dibasic
sodium phosphate 3.42 to 7.56 grams (g) and monobasic sodium phosphate
9.1 to 20.2 g (20 to 45 mL dibasic sodium phosphate/monobasic sodium
phosphate oral solution) as a single daily dose. ``Do not take more than
45 mL (9 teaspoonfuls or 3 tablespoonfuls) in a 24-hour period.''
Children 10 and 11 years of age: Oral dosage is dibasic sodium phosphate
1.71 to 3.78 g and monobasic sodium phosphate 4.5 to 10.1 g (10 to 20 mL
dibasic sodium phosphate/monobasic sodium phosphate oral solution) as a
single daily dose. ``Do not take more than 20 mL (4 teaspoonfuls) in a
24-hour period.'' Children 5 to 9 years of age: Oral dosage is dibasic
sodium phosphate 0.86 to 1.89 g and monobasic sodium phosphate 2.2 to
5.05 g (5 to 10 mL dibasic sodium phosphate/monobasic sodium phosphate
oral solution) as a single daily dose. ``Do not take more than 10 mL (2
teaspoonfuls) in a 24-hour period.'' Children under 5 years of age: ask
a doctor.
(c) After June 22, 1998, for package size limitation and September
18, 1998, for labeling in accord with paragraph (b) of this section, any
such OTC drug product initially introduced or initially delivered for
introduction into interstate commerce, or any such drug product that is
repackaged or relabeled after these dates regardless of the date the
product was manufactured, initially introduced, or initially delivered
for introduction into interstate commerce, that is not in compliance
with this section is subject to regulatory action.
[63 FR 27843, May 21, 1998]
Sec. 201.308 Ipecac syrup; warnings and directions for use for over-the-counter sale.
(a) It is estimated that each year about 500,000 accidental
poisonings occur in the United States and result in approximately 1,500
deaths, of which over 400 are children. In the emergency treatment of
these poisonings, ipecac syrup is considered the emetic of choice. The
immediate availability of this drug for use in such situations is
critical, since rapid treatment may be the difference between life and
death. The restriction of this drug to prescription sale limits its
availability in emergencies. On the other hand, it is the consensus of
informed medical opinion that ipecac syrup should be used only under
medical supervision in the emergency treatment of poisonings. In view of
these facts, the question of whether ipecac syrup labeled as an
emergency treatment for use in poisonings should be available over the
counter has been controversial.
(b) In connection with its study of this problem, the Food and Drug
Administration has obtained the views of medical authorities. It is the
unanimous recommendation of the American Academy of Pediatrics, the
American
[[Page 65]]
Association of Poison Control Centers, the American Medical Association,
and the Medical Advisory Board of the Food and Drug Administration that
ipecac syrup in 1 fluid ounce containers be permitted to be sold without
prescription so that it will be readily available in the household for
emergency treatment of poisonings, under medical supervision, and that
the drug be appropriately packaged and labeled for this purpose.
(c) In view of the above recommendations, the Commissioner of Food
and Drugs has determined that it is in the interest of the public health
for ipecac syrup to be available for sale without prescription, provided
that it is packaged in a quantity of 1 fluid ounce (30 milliliters), and
its label bears, in addition to other required label information, the
following, in a prominent and conspicuous manner:
(1) A statement conspicuously boxed and in red letters, to the
effect: ``For emergency use to cause vomiting in poisoning. Before
using, call physician, the Poison Control Center, or hospital emergency
room immediately for advice.''
(2) A warning to the effect: ``Warning--Keep out of reach of
children. Do not use in unconscious persons. Ordinarily, this drug
should not be used if strychnine, corrosives such as alkalies (lye) and
strong acids, or petroleum distillates such as kerosine, gasoline, coal
oil, fuel oil, paint thinner, or cleaning fluid have been ingested.''
(3) Usual dosage: 1 tablespoon (15 milliliters) in persons over 1
year of age.
Sec. 201.309 Acetophenetidin (phenacetin)-containing preparations; necessary warning statement.
(a) In 1961, the Food and Drug Administration, pursuant to its
statutory responsibility for the safety and effectiveness of drugs
shipped in interstate commerce, began an active investigation of reports
of possible toxic effects and renal damage due to misuse of the drug
acetophenetidin. This study led to the decision that there was probable
cause to conclude that misuse and prolonged use of the drug were in fact
responsible for kidney lesions and disease. The Commissioner of Food and
Drugs, in December 1963, appointed an ad hoc Advisory Committee of
Inquiry on Possible Nephrotoxicity Associated With the Abuse of
Acetophenetidin (Phenacetin)-Containing Preparations. This committee,
composed of scientists in the fields of pharmacology and medicine, on
April 23, 1964, submitted its findings and conclusions in the matter and
recommended that all acetophenetidin (phenacetin)-containing
preparations bear a warning as provided in section 502(f)(2) of the
Federal Food, Drug, and Cosmetic Act.
(b) On the basis of the studies made by the Food and Drug
Administration and the report of the Advisory Committee, the
Commissioner of Food and Drugs has concluded that it is necessary for
the protection of users that the label and labeling of all
acetophenetidin (phenacetin)-containing preparations bear a warning
statement to the following effect: ``Warning--This medication may damage
the kidneys when used in large amounts or for a long period of time. Do
not take more than the recommended dosage, nor take regularly for longer
than 10 days without consulting your physician.''
Sec. 201.310 Phenindione; labeling of drug preparations intended for use by man.
(a) Reports in the medical literature and data accumulated by the
Food and Drug Administration indicate that phenindione, a synthetic
anticoagulant drug, has caused a number of cases of agranulocytosis
(with two fatalities). There are also reports implicating the drug in
cases of hepatitis and hypersensitivity reactions. In view of the
potentially serious effects found to be associated with preparations of
this drug intended for use by man, the Commissioner of Food and Drugs
will regard such preparations as misbranded within the meaning of
section 502(f) (1) and (2) of the Federal Food, Drug, and Cosmetic Act,
unless the label and labeling on or within the package from which the
drug is to be dispensed, and any other labeling furnishing or purporting
to furnish information for use of the drug, bear a conspicuous warning
statement to the following effect: ``Warning: Agranulocytosis and
hepatitis have been associated with the use
[[Page 66]]
of phenindione. Patients should be instructed to report promptly
prodromal symptoms such as marked fatigue, chill, fever, and sore
throat. Periodic blood studies and liver function tests should be
performed. Use of the drug should be discontinued if leukopenia occurs
or if evidence of hypersensitivity, such as dermatitis or fever,
appears.''
(b) Regulatory action may be initiated with respect to preparations
of phenindione intended for use by man found within the jurisdiction of
the act on or after November 25, 1961, unless such preparations are
labeled in accordance with paragraph (a) of this section.
Sec. 201.311 [Reserved]
Sec. 201.312 Magnesium sulfate heptahydrate; label declaration on drug products.
Magnesium sulfate heptahydrate should be listed on the label of a
drug product as epsom salt, which is its common or usual name.
Sec. 201.313 Estradiol labeling.
The article presently recognized in The National Formulary under the
heading ``Estradiol'' and which is said to be ``17-cis-beta estradiol''
is the same substance formerly recognized in the United States
Pharmacopeia under the designation ``Alpha Estradiol.'' The substance
should no longer be referred to in drug labeling as ``Alpha Estradiol.''
The Food and Drug Administration would not object to label references to
the article as simply ``Estradiol''; nor would it object if the label of
a preparation containing this substance referred to the presence of
``Estradiol (formerly known as Alpha Estradiol).''
Sec. 201.314 Labeling of drug preparations containing salicylates.
(a) The label of any oral drug preparation intended for sale without
prescription and which contains any salicylate ingredient (including
aspirin, salicylamide, other salicylates, and combinations) must
conspicuously bear, on a clearly contrasting background, the warning
statement: ``Keep out of reach of children [highlighted in bold type].
In case of overdose, get medical help or contact a Poison Control Center
right away,'' or ``Keep out of reach of children [highlighted in bold
type],'' except that if the article is an aspirin preparation, it shall
bear the first of these warning statements. Such a warning statement is
required for compliance with section 502(f)(2) of the Federal Food,
Drug, and Cosmetic Act and is intended to guard against accidental
poisonings. Safety closures that prevent access to the drug by young
children are also recommended to guard against accidental poisonings.
(b) Effervescent preparations and preparations containing para-
aminosalicylate as the only salicylate ingredient are exempted from this
labeling requirement.
(c) Aspirin tablets sold as such and containing no other active
ingredients, except tablets which cannot be readily subdivided into a
child's dose because of their coating or size, should always bear dosage
directions for each age group down to 3 years of age, with a statement
such as ``For children under 3 years of age, consult your physician.''
It is recommended that:
(1) Aspirin tablets especially made for pediatric use be produced
only in 1\1/4\-grain size to reduce the hazard of errors in dosage;
(2) By June 1, 1967, manufacturers and distributors of 1\1/4\-grain
size aspirin tablets discontinue the distribution of such tablets in
retail containers containing more than 36 tablets, to reduce the hazard
of accidental poisoning;
(3) The flavoring of 5-grain aspirin tablets or other ``adult
aspirin tablets'' be discontinued; and
(4) Labeling giving undue emphasis to the pleasant flavor of
flavored aspirin tablets be discontinued.
(d) Salicylate preparations other than aspirin tablets sold as such
may, at the option of the distributor, be labeled for use by adults
only. If their labeling and advertising clearly offer them for
administration to adults only.
(e)(1) It is the obligation of the distributor who labels a
salicylate preparation for administration to children to make certain
that the article is suitable for such use and labeled with adequate
directions for use in the age group for which it is offered, but in no
[[Page 67]]
case should such an article bear directions for use in children under 3
years of age. If the directions provide for administration to children
as young as 3 years of age, the label should bear the statement, ``For
children under 3 years of age consult your physician.'' However, if the
directions provide for administration to children only of an age greater
than 3 years (for example, the dosage instructions provide for
administration of the article to children only down to age 6), the label
should bear a statement such as, ``For younger children consult your
physician.''
(2) A statement such as, ``For children under 3 years of age consult
your physician'' or ``For younger children consult your physician'' is
not required on the label of an article clearly offered for
administration to adults only.
(f) If the labeling or advertising of a salicylate preparation
offers it for use in arthritis or rheumatism, the label and labeling
should clearly state that the beneficial effects claimed are limited to:
``For the temporary relief of minor aches and pains of arthritis and
rheumatism.'' The qualifying phrase ``for the temporary relief of minor
aches and pains'' should appear with the same degree of prominence and
conspicuousness as the phrase ``arthritis and rheumatism''. The label
and labeling should bear in juxtaposition with such directions for use
conspicuous warning statements to the effect: ``Caution: If pain
persists for more than 10 days, or redness is present, or in conditions
affecting children under 12 years of age, consult a physician
immediately.'' The salicylate dosage should not exceed 60 grains in a
24-hour period or 10 grains in a 4-hour period. If the article contains
other analgesics, the salicylate dosage should be appropriately reduced.
(g)(1) The label of any drug containing more than 5 percent methyl
salicylate (wintergreen oil) should bear a conspicuous warning such as:
``Do not use otherwise than as directed.'' These drug products must also
include the ``Keep out of reach of children'' warning and the accidental
ingestion warning as required in Sec. 330.1(g) of this chapter.
(2) If the preparation is a counterirritant or rubefacient, it
should also bear a caution such as, ``Caution: Discontinue use if
excessive irritation of the skin develops. Avoid getting into the eyes
or on mucous membranes.'' (See also Sec. 201.303.)
(h)(1) The labeling of orally or rectally administered over-the-
counter aspirin and aspirin-containing drug products subject to this
paragraph is required to prominently bear a warning. The warning shall
be as follows: ``Children and teenagers should not use this medicine for
chicken pox or flu symptoms before a doctor is consulted about Reye
syndrome, a rare but serious illness reported to be associated with
aspirin.''
(2) This warning statement shall appear on the immediate container
labeling. In cases where the immediate container is not the retail
package, the retail package also must bear the warning statement. In
addition, the warning statement shall appear on any labeling that
contains warnings and, in such cases, the warning statement shall be the
first warning statement under the heading ``Warnings.''
(3) Over-the-counter drug products subject to this paragraph and
labeled solely for use by children (pediatric products) shall not
recommend the product for use in treating flu or chicken pox.
(4) Any product subject to this paragraph that is not labeled as
required by this paragraph and that is initially introduced or initially
delivered for introduction into interstate commerce after June 5, 1986,
is misbranded under sections 201(n) and 502 (a) and (f) of the Federal
Food, Drug, and Cosmetic Act.
[40 FR 13998, Mar. 27, 1985, as amended at 51 FR 8182, Mar. 7, 1986; 53
FR 21637, June 9, 1988; 53 FR 24830, June 30, 1988; 64 FR 13291, Mar.
17, 1999]
Effective Date Note: At 64 FR 13291, Mar. 17, 1999, Sec. 201.314 was
amended by revising the first two sentences in paragraph (a) and by
revising paragraphs (g)(1) and (h)(1), effective Apr. 16, 1999. For the
convenience of the user the superseded text is set forth as follows:
Sec. 201.314 Labeling of drug preparations containing salicylates.
(a) The label of any oral drug preparation intended for sale without
prescription and which contains any salicylate ingredient (including
aspirin, salicylamide, other salicylates, and combinations) must bear a
[[Page 68]]
conspicuous warning statement in heavy block type on clearly contrasting
background, such as: ``Warning--Keep this and all medicines out of
children's reach. In case of accidental overdose, contact a physician
immediately,'' or ``Warning--Keep out of the reach of children,'' except
that if the article is an aspirin preparation, it shall bear the first
of these warning statements.* * *
* * * * *
(g)(1) The label of any drug containing more than 5 percent methyl
salicylate (wintergreen oil) should bear a conspicuous warning such as:
``Warning: Do not use otherwise than as directed. Keep out of the reach
of children to avoid accidental poisoning.''
* * * * *
(h)(1) The labeling of orally or rectally administered over-the-
counter aspirin and aspirin-containing drug products subject to this
paragraph is required to prominently bear a warning. The warning shall
be as follows: ``WARNING: Children and teenagers should not use this
medicine for chicken pox or flu symptoms before a doctor is consulted
about Reye syndrome, a rare but serious illness reported to be
associated with aspirin.''
* * * * *
Sec. 201.315 Over-the-counter drugs for minor sore throats; suggested warning.
The Food and Drug Administration has studied the problem of the
labeling of lozenges or troches containing a local anesthetic, chewing
gum containing aspirin, various mouth washes and gargles and other
articles sold over the counter for the relief of minor irritations of
the mouth or throat. It will not object to the labeling of suitable
articles of this type ``For the temporary relief of minor sore
throats'', provided this is immediately followed in the labeling with a
warning statement in prominent type essentially as follows: ``Warning--
Severe or persistent sore throat or sore throat accompanied by high
fever, headache, nausea, and vomiting may be serious. Consult physician
promptly. Do not use more than 2 days or administer to children under 3
years of age unless directed by physician.''
Sec. 201.316 Drugs with thyroid hormone activity for human use; required warning.
(a) Drugs with thyroid hormone activity have been promoted for, and
continue to be dispensed and prescribed for, use in the treatment of
obesity, although their safety and effectiveness for that use have never
been established.
(b) Drugs for human use with thyroid hormone activity are misbranded
within the meaning of section 502 of the Federal Food, Drug, and
Cosmetic Act unless their labeling bears the following boxed warning at
the beginning of the ``Warnings'' section:
------------------------------------------------------------------
Drugs with thyroid hormone activity, alone or together
with other therapeutic agents, have been used for the
treatment of obesity. In euthyroid patients, doses within
the range of daily hormonal requirements are ineffective for
weight reduction. Larger doses may produce serious or even
life-threatening manifestations of toxicity, particularly
when given in association with sympathomimetic amines such
as those used for their anorectic effects.
------------------------------------------------------------------
[43 FR 22009, May 23, 1978]
Sec. 201.317 Digitalis and related cardiotonic drugs for human use in oral dosage forms; required warning.
(a) Digitalis and related cardiotonic drugs for human use in oral
dosage forms have been promoted for, and continue to be dispensed and
prescribed for, use in the treatment of obesity, although their safety
and effectiveness for that use have never been established.
(b) Digitalis and related cardiotonic drugs for human use in oral
dosage forms are misbranded within the meaning of section 502 of the
Federal Food, Drug, and Cosmetic Act unless their labeling bears the
following boxed warning at the beginning of the ``Warnings'' section:
[[Page 69]]
------------------------------------------------------------------
Digitalis alone or with other drugs has been used in the
treatment of obesity. This use of digoxin or other digitalis
glycosides is unwarranted. Moreover, since they may cause
potentially fatal arrhythmias or other adverse effects, the
use of these drugs in the treatment of obesity is dangerous.
------------------------------------------------------------------
(c) This section does not apply to digoxin products for oral use,
which shall be labeled according to the requirements of Sec. 310.500 of
this chapter.
[43 FR 22009, May 23, 1978]
Sec. 201.319 Water-soluble gums, hydrophilic gums, and hydrophilic mucilloids (including, but not limited to agar, alginic acid, calcium polycarbophil,
carboxymethylcellulose sodium, carrageenan, chondrus,
glucomannan ((B-1,4 linked) polymannose acetate), guar gum,
karaya gum, kelp, methylcellulose, plantago seed (psyllium),
polycarbophil tragacanth, and xanthan gum) as active
ingredients; required warnings and directions.
(a) Reports in the medical literature and data accumulated by the
Food and Drug Administration indicate that esophageal obstruction and
asphyxiation have been associated with the ingestion of water-soluble
gums, hydrophilic gums, and hydrophilic mucilloids including, but not
limited to, agar, alginic acid, calcium polycarbophil,
carboxymethylcellulose sodium, carrageenan, chondrus, glucomannan ((B-
1,4 linked) polymannose acetate), guar gum, karaya gum, kelp,
methylcellulose, plantago seed (psyllium), polycarbophil, tragacanth,
and xanthan gum. Esophageal obstruction and asphyxiation due to orally-
administered drug products containing water-soluble gums, hydrophilic
gums, and hydrophylic mucilloids as active ingredients are significant
health risks when these products are taken without adequate fluid or
when they are used by individuals with esophageal narrowing or
dysfunction, or with difficulty in swallowing. Additional labeling is
needed for the safe and effective use of any OTC drug product for human
use containing a water-soluble gum, hydrophilic gum, or hydrophilic
mucilloid as an active ingredient when marketed in a dry or incompletely
hydrated form to include, but not limited to, the following dosage
forms: capsules, granules, powders, tablets, and wafers.
(b) Any drug products for human use containing a water-soluble gum,
hydrophilic gum, or hydrophilic mucilloid as an active ingredient in an
oral dosage form when marketed in a dry or incompletely hydrated form as
described in paragraph (a) of this section are misbranded within the
meaning of section 502 of the Federal Food, Drug, and Cosmetic Act
unless their labeling bears the following warnings (under the subheading
``Choking'') and directions:
```Choking' [highlighted in bold type]: Taking this product without
adequate fluid may cause it to swell and block your throat or esophagus
and may cause choking. Do not take this product if you have difficulty
in swallowing. If you experience chest pain, vomiting, or difficulty in
swallowing or breathing after taking this product, seek immediate
medical attention;'' and
```Directions' [highlighted in bold type]:'' (Select one of the
following, as appropriate: ``Take'' or ``Mix'') ``this product (child or
adult dose) with at least 8 ounces (a full glass) of water or other
fluid. Taking this product without enough liquid may cause choking. See
choking warning.''
(c) After February 28, 1994, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce, or any such drug product that is repackaged or relabeled after
this date regardless of the date the product was manufactured, initially
introduced, or initially delivered for introduction into interstate
commerce, that is not in compliance with this section is subject to
regulatory action.
[58 FR 45201, Aug. 26, 1993, as amended at 64 FR 13292, Mar. 17, 1999]
Effective Date Note: At 64 FR 13292, Mar. 17, 1999, Sec. 201.319 was
amended by revising paragraph (b), effective Apr. 16, 1999. For the
convenience of the user the superseded text is set forth as follows:
[[Page 70]]
Sec. 201.319 Water-soluble gums, hydrophilic gums, and hydrophilic
mucilloids (including, but not limited to agar, alginic acid,
calcium polycarbophil, carboxymethylcellulose sodium,
carrageenan, chondrus, glucomannan ((B-1,4, linked)
polymannose acetate), guar gum, karaya gum, kelp,
methylcellulose, plantago seed (psyllium), polycarbophil,
tragacanth, and xanthan gum) as active ingredients; required
warnings and directions.
* * * * *
(b) Any drug products for human use containing a water-soluble gum,
hydrophilic gum, or hydrophilic mucilloid as an active ingredient in an
oral dosage form when marketed in a dry or incompletely hydrated form as
described in paragraph (a) of this section are misbranded within the
meaning of section 502 of the Federal Food, Drug, and Cosmetic Act
unless their labeling bears the following warnings and directions in
bold print and capital letters:
``WARNINGS: TAKING THIS PRODUCT WITHOUT ADEQUATE FLUID MAY CAUSE IT
TO SWELL AND BLOCK YOUR THROAT OR ESOPHAGUS AND MAY CAUSE CHOKING. DO
NOT TAKE THIS PRODUCT IF YOU HAVE DIFFICULTY IN SWALLOWING. IF YOU
EXPERIENCE CHEST PAIN, VOMITING, OR DIFFICULTY IN SWALLOWING OR
BREATHING AFTER TAKING THIS PRODUCT, SEEK IMMEDIATE MEDICAL ATTENTION.''
DIRECTIONS:'' (Select one of the following, as appropriate: ``TAKE''
or ``MIX'') ``THIS PRODUCT (CHILD OR ADULT DOSE) WITH AT LEAST 8 OUNCES
(A FULL GLASS) OF WATER OR OTHER FLUID. TAKING THIS PRODUCT WITHOUT
ENOUGH LIQUID MAY CAUSE CHOKING. SEE WARNINGS.''
* * * * *
Sec. 201.320 Warning statements for drug products containing or manufactured with chlorofluorocarbons or other ozone-depleting substances.
(a)(1) All drug products containing or manufactured with
chlorofluorocarbons, halons, carbon tetrachloride, methyl chloride, or
any other class I substance designated by the Environmental Protection
Agency (EPA) shall, except as provided in paragraph (b) or (c) of this
section, bear the following warning statement:
Warning: Contains [or Manufactured with, if applicable] [insert name
of substance], a substance which harms public health and the environment
by destroying ozone in the upper atmosphere.
(2) The warning statement shall be clearly legible and conspicuous
on the product, its immediate container, its outer packaging, or other
labeling in accordance with the requirements of 40 CFR part 82 and
appear with such prominence and conspicuousness as to render it likely
to be read and understood by consumers under normal conditions of
purchase.
(b)(1) For prescription drug products for human use, the following
alternative warning statement may be used:
Note: The indented statement below is required by the Federal
government's Clean Air Act for all products containing or manufactured
with chlorofluorocarbons (CFC's) [or name of other class I substance, if
applicable]:
This product contains [or is manufactured with, if applicable]
[insert name of substance], a substance which harms the environment by
destroying ozone in the upper atmosphere.
Your physician has determined that this product is likely to help
your personal health. USE THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO
DO OTHERWISE BY YOUR PHYSICIAN. If you have any questions about
alternatives, consult with your physician.
(2) The warning statement shall be clearly legible and conspicuous
on the product, its immediate container, its outer packaging, or other
labeling in accordance with the requirements of 40 CFR part 82 and
appear with such prominence and conspicuousness as to render it likely
to be read and understood by consumers under normal conditions of
purchase.
(3) If the warning statement in paragraph (b)(1) of this section is
used, the following warning statement must be placed on the package
labeling intended to be read by the physician (physician package insert)
after the ``How supplied'' section, which describes special handling and
storage conditions on the physician labeling:
Note: The indented statement below is required by the Federal
government's Clean Air Act for all products containing or manufactured
with chlorofluorocarbons (CFC's) [or name of other class I substance, if
applicable]:
Warning: Contains [or Manufactured with, if applicable] [insert name
of substance], a substance which harms public health and the environment
by destroying ozone in the upper atmosphere.
[[Page 71]]
A notice similar to the above WARNING has been placed in the
information for the patient [or patient information leaflet, if
applicable] of this product under the Environmental Protection Agency's
(EPA's) regulations. The patient's warning states that the patient
should consult his or her physician if there are questions about
alternatives.
(c)(1) For over-the-counter drug products for human use, the
following alternative warning statement may be used:
Note: The indented statement below is required by the Federal
government's Clean Air Act for all products containing or manufactured
with chlorofluorocarbons (CFC's) [or other class I substance, if
applicable]:
Warning: Contains [or Manufactured with, if applicable] [insert name
of substance], a substance which harms public health and environment by
destroying ozone in the upper atmosphere.
CONSULT WITH YOUR PHYSICIAN OR HEALTH PROFESSIONAL IF YOU HAVE ANY
QUESTION ABOUT THE USE OF THIS PRODUCT.
(2) The warning statement shall be clearly legible and conspicuous
on the product, its immediate container, its outer packaging, or other
labeling in accordance with the requirements of 40 CFR part 82 and
appear with such prominence and conspicuousness as to render it likely
to be read and understood by consumers under normal conditions of
purchase.
(d) This section does not replace or relieve a person from any
requirements imposed under 40 CFR part 82.
[61 FR 20100, May 3, 1996]
Sec. 201.322 Over-the-counter drug products containing internal analgesic/antipyretic active ingredients; required alcohol warning.
(a) People who regularly consume large quantities of alcohol (three
or more drinks every day) have an increased risk of adverse effects
(possible liver damage or gastrointestinal bleeding). OTC drug products
containing internal analgesic/antipyretic active ingredients may cause
similar adverse effects. FDA concludes that the labeling of OTC drug
products containing internal analgesic/antipyretic active ingredients
should advise consumers with a history of heavy alcohol use to consult a
physician. Accordingly, any OTC drug product, labeled for adult use,
containing any internal analgesic/antipyretic active ingredients
(including, but not limited to, acetaminophen, aspirin, carbaspirin
calcium, choline salicylate, ibuprofen, ketoprofen, magnesium
salicylate, naproxen sodium, and sodium salicylate) alone or in
combination shall bear an alcohol warning statement in its labeling as
follows:
(1) Acetaminophen. ``Alcohol Warning'' [heading in boldface type]:
``If you consume 3 or more alcoholic drinks every day, ask your doctor
whether you should take acetaminophen or other pain relievers/fever
reducers. Acetaminophen may cause liver damage.''
(2) Nonsteroidal anti-inflammatory analgesic/antipyretic active
ingredients--including but not limited to aspirin, carbaspirin calcium,
choline salicylate, ibuprofen, ketoprofen, magnesium salicylate,
naproxen sodium, and sodium salicylate. ``Alcohol Warning'' [heading in
boldface type]: ``If you consume 3 or more alcoholic drinks every day,
ask your doctor whether you should take [insert one nonsteroidal anti-
inflammatory analgesic/antipyretic active ingredient] or other pain
relievers/fever reducers. [Insert one nonsteroidal anti-inflammatory
analgesic/antipyretic active ingredient] may cause stomach bleeding.''
(3) Combinations of acetaminophen with nonsteroidal anti-
inflammatory analgesic/antipyretic active ingredients--including but not
limited to aspirin, carbaspirin calcium, choline salicylate, ibuprofen,
ketoprofen, magnesium salicylate, naproxen sodium, and sodium
salicylate. ``Alcohol Warning'' [heading in boldface type]: ``If you
consume 3 or more alcoholic drinks every day, ask your doctor whether
you should take [insert acetaminophen and one nonsteroidal anti-
inflammatory analgesic/antipyretic active ingredient--including, but not
limited to aspirin, carbaspirin calcium, choline salicylate, magnesium
salicylate, or sodium salicylate] or other pain relievers/fever
reducers. [Acetaminophen and (insert one nonsteroidal anti-inflammatory
analgesic/antipyretic ingredient--including, but not limited to aspirin,
carbaspirin calcium, choline salicylate, magnesium salicylate, or sodium
salicylate] may cause liver damage and stomach bleeding.''
[[Page 72]]
(b) Requirements to supplement approved application. Holders of
approved applications for OTC drug products that contain internal
analgesic/antipyretic active ingredients that are subject to the
requirements of paragraph (a) of this section must submit supplements
under Sec. 314.70(c) of this chapter to include the required warning in
the product's labeling. Such labeling may be put into use without
advance approval of FDA provided it includes the exact information
included in paragraph (a) of this section.
(c) Any drug product subject to this section that is not labeled as
required and that is initially introduced or initially delivered for
introduction into interstate commerce after April 23, 1999, is
misbranded under section 502 of the Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 352) and is subject to regulatory action.
[63 FR 56801, Oct. 23, 1998]
Effective Date Note: At 63 FR 56801, Oct. 23, 1998, Sec. 201.322 was
added, effective Apr. 23, 1999.
Appendix A to Part 201--Examples of Graphic Enhancements Used by FDA
I. Section 201.66 Standard Labeling Format
A. Overall
1. The ``Drug Facts'' labeling is set off in a box or similar
enclosure by the use of a barline with all black type printed on a
white, color contrasting background.
B. Typeface and size
1. ``Drug Facts'' is set in 14 point Helvetica Bold Italic, left
justified.
2. ``Drug Facts (continued)'' is set in 8 point Helvetica Bold
Italic for the words ``Drug Facts'' and 8 point Helvetica Regular for
the word ``(continued)'' and is left justified.
3. The headings (e.g., ``Directions'') are set in 8 point Helvetica
Bold Italic, left justified.
4. The subheadings (e.g., ``Ask a doctor or pharmacist before use if
you are'') are set in 6 point Helvetica Bold, left justified.
5. The information is set in 6 point Helvetica Regular with 6.5
point leading, left justified.
6. The heading ``Purpose'' is right justified.
7. The bullet is a 5-point solid square.
8. Two em spacing separates bullets when more than one bullet is on
the same line.
9. A table format is used for 3 or more dosage directions.
10. A graphic appears at the bottom of the first panel leading the
reader to the next panel.
C. Barlines and hairlines
1. A 2.5-point horizontal barline extends to each end of the ``Drug
Facts'' box (or similar enclosure), providing separation between each of
the headings.
2. A 0.5-point horizontal hairline extends within 2 spaces on either
side of the ``Drug Facts'' box (or similar enclosure), immediately
following the title and immediately preceding the subheadings.
3. A 0.5-point horizontal hairline follows the title, immediately
preceding the heading, when a heading appears on a subsequent panel
immediately after the ``Drug Facts (continued)'' title.
D. Box or Enclosure
1. All information is enclosed by a 2.5-point barline.
II. Section 201.66 Modified Labeling Format
A. Overall
1. The ``Drug Facts'' labeling is presented in all black type
printed on a white color contrasting background.
B. Typeface and size
1. ``Drug Facts'' is set in 9 point Helvetica Bold Italic, left
justified.
2. The headings (e.g., ``Directions'') are set in 8 point Helvetica
Bold Italic, left justified.
3. The subheadings (e.g., ``Ask a doctor or pharmacist before use if
you are'') are set in 6 point Helvetica Bold, left justified.
4. The information is set in 6 point Helvetica Regular with 6.5
point leading, left justified.
5. The heading ``Purpose'' is right justified.
6. The bullet is a 5-point solid square.
7. Bulleted information may start on same line as headings (except
for the ``Warnings'' heading) and subheadings, with 2 em spacing
separating bullets, and need not be vertically aligned.
C. Barlines and hairlines
1. A 2.5-point horizontal barline extends to each end of the ``Drug
Facts'' box (or similar enclosure), providing separation between each of
the headings.
2. A 0.5-point horizontal hairline extends within 2 spaces on either
side of the ``Drug Facts'' box (or similar enclosure), immediately
following the title and immediately preceding the subheadings.
[[Page 73]]
D. Box or Enclosure
1. All information is set off by color contrast. No barline is used.
III. Examples of Sec. 201.66 Standard Labeling and Modified Labeling
Formats
A. Section 201.66 Standard Labeling Format
[GRAPHIC] [TIFF OMITTED] TR17MR99.007
B. Section 201.66 Modified Labeling Format
[GRAPHIC] [TIFF OMITTED] TR17MR99.008
[[Page 74]]
Effective Date Note: At 64 FR 13292, Mar. 17, 1999, appendix A was
added to part 201, effective Apr. 16, 1999.
PART 202--PRESCRIPTION DRUG ADVERTISING--Table of Contents
Authority: 21 U.S.C. 321, 331, 352, 355, 360b, 371.
Sec. 202.1 Prescription-drug advertisements.
(a)(1) The ingredient information required by section 502(n) of the
Federal Food, Drug, and Cosmetic Act shall appear together, without any
intervening written, printed, or graphic matter, except the proprietary
names of ingredients, which may be included with the listing of
established names.
(2) The order of listing of ingredients in the advertisement shall
be the same as the order of listing of ingredients on the label of the
product, and the information presented in the advertisement concerning
the quantity of each such ingredient shall be the same as the
corresponding information on the label of the product.
(3) The advertisement shall not employ a fanciful proprietary name
for the drug or any ingredient in such a manner as to imply that the
drug or ingredient has some unique effectiveness or composition, when,
in fact, the drug or ingredient is a common substance, the limitations
of which are readily recognized when the drug or ingredient is listed by
its established name.
(4) The advertisement shall not feature inert or inactive
ingredients in a manner that creates an impression of value greater than
their true functional role in the formulation.
(5) The advertisement shall not designate a drug or ingredient by a
proprietary name that, because of similarity in spelling or
pronunciation, may be confused with the proprietary name or the
established name of a different drug or ingredient.
(b)(1) If an advertisement for a prescription drug bears a
proprietary name or designation for the drug or any ingredient thereof,
the established name, if such there be, corresponding to such
proprietary name or designation shall accompany such proprietary name or
designation each time it is featured in the advertisement for the drug;
but, except as provided below in this subparagraph, the established name
need not be used with the proprietary name or designation in the running
text of the advertisement. On any page of an advertisement in which the
proprietary name or designation is not featured but is used in the
running text, the established name shall be used at least once in the
running text in association with such proprietary name or designation
and in the same type size used in the running text: Provided, however,
That if the proprietary name or designation is used in the running text
in larger size type, the established name shall be used at least once in
association with, and in type at least half as large as the type used
for, the most prominent presentation of the proprietary name or
designation in such running text. If any advertisement includes a column
with running text containing detailed information as to composition,
prescribing, side effects, or contraindications and the proprietary name
or designation is used in such column but is not featured above or below
the column, the established name shall be used at least once in such
column of running text in association with such proprietary name or
designation and in the same type size used in such column of running
text: Provided, however, That if the proprietary name or designation is
used in such column of running text in larger size type, the established
name shall be used at least once in association with, and in type at
least half as large as the type used for, the most prominent
presentation of the proprietary name or designation in such column of
running text. Where the established name is required to accompany or to
be used in association with the proprietary name or designation, the
established name shall be placed in direct conjunction with the
proprietary name or designation, and the relationship between the
proprietary name or designation and the established name shall be made
clear by use of a phrase such as ``brand of'' preceding the established
name, by brackets surrounding the established name, or by other suitable
means.
(2) The established name shall be printed in letters that are at
least half
[[Page 75]]
as large as the letters comprising the proprietary name or designation
with which it is joined, and the established name shall have a
prominence commensurate with the prominence with which such proprietary
name or designation appears, taking into account all pertinent factors,
including typography, layout, contrast, and other printing features.
(c) In the case of a prescription drug containing two or more active
ingredients, if the advertisement bears a proprietary name or
designation for such mixture and there is no established name
corresponding to such proprietary name or designation, the quantitative
ingredient information required in the advertisement by section 502(n)
of the act shall be placed in direct conjunction with the most prominent
display of the proprietary name or designation. The prominence of the
quantitative ingredient information shall bear a reasonable relationship
to the prominence of the proprietary name.
(d)(1) If the advertisement employs one proprietary name or
designation to refer to a combination of active ingredients present in
more than one preparation (the individual preparations differing from
each other as to quantities of active ingredients and/or the form of the
finished preparation) and there is no established name corresponding to
such proprietary name or designation, a listing showing the established
names of the active ingredients shall be placed in direct conjunction
with the most prominent display of such proprietary name or designation.
The prominence of this listing of active ingredients shall bear a
reasonable relationship to the prominence of the proprietary name and
the relationship between such proprietary name or designation, and the
listing of active ingredients shall be made clear by use of such phrase
as ``brand of'', preceding the listing of active ingredients.
(2) The advertisement shall prominently display the name of at least
one specific dosage form and shall have the quantitative ingredient
information required by section 502(n) of the act in direct conjunction
with such display. If other dosage forms are listed in the
advertisement, the quantitative ingredient information for such dosage
forms shall appear in direct conjunction and in equal prominence with
the most prominent listing of the names of such dosage forms.
(e) True statement of information in brief summary relating to side
effects, contraindications, and effectiveness:
(1) When required. All advertisements for any prescription drug
(``prescription drug'' as used in this section means drugs defined in
section 503(b)(1) of the act and Sec. 201.105, applicable to drugs for
use by man and veterinary drugs, respectively), except advertisements
described in paragraph (e)(2) of this section, shall present a true
statement of information in brief summary relating to side effects,
contraindications (when used in this section ``side effects,
contraindications'' include side effects, warnings, precautions, and
contraindications and include any such information under such headings
as cautions, special considerations, important notes, etc.) and
effectiveness. Advertisements broadcast through media such as radio,
television, or telephone communications systems shall include
information relating to the major side effects and contraindications of
the advertised drugs in the audio or audio and visual parts of the
presentation and unless adequate provision is made for dissemination of
the approved or permitted package labeling in connection with the
broadcast presentation shall contain a brief summary of all necessary
information related to side effects and contraindications.
(2) Exempt advertisements. The following advertisements are exempt
from the requirements of paragraph (e)(1) of this section under the
conditions specified:
(i) Reminder advertisements. Reminder advertisements are those which
call attention to the name of the drug product but do not include
indications or dosage recommendations for use of the drug product. These
reminder advertisements shall contain only the proprietary name of the
drug product, if any; the established name of the drug product, if any;
the established name of each active ingredient in the drug product; and,
optionally, information relating to quantitative ingredient statements,
dosage form, quantity of
[[Page 76]]
package contents, price, the name and address of the manufacturer,
packer, or distributor or other written, printed, or graphic matter
containing no representation or suggestion relating to the advertised
drug product. If the Commissioner finds that there is evidence of
significant incidence of fatalities or serious injury associated with
the use of a particular prescription drug, he may withdraw this
exemption by so notifying the manufacturer, packer, or distributor of
the drug by letter. Reminder advertisements, other than those solely
intended to convey price information including, but not limited to,
those subject to the requirements of Sec. 200.200 of this chapter, are
not permitted for a prescription drug product whose labeling contains a
boxed warning relating to a serious hazard associated with the use of
the drug product. Reminder advertisements which are intended to provide
consumers with information concerning the price charged for a
prescription for a drug product are exempt from the requirements of this
section if they meet all of the conditions contained in Sec. 200.200 of
this chapter. Reminder advertisements, other than those subject to the
requirements of Sec. 200.200 of this chapter, are not permitted for a
drug for which an announcement has been published pursuant to a review
on the labeling claims for the drug by the National Academy of Sciences/
National Research Council (NAS/NRC), Drug Efficacy Study Group, and for
which no claim has been evaluated as higher than ``possibly effective.''
If the Commissioner finds the circumstances are such that a reminder
advertisement may be misleading to prescribers of drugs subject to NAS/
NRC evaluation, such advertisements will not be allowed and the
manufacturer, packer, or distributor will be notified either in the
publication of the conclusions on the effectiveness of the drug or by
letter.
(ii) Advertisements of bulk-sale drugs. Advertisements of bulk-sale
drugs that promote sale of the drug in bulk packages in accordance with
the practice of the trade solely to be processed, manufactured, labeled,
or repackaged in substantial quantities and that contain no claims for
the therapeutic safety or effectiveness of the drug.
(iii) Advertisements of prescription-compounding drugs.
Advertisements of prescription-compounding drugs that promote sale of a
drug for use as a prescription chemical or other compound for use by
registered pharmacists in compounding prescriptions if the drug
otherwise complies with the conditions for the labeling exemption
contained in Sec. 201.120 and the advertisement contains no claims for
the therapeutic safety or effectiveness of the drug.
(3) Scope of information to be included; applicability to the entire
advertisement. (i) The requirement of a true statement of information
relating to side effects, contraindications, and effectiveness applies
to the entire advertisement. Untrue or misleading information in any
part of the advertisement will not be corrected by the inclusion in
another distinct part of the advertisement of a brief statement
containing true information relating to side effects, contraindications,
and effectiveness of the drug. If any part or theme of the advertisement
would make the advertisement false or misleading by reason of the
omission of appropriate qualification or pertinent information, that
part or theme shall include the appropriate qualification or pertinent
information, which may be concise if it is supplemented by a prominent
reference on each page to the presence and location elsewhere in the
advertisement of a more complete discussion of such qualification or
information.
(ii) The information relating to effectiveness is not required to
include information relating to all purposes for which the drug is
intended but may optionally be limited to a true statement of the
effectiveness of the drug for the selected purpose(s) for which the drug
is recommended or suggested in the advertisement. The information
relating to effectiveness shall include specific indications for use of
the drug for purposes claimed in the advertisement; for example, when an
advertisement contains a broad claim that a drug is an antibacterial
agent, the advertisement shall name a type or types of infections and
microorganisms for which the drug is effective clinically as
specifically as
[[Page 77]]
required, approved, or permitted in the drug package labeling.
(iii) The information relating to side effects and contraindications
shall disclose each specific side effect and contraindication (which
include side effects, warnings, precautions, and contraindications and
include any such information under such headings as cautions, special
considerations, important notes, etc.; see paragraph (e)(1) of this
section) contained in required, approved, or permitted labeling for the
advertised drug dosage form(s): Provided, however,
(a) The side effects and contraindications disclosed may be limited
to those pertinent to the indications for which the drug is recommended
or suggested in the advertisement to the extent that such limited
disclosure has previously been approved or permitted in drug labeling
conforming to the provisions of Secs. 201.100 or 201.105; and
(b) The use of a single term for a group of side effects and
contraindications (for example, ``blood dyscrasias'' for disclosure of
``leukopenia,'' ``agranulocytosis,'' and ``neutropenia'') is permitted
only to the extent that the use of such a single term in place of
disclosure of each specific side effect and contraindication has been
previously approved or permitted in drug labeling conforming to the
provisions of Secs. 201.100 or 201.105.
(4) Substance of information to be included in brief summary. (i)(a)
An advertisement for a prescription drug covered by a new-drug
application approved pursuant to section 505 of the act after October
10, 1962 or section 512 of the act after August 1, 1969, or any approved
supplement thereto, shall not recommend or suggest any use that is not
in the labeling accepted in such approved new-drug application or
supplement. The advertisement shall present information from labeling
required, approved, or permitted in a new-drug application relating to
each specific side effect and contraindication in such labeling that
relates to the uses of the advertised drug dosage form(s) or shall
otherwise conform to the provisions of paragraph (e)(3)(iii) of this
section.
(b) If a prescription drug was covered by a new-drug application or
a supplement thereto that became effective prior to October 10, 1962, an
advertisement may recommend or suggest:
(1) Uses contained in the labeling accepted in such new-drug
application and any effective, approved, or permitted supplement
thereto.
(2) Additional uses contained in labeling in commercial use on
October 9, 1962, to the extent that such uses did not cause the drug to
be an unapproved ``new drug'' as ``new drug'' was defined in section
201(p) of the act as then in force, and to the extent that such uses
would be permitted were the drug subject to paragraph (e)(4)(iii) of
this section.
(3) Additional uses contained in labeling in current commercial use
to the extent that such uses do not cause the drug to be an unapproved
``new drug'' as defined in section 201(p) of the act as amended or a
``new animal drug'' as defined in section 201(v) of the act as amended.
The advertisement shall present information from labeling required,
approved, or permitted in a new-drug application relating to each
specific side effect and contraindication in such labeling that relates
to the uses of the advertised drug dosage form(s) or shall otherwise
conform to the provisions of paragraph (e)(3)(iii) of this section.
(ii) In the case of an advertisement for a prescription drug other
than a drug the labeling of which causes it to be an unapproved ``new
drug'' and other than drugs covered by paragraph (e)(4)(i) of this
section, an advertisement may recommend and suggest the drug only for
those uses contained in the labeling thereof:
(a) For which the drug is generally recognized as safe and effective
among experts qualified by scientific training and experience to
evaluate the safety and effectiveness of such drugs; or
(b) For which there exists substantial evidence of safety and
effectiveness, consisting of adequate and well-controlled
investigations, including clinical investigations (as used in this
section ``clinical investigations,'' ``clinical experience,'' and
``clinical significance'' mean in the case of drugs intended for
administration to man, investigations, experience, or significance in
humans, and in the case of drugs intended for administration to
[[Page 78]]
other animals, investigations, experience, or significance in the specie
or species for which the drug is advertised), by experts qualified by
scientific training and experience to evaluate the safety and
effectiveness of the drug involved, on the basis of which it can fairly
and responsibly be concluded by such experts that the drug is safe and
effective for such uses; or
(c) For which there exists substantial clinical experience (as used
in this section this means substantial clinical experience adequately
documented in medical literature or by other data (to be supplied to the
Food and Drug Administration, if requested)), on the basis of which it
can fairly and responsibly be concluded by qualified experts that the
drug is safe and effective for such uses; or
(d) For which safety is supported under any of the preceding clauses
in paragraphs (e)(4)(iii) (a), (b), and (c) of this section and
effectiveness is supported under any other of such clauses.
The advertisement shall present information relating to each specific
side effect and contraindication that is required, approved, or
permitted in the package labeling by Secs. 201.100 or 201.105 of this
chapter of the drug dosage form(s) or shall otherwise conform to the
provisions of paragraph (e)(3)(iii) of this section.
(5) ``True statement'' of information. An advertisement does not
satisfy the requirement that it present a ``true statement'' of
information in brief summary relating to side effects,
contraindications, and effectiveness if:
(i) It is false or misleading with respect to side effects,
contraindications, or effectiveness; or
(ii) It fails to present a fair balance between information relating
to side effects and contraindications and information relating to
effectiveness of the drug in that the information relating to
effectiveness is presented in greater scope, depth, or detail than is
required by section 502(n) of the act and this information is not fairly
balanced by a presentation of a summary of true information relating to
side effects and contraindications of the drug; Provided, however, That
no advertisement shall be considered to be in violation of this section
if the presentation of true information relating to side effects and
contraindications is comparable in depth and detail with the claims for
effectiveness or safety.
(iii) It fails to reveal facts material in the light of its
representations or material with respect to consequences that may result
from the use of the drug as recommended or suggested in the
advertisement.
(6) Advertisements that are false, lacking in fair balance, or
otherwise misleading. An advertisement for a prescription drug is false,
lacking in fair balance, or otherwise misleading, or otherwise violative
of section 502(n) of the act, among other reasons, if it:
(i) Contains a representation or suggestion, not approved or
permitted for use in the labeling, that a drug is better, more
effective, useful in a broader range of conditions or patients (as used
in this section patients means humans and in the case of veterinary
drugs, other animals), safer, has fewer, or less incidence of, or less
serious side effects or contraindications than has been demonstrated by
substantial evidence or substantial clinical experience (as described in
paragraphs (e)(4)(ii) (b) and (c) of this section) whether or not such
representations are made by comparison with other drugs or treatments,
and whether or not such a representation or suggestion is made directly
or through use of published or unpublished literature, quotations, or
other references.
(ii) Contains a drug comparison that represents or suggests that a
drug is safer or more effective than another drug in some particular
when it has not been demonstrated to be safer or more effective in such
particular by substantial evidence or substantial clinical experience.
(iii) Contains favorable information or opinions about a drug
previously regarded as valid but which have been rendered invalid by
contrary and more credible recent information, or contains literature
references or quotations that are significantly more favorable to the
drug than has been demonstrated by substantial evidence or substantial
clinical experience.
(iv) Contains a representation or suggestion that a drug is safer
than it has been demonstrated to be by substantial
[[Page 79]]
evidence or substantial clinical experience, by selective presentation
of information from published articles or other references that report
no side effects or minimal side effects with the drug or otherwise
selects information from any source in a way that makes a drug appear to
be safer than has been demonstrated.
(v) Presents information from a study in a way that implies that the
study represents larger or more general experience with the drug than it
actually does.
(vi) Contains references to literature or studies that misrepresent
the effectiveness of a drug by failure to disclose that claimed results
may be due to concomitant therapy, or by failure to disclose the
credible information available concerning the extent to which claimed
results may be due to placebo effect (information concerning placebo
effect is not required unless the advertisement promotes the drug for
use by man).
(vii) Contains favorable data or conclusions from nonclinical
studies of a drug, such as in laboratory animals or in vitro, in a way
that suggests they have clinical significance when in fact no such
clinical significance has been demonstrated.
(viii) Uses a statement by a recognized authority that is apparently
favorable about a drug but fails to refer to concurrent or more recent
unfavorable data or statements from the same authority on the same
subject or subjects.
(ix) Uses a quote or paraphrase out of context to convey a false or
misleading idea.
(x) Uses literature, quotations, or references that purport to
support an advertising claim but in fact do not support the claim or
have relevance to the claim.
(xi) Uses literature, quotations, or references for the purpose of
recommending or suggesting conditions of drug use that are not approved
or permitted in the drug package labeling.
(xii) Offers a combination of drugs for the treatment of patients
suffering from a condition amenable to treatment by any of the
components rather than limiting the indications for use to patients for
whom concomitant therapy as provided by the fixed combination drug is
indicated, unless such condition is included in the uses permitted under
paragraph (e)(4) of this section.
(xiii) Uses a study on normal individuals without disclosing that
the subjects were normal, unless the drug is intended for use on normal
individuals.
(xiv) Uses ``statistics'' on numbers of patients, or counts of
favorable results or side effects, derived from pooling data from
various insignificant or dissimilar studies in a way that suggests
either that such ``statistics'' are valid if they are not or that they
are derived from large or significant studies supporting favorable
conclusions when such is not the case.
(xv) Uses erroneously a statistical finding of ``no significant
difference'' to claim clinical equivalence or to deny or conceal the
potential existence of a real clinical difference.
(xvi) Uses statements or representations that a drug differs from or
does not contain a named drug or category of drugs, or that it has a
greater potency per unit of weight, in a way that suggests falsely or
misleadingly or without substantial evidence or substantial clinical
experience that the advertised drug is safer or more effective than such
other drug or drugs.
(xvii) Uses data favorable to a drug derived from patients treated
with dosages different from those recommended in approved or permitted
labeling if the drug advertised is subject to section 505 of the act,
or, in the case of other drugs, if the dosages employed were different
from those recommended in the labeling and generally recognized as safe
and effective. This provision is not intended to prevent citation of
reports of studies that include some patients treated with dosages
different from those authorized, if the results in such patients are not
used.
(xviii) Uses headline, subheadline, or pictorial or other graphic
matter in a way that is misleading.
(xix) Represents or suggests that drug dosages properly recommended
for use in the treatment of certain classes of patients or disease
conditions are safe and effective for the treatment of other classes of
patients or disease conditions when such is not the case.
[[Page 80]]
(xx) Presents required information relating to side effects or
contraindications by means of a general term for a group in place of
disclosing each specific side effect and contraindication (for example
employs the term blood dyscrasias instead of ``leukopenia,''
``agranulocytosis,'' ``neutropenia,'' etc.) unless the use of such
general term conforms to the provisions of paragraph (e)(3)(iii) of this
section.
Provided, however, That any provision of this paragraph shall be waived
with respect to a specified advertisement as set forth in a written
communication from the Food and Drug Administration on a petition for
such a waiver from a person who would be adversely affected by the
enforcement of such provision on the basis of a showing that the
advertisement is not false, lacking in fair balance, or otherwise
misleading, or otherwise violative of section 502(n) of the act. A
petition for such a waiver shall set forth clearly and concisely the
petitioner's interest in the advertisement, the specific provision of
this paragraph from which a waiver is sought, a complete copy of the
advertisement, and a showing that the advertisement is not false,
lacking in fair balance, or otherwise misleading, or otherwise violative
of section 502(n) of the act.
(7) Advertisements that may be false, lacking in fair balance, or
otherwise misleading. An advertisement may be false, lacking in fair
balance, or otherwise misleading or otherwise violative of section
502(n) of the act if it:
(i) Contains favorable information or conclusions from a study that
is inadequate in design, scope, or conduct to furnish significant
support for such information or conclusions.
(ii) Uses the concept of ``statistical significance'' to support a
claim that has not been demonstrated to have clinical significance or
validity, or fails to reveal the range of variations around the quoted
average results.
(iii) Uses statistical analyses and techniques on a retrospective
basis to discover and cite findings not soundly supported by the study,
or to suggest scientific validity and rigor for data from studies the
design or protocol of which are not amenable to formal statistical
evaluations.
(iv) Uses tables or graphs to distort or misrepresent the
relationships, trends, differences, or changes among the variables or
products studied; for example, by failing to label abscissa and ordinate
so that the graph creates a misleading impression.
(v) Uses reports or statements represented to be statistical
analyses, interpretations, or evaluations that are inconsistent with or
violate the established principles of statistical theory, methodology,
applied practice, and inference, or that are derived from clinical
studies the design, data, or conduct of which substantially invalidate
the application of statistical analyses, interpretations, or
evaluations.
(vi) Contains claims concerning the mechanism or site of drug action
that are not generally regarded as established by scientific evidence by
experts qualified by scientific training and experience without
disclosing that the claims are not established and the limitations of
the supporting evidence.
(vii) Fails to provide sufficient emphasis for the information
relating to side effects and contraindications, when such information is
contained in a distinct part of an advertisement, because of repetition
or other emphasis in that part of the advertisement of claims for
effectiveness or safety of the drug.
(viii) Fails to present information relating to side effects and
contraindications with a prominence and readability reasonably
comparable with the presentation of information relating to
effectiveness of the drug, taking into account all implementing factors
such as typography, layout, contrast, headlines, paragraphing, white
space, and any other techniques apt to achieve emphasis.
(ix) Fails to provide adequate emphasis (for example, by the use of
color scheme, borders, headlines, or copy that extends across the
gutter) for the fact that two facing pages are part of the same
advertisement when one page contains information relating to side
effects and contraindications.
(x) In an advertisement promoting use of the drug in a selected
class of patients (for example, geriatric patients or depressed
patients), fails to present with adequate emphasis the significant
[[Page 81]]
side effects and contraindications or the significant dosage
considerations, when dosage recommendations are included in an
advertisement, especially applicable to that selected class of patients.
(xi) Fails to present on a page facing another page (or on another
full page) of an advertisement on more than one page, information
relating to side effects and contraindications when such information is
in a distinct part of the advertisement.
(xii) Fails to include on each page or spread of an advertisement
the information relating to side effects and contraindications or a
prominent reference to its presence and location when it is presented as
a distinct part of an advertisement.
(xiii) Contains information from published or unpublished reports or
opinions falsely or misleadingly represented or suggested to be
authentic or authoritative.
(f)-(i) [Reserved]
(j)(1) No advertisement concerning a particular prescription drug
may be disseminated without prior approval by the Food and Drug
Administration if:
(i) The sponsor or the Food and Drug Administration has received
information that has not been widely publicized in medical literature
that the use of the drug may cause fatalities or serious damage;
(ii) The Commissioner (or in his absence the officer acting as
Commissioner), after evaluating the reliability of such information, has
notified the sponsor that the information must be a part of the
advertisements for the drug; and
(iii) The sponsor has failed within a reasonable time as specified
in such notification to present to the Food and Drug Administration a
program, adequate in light of the nature of the information, for
assuring that such information will be publicized promptly and
adequately to the medical profession in subsequent advertisements.
If the Commissioner finds that the program presented is not being
followed, he will notify the sponsor that prior approval of all
advertisements for the particular drug will be required. Nothing in this
paragraph is to be construed as limiting the Commissioner's or the
Secretary's rights, as authorized by law, to issue publicity, to suspend
any new-drug application, to decertify any antibiotic, or to recommend
any regulatory action.
(2) Within a reasonable time after information concerning the
possibility that a drug may cause fatalities or serious damage has been
widely publicized in medical literature, the Food and Drug
Administration shall notify the sponsor of the drug by mail that prior
approval of advertisements for the drug is no longer necessary.
(3) Dissemination of an advertisement not in compliance with this
paragraph shall be deemed to be an act that causes the drug to be
misbranded under section 502(n) of the act.
(4) Any advertisement may be submitted to the Food and Drug
Administration prior to publication for comment. If the advertiser is
notified that the submitted advertisement is not in violation and, at
some subsequent time, the Food and Drug Administration changes its
opinion, the advertiser will be so notified and will be given a
reasonable time for correction before any regulatory action is taken
under this section. Notification to the advertiser that a proposed
advertisement is or is not considered to be in violation shall be in
written form.
(5) The sponsor shall have an opportunity for a regulatory hearing
before the Food and Drug Administration pursuant to part 16 of this
chapter with respect to any determination that prior approval is
required for advertisements concerning a particular prescription drug,
or that a particular advertisement is not approvable.
(k) An advertisement issued or caused to be issued by the
manufacturer, packer, or distributor of the drug promoted by the
advertisement and which is not in compliance with section 502(n) of the
act and the applicable regulations thereunder shall cause stocks of such
drug in possession of the person responsible for issuing or causing the
issuance of the advertisement, and stocks of the drug distributed by
such person and still in the channels of commerce, to be misbranded
under section 502(n) of the act.
[[Page 82]]
(l)(1) Advertisements subject to section 502(n) of the act include
advertisements in published journals, magazines, other periodicals, and
newspapers, and advertisements broadcast through media such as radio,
television, and telephone communication systems.
(2) Brochures, booklets, mailing pieces, detailing pieces, file
cards, bulletins, calendars, price lists, catalogs, house organs,
letters, motion picture films, film strips, lantern slides, sound
recordings, exhibits, literature, and reprints and similar pieces of
printed, audio, or visual matter descriptive of a drug and references
published (for example, the ``Physicians Desk Reference'') for use by
medical practitioners, pharmacists, or nurses, containing drug
information supplied by the manufacturer, packer, or distributor of the
drug and which are disseminated by or on behalf of its manufacturer,
packer, or distributor are hereby determined to be labeling as defined
in section 201(m) of the act.
[40 FR 14016, Mar. 27, 1975, as amended at 40 FR 58799, Dec. 18, 1975;
41 FR 48266, Nov. 2, 1976; 42 FR 15674, Mar. 22, 1977; 60 FR 38480, July
27, 1995; 64 FR 400, Jan. 5, 1999]
Effective Date Note 1: At 44 FR 37467, June 26, 1979,
Sec. 202.1(e)(6) (ii) and (vii) were revised. At 44 FR 74817, Dec. 18,
1979, paragraphs (e)(6) (ii) and (vii) were stayed indefinitely. For the
convenience of the user, paragraphs (e)(6) (ii) and (vii), published at
44 FR 37467, are set forth below:
Sec. 202.1 Prescription-drug advertisements.
* * * * *
(e) * * *
(6) * * *
(ii) Represents or suggests that a prescription drug is safer or
more effective than another drug in some particular when the difference
has not been demonstrated by substantial evidence. An advertisement for
a prescription drug may not, either directly or by implication, e.g., by
use of comparative test data or reference to published reports,
represent that the drug is safer or more effective than another drug,
nor may an advertisement contain a quantitative statement of safety or
effectiveness (a) unless the representation has been approved as part of
the labeling in a new drug application or biologic license, or (b) if
the drug is not a new drug or biologic, unless the representation of
safety or effectiveness is supported by substantial evidence derived
from adequate and well-controlled studies as defined in
Sec. 314.111(a)(5)(ii) of this chapter, or unless the requirement for
adequate and well-controlled studies is waived as provided in
Sec. 314.111(a)(5)(ii) of this chapter.
* * * * *
(vii) Suggests, on the basis of favorable data or conclusions from
nonclinical studies of a prescription drug, such as studies in
laboratory animals or in vitro, that the studies have clinical
significance, if clinical significance has not been demonstrated. Data
that demonstrate activity or effectiveness for a prescription drug in
animal or in vitro tests and have not been shown by adequate and well-
controlled clinical studies to pertain to clinical use may be used in
advertising except that (a), in the case of anti-infective drugs, in
vitro data may be included in the advertisement, if data are immediately
preceded by the statement ``The following in vitro data are available
but their clinical significance is unknown'' and (b), in the case of
other drug classes, in vitro and animal data that have not been shown to
pertain to clinical use by adequate and well-controlled clinical studies
as defined in Sec. 314.111(a)(5)(ii) of this chapter may not be used
unless the requirement for adequate and well-controlled studies is
waived as provided in Sec. 314.111(a)(5)(ii) of this chapter.
* * * * *
Effective Date Note 2: At 64 FR 400, Jan. 5, 1999, Sec. 202.1 was
amended by removing paragraph (e)(4)(ii) and redesignating paragraph
(e)(4)(iii) as paragraph (e)(4)(ii), by removing the words ``paragraphs
(e)(4)(i) and (ii)'' from newly redesignated paragraph (e)(4)(ii) and by
adding in their place the words ``paragraph (e)(4)(i)'', by removing
``(e)(4)(iii)'' and by adding in its place ``(e)(4)(ii)'' in paragraph
(e)(6)(i), by removing ``, 507, or 512'' from paragraph (e)(6)(xvii), by
removing the phrase ``or antibiotic'' from indefinitely stayed paragraph
(e)(6)(ii)(a); and by removing the phrase ``or a certified or released
antibiotic,'' from indefinitely stayed paragraph (e)(6)(ii)(b),
effective May 20, 1999. For the convenience of the user, the superseded
text is set forth as follows:
Sec. 202.1 Prescription-drug advertisements.
* * * * *
(e) * * *
(4) * * *
(ii) An advertisement for a prescription drug subject to
certification under section 507 or 512 of the act shall not recommend or
suggest any use that is not in the labeling
[[Page 83]]
covered by the certification or the applicable certification regulations
or regulations providing for exemption from certification. The
advertisement shall present information from such labeling covered by
the certification or the applicable certification regulations or
regulations providing for exemption from certification, relating to each
specific side effect and contraindication in such labeling and such
regulations for the advertised drug dosage form(s) or shall otherwise
conform to the provisions of paragraph (e)(3)(iii) of this section.
* * * * *
PART 205--GUIDELINES FOR STATE LICENSING OF WHOLESALE PRESCRIPTION DRUG DISTRIBUTORS--Table of Contents
Sec.
205.1 Scope.
205.2 Purpose.
205.3 Definitions.
205.4 Wholesale drug distributor licensing requirement.
205.5 Minimum required information for licensure.
205.6 Minimum qualifications.
205.7 Personnel.
205.8 Violations and penalties.
205.50 Minimum requirements for the storage and handling of
prescription drugs and for the establishment and maintenance
of prescription drug distribution records.
Authority: 21 U.S.C. 351, 352, 353, 371, 374.
Source: 55 FR 38023, Sept. 14, 1990, unless otherwise noted.
Sec. 205.1 Scope.
This part applies to any person, partnership, corporation, or
business firm in a State engaging in the wholesale distribution of human
prescription drugs in interstate commerce.
Sec. 205.2 Purpose.
The purpose of this part is to implement the Prescription Drug
Marketing Act of 1987 by providing minimum standards, terms, and
conditions for the licensing by State licensing authorities of persons
who engage in wholesale distributions in interstate commerce of
prescription drugs.
Sec. 205.3 Definitions.
(a) Blood means whole blood collected from a single donor and
processed either for transfusion or further manufacturing.
(b) Blood component means that part of blood separated by physical
or mechanical means.
(c) Drug sample means a unit of a prescription drug that is not
intended to be sold and is intended to promote the sale of the drug.
(d) Manufacturer means anyone who is engaged in manufacturing,
preparing, propagating, compounding, processing, packaging, repackaging,
or labeling of a prescription drug.
(e) Prescription drug means any human drug required by Federal law
or regulation to be dispensed only by a prescription, including finished
dosage forms and active ingredients subject to section 503(b) of the
Federal Food, Drug, and Cosmetic Act.
(f) Wholesale distribution and wholesale distribution means
distribution of prescription drugs to persons other than a consumer or
patient, but does not include:
(1) Intracompany sales;
(2) The purchase or other acquisition by a hospital or other health
care entity that is a member of a group purchasing organization of a
drug for its own use from the group purchasing organization or from
other hospitals or health care entities that are members of such
organizations;
(3) The sale, purchase, or trade of a drug or an offer to sell,
purchase, or trade a drug by a charitable organization described in
section 501(c)(3) of the Internal Revenue Code of 1954 to a nonprofit
affiliate of the organization to the extent otherwise permitted by law;
(4) The sale, purchase, or trade of a drug or an offer to sell,
purchase, or trade a drug among hospitals or other health care entities
that are under common control; for purposes of this section, common
control means the power to direct or cause the direction of the
management and policies of a person or an organization, whether by
ownership of stock, voting rights, by contract, or otherwise;
(5) The sale, purchase, or trade of a drug or an offer to sell,
purchase, or trade a drug for emergency medical reasons; for purposes of
this section, emergency medical reasons includes
[[Page 84]]
transfers of prescription drugs by a retail pharmacy to another retail
pharmacy to alleviate a temporary shortage;
(6) The sale, purchase, or trade of a drug, an offer to sell,
purchase, or trade a drug, or the dispensing of a drug pursuant to a
prescription;
(7) The distribution of drug samples by manufacturers'
representatives or distributors' representatives; or
(8) The sale, purchase, or trade of blood and blood components
intended for transfusion.
(g) Wholesale distributor means any one engaged in wholesale
distribution of prescription drugs, including, but not limited to,
manufacturers; repackers; own-label distributors; private-label
distributors; jobbers; brokers; warehouses, including manufacturers' and
distributors' warehouses, chain drug warehouses, and wholesale drug
warehouses; independent wholesale drug traders; and retail pharmacies
that conduct wholesale distributions.
Sec. 205.4 Wholesale drug distributor licensing requirement.
Every wholesale distributor in a State who engages in wholesale
distributions of prescription drugs in interstate commerce must be
licensed by the State licensing authority in accordance with this part
before engaging in wholesale distributions of prescription drugs in
interstate commerce.
Sec. 205.5 Minimum required information for licensure.
(a) The State licensing authority shall require the following
minimum information from each wholesale drug distributor as part of the
license described in Sec. 205.4 and as part of any renewal of such
license:
(1) The name, full business address, and telephone number of the
licensee;
(2) All trade or business names used by the licensee;
(3) Addresses, telephone numbers, and the names of contact persons
for all facilities used by the licensee for the storage, handling, and
distribution of prescription drugs;
(4) The type of ownership or operation (i.e., partnership,
corporation, or sole proprietorship); and
(5) The name(s) of the owner and/or operator of the licensee,
including:
(i) If a person, the name of the person;
(ii) If a partnership, the name of each partner, and the name of the
partnership;
(iii) If a corporation, the name and title of each corporate officer
and director, the corporate names, and the name of the State of
incorporation; and
(iv) If a sole proprietorship, the full name of the sole proprietor
and the name of the business entity.
(b) The State licensing authority may provide for a single license
for a business entity operating more than one facility within that
State, or for a parent entity with divisions, subsidiaries, and/or
affiliate companies within that State when operations are conducted at
more than one location and there exists joint ownership and control
among all the entities.
(c) Changes in any information in paragraph (a) of this section
shall be submitted to the State licensing authority as required by such
authority.
(Approved by the Office of Management and Budget under control number
0910-0251)
Sec. 205.6 Minimum qualifications.
(a) The State licensing authority shall consider, at a minimum, the
following factors in reviewing the qualifications of persons who engage
in wholesale distribution of prescription drugs within the State:
(1) Any convictions of the applicant under any Federal, State, or
local laws relating to drug samples, wholesale or retail drug
distribution, or distribution of controlled substances;
(2) Any felony convictions of the applicant under Federal, State, or
local laws;
(3) The applicant's past experience in the manufacture or
distribution of prescription drugs, including controlled substances;
(4) The furnishing by the applicant of false or fraudulent material
in any application made in connection with drug manufacturing or
distribution;
(5) Suspension or revocation by Federal, State, or local government
of any
[[Page 85]]
license currently or previously held by the applicant for the
manufacture or distribution of any drugs, including controlled
substances;
(6) Compliance with licensing requirements under previously granted
licenses, if any;
(7) Compliance with requirements to maintain and/or make available
to the State licensing authority or to Federal, State, or local law
enforcement officials those records required under this section; and
(8) Any other factors or qualifications the State licensing
authority considers relevant to and consistent with the public health
and safety.
(b) The State licensing authority shall have the right to deny a
license to an applicant if it determines that the granting of such a
license would not be in the public interest.
Sec. 205.7 Personnel.
The State licensing authority shall require that personnel employed
in wholesale distribution have appropriate education and/or experience
to assume responsibility for positions related to compliance with State
licensing requirements.
Sec. 205.8 Violations and penalties.
(a) State licensing laws shall provide for the suspension or
revocation of licenses upon conviction of violations of Federal, State,
or local drug laws or regulations, and may provide for fines,
imprisonment, or civil penalties.
(b) State licensing laws shall provide for suspension or revocation
of licenses, where appropriate, for violations of its provisions.
Sec. 205.50 Minimum requirements for the storage and handling of prescription drugs and for the establishment and maintenance of prescription drug distribution
records.
The State licensing law shall include the following minimum
requirements for the storage and handling of prescription drugs, and for
the establishment and maintenance of prescription drug distribution
records by wholesale drug distributors and their officers, agents,
representatives, and employees:
(a) Facilities. All facilities at which prescription drugs are
stored, warehoused, handled, held, offered, marketed, or displayed
shall:
(1) Be of suitable size and construction to facilitate cleaning,
maintenance, and proper operations;
(2) Have storage areas designed to provide adequate lighting,
ventilation, temperature, sanitation, humidity, space, equipment, and
security conditions;
(3) Have a quarantine area for storage of prescription drugs that
are outdated, damaged, deteriorated, misbranded, or adulterated, or that
are in immediate or sealed, secondary containers that have been opened;
(4) Be maintained in a clean and orderly condition; and
(5) Be free from infestation by insects, rodents, birds, or vermin
of any kind.
(b) Security. (1) All facilities used for wholesale drug
distribution shall be secure from unauthorized entry.
(i) Access from outside the premises shall be kept to a minimum and
be well-controlled.
(ii) The outside perimeter of the premises shall be well-lighted.
(iii) Entry into areas where prescription drugs are held shall be
limited to authorized personnel.
(2) All facilities shall be equipped with an alarm system to detect
entry after hours.
(3) All facilities shall be equipped with a security system that
will provide suitable protection against theft and diversion. When
appropriate, the security system shall provide protection against theft
or diversion that is facilitated or hidden by tampering with computers
or electronic records.
(c) Storage. All prescription drugs shall be stored at appropriate
temperatures and under appropriate conditions in accordance with
requirements, if any, in the labeling of such drugs, or with
requirements in the current edition of an official compendium, such as
the United States Pharmacopeia/National Formulary (USP/NF).
(1) If no storage requirements are established for a prescription
drug, the drug may be held at ``controlled'' room temperature, as
defined in an official compendium, to help ensure that its identity,
strength, quality, and purity are not adversely affected.
[[Page 86]]
(2) Appropriate manual, electromechanical, or electronic temperature
and humidity recording equipment, devices, and/or logs shall be utilized
to document proper storage of prescription drugs.
(3) The recordkeeping requirements in paragraph (f) of this section
shall be followed for all stored drugs.
(d) Examination of materials. (1) Upon receipt, each outside
shipping container shall be visually examined for identity and to
prevent the acceptance of contaminated prescription drugs or
prescription drugs that are otherwise unfit for distribution. This
examination shall be adequate to reveal container damage that would
suggest possible contamination or other damage to the contents.
(2) Each outgoing shipment shall be carefully inspected for identity
of the prescription drug products and to ensure that there is no
delivery of prescription drugs that have been damaged in storage or held
under improper conditions.
(3) The recordkeeping requirements in paragraph (f) of this section
shall be followed for all incoming and outgoing prescription drugs.
(e) Returned, damaged, and outdated prescription drugs. (1)
Prescription drugs that are outdated, damaged, deteriorated, misbranded,
or adulterated shall be quarantined and physically separated from other
prescription drugs until they are destroyed or returned to their
supplier.
(2) Any prescription drugs whose immediate or sealed outer or sealed
secondary containers have been opened or used shall be identified as
such, and shall be quarantined and physically separated from other
prescription drugs until they are either destroyed or returned to the
supplier.
(3) If the conditions under which a prescription drug has been
returned cast doubt on the drug's safety, identity, strength, quality,
or purity, then the drug shall be destroyed, or returned to the
supplier, unless examination, testing, or other investigation proves
that the drug meets appropriate standards of safety, identity, strength,
quality, and purity. In determining whether the conditions under which a
drug has been returned cast doubt on the drug's safety, identity,
strength, quality, or purity, the wholesale drug distributor shall
consider, among other things, the conditions under which the drug has
been held, stored, or shipped before or during its return and the
condition of the drug and its container, carton, or labeling, as a
result of storage or shipping.
(4) The recordkeeping requirements in paragraph (f) of this section
shall be followed for all outdated, damaged, deteriorated, misbranded,
or adulterated prescription drugs.
(f) Recordkeeping. (1) Wholesale drug distributors shall establish
and maintain inventories and records of all transactions regarding the
receipt and distribution or other disposition of prescription drugs.
These records shall include the following information:
(i) The source of the drugs, including the name and principal
address of the seller or transferor, and the address of the location
from which the drugs were shipped;
(ii) The identity and quantity of the drugs received and distributed
or disposed of; and
(iii) The dates of receipt and distribution or other disposition of
the drugs.
(2) Inventories and records shall be made available for inspection
and photocopying by authorized Federal, State, or local law enforcement
agency officials for a period of 2 years following disposition of the
drugs.
(3) Records described in this section that are kept at the
inspection site or that can be immediately retrieved by computer or
other electronic means shall be readily available for authorized
inspection during the retention period. Records kept at a central
location apart from the inspection site and not electronically
retrievable shall be made available for inspection within 2 working days
of a request by an authorized official of a Federal, State, or local law
enforcement agency.
(g) Written policies and procedures. Wholesale drug distributors
shall establish, maintain, and adhere to written policies and
procedures, which shall be followed for the receipt, security, storage,
inventory, and distribution of prescription drugs, including policies
and procedures for identifying, recording, and reporting losses or
[[Page 87]]
thefts, and for correcting all errors and inaccuracies in inventories.
Wholesale drug distributors shall include in their written policies and
procedures the following:
(1) A procedure whereby the oldest approved stock of a prescription
drug product is distributed first. The procedure may permit deviation
from this requirement, if such deviation is temporary and appropriate.
(2) A procedure to be followed for handling recalls and withdrawals
of prescription drugs. Such procedure shall be adequate to deal with
recalls and withdrawals due to:
(i) Any action initiated at the request of the Food and Drug
Administration or other Federal, State, or local law enforcement or
other government agency, including the State licensing agency;
(ii) Any voluntary action by the manufacturer to remove defective or
potentially defective drugs from the market; or
(iii) Any action undertaken to promote public health and safety by
replacing of existing merchandise with an improved product or new
package design.
(3) A procedure to ensure that wholesale drug distributors prepare
for, protect against, and handle any crisis that affects security or
operation of any facility in the event of strike, fire, flood, or other
natural disaster, or other situations of local, State, or national
emergency.
(4) A procedure to ensure that any outdated prescription drugs shall
be segregated from other drugs and either returned to the manufacturer
or destroyed. This procedure shall provide for written documentation of
the disposition of outdated prescription drugs. This documentation shall
be maintained for 2 years after disposition of the outdated drugs.
(h) Responsible persons. Wholesale drug distributors shall establish
and maintain lists of officers, directors, managers, and other persons
in charge of wholesale drug distribution, storage, and handling,
including a description of their duties and a summary of their
qualifications.
(i) Compliance with Federal, State, and local law. Wholesale drug
distributors shall operate in compliance with applicable Federal, State,
and local laws and regulations.
(1) Wholesale drug distributors shall permit the State licensing
authority and authorized Federal, State, and local law enforcement
officials to enter and inspect their premises and delivery vehicles, and
to audit their records and written operating procedures, at reasonable
times and in a reasonable manner, to the extent authorized by law.
(2) Wholesale drug distributors that deal in controlled substances
shall register with the appropriate State controlled substance authority
and with the Drug Enforcement Administration (DEA), and shall comply
with all applicable State, local, and DEA regulations.
(j) Salvaging and reprocessing. Wholesale drug distributors shall be
subject to the provisions of any applicable Federal, State, or local
laws or regulations that relate to prescription drug product salvaging
or reprocessing, including parts 207, 210, and 211 of this chapter.
(Approved by the Office of Management and Budget under control number
0910-0251)
PART 206--IMPRINTING OF SOLID ORAL DOSAGE FORM DRUG PRODUCTS FOR HUMAN USE--Table of Contents
Sec.
206.1 Scope.
206.3 Definitions.
206.7 Exemptions.
206.10 Code imprint required.
Authority: 21 U.S.C. 321, 331, 351, 352, 355, 371; 42 U.S.C. 262.
Source: 58 FR 47958, Sept. 13, 1993, unless otherwise noted.
Sec. 206.1 Scope.
This part applies to all solid oral dosage form human drug products,
including prescription drug products, over-the-counter drug products,
biological drug products, and homeopathic drug products, unless
otherwise exempted under Sec. 206.7.
Sec. 206.3 Definitions.
The following definitions apply to this part:
[[Page 88]]
The act means the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
301 et seq.).
Debossed means imprinted with a mark below the dosage form surface.
Drug product means a finished dosage form, e.g., a tablet or capsule
that contains a drug substance, generally, but not necessarily, in
association with one or more other ingredients.
Embossed means imprinted with a mark raised above the dosage form
surface.
Engraved means imprinted with a code that is cut into the dosage
form surface after it has been completed.
Imprinted means marked with an identification code by means of
embossing, debossing, engraving, or printing with ink.
Manufacturer means the manufacturer as described in Secs. 201.1 and
600.3(t) of this chapter.
Solid oral dosage form means capsules, tablets, or similar drug
products intended for oral use.
Sec. 206.7 Exemptions.
(a) The following classes of drug products are exempt from
requirements of this part:
(1) Drug products intended for use in a clinical investigation under
section 505(i) of the act, but not including drugs distributed under a
treatment IND under part 312 of this chapter or distributed as part of a
nonconcurrently controlled study. Placebos intended for use in a
clinical investigation are exempt from the requirements of this part if
they are designed to copy the active drug products used in that
investigation.
(2) Drugs, other than reference listed drugs, intended for use in
bioequivalence studies.
(3) Drugs that are extemporaneously compounded by a licensed
pharmacist, upon receipt of a valid prescription for an individual
patient from a practitioner licensed by law to prescribe or administer
drugs, to be used solely by the patient for whom they are prescribed.
(4) Radiopharmaceutical drug products.
(b) Exemption of drugs because of size or unique physical
characteristics:
(1) For a drug subject to premarket approval, FDA may provide an
exemption from the requirements of Sec. 206.10 upon a showing that the
product's size, shape, texture, or other physical characteristics make
imprinting technologically infeasible or impossible.
(i) Exemption requests for products with approved applications shall
be made in writing to the appropriate review division in the Center for
Drug Evaluation and Research (CDER) or the Center for Biologics
Evaluation and Research (CBER), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857. If FDA denies the request, the holder
of the approved application will have 1 year after the date of an agency
denial to imprint the drug product.
(ii) Exemption requests for products that have not yet received
approval shall be made in writing to the appropriate review division in
CDER or CBER.
(2) Any product not subject to premarket approval is exempt from the
requirement of Sec. 206.10 if, based on the product's size, shape,
texture, or other physical characteristics, the manufacturer or
distributor of the product is prepared to demonstrate that imprinting
the dosage form is technologically infeasible or impossible.
(c) For drugs that are administered solely in controlled health care
settings and not provided to patients for self-administration, sponsors
may submit requests for exemptions from the requirements of this rule.
Controlled settings include physicians' offices and other health care
facilities. Exemption requests should be submitted in writing to the
appropriate review division in CDER or CBER.
Sec. 206.10 Code imprint required.
(a) Unless exempted under Sec. 206.7, no drug product in solid oral
dosage form may be introduced or delivered for introduction into
interstate commerce unless it is clearly marked or imprinted with a code
imprint that, in conjunction with the product's size, shape, and color,
permits the unique identification of the drug product and the
manufacturer or distributor of the product. Identification of the drug
product requires identification of its
[[Page 89]]
active ingredients and its dosage strength. Inclusion of a letter or
number in the imprint, while not required, is encouraged as a more
effective means of identification than a symbol or logo by itself.
Homeopathic drug products are required only to bear an imprint that
identifies the manufacturer and their homeopathic nature.
(b) A holder of an approved application who has, under Sec. 314.70
(b)(2)(xi) or (b)(2)(xii) of this chapter, supplemented its application
to provide for a new imprint is not required to bring its product into
compliance with this section during the pendency of the agency's review.
Once the review is complete, the drug product is subject to the
requirements of the rule.
(c) A solid oral dosage form drug product that does not meet the
requirement for imprinting in paragraph (a) of this section and is not
exempt from the requirement may be considered adulterated and misbranded
and may be an unapproved new drug.
(d) For purposes of this section, code imprint means any single
letter or number or any combination of letters and numbers, including,
e.g., words, company name, and National Drug Code, or a mark, symbol,
logo, or monogram, or a combination of letters, numbers, and marks or
symbols, assigned by a drug firm to a specific drug product.
[58 FR 47958, Sept. 13, 1993, as amended at 60 FR 19846, Apr. 21, 1995]
PART 207--REGISTRATION OF PRODUCERS OF DRUGS AND LISTING OF DRUGS IN COMMERCIAL DISTRIBUTION--Table of Contents
Subpart A--General
Sec.
207.3 Definitions.
207.7 Establishment registration and product listing for human blood
and blood products and for medical devices.
Subpart B--Exemptions
207.10 Exemptions for domestic establishments.
Subpart C--Procedures for Domestic Drug Establishments
207.20 Who must register and submit a drug list.
207.21 Times for registration and drug listing.
207.22 How and where to register and list drugs.
207.25 Information required in registration and drug listing.
207.26 Amendments to registration.
207.30 Updating drug listing information.
207.31 Additional drug listing information.
207.35 Notification of registrant; drug establishment registration
number and drug listing number.
207.37 Inspection of registrations and drug listings.
207.39 Misbranding by reference to registration or to registration
number.
Subpart D--Procedure for Foreign Drug Establishments
207.40 Drug listing requirements for foreign drug establishments.
Authority: 21 U.S.C. 331, 351, 352, 355, 360, 360b, 371, 374; 42
U.S.C. 262.
Source: 45 FR 38043, June 6, 1980, unless otherwise noted.
Subpart A--General
Sec. 207.3 Definitions.
(a) The following definitions apply to this part:
(1) Act means the Federal Food, Drug, and Cosmetic Act approved June
25, 1938 (52 Stat. 1040 et seq., as amended (21 U.S.C. 301-392)), except
as otherwise provided.
(2) Advertising and labeling include the promotional material
described in Sec. 202.1(l) (1) and (2) respectively.
(3) Any material change includes but is not limited to any change in
the name of the drug, any change in the identity or quantity of the
active ingredient(s), any change in the identity or quantity of the
inactive ingredient(s) where quantitative listing of all ingredients is
required by Sec. 207.31(a)(2), any significant change in the labeling of
a prescription drug, and any significant change in the label or package
insert of an over-the-counter drug. Changes that are not significant
include changes in arrangement or printing or changes of an editorial
nature.
(4) Bulk drug substance means any substance that is represented for
use in a drug and that, when used in the manufacturing, processing, or
packaging of a drug, becomes an active ingredient or a finished dosage
form of the drug, but
[[Page 90]]
the term does not include intermediates used in the synthesis of such
substances.
(5) Commercial distribution means any distribution of a human drug
except for investigational use under part 312 of this chapter, and any
distribution of an animal drug or an animal feed bearing or containing
an animal drug for noninvestigational uses, but the term does not
include internal or interplant transfer of a bulk drug substance between
registered domestic establishments within the same parent, subsidiary,
and/or affiliate company.
(6) Drug product salvaging means the act of segregating drug
products that may have been subjected to improper storage conditions,
such as extremes in temperature, humidity, smoke, fumes, pressure, age,
or radiation, for the purpose of returning some or all of the products
to the marketplace.
(7) Establishment means a place of business under one management at
one general physical location. The term includes, among others,
independent laboratories that engage in control activities for a
registered drug establishment (e.g., consulting laboratories),
manufacturers of medicated feeds and of vitamin products that are drugs
in accordance with section 201(g) of the act, human blood donor centers,
and animal facilities used for the production or control testing of
licensed biologicals, and establishments engaged in drug product
salvaging.
(8) Manufacturing or processing means the manufacture, preparation,
propagation, compounding, or processing of a drug or drugs as used in
section 510 of the act and is the making by chemical, physical,
biological, or other procedures of any articles that meet the definition
of drugs in section 201(g) of the act. The term includes manipulation,
sampling, testing, or control procedures applied to the final product or
to any part of the process. The term also includes repackaging or
otherwise changing the container, wrapper, or labeling of any drug
package to further the distribution of the drug from the original place
of manufacture to the person who makes final delivery or sale to the
ultimate consumer.
(9) Representative sampling of advertisements means typical
advertising material (excluding labeling as determined in Sec. 202.1(l)
(1) and (2)) that gives a balanced picture of the promotional claims
used for the drug, e.g., if more than one medical journal advertisement
is used but the promotional content is essentially identical, only one
need be submitted.
(10) Representative sampling of any other labeling means typical
labeling material (excluding labels and package inserts) that gives a
balanced picture of the promotional claims used for the drug, e.g., if
more than one brochure is used but the promotional content is
essentially identical, only one need be submitted.
(b) The definitions and interpretations of terms in sections 201,
502(e), and 510 of the act apply to the use of terms in this part.
[45 FR 38043, June 6, 1980, as amended at 55 FR 11576, Mar. 29, 1990]
Sec. 207.7 Establishment registration and product listing for human blood and blood products and for medical devices.
(a) Owners and operators of human blood and blood product
establishments shall register and list their products with the Division
of Product Certification, Office of Biological Product Review (HFB-240),
Center for Biologics Evaluation and Research, 8800 Rockville Pike,
Bethesda, MD 20892, on Form FDA-2830 (Blood Establishment Registration
and Product Listing), in acordance with part 607. Such owners and
operators who also manufature or process other drug products at the same
establishment shall, in addition, register and list all such other drug
products with the Drug Listing Branch in accordance with this part.
(b) [Reserved]
(c) Owners and operators of establishments engaged in manufacture or
processing of medical devices shall register and list their products
with the Center for Devices and Radiological Health, FDA, on Form FDA-
2891 (Initial Registration of Device Establishments), FDA-2891a
(Registration of Device Establishment), and FDA-2892 (Medical Device
Listing), in accordance with part 807.
(d) Owners and operators of establishments engaged in the
manufacture or
[[Page 91]]
processing at the same establishment of both drug products and medical
devices shall (1) register with the Drug Listing Branch (HFD-334),
Center for Drug Evaluation and Research, FDA, and list their drug
products in accordance with this part, and (2) register with the Center
for Devices and Radiological Health and list their medical devices in
accordance with part 807.
[45 FR 38043, June 6, 1980, as amended at 50 FR 8995, Mar. 6, 1985; 55
FR 11576, Mar. 29, 1990]
Subpart B--Exemptions
Sec. 207.10 Exemptions for domestic establishments.
The following classes of persons are exempt from registration and
drug listing in accordance with this part under section 510(g) (1), (2),
and (3) of the act, or because FDA has found, under section 510(g)(4),
that their registration is not necessary for the protection of the
public health.
(a) Pharmacies that operate under applicable local laws regulating
dispensing of prescription drugs and that do not manufacture or process
drugs for sale other than in the regular course of the practice of the
profession of pharmacy, including dispensing and selling drugs at
retail. The supplying of prescription drugs by these pharmacies to a
practitioner licensed to administer these drugs for his or her use in
the course of professional practice or to other pharmacies to meet
temporary inventory shortages are not acts that require pharmacies to
register.
(b) Hospitals, clinics, and public health agencies that maintain
establishments in conformance with any applicable local laws regulating
the practices of pharmacy or medicine and that regularly engage in
dispensing prescription drugs, other than human blood or blood products,
upon prescription of practitioners licensed by law to administer these
drugs to patients under their professional care.
(c) Practitioners who are licensed by law to prescribe or administer
drugs and who manufacture or process drugs solely for use in their
professional practice.
(d) Persons who manufacture or process drugs not for sale but solely
for use in research, teaching, or chemical analysis.
(e) Manufacturers of harmless inactive ingredients that are
excipients, colorings, flavorings, emulsifiers, lubricants,
preservatives, or solvents that become components of drugs, and who
otherwise would not be required to register under this part.
(f) Persons who manufacture Type B or Type C medicated feed using
Category I, Type A medicated articles; Category I, Type B medicated
feeds; and/or Category II, Type B medicated feeds, as defined in
Sec. 558.3 of this chapter, as drug sources.
(g) Any manufacturer of a virus, serum, toxin, or analogous product
intended for treatment of domestic animals who holds an unsuspended and
unrevoked license issued by the Secretary of Agriculture under the
animal virus-serum-toxin law of March 4, 1913 (37 Stat. 832 (21 U.S.C.
151 et seq.)), provided that this exemption from registration applies
only to the manufacture or processing of that animal virus, serum,
toxin, or analogous product.
(h) Carriers, in their receipt, carriage, holding, or delivery of
drugs in the usual course of business as carriers.
[45 FR 38043, June 6, 1980, as amended at 51 FR 7389, Mar. 3, 1986]
Subpart C--Procedures for Domestic Drug Establishments
Sec. 207.20 Who must register and submit a drug list.
(a) Owners or operators of all drug establishments, not exempt under
section 510(g) of the act or subpart D of this part 207, that engage in
the manufacture, preparation, propagation, compounding, or processing of
a drug or drugs are required to register and to submit a list of every
drug in commercial distribution (except that listing information may be
submitted by the parent, subsidiary, and/or affiliate company for all
establishments when operations are conducted at more than one
establishment and there exists joint ownership and control among all the
establishments). Such owners or operators are required to register and
to submit a list of every drug in commercial distribution (except that
listing information may be submitted by
[[Page 92]]
the parent, subsidiary, and/or affiliate company for all establishments
when operations are conducted at more than one establishment and there
exists joint ownership and control among all the establishments),
whether or not the output of such establishment or any particular drug
so listed enters interstate commerce, except that drug listing is not
required at this time for the manufacturing, preparation, propagation,
compounding, or processing of an animal feed (including a Type B and
Type C medicated feed) bearing or containing an animal drug, nor is drug
listing required for establishments engaged in drug product salvaging.
No owner or operator may register an establishment, if any part of the
establishment is registered by any other owner or operator.
(b) Owners or operators of establishments not otherwise required to
register under section 510 of the act that distribute under their own
label or trade name a drug manufactured or processed by a registered
establishment may elect to submit listing information directly to FDA
and to obtain a Labeler Code. A distributor who submits drug listing
information shall include the registration number of the drug
establishment that manufactured, prepared, propagated, compounded, or
processed each drug listed. All distributors who submit drug listing
information to FDA assume full responsibility for compliance with all of
the requirements of this part. Each such distributor at the time of
submitting or updating drug listing information as required under
Sec. 207.30 shall certify to the registered establishment that the
submission has been made by providing a signed copy of Form FDA-2656
(Registration of Drug Establishment) to the registered establishment
that manufactures or processes the drug. Each such distributor shall
submit the original of Form FDA-2656 showing this certification to FDA,
and shall accompany the certification with a list showing the National
Drug Code number that the distributor has assigned to each drug product.
If a distributor does not elect to submit drug listing information
directly to FDA and to obtain a Labeler Code, the registered
establishment shall submit the drug listing information. Distributors or
registered establishments shall use Form FDA-2658 (Registered
Establishments' Report of Private Label Distributors) to submit drug
listing information or to request a Labeler Code, or both.
(c) Before beginning manufacture or processing of a drug subject to
one of the following applications, an owner or operator of an
establishment is required to register before the agency approves it: a
new drug application, a new animal drug application, a medicated feed
application, or an establishment license application to manufacture a
biological product.
(d) No registration fee is required.
(e) Registration and listing do not constitute an admission, or
agreement, or determination that a product is a drug as defined in
section 201(g) of the act.
[45 FR 38043, June 6, 1980, as amended at 45 FR 32293, May 16, 1980; 52
FR 2682, Jan. 26, 1987; 55 FR 11576, Mar. 29, 1990; 64 FR 400, Jan. 5,
1999]
Effective Date Note: At 64 FR 400, Jan. 5, 1999, Sec. 207.20 was
amended by removing the words ``an antibiotic application,'' from
paragraph (c), effective May 20, 1999.
Sec. 207.21 Times for registration and drug listing.
(a) The owner or operator of an establishment entering into the
manufacture or processing of a drug or drugs shall register the
establishment within 5 days after the beginning of the operation and
shall submit a list of every drug in commercial distribution at that
time. If the owner or operator of the establishment has not previously
entered into such an operation, the owner or operator shall register
within 5 days after submitting a new drug application, new animal drug
application, medicated feed application, or an establishment license
application to manufacture a biological product. Owners or operators of
all establishments engaged in the drug activities described in
Sec. 207.3(a)(8) shall register annually within 30 days after receiving
registration forms from FDA. FDA will mail Forms FDA-2656 (Registration
of Drug Establishment) to registered establishments according to a
schedule based on the first letter of the name of the establishment's
parent company as
[[Page 93]]
stated on the firm's registration form. If no parent company name is
given on that form, the schedule is based on the first letter of the
establishment's name. In scheduling the mailing of forms based on the
first letter of the company name, FDA will not consider the word ``the''
when it appears as the first word in the name of the parent company or
establishment.
The schedule is as follows:
------------------------------------------------------------------------
First letter of company name Date FDA will mail forms
------------------------------------------------------------------------
A or B................................... January
C, D, or E............................... February
F, G, or H............................... March
I, J, K, L. or M......................... April
N, O, P, Q, or R......................... May
S or T................................... June
U, V, W, X, Y, or Z...................... July
------------------------------------------------------------------------
(b) Owners and operators of all registered establishments shall
update their drug listing information every June and December.
[45 FR 38043, June 6, 1980, as amended at 55 FR 11576, Mar. 29, 1990; 64
FR 400, Jan. 5, 1999]
Effective Date Note: At 64 FR 400, Jan. 5, 1999, Sec. 207.21 was
amended by removing the words ``antibiotic application,'' from the
second sentence of paragraph (a), effective May 20, 1999.
Sec. 207.22 How and where to register and list drugs.
(a) An establishment shall register the first time on Form FDA-2656
(Registration of Drug Establishment), obtainable on request from the
Drug Listing Branch (HFD-334), Center for Drug Evaluation and Research,
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, or
from FDA district offices. An establishment whose drug registration for
that year was validated under Sec. 207.35 shall make subsequent annual
registration on Form FDA-2656 as described in Sec. 207.21(a) by mailing
the completed form to the above address within 30 days after receipt
from FDA.
(b) The first list of drugs and later June and December updatings
shall be on Form FDA-2657 (Drug Product Listing), obtainable upon
request as described in paragraph (a) of this section. An establishment
may submit, in lieu of Form FDA-2657, tapes for computer inputs
containing the information specified in Form FDA-2657 if formats
proposed for this use were reviewed and approved by the Drug Listing
Branch (HFD-334), Center for Drug Evaluation and Research, FDA.
[45 FR 38043, June 6, 1980, as amended at 50 FR 8995, Mar. 6, 1985; 55
FR 11576, Mar. 29, 1990]
Sec. 207.25 Information required in registration and drug listing.
(a) Form FDA-2656 (Registration of Drug Establishment) provides for
furnishing or confirming information required by the act. This
information includes, for each establishment, the name and full address
of the drug establishment; 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
the establishment. The term name of the owner or operator includes 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.
(b) Form FDA-2657 (Drug Product Listing) provides that information
required by the act be furnished as follows:
(1) A list of drugs, including bulk drug substances and Type A
articles for use in the manufacture of animal feeds as well as finished
dosage forms, by established name and by proprietary name, that are
being manufactured or processed for commercial distribution and that
have not been included in any list previously submitted to FDA on Form
FDA-2657 or in conjunction with the FDA voluntary inventory on Form FDA-
2422 (Survey Report of Marketed Drugs), or Form FDA-2250 (National Drug
Code Directory Input).
(2) For each drug listed that the registrant regards as subject to
section 505 or 512 of the act, the new drug application number,
abbreviated new drug application number, or new animal drug application
number and a copy of all current labeling, except that only one
representative container or carton label need be submitted where
differences exist only in the quantity of contents statement.
(3) For each drug listed that the registrant regards as subject to
section 351
[[Page 94]]
of the Public Health Service Act, the license number of the
manufacturer.
(4) For each human prescription drug listed that the registrant
regards as not subject to section 505 of the act or 351 of the Public
Health Service Act, and that is not manufactured by a registered blood
bank, a copy of all current labeling (except that only one
representative container or carton label need be submitted where
differences exist only in the quantity of contents statement) and a
representative sampling of advertisements.
(5) For each human over-the-counter drug listed, or each animal drug
listed, that the registrant regards as not subject to section 505 or 512
of the act or 351 of the Public Health Service Act, a copy of the label
(except that only one representative container or carton label need be
submitted where differences exist only in the quantity of contents
statement), the package insert, and a representative sampling of any
other labeling.
(6) For each prescription or over-the-counter drug so listed that
the registrant regards as not subject to section 505 or 512 of the act
or 351 of the Public Health Service Act, and that is not manufactured by
a registered blood bank, a quantitative listing of the active
ingredient(s). Unless the quantitative listing is expressed as a
percentage in the offical compendium or the ingredient is a
nonantibiotic ingredient in a Type A medicated article for use in the
manufacture of animal feeds, the quantity of an ingredient shall be
expressed in terms of the amount, not the percent, of that ingredient in
each dosage unit or, if the drug is not in unit dosage form, the amount
of the ingredient in a specific unit of weight or measure of the drug.
For a drug formulation that is a Type A medicated article subject to
Sec. 207.35(b)(2)(iii), the registrant may limit the quantitative
listing of ingredients to each variation of level of active drug
ingredient.
(7) For each drug listed, the registration number of every drug
establishment within the parent company at which it is manufactured or
processed.
(8) For each drug listed, the National Drug Code (NDC) number. If
FDA has not assigned an NDC Labeler Code, the registrant shall include a
Product Code and Package Code and FDA will assign a Labeler Code as
described in Sec. 207.35(b)(2)(i).
(c) For each drug product listed that is subject to the imprinting
requirements of part 206 of this chapter, including products that are
exempted under Sec. 206.7(b), drug companies must submit a document that
provides the name of the product, its active ingredient(s), dosage
strength, National Drug Code number, the name of its manufacturer or
distributor, its size, shape, color, and code imprint (if any), and any
other characteristic that identifies the product as unique.
[45 FR 38043, June 6, 1980, as amended at 52 FR 2682, Jan. 26, 1987; 55
FR 11577, Mar. 29, 1990; 58 FR 47959, Sept. 13, 1993; 63 FR 26698, May
13, 1998; 64 FR 400, Jan. 5, 1999]
Effective Date Note: At 64 FR 400, Jan. 5, 1999, Sec. 207.25 was
amended by removing ``507,'' and by removing the phrase ``new animal
drug application number, or antibiotic application number'' from
paragraph (b)(2) and by adding in its place the phrase ``or new animal
drug application number'', by removing ``or 507'' from paragraph (b)(4),
and by removing ``507,'' from paragraph (b)(5) and paragraph (b)(6),
effective May 20, 1999.
Sec. 207.26 Amendments to registration.
Changes in individual ownership, corporate or partnership structure
location or drug-handling activity, shall be submitted by Form FDA-2656
(Registration of Drug Establishment) as amendment to registration within
5 days of such changes. A change in a registered establishment's firm
name within 6 months of the registration of the establishment is
required to be supported by a signed statement of the establishment's
owner or operator that the change is not made for the purpose of
changing the name of the manufacturer of a drug product under Sec. 201.1
of this chapter. 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.
[45 FR 25777, Apr. 15, 1980, as amended at 55 FR 11577, Mar. 29, 1990]
Sec. 207.30 Updating drug listing information.
(a) After submitting the initial drug listing information, every
person who
[[Page 95]]
is required to list drugs under Sec. 207.20 shall submit on Form FDA-
2657 (Drug Product Listing) during each subsequent June and December, or
at the discretion of the registrant when the change occurs, the
following information:
(1) A list of each drug introduced by the registrant for commerical
distribution which has not been included in any list previously
submitted. The registrant shall provide all of the information required
by Sec. 207.25(b) for each such drug.
(2) A list of each drug formerly listed in accordance with
Sec. 207.25(b) for which commercial distribution has been discontinued,
including for each drug so listed the National Drug Code (NDC) number,
the identity by established name and by 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 drug for which a notice of discontinuance was
submitted under paragraph (a)(2) of this section and for which
commercial distribution has been resumed, including for each drug so
listed the NDC number, the identity by established name and by
proprietary name, the date of resumption, and any other information
required by Sec. 207.25(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 report is required.
Sec. 207.31 Additional drug listing information.
(a) In addition to the information routinely required by
Secs. 207.25 and 207.30, FDA may require submission of the following
information by letter or by Federal Register notice:
(1) For a particular prescription drug so listed that the registrant
regards as not subject to section 505 of the act, upon request by FDA
for good cause, a copy of all advertisements.
(2) For a particular drug product so listed that the registrant
regards as not subject to section 505 or 512 of the act, upon a finding
by FDA that it is necessary to carry out the purposes of the act, a
quantitative listing of all ingredients.
(3) For a particular drug product, upon request by FDA, a brief
statement of the basis for the registrant's belief that the drug product
is not subject to section 505 or 512 of the act.
(4) For each registrant, upon a finding by FDA that it is necessary
to carry out the purposes of the act, a list of each listed drug product
containing a particular ingredient.
(b) It is requested but not required that a qualitative listing of
the inactive ingredients be submitted for all listed drugs in the format
prescribed in Form FDA-2657 (Drug Product Listing).
(c) It is requested but not required that a quantitative listing of
the active ingredients be submitted for all drugs listed that are
subject to section 505 or 512 of the act or section 351 of the Public
Health Service Act.
[45 FR 38043, June 6, 1980, as amended at 63 FR 26698, May 13, 1998; 64
FR 400, Jan. 5, 1999]
Effective Date Note: At 64 FR 400, Jan. 5, 1999, Sec. 207.31 was
amended by removing the phrase ``or 507'' from paragraph (a)(1) and by
removing ``507,'' from paragraphs (a)(2) and (a)(3), and paragraph (c),
effective May 20, 1999
Sec. 207.35 Notification of registrant; drug establishment registration number and drug listing number.
(a) FDA will provide to the registrant a validated copy of Form FDA-
2656 (Registration of Drug Establishment) as evidence of registration.
This validated copy will be sent to the mailing address shown on the
form. FDA will assign a permanent registration number to each drug
establishment registered in accordance with these regulations.
(b) Using the National Drug Code (NDC) numbering system, FDA assigns
a drug listing number to each drug or class of drugs listed as follows:
(1) If a drug is already listed in the National Drug Code System or
in the National Health Related Items Code System, the number is the same
as that assigned under those codes. FDA adds a lead zero to the first
three characters of the code, which identifies the manufacturer or
distributor, to expand the ``Labeler Code'' segment to four characters.
The National Drug Code,
[[Page 96]]
Product Code, and Package Code configurations used to describe these
drugs, or any drugs added to the product line, remain the same, i.e., a
four-character Product Code and a two-character Package Code. A
manufacturer or distributor may either retain alphanumeric characters
that are already used in the Product Code and Package Code segments of
the National Drug Code or convert these alphanumeric characters to all
numeric digits. The manufacturer or distributor shall inform FDA of a
decision to convert the alphanumeric characters to all numeric digits.
(2) If a registered establishment or distributor has not previously
participated in the National Drug Code System or in the National Health
Related Items Code System, FDA uses the National Drug Code numbering
system in assigning a number, as follows (only numerals are used):
(i) The first 5 numeric characters of the 10-character code identify
the manufacturer or distributor and are known as the Labeler Code. FDA
will expand the Labeler Code from five to six numeric characters when
the available five-character code combinations are exhausted. FDA will
assign Labeler Code numbers and provide them to the registrant along
with the validated copy of Form FDA-2656. Any registered firm that does
not have an assigned Labeler Code will be assigned one when registration
and listing information are submitted.
(ii) The last 5 numeric characters of the 10-character code identify
the drug and the trade package size and type. The segment that
identifies the drug formulation is known as the Product Code and the
segment that identifies the trade package size and type is known as the
Package Code. The manufacturer or distributor will assign the Product
Code and the Package Code before drug listing and include these codes in
Form FDA-2657 (Drug Product Listing). The manufacturer or distributor
may use either of two methods in assigning the Product and Package
Codes: a 3-2 Product-Package Code configuration (e.g., 542-12) or a 4-1
Product-Package Code configuration (e.g., 5421-2). A manufacturer or
distributor with a given Labeler Code shall use only one such Product-
Package Code configuration and shall use this same configuration in
assigning the Product-Package Codes for all drugs included in the drug
listing. The manufacturer or distributor shall report to FDA the
Product-Package Code configuration used in assigning these codes.
(iii) If the drug formulation is a Type A medicated article intended
for use in the manufacture of an animal feed, FDA assigns a separate
Product Code only for each variation of level of active drug ingredient.
(3) FDA requests but does not require that the NDC number appear on
all drug labels and in other drug labeling, including the label of any
prescription drug container furnished to a consumer. If the NDC number
is shown on a drug label, it shall be placed as follows:
(i) The NDC number shall appear prominently in the top third of the
principal display panel of the label on the immediate container and of
any outside container or wrapper. Instead of appearing in the top third
of the label, the NDC number may appear as part of and contiguous to any
bar-code symbol for any drug product if two conditions are met. First,
the symbol appears prominently on the immediate container and on any
outside container or wrapper and in a conspicuous location; this
condition is not satisfied by the appearance of the symbol only on the
natural bottom of a container or wrapper. Second, the bar-code symbol is
compatible with the NDC, i.e., the symbol provides a format capable of
encoding the numeric characters of an NDC Number. The term principal
display panel, as used in this paragraph, means that part of a label
most likely to be displayed, presented, shown, or examined under
customary conditions of display to the consumer (for over-the-counter
drug products) or to the dispenser (for prescription drug products).
(ii) The NDC number shall be preceded by the prefix ``NDC'' or ``N''
when it is used on a label or in labeling. The prefix used for a drug
product shall be used consistently on the label of the immediate
container, outside container, or wrapper, if any, and on other labeling
for that drug product.
[[Page 97]]
(iii) The Product-Package Code configuration shall be indicated and
the segments of the number shall be separated by a dash, e.g., NDC
15643-542-12 or N 15643-542-12.
(iv) All 10 characters shall appear and the leading zeros in any
segment of the NDC number shall be shown, except that leading zeros may
be omitted from any segment of the NDC number when the NDC number is
used for product identification by direct imprinting on dosage forms or
in the case of containers too small or otherwise unable to accommodate a
label with sufficent space to bear both required and optional labeling
information.
(v) The placing of the assigned NDC number on a label or in other
labeling does not require the submission of a supplemental new drug
application, supplemental new animal drug application.
(4)(i) If any change occurs in those product characteristics that
clearly distinguish one drug product version from another, the
registrant shall assign a new NDC number to the new product version and
submit that information to FDA. Such a change includes, but is not
limited to, a change in active ingredient(s); strength or concentration
of active ingredient(s); dosage form; route of administration, if it
also includes a change in product formulation; product name; and a
change in marketing status from prescription to over-the-counter or
over-the-counter to prescription. If, by notice in the Federal Register,
FDA requires a change in drug product characteristics and determines the
change will require assignment of a new product code to the reformulated
product, FDA will announce its determination in the Federal Register
publication that requires the change, setting forth its reasoning and
justification for its determination. If a change only in the trade
package is involved, the registrant may revise the trade package code
without the assignment of a new product code segment, but shall inform
FDA of the new code for the trade package and the characteristics of the
new trade package.
(ii) When a registrant has discontinued a drug product, its product
code may be reassigned to another drug product 5 years after the
expiration date of the discontinued product, or, if there is no
expiration date, 5 years after the last shipment of the discontinued
product into commercial distribution. Reuse of product codes may occur,
under the specified conditions, regardless of the NDC, Product Code, and
Package Code configuration used.
(c) Although registration and drug listing are required to engage in
the drug activities described in Sec. 207.20, validation of
registration and the assignment of a drug listing number do not, in
themselves, establish that the holder of the registration is legally
qualified to deal in such drugs.
[45 FR 38043, June 6, 1980, as amended at 48 FR 54007, Nov. 30, 1983; 52
FR 2682, Jan. 26, 1987; 55 FR 11577, Mar. 29, 1990; 64 FR 400, Jan. 5,
1999]
Effective Date Note: At 64 FR 400, Jan. 5, 1999, Sec. 207.35 was
amended by removing the phrase ``, or supplemental antibiotic
application'' from paragraph (b)(3)(v), effective May 20, 1999.
Sec. 207.37 Inspection of registrations and drug listings.
(a) A copy of the Form FDA-2656 (Registration of Drug Establishment)
filed by the registrant will be available for inspection in accordance
with section 510(f) of the act, at the Drug Listing Branch (HFD-334),
Center for Drug Evaluation and Research, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857. In addition, there will be
available for inspection at each of the FDA district offices the same
information concerning firms within the geographical area of each
district office. Upon request and receipt of a self-addressed stamped
envelope, the Drug Listing Branch, Center for Drug Evaluation and
Research or appropriate FDA district office will verify registration
number or provide the location of a registered establishment.
(1) The following types of information submitted under the drug
listing requirements will be available for public disclosure when
compiled:
(i) A list of all drug products.
(ii) A list of all drug products arranged by labeled indications or
pharmacological category.
[[Page 98]]
(iii) A list of all drug products arranged by manufacturer.
(iv) A list of a drug product's active ingredients.
(v) A list of drug products newly marketed or for which marketing is
resumed.
(vi) A list of drug products discontinued.
(vii) Labeling.
(viii) Advertising.
(ix) Information that has become a matter of public knowledge.
(x) A list of drug products containing a particular active
ingredient.
(xi) A list of all code imprints.
(2) The following types of information submitted in accordance with
the drug listing requirements will not be available for public
disclosure (except that any of the information will be available for
public disclosure if it has become a matter of public knowledge or if
FDA finds that confidentiality would be inconsistent with protection of
the public health):
(i) Any information submitted as the basis upon which it has been
determined that a particular drug product is not subject to section 505
or 512 of the act.
(ii) A list of a drug product's inactive ingredients.
(iii) A list of drugs containing a particular inactive ingredient.
(b) Requests for information about registrations and drug listings
of an establishment should be directed to Drug Listing Branch (HFD-334),
Center for Drug Evaluation and Research, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857 or, with respect to the
information described in paragraph (a) of this section, to the FDA
district office responsible for the geographical area in which the
establishment is located.
[45 FR 38043, June 6, 1980, as amended at 50 FR 8996, Mar. 6, 1985; 55
FR 11577, Mar. 29, 1990; 58 FR 47959, Sept. 13, 1993; 63 FR 26698, May
13, 1998; 64 FR 400, Jan. 5, 1999]
Effective Date Note: At 64 FR 400, Jan. 5, 1999, Sec. 207.37 was
amended by removing ``507,'' from paragraph (a)(2)(i), effective May 20,
1999.
Sec. 207.39 Misbranding by reference to registration or to registration number.
Registration of a drug establishment or drug wholesaler, 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 registration or possession of registration number or NDC number is
misleading and constitutes misbranding.
Subpart D--Procedure for Foreign Drug Establishments
Sec. 207.40 Drug listing requirements for foreign drug establishments.
(a) Every foreign drug establishment whose drugs are imported or
offered for import into the United States shall comply with the drug
listing requirements in subpart C of this part, unless exempt under
subpart B of this part, whether or not it is also registered.
(b) No drug, unless it is listed as required in subpart C of this
part, may be imported from a foreign drug establishment into the United
States except a drug imported or offered for import under the
investigational use provisions of part 312 of this chapter. Foreign drug
establishments shall submit the drug listing information in the English
language.
(c) Every foreign drug establishment shall submit, as part of drug
listing, the name and address of the establishment and the name of the
individual responsible for submitting drug listing information. The
establishment shall report to FDA any changes in this information at the
intervals specified in Sec. 207.30(a) for updating drug listing
information.
[45 FR 38043, June 6, 1980, as amended at 55 FR 11577, Mar. 29, 1990]
PART 208--MEDICATION GUIDES FOR PRESCRIPTION DRUG PRODUCTS (Eff. 6-1-99)--Table of Contents
Subpart A--General Provisions
Sec.
208.1 Scope and purpose.
208.3 Definitions.
[[Page 99]]
Subpart B--General Requirements for a Medication Guide
208.20 Content and format of a Medication Guide.
208.24 Distributing and dispensing a Medication Guide.
208.26 Exemptions and deferrals.
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 360,
371, 374; 42 U.S.C. 262.
Source: 63 FR 66396, Dec. 1, 1998, unless otherwise noted.
Effective Date Note: At 63 FR 66396, Dec. 1, 1998, part 208 was
added, effective June 1, 1999.
Subpart A--General Provisions
Sec. 208.1 Scope and purpose.
(a) This part sets forth requirements for patient labeling for human
prescription drug products, including biological products, that the Food
and Drug Administration (FDA) determines pose a serious and significant
public health concern requiring distribution of FDA-approved patient
information. It applies primarily to human prescription drug products
used on an outpatient basis without direct supervision by a health
professional. This part shall apply to new prescriptions and refill
prescriptions.
(b) The purpose of patient labeling for human prescription drug
products required under this part is to provide information when the FDA
determines in writing that it is necessary to patients' safe and
effective use of drug products.
(c) Patient labeling will be required if the FDA determines that one
or more of the following circumstances exists:
(1) The drug product is one for which patient labeling could help
prevent serious adverse effects.
(2) The drug product is one that has serious risk(s) (relative to
benefits) of which patients should be made aware because information
concerning the risk(s) could affect patients' decision to use, or to
continue to use, the product.
(3) The drug product is important to health and patient adherence to
directions for use is crucial to the drug's effectiveness.
Sec. 208.3 Definitions.
For the purposes of this part, the following definitions shall
apply:
(a) Authorized dispenser means an individual licensed, registered,
or otherwise permitted by the jurisdiction in which the individual
practices to provide drug products on prescription in the course of
professional practice.
(b) Dispense to patients means the act of delivering a prescription
drug product to a patient or an agent of the patient either:
(1) By a licensed practitioner or an agent of a licensed
practitioner, either directly or indirectly, for self-administration by
the patient, or the patient's agent, or outside the licensed
practitioner's direct supervision; or
(2) By an authorized dispenser or an agent of an authorized
dispenser under a lawful prescription of a licensed practitioner.
(c) Distribute means the act of delivering, other than by
dispensing, a drug product to any person.
(d) Distributor means a person who distributes a drug product.
(e) Drug product means a finished dosage form, e.g., tablet,
capsule, or solution, that contains an active drug ingredient,
generally, but not necessarily, in association with inactive
ingredients. For purposes of this part, drug product also means
biological product within the meaning of section 351(a) of the Public
Health Service Act.
(f) Licensed practitioner means an individual licensed, registered,
or otherwise permitted by the jurisdiction in which the individual
practices to prescribe drug products in the course of professional
practice.
(g) Manufacturer means for a drug product that is not also a
biological product, both the manufacturer as described in Sec. 201.1 and
the applicant as described in Sec. 314.3(b) of this chapter, and for a
drug product that is also a biological product, the manufacturer as
described in Sec. 600.3(t) of this chapter.
(h) Medication Guide means FDA-approved patient labeling conforming
to the specifications set forth in this part and other applicable
regulations.
(i) Packer means a person who packages a drug product.
[[Page 100]]
(j) Patient means any individual with respect to whom a drug product
is intended to be, or has been, used.
(k) Serious risk or serious adverse effect means an adverse drug
experience, or the risk of such an experience, as that term is defined
in Secs. 310.305, 312.32, 314.80, and 600.80 of this chapter.
Subpart B--General Requirements for a Medication Guide
Sec. 208.20 Content and format of a Medication Guide.
(a) A Medication Guide shall meet all of the following conditions:
(1) The Medication Guide shall be written in English, in
nontechnical, understandable language, and shall not be promotional in
tone or content.
(2) The Medication Guide shall be scientifically accurate and shall
be based on, and shall not conflict with, the approved professional
labeling for the drug product under Sec. 201.57 of this chapter, but the
language of the Medication Guide need not be identical to the sections
of approved labeling to which it corresponds.
(3) The Medication Guide shall be specific and comprehensive.
(4) The letter height or type size shall be no smaller than 10
points (1 point = 0.0138 inches) for all sections of the Medication
Guide, except the manufacturer's name and address and the revision date.
(5) The Medication Guide shall be legible and clearly presented.
Where appropriate, the Medication Guide shall also use boxes, bold or
underlined print, or other highlighting techniques to emphasize specific
portions of the text.
(6) The words ``Medication Guide'' shall appear prominently at the
top of the first page of a Medication Guide. The verbatim statement
``This Medication Guide has been approved by the U.S. Food and Drug
Administration'' shall appear at the bottom of a Medication Guide.
(7) The brand and established or proper name of the drug product
shall appear immediately below the words ``Medication Guide.'' The
established or proper name shall be no less than one-half the height of
the brand name.
(b) A Medication Guide shall contain those of the following headings
relevant to the drug product and to the need for the Medication Guide in
the specified order. Each heading shall contain the specific information
as follows:
(1) The brand name (e.g., the trademark or proprietary name), if
any, and established or proper name. Those products not having an
established or proper name shall be designated by their active
ingredients. The Medication Guide shall include the phonetic spelling of
either the brand name or the established name, whichever is used
throughout the Medication Guide.
(2) The heading, ``What is the most important information I should
know about (name of drug)?'' followed by a statement describing the
particular serious and significant public health concern that has
created the need for the Medication Guide. The statement should describe
specifically what the patient should do or consider because of that
concern, such as, weighing particular risks against the benefits of the
drug, avoiding particular behaviors (e.g., activities, drugs), observing
certain events (e.g., symptoms, signs) that could prevent or mitigate a
serious adverse effect, or engaging in particular behaviors (e.g.,
adhering to the dosing regimen).
(3) The heading, ``What is (name of drug)?'' followed by a section
that identifies a drug product's indications for use. The Medication
Guide may not identify an indication unless the indication is identified
in the indications and usage section of the professional labeling for
the product required under Sec. 201.57 of this chapter. In appropriate
circumstances, this section may also explain the nature of the disease
or condition the drug product is intended to treat, as well as the
benefit(s) of treating the condition.
(4) The heading, ``Who should not take (name of drug)?'' followed by
information on circumstances under which the drug product should not be
used for its labeled indication (its contraindications). The Medication
Guide shall contain directions regarding what to do if any of the
contraindications apply to a patient, such as contacting
[[Page 101]]
the licensed practitioner or discontinuing use of the drug product.
(5) The heading, ``How should I take (name of drug)?'' followed by
information on the proper use of the drug product, such as:
(i) A statement stressing the importance of adhering to the dosing
instructions, if this is particularly important;
(ii) A statement describing any special instructions on how to
administer the drug product, if they are important to the drug's safety
or effectiveness;
(iii) A statement of what patients should do in case of overdose of
the drug product; and
(iv) A statement of what patients should do if they miss taking a
scheduled dose(s) of the drug product, where there are data to support
the advice, and where the wrong behavior could cause harm or lack of
effect.
(6) The heading ``What should I avoid while taking (name of drug)?''
followed by a statement or statements of specific, important precautions
patients should take to ensure proper use of the drug, including:
(i) A statement that identifies activities (such as driving or
sunbathing), and drugs, foods, or other substances (such as tobacco or
alcohol) that patients should avoid when using the medication;
(ii) A statement of the risks to mothers and fetuses from the use of
the drug during pregnancy, if specific, important risks are known;
(iii) A statement of the risks of the drug product to nursing
infants, if specific, important risks are known;
(iv) A statement about pediatric risks, if the drug product has
specific hazards associated with its use in pediatric patients;
(v) A statement about geriatric risks, if the drug product has
specific hazards associated with its use in geriatric patients; and
(vi) A statement of special precautions, if any, that apply to the
safe and effective use of the drug product in other identifiable patient
populations.
(7) The heading, ``What are the possible or reasonably likely side
effects of (name of drug)?'' followed by:
(i) A statement of the adverse reactions reasonably likely to be
caused by the drug product that are serious or occur frequently.
(ii) A statement of the risk, if there is one, of patients'
developing dependence on the drug product.
(8) General information about the safe and effective use of
prescription drug products, including:
(i) The verbatim statement that ``Medicines are sometimes prescribed
for purposes other than those listed in a Medication Guide'' followed by
a statement that patients should ask health professionals about any
concerns, and a reference to the availability of professional labeling;
(ii) A statement that the drug product should not be used for a
condition other than that for which it is prescribed, or given to other
persons;
(iii) The name and place of business of the manufacturer, packer, or
distributor of a drug product that is not also a biological product, or
the name and place of business of the manufacturer or distributor of a
drug product that is also a biological product, and in any case the name
and place of business of the dispenser of the product may also be
included; and
(iv) The date, identified as such, of the most recent revision of
the Medication Guide placed immediately after the last section.
(9) Additional headings and subheadings may be interspersed
throughout the Medication Guide, if appropriate.
Sec. 208.24 Distributing and dispensing a Medication Guide.
(a) The manufacturer of a drug product for which a Medication Guide
is required under this part shall obtain FDA approval of the Medication
Guide before the Medication Guide may be distributed.
(b) Each manufacturer who ships a container of drug product for
which a Medication Guide is required under this part is responsible for
ensuring that Medication Guides are available for distribution to
patients by either:
(1) Providing Medication Guides in sufficient numbers to
distributors, packers, or authorized dispensers to
[[Page 102]]
permit the authorized dispenser to provide a Medication Guide to each
patient receiving a prescription for the drug product; or
(2) Providing the means to produce Medication Guides in sufficient
numbers to distributors, packers, or authorized dispensers to permit the
authorized dispenser to provide a Medication Guide to each patient
receiving a prescription for the drug product.
(c) Each distributor or packer that receives Medication Guides, or
the means to produce Medication Guides, from a manufacturer under
paragraph (b) of this section shall provide those Medication Guides, or
the means to produce Medication Guides, to each authorized dispenser to
whom it ships a container of drug product.
(d) The label of each container or package, where the container
label is too small, of drug product for which a Medication Guide is
required under this part shall instruct the authorized dispenser to
provide a Medication Guide to each patient to whom the drug product is
dispensed, and shall state how the Medication Guide is provided. These
statements shall appear on the label in a prominent and conspicuous
manner.
(e) Each authorized dispenser of a prescription drug product for
which a Medication Guide is required under this part shall, when the
product is dispensed to a patient (or to a patient's agent), provide a
Medication Guide directly to each patient (or to the patient's agent)
unless an exemption applies under Sec. 208.26.
(f) An authorized dispenser or wholesaler is not subject to section
510 of the Federal Food, Drug, and Cosmetic Act, which requires the
registration of producers of drugs and the listing of drugs in
commercial distribution, solely because of an act performed by the
authorized dispenser or wholesaler under this part.
Sec. 208.26 Exemptions and deferrals.
(a) FDA on its own initiative, or in response to a written request
from an applicant, may exempt or defer any Medication Guide content or
format requirement, except those requirements in Sec. 208.20 (a)(2) and
(a)(6), on the basis that the requirement is inapplicable, unnecessary,
or contrary to patients' best interests. Requests from applicants should
be submitted to the director of the FDA division responsible for
reviewing the marketing application for the drug product, or for a
biological product, to the application division in the office with
product responsibility.
(b) If the licensed practitioner who prescribes a drug product
subject to this part determines that it is not in a particular patient's
best interest to receive a Medication Guide because of significant
concerns about the effect of a Medication Guide, the licensed
practitioner may direct that the Medication Guide not be provided to the
particular patient. However, the authorized dispenser of a prescription
drug product subject to this part shall provide a Medication Guide to
any patient who requests information when the drug product is dispensed
regardless of any such direction by the licensed practitioner.
PART 210--CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL--Table of Contents
Sec.
210.1 Status of current good manufacturing practice regulations.
210.2 Applicability of current good manufacturing practice regulations.
210.3 Definitions.
Authority: 21 U.S.C. 321, 351, 352, 355, 360b, 371, 374.
Source: 43 FR 45076, Sept, 29, 1978, unless otherwise noted.
Sec. 210.1 Status of current good manufacturing practice regulations.
(a) The regulations set forth in this part and in parts 211 through
226 of this chapter contain the minimum current good manufacturing
practice for methods to be used in, and the facilities or controls to be
used for, the manufacture, processing, packing, or holding of a drug to
assure that such drug meets the requirements of the act as to safety,
and has the identity and strength and meets the quality and purity
characteristics that it purports or is represented to possess.
[[Page 103]]
(b) The failure to comply with any regulation set forth in this part
and in parts 211 through 226 of this chapter in the manufacture,
processing, packing, or holding of a drug shall render such drug to be
adulterated under section 501(a)(2)(B) of the act and such drug, as well
as the person who is responsible for the failure to comply, shall be
subject to regulatory action.
Sec. 210.2 Applicability of current good manufacturing practice regulations.
(a) The regulations in this part and in parts 211 through 226 of
this chapter as they may pertain to a drug and in parts 600 through 680
of this chapter as they may pertain to a biological product for human
use, shall be considered to supplement, not supersede, each other,
unless the regulations explicitly provide otherwise. In the event that
it is impossible to comply with all applicable regulations in these
parts, the regulations specifically applicable to the drug in question
shall supersede the more general.
(b) If a person engages in only some operations subject to the
regulations in this part and in parts 211 through 226 and parts 600
through 680 of this chapter, and not in others, that person need only
comply with those regulations applicable to the operations in which he
or she is engaged.
Sec. 210.3 Definitions.
(a) The definitions and interpretations contained in section 201 of
the act shall be applicable to such terms when used in this part and in
parts 211 through 226 of this chapter.
(b) The following definitions of terms apply to this part and to
parts 211 through 226 of this chapter.
(1) Act means the Federal Food, Drug, and Cosmetic Act, as amended
(21 U.S.C. 301 et seq.).
(2) Batch means a specific quantity of a drug or other material that
is intended to have uniform character and quality, within specified
limits, and is produced according to a single manufacturing order during
the same cycle of manufacture.
(3) Component means any ingredient intended for use in the
manufacture of a drug product, including those that may not appear in
such drug product.
(4) Drug product means a finished dosage form, for example, tablet,
capsule, solution, etc., that contains an active drug ingredient
generally, but not necessarily, in association with inactive
ingredients. The term also includes a finished dosage form that does not
contain an active ingredient but is intended to be used as a placebo.
(5) Fiber means any particulate contaminant with a length at least
three times greater than its width.
(6) Non-fiber-releasing filter means any filter, which after any
appropriate pretreatment such as washing or flushing, will not release
fibers into the component or drug product that is being filtered. All
filters composed of asbestos are deemed to be fiber-releasing filters.
(7) Active ingredient means any component that is intended to
furnish pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment, or prevention of disease, or to
affect the structure or any function of the body of man or other
animals. The term includes those components that may undergo chemical
change in the manufacture of the drug product and be present in the drug
product in a modified form intended to furnish the specified activity or
effect.
(8) Inactive ingredient means any component other than an active
ingredient.
(9) In-process material means any material fabricated, compounded,
blended, or derived by chemical reaction that is produced for, and used
in, the preparation of the drug product.
(10) Lot means a batch, or a specific identified portion of a batch,
having uniform character and quality within specified limits; or, in the
case of a drug product produced by continuous process, it is a specific
identified amount produced in a unit of time or quantity in a manner
that assures its having uniform character and quality within specified
limits.
(11) Lot number, control number, or batch number means any
distinctive combination of letters, numbers, or symbols, or any
combination of them, from which the complete history of the manufacture,
processing, packing, holding, and distribution of a batch or lot of drug
product or other material can be determined.
[[Page 104]]
(12) Manufacture, processing, packing, or holding of a drug product
includes packaging and labeling operations, testing, and quality control
of drug products.
(13) The term medicated feed means any Type B or Type C medicated
feed as defined in Sec. 558.3 of this chapter. The feed contains one or
more drugs as defined in section 201(g) of the act. The manufacture of
medicated feeds is subject to the requirements of part 225 of this
chapter.
(14) The term medicated premix means a Type A medicated article as
defined in Sec. 558.3 of this chapter. The article contains one or more
drugs as defined in section 201(g) of the act. The manufacture of
medicated premixes is subject to the requirements of part 226 of this
chapter.
(15) Quality control unit means any person or organizational element
designated by the firm to be responsible for the duties relating to
quality control.
(16) Strength means:
(i) The concentration of the drug substance (for example, weight/
weight, weight/volume, or unit dose/volume basis), and/or
(ii) The potency, that is, the therapeutic activity of the drug
product as indicated by appropriate laboratory tests or by adequately
developed and controlled clinical data (expressed, for example, in terms
of units by reference to a standard).
(17) Theoretical yield means the quantity that would be produced at
any appropriate phase of manufacture, processing, or packing of a
particular drug product, based upon the quantity of components to be
used, in the absence of any loss or error in actual production.
(18) Actual yield means the quantity that is actually produced at
any appropriate phase of manufacture, processing, or packing of a
particular drug product.
(19) Percentage of theoretical yield means the ratio of the actual
yield (at any appropriate phase of manufacture, processing, or packing
of a particular drug product) to the theoretical yield (at the same
phase), stated as a percentage.
(20) Acceptance criteria means the product specifications and
acceptance/rejection criteria, such as acceptable quality level and
unacceptable quality level, with an associated sampling plan, that are
necessary for making a decision to accept or reject a lot or batch (or
any other convenient subgroups of manufactured units).
(21) Representative sample means a sample that consists of a number
of units that are drawn based on rational criteria such as random
sampling and intended to assure that the sample accurately portrays the
material being sampled.
(22) Gang-printed labeling means labeling derived from a sheet of
material on which more than one item of labeling is printed.
[43 FR 45076, Sept. 29, 1978, as amended at 51 FR 7389, Mar. 3, 1986; 58
FR 41353, Aug. 3, 1993]
PART 211--CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS--Table of Contents
Subpart A--General Provisions
Sec.
211.1 Scope.
211.3 Definitions.
Subpart B--Organization and Personnel
211.22 Responsibilities of quality control unit.
211.25 Personnel qualifications.
211.28 Personnel responsibilities.
211.34 Consultants.
Subpart C--Buildings and Facilities
211.42 Design and construction features.
211.44 Lighting.
211.46 Ventilation, air filtration, air heating and cooling.
211.48 Plumbing.
211.50 Sewage and refuse.
211.52 Washing and toilet facilities.
211.56 Sanitation.
211.58 Maintenance.
Subpart D--Equipment
211.63 Equipment design, size, and location.
211.65 Equipment construction.
211.67 Equipment cleaning and maintenance.
211.68 Automatic, mechanical, and electronic equipment.
211.72 Filters.
[[Page 105]]
Subpart E--Control of Components and Drug Product Containers and
Closures
211.80 General requirements.
211.82 Receipt and storage of untested components, drug product
containers, and closures.
211.84 Testing and approval or rejection of components, drug product
containers, and closures.
211.86 Use of approved components, drug product containers, and
closures.
211.87 Retesting of approved components, drug product containers, and
closures.
211.89 Rejected components, drug product containers, and closures.
211.94 Drug product containers and closures.
Subpart F--Production and Process Controls
211.100 Written procedures; deviations.
211.101 Charge-in of components.
211.103 Calculation of yield.
211.105 Equipment identification.
211.110 Sampling and testing of in-process materials and drug products.
211.111 Time limitations on production.
211.113 Control of microbiological contamination.
211.115 Reproccessing.
Subpart G--Packaging and Labeling Control
211.122 Materials examination and usage criteria.
211.125 Labeling issuance.
211.130 Packaging and labeling operations.
211.132 Tamper-evident packaging requirements for over-the-counter
(OTC) human drug products.
211.134 Drug product inspection.
211.137 Expiration dating.
Subpart H--Holding and Distribution
211.142 Warehousing procedures.
211.150 Distribution procedures.
Subpart I--Laboratory Controls
211.160 General requirements.
211.165 Testing and release for distribution.
211.166 Stability testing.
211.167 Special testing requirements.
211.170 Reserve samples.
211.173 Laboratory animals.
211.176 Penicillin contamination.
Subpart J--Records and Reports
211.180 General requirements.
211.182 Equipment cleaning and use log.
211.184 Component, drug product container, closure, and labeling
records.
211.186 Master production and control records.
211.188 Batch production and control records.
211.192 Production record review.
211.194 Laboratory records.
211.196 Distribution records.
211.198 Complaint files.
Subpart K--Returned and Salvaged Drug Products
211.204 Returned drug products.
211.208 Drug product salvaging.
Authority: 21 U.S.C. 321, 351, 352, 355, 360b, 371, 374.
Source: 43 FR 45077, Sept. 29, 1978, unless otherwise noted.
Subpart A--General Provisions
Sec. 211.1 Scope.
(a) The regulations in this part contain the minimum current good
manufacturing practice for preparation of drug products for
administration to humans or animals.
(b) The current good manufacturing practice regulations in this
chapter, as they pertain to drug products, and in parts 600 through 680
of this chapter, as they pertain to biological products for human use,
shall be considered to supplement, not supersede, the regulations in
this part unless the regulations explicitly provide otherwise. In the
event it is impossible to comply with applicable regulations both in
this part and in other parts of this chapter or in parts 600 through 680
of this chapter, the regulation specifically applicable to the drug
product in question shall supersede the regulation in this part.
(c) Pending consideration of a proposed exemption, published in the
Federal Register of September 29, 1978, the requirements in this part
shall not be enforced for OTC drug products if the products and all
their ingredients are ordinarily marketed and consumed as human foods,
and which products may also fall within the legal definition of drugs by
virtue of their intended use. Therefore, until further notice,
regulations under part 110 of this chapter, and where applicable, parts
113 to 129 of this chapter, shall be applied in determining whether
these OTC drug products that are also foods are manufactured, processed,
packed, or held
[[Page 106]]
under current good manufacturing practice.
[43 FR 45077, Sept. 29, 1978, as amended at 62 FR 66522, Dec. 19, 1997]
Sec. 211.3 Definitions.
The definitions set forth in Sec. 210.3 of this chapter apply in
this part.
Subpart B--Organization and Personnel
Sec. 211.22 Responsibilities of quality control unit.
(a) There shall be a quality control unit that shall have the
responsibility and authority to approve or reject all components, drug
product containers, closures, in-process materials, packaging material,
labeling, and drug products, and the authority to review production
records to assure that no errors have occurred or, if errors have
occurred, that they have been fully investigated. The quality control
unit shall be responsible for approving or rejecting drug products
manufactured, processed, packed, or held under contract by another
company.
(b) Adequate laboratory facilities for the testing and approval (or
rejection) of components, drug product containers, closures, packaging
materials, in-process materials, and drug products shall be available to
the quality control unit.
(c) The quality control unit shall have the responsibility for
approving or rejecting all procedures or specifications impacting on the
identity, strength, quality, and purity of the drug product.
(d) The responsibilities and procedures applicable to the quality
control unit shall be in writing; such written procedures shall be
followed.
Sec. 211.25 Personnel qualifications.
(a) Each person engaged in the manufacture, processing, packing, or
holding of a drug product shall have education, training, and
experience, or any combination thereof, to enable that person to perform
the assigned functions. Training shall be in the particular operations
that the employee performs and in current good manufacturing practice
(including the current good manufacturing practice regulations in this
chapter and written procedures required by these regulations) as they
relate to the employee's functions. Training in current good
manufacturing practice shall be conducted by qualified individuals on a
continuing basis and with sufficient frequency to assure that employees
remain familiar with CGMP requirements applicable to them.
(b) Each person responsible for supervising the manufacture,
processing, packing, or holding of a drug product shall have the
education, training, and experience, or any combination thereof, to
perform assigned functions in such a manner as to provide assurance that
the drug product has the safety, identity, strength, quality, and purity
that it purports or is represented to possess.
(c) There shall be an adequate number of qualified personnel to
perform and supervise the manufacture, processing, packing, or holding
of each drug product.
Sec. 211.28 Personnel responsibilities.
(a) Personnel engaged in the manufacture, processing, packing, or
holding of a drug product shall wear clean clothing appropriate for the
duties they perform. Protective apparel, such as head, face, hand, and
arm coverings, shall be worn as necessary to protect drug products from
contamination.
(b) Personnel shall practice good sanitation and health habits.
(c) Only personnel authorized by supervisory personnel shall enter
those areas of the buildings and facilities designated as limited-access
areas.
(d) Any person shown at any time (either by medical examination or
supervisory observation) to have an apparent illness or open lesions
that may adversely affect the safety or quality of drug products shall
be excluded from direct contact with components, drug product
containers, closures, in-process materials, and drug products until the
condition is corrected or determined by competent medical personnel not
to jeopardize the safety or quality of drug products. All personnel
shall be instructed to report to supervisory personnel any health
conditions that may
[[Page 107]]
have an adverse effect on drug products.
Sec. 211.34 Consultants.
Consultants advising on the manufacture, processing, packing, or
holding of drug products shall have sufficient education, training, and
experience, or any combination thereof, to advise on the subject for
which they are retained. Records shall be maintained stating the name,
address, and qualifications of any consultants and the type of service
they provide.
Subpart C--Buildings and Facilities
Sec. 211.42 Design and construction features.
(a) Any building or buildings used in the manufacture, processing,
packing, or holding of a drug product shall be of suitable size,
construction and location to facilitate cleaning, maintenance, and
proper operations.
(b) Any such building shall have adequate space for the orderly
placement of equipment and materials to prevent mixups between different
components, drug product containers, closures, labeling, in-process
materials, or drug products, and to prevent contamination. The flow of
components, drug product containers, closures, labeling, in-process
materials, and drug products through the building or buildings shall be
designed to prevent contamination.
(c) Operations shall be performed within specifically defined areas
of adequate size. There shall be separate or defined areas or such other
control systems for the firm's operations as are necessary to prevent
contamination or mixups during the course of the following procedures:
(1) Receipt, identification, storage, and withholding from use of
components, drug product containers, closures, and labeling, pending the
appropriate sampling, testing, or examination by the quality control
unit before release for manufacturing or packaging;
(2) Holding rejected components, drug product containers, closures,
and labeling before disposition;
(3) Storage of released components, drug product containers,
closures, and labeling;
(4) Storage of in-process materials;
(5) Manufacturing and processing operations;
(6) Packaging and labeling operations;
(7) Quarantine storage before release of drug products;
(8) Storage of drug products after release;
(9) Control and laboratory operations;
(10) Aseptic processing, which includes as appropriate:
(i) Floors, walls, and ceilings of smooth, hard surfaces that are
easily cleanable;
(ii) Temperature and humidity controls;
(iii) An air supply filtered through high-efficiency particulate air
filters under positive pressure, regardless of whether flow is laminar
or nonlaminar;
(iv) A system for monitoring environmental conditions;
(v) A system for cleaning and disinfecting the room and equipment to
produce aseptic conditions;
(vi) A system for maintaining any equipment used to control the
aseptic conditions.
(d) Operations relating to the manufacture, processing, and packing
of penicillin shall be performed in facilities separate from those used
for other drug products for human use.
[43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091, Jan. 20, 1995]
Sec. 211.44 Lighting.
Adequate lighting shall be provided in all areas.
Sec. 211.46 Ventilation, air filtration, air heating and cooling.
(a) Adequate ventilation shall be provided.
(b) Equipment for adequate control over air pressure, micro-
organisms, dust, humidity, and temperature shall be provided when
appropriate for the manufacture, processing, packing, or holding of a
drug product.
(c) Air filtration systems, including prefilters and particulate
matter air filters, shall be used when appropriate on air supplies to
production areas. If air is recirculated to production areas, measures
shall be taken to control recirculation of dust from production. In
[[Page 108]]
areas where air contamination occurs during production, there shall be
adequate exhaust systems or other systems adequate to control
contaminants.
(d) Air-handling systems for the manufacture, processing, and
packing of penicillin shall be completely separate from those for other
drug products for human use.
Sec. 211.48 Plumbing.
(a) Potable water shall be supplied under continuous positive
pressure in a plumbing system free of defects that could contribute
contamination to any drug product. Potable water shall meet the
standards prescribed in the Environmental Protection Agency's Primary
Drinking Water Regulations set forth in 40 CFR part 141. Water not
meeting such standards shall not be permitted in the potable water
system.
(b) Drains shall be of adequate size and, where connected directly
to a sewer, shall be provided with an air break or other mechanical
device to prevent back-siphonage.
[43 FR 45077, Sept. 29, 1978, as amended at 48 FR 11426, Mar. 18, 1983]
Sec. 211.50 Sewage and refuse.
Sewage, trash, and other refuse in and from the building and
immediate premises shall be disposed of in a safe and sanitary manner.
Sec. 211.52 Washing and toilet facilities.
Adequate washing facilities shall be provided, including hot and
cold water, soap or detergent, air driers or single-service towels, and
clean toilet facilities easily accesible to working areas.
Sec. 211.56 Sanitation.
(a) Any building used in the manufacture, processing, packing, or
holding of a drug product shall be maintained in a clean and sanitary
condition, Any such building shall be free of infestation by rodents,
birds, insects, and other vermin (other than laboratory animals). Trash
and organic waste matter shall be held and disposed of in a timely and
sanitary manner.
(b) There shall be written procedures assigning responsibility for
sanitation and describing in sufficient detail the cleaning schedules,
methods, equipment, and materials to be used in cleaning the buildings
and facilities; such written procedures shall be followed.
(c) There shall be written procedures for use of suitable
rodenticides, insecticides, fungicides, fumigating agents, and cleaning
and sanitizing agents. Such written procedures shall be designed to
prevent the contamination of equipment, components, drug product
containers, closures, packaging, labeling materials, or drug products
and shall be followed. Rodenticides, insecticides, and fungicides shall
not be used unless registered and used in accordance with the Federal
Insecticide, Fungicide, and Rodenticide Act (7 U.S.C. 135).
(d) Sanitation procedures shall apply to work performed by
contractors or temporary employees as well as work performed by full-
time employees during the ordinary course of operations.
Sec. 211.58 Maintenance.
Any building used in the manufacture, processing, packing, or
holding of a drug product shall be maintained in a good state of repair.
Subpart D--Equipment
Sec. 211.63 Equipment design, size, and location.
Equipment used in the manufacture, processing, packing, or holding
of a drug product shall be of appropriate design, adequate size, and
suitably located to facilitate operations for its intended use and for
its cleaning and maintenance.
Sec. 211.65 Equipment construction.
(a) Equipment shall be constructed so that surfaces that contact
components, in-process materials, or drug products shall not be
reactive, additive, or absorptive so as to alter the safety, identity,
strength, quality, or purity of the drug product beyond the official or
other established requirements.
(b) Any substances required for operation, such as lubricants or
coolants, shall not come into contact with components, drug product
containers, closures, in-process materials, or drug
[[Page 109]]
products so as to alter the safety, identity, strength, quality, or
purity of the drug product beyond the official or other established
requirements.
Sec. 211.67 Equipment cleaning and maintenance.
(a) Equipment and utensils shall be cleaned, maintained, and
sanitized at appropriate intervals to prevent malfunctions or
contamination that would alter the safety, identity, strength, quality,
or purity of the drug product beyond the official or other established
requirements.
(b) Written procedures shall be established and followed for
cleaning and maintenance of equipment, including utensils, used in the
manufacture, processing, packing, or holding of a drug product. These
procedures shall include, but are not necessarily limited to, the
following:
(1) Assignment of responsibility for cleaning and maintaining
equipment;
(2) Maintenance and cleaning schedules, including, where
appropriate, sanitizing schedules;
(3) A description in sufficient detail of the methods, equipment,
and materials used in cleaning and maintenance operations, and the
methods of disassembling and reassembling equipment as necessary to
assure proper cleaning and maintenance;
(4) Removal or obliteration of previous batch identification;
(5) Protection of clean equipment from contamination prior to use;
(6) Inspection of equipment for cleanliness immediately before use.
(c) Records shall be kept of maintenance, cleaning, sanitizing, and
inspection as specified in Secs. 211.180 and 211.182.
Sec. 211.68 Automatic, mechanical, and electronic equipment.
(a) Automatic, mechanical, or electronic equipment or other types of
equipment, including computers, or related systems that will perform a
function satisfactorily, may be used in the manufacture, processing,
packing, and holding of a drug product. If such equipment is so used, it
shall be routinely calibrated, inspected, or checked according to a
written program designed to assure proper performance. Written records
of those calibration checks and inspections shall be maintained.
(b) Appropriate controls shall be exercised over computer or related
systems to assure that changes in master production and control records
or other records are instituted only by authorized personnel. Input to
and output from the computer or related system of formulas or other
records or data shall be checked for accuracy. The degree and frequency
of input/output verification shall be based on the complexity and
reliability of the computer or related system. A backup file of data
entered into the computer or related system shall be maintained except
where certain data, such as calculations performed in connection with
laboratory analysis, are eliminated by computerization or other
automated processes. In such instances a written record of the program
shall be maintained along with appropriate validation data. Hard copy or
alternative systems, such as duplicates, tapes, or microfilm, designed
to assure that backup data are exact and complete and that it is secure
from alteration, inadvertent erasures, or loss shall be maintained.
[43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091, Jan. 20, 1995]
Sec. 211.72 Filters.
Filters for liquid filtration used in the manufacture, processing,
or packing of injectable drug products intended for human use shall not
release fibers into such products. Fiber-releasing filters may not be
used in the manufacture, processing, or packing of these injectable drug
products unless it is not possible to manufacture such drug products
without the use of such filters. If use of a fiber-releasing filter is
necessary, an additional non-fiber-releasing filter of 0.22 micron
maximum mean porosity (0.45 micron if the manufacturing conditions so
dictate) shall subsequently be used to reduce the content of particles
in the injectable drug product. Use of an asbestos-containing filter,
with or without subsequent use of a specific non-fiber-releasing filter,
is permissible only upon submission of proof to the appropriate bureau
of the Food and Drug Administration that use of a non-
[[Page 110]]
fiber-releasing filter will, or is likely to, compromise the safety or
effectiveness of the injectable drug product.
Subpart E--Control of Components and Drug Product Containers and
Closures
Sec. 211.80 General requirements.
(a) There shall be written procedures describing in sufficient
detail the receipt, identification, storage, handling, sampling,
testing, and approval or rejection of components and drug product
containers and closures; such written procedures shall be followed.
(b) Components and drug product containers and closures shall at all
times be handled and stored in a manner to prevent contamination.
(c) Bagged or boxed components of drug product containers, or
closures shall be stored off the floor and suitably spaced to permit
cleaning and inspection.
(d) Each container or grouping of containers for components or drug
product containers, or closures shall be identified with a distinctive
code for each lot in each shipment received. This code shall be used in
recording the disposition of each lot. Each lot shall be appropriately
identified as to its status (i.e., quarantined, approved, or rejected).
Sec. 211.82 Receipt and storage of untested components, drug product containers, and closures.
(a) Upon receipt and before acceptance, each container or grouping
of containers of components, drug product containers, and closures shall
be examined visually for appropriate labeling as to contents, container
damage or broken seals, and contamination.
(b) Components, drug product containers, and closures shall be
stored under quarantine until they have been tested or examined, as
appropriate, and released. Storage within the area shall conform to the
requirements of Sec. 211.80.
Sec. 211.84 Testing and approval or rejection of components, drug product containers, and closures.
(a) Each lot of components, drug product containers, and closures
shall be withheld from use until the lot has been sampled, tested, or
examined, as appropriate, and released for use by the quality control
unit.
(b) Representative samples of each shipment of each lot shall be
collected for testing or examination. The number of containers to be
sampled, and the amount of material to be taken from each container,
shall be based upon appropriate criteria such as statistical criteria
for component variability, confidence levels, and degree of precision
desired, the past quality history of the supplier, and the quantity
needed for analysis and reserve where required by Sec. 211.170.
(c) Samples shall be collected in accordance with the following
procedures:
(1) The containers of components selected shall be cleaned where
necessary, by appropriate means.
(2) The containers shall be opened, sampled, and resealed in a
manner designed to prevent contamination of their contents and
contamination of other components, drug product containers, or closures.
(3) Sterile equipment and aseptic sampling techniques shall be used
when necessary.
(4) If it is necessary to sample a component from the top, middle,
and bottom of its container, such sample subdivisions shall not be
composited for testing.
(5) Sample containers shall be identified so that the following
information can be determined: name of the material sampled, the lot
number, the container from which the sample was taken, the date on which
the sample was taken, and the name of the person who collected the
sample.
(6) Containers from which samples have been taken shall be marked to
show that samples have been removed from them.
(d) Samples shall be examined and tested as follows:
(1) At least one test shall be conducted to verify the identity of
each component of a drug product. Specific identity tests, if they
exist, shall be used.
(2) Each component shall be tested for conformity with all
appropriate written specifications for purity,
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strength, and quality. In lieu of such testing by the manufacturer, a
report of analysis may be accepted from the supplier of a component,
provided that at least one specific identity test is conducted on such
component by the manufacturer, and provided that the manufacturer
establishes the reliability of the supplier's analyses through
appropriate validation of the supplier's test results at appropriate
intervals.
(3) Containers and closures shall be tested for conformance with all
appropriate written procedures. In lieu of such testing by the
manufacturer, a certificate of testing may be accepted from the
supplier, provided that at least a visual identification is conducted on
such containers/closures by the manufacturer and provided that the
manufacturer establishes the reliability of the supplier's test results
through appropriate validation of the supplier's test results at
appropriate intervals.
(4) When appropriate, components shall be microscopically examined.
(5) Each lot of a component, drug product container, or closure that
is liable to contamination with filth, insect infestation, or other
extraneous adulterant shall be examined against established
specifications for such contamination.
(6) Each lot of a component, drug product container, or closure that
is liable to microbiological contamination that is objectionable in view
of its intended use shall be subjected to microbiological tests before
use.
(e) Any lot of components, drug product containers, or closures that
meets the appropriate written specifications of identity, strength,
quality, and purity and related tests under paragraph (d) of this
section may be approved and released for use. Any lot of such material
that does not meet such specifications shall be rejected.
[43 FR 45077, Sept. 29, 1978, as amended at 63 FR 14356, Mar. 25, 1998]
Sec. 211.86 Use of approved components, drug product containers, and closures.
Components, drug product containers, and closures approved for use
shall be rotated so that the oldest approved stock is used first.
Deviation from this requirement is permitted if such deviation is
temporary and appropriate.
Sec. 211.87 Retesting of approved components, drug product containers, and closures.
Components, drug product containers, and closures shall be retested
or reexamined, as appropriate, for identity, strength, quality, and
purity and approved or rejected by the quality control unit in
accordance with Sec. 211.84 as necessary, e.g., after storage for long
periods or after exposure to air, heat or other conditions that might
adversely affect the component, drug product container, or closure.
Sec. 211.89 Rejected components, drug product containers, and closures.
Rejected components, drug product containers, and closures shall be
identified and controlled under a quarantine system designed to prevent
their use in manufacturing or processing operations for which they are
unsuitable.
Sec. 211.94 Drug product containers and closures.
(a) Drug product containers and closures shall not be reactive,
additive, or absorptive so as to alter the safety, identity, strength,
quality, or purity of the drug beyond the official or established
requirements.
(b) Container closure systems shall provide adequate protection
against foreseeable external factors in storage and use that can cause
deterioration or contamination of the drug product.
(c) Drug product containers and closures shall be clean and, where
indicated by the nature of the drug, sterilized and processed to remove
pyrogenic properties to assure that they are suitable for their intended
use.
(d) Standards or specifications, methods of testing, and, where
indicated, methods of cleaning, sterilizing, and processing to remove
pyrogenic properties shall be written and followed for drug product
containers and closures.
[[Page 112]]
Subpart F--Production and Process Controls
Sec. 211.100 Written procedures; deviations.
(a) There shall be written procedures for production and process
control designed to assure that the drug products have the identity,
strength, quality, and purity they purport or are represented to
possess. Such procedures shall include all requirements in this subpart.
These written procedures, including any changes, shall be drafted,
reviewed, and approved by the appropriate organizational units and
reviewed and approved by the quality control unit.
(b) Written production and process control procedures shall be
followed in the execution of the various production and process control
functions and shall be documented at the time of performance. Any
deviation from the written procedures shall be recorded and justified.
Sec. 211.101 Charge-in of components.
Written production and control procedures shall include the
following, which are designed to assure that the drug products produced
have the identity, strength, quality, and purity they purport or are
represented to possess:
(a) The batch shall be formulated with the intent to provide not
less than 100 percent of the labeled or established amount of active
ingredient.
(b) Components for drug product manufacturing shall be weighed,
measured, or subdivided as appropriate. If a component is removed from
the original container to another, the new container shall be identified
with the following information:
(1) Component name or item code;
(2) Receiving or control number;
(3) Weight or measure in new container;
(4) Batch for which component was dispensed, including its product
name, strength, and lot number.
(c) Weighing, measuring, or subdividing operations for components
shall be adequately supervised. Each container of component dispensed to
manufacturing shall be examined by a second person to assure that:
(1) The component was released by the quality control unit;
(2) The weight or measure is correct as stated in the batch
production records;
(3) The containers are properly identified.
(d) Each component shall be added to the batch by one person and
verified by a second person.
Sec. 211.103 Calculation of yield.
Actual yields and percentages of theoretical yield shall be
determined at the conclusion of each appropriate phase of manufacturing,
processing, packaging, or holding of the drug product. Such calculations
shall be performed by one person and independently verified by a second
person.
Sec. 211.105 Equipment identification.
(a) All compounding and storage containers, processing lines, and
major equipment used during the production of a batch of a drug product
shall be properly identified at all times to indicate their contents
and, when necessary, the phase of processing of the batch.
(b) Major equipment shall be identified by a distinctive
identification number or code that shall be recorded in the batch
production record to show the specific equipment used in the manufacture
of each batch of a drug product. In cases where only one of a particular
type of equipment exists in a manufacturing facility, the name of the
equipment may be used in lieu of a distinctive identification number or
code.
Sec. 211.110 Sampling and testing of in-process materials and drug products.
(a) To assure batch uniformity and integrity of drug products,
written procedures shall be established and followed that describe the
in-process controls, and tests, or examinations to be conducted on
appropriate samples of in-process materials of each batch. Such control
procedures shall be established to monitor the output and to validate
the performance of those manufacturing processes that may be responsible
for causing variability in the characteristics of in-process material
[[Page 113]]
and the drug product. Such control procedures shall include, but are not
limited to, the following, where appropriate:
(1) Tablet or capsule weight variation;
(2) Disintegration time;
(3) Adequacy of mixing to assure uniformity and homogeneity;
(4) Dissolution time and rate;
(5) Clarity, completeness, or pH of solutions.
(b) Valid in-process specifications for such characteristics shall
be consistent with drug product final specifications and shall be
derived from previous acceptable process average and process variability
estimates where possible and determined by the application of suitable
statistical procedures where appropriate. Examination and testing of
samples shall assure that the drug product and in-process material
conform to specifications.
(c) In-process materials shall be tested for identity, strength,
quality, and purity as appropriate, and approved or rejected by the
quality control unit, during the production process, e.g., at
commencement or completion of significant phases or after storage for
long periods.
(d) Rejected in-process materials shall be identified and controlled
under a quarantine system designed to prevent their use in manufacturing
or processing operations for which they are unsuitable.
Sec. 211.111 Time limitations on production.
When appropriate, time limits for the completion of each phase of
production shall be established to assure the quality of the drug
product. Deviation from established time limits may be acceptable if
such deviation does not compromise the quality of the drug product. Such
deviation shall be justified and documented.
Sec. 211.113 Control of microbiological contamination.
(a) Appropriate written procedures, designed to prevent
objectionable microorganisms in drug products not required to be
sterile, shall be established and followed.
(b) Appropriate written procedures, designed to prevent
microbiological contamination of drug products purporting to be sterile,
shall be established and followed. Such procedures shall include
validation of any sterilization process.
Sec. 211.115 Reprocessing.
(a) Written procedures shall be established and followed prescribing
a system for reprocessing batches that do not conform to standards or
specifications and the steps to be taken to insure that the reprocessed
batches will conform with all established standards, specifications, and
characteristics.
(b) Reprocessing shall not be performed without the review and
approval of the quality control unit.
Subpart G--Packaging and Labeling Control
Sec. 211.122 Materials examination and usage criteria.
(a) There shall be written procedures describing in sufficient
detail the receipt, identification, storage, handling, sampling,
examination, and/or testing of labeling and packaging materials; such
written procedures shall be followed. Labeling and packaging materials
shall be representatively sampled, and examined or tested upon receipt
and before use in packaging or labeling of a drug product.
(b) Any labeling or packaging materials meeting appropriate written
specifications may be approved and released for use. Any labeling or
packaging materials that do not meet such specifications shall be
rejected to prevent their use in operations for which they are
unsuitable.
(c) Records shall be maintained for each shipment received of each
different labeling and packaging material indicating receipt,
examination or testing, and whether accepted or rejected.
(d) Labels and other labeling materials for each different drug
product, strength, dosage form, or quantity of contents shall be stored
separately with suitable identification. Access to the storage area
shall be limited to authorized personnel.
[[Page 114]]
(e) Obsolete and outdated labels, labeling, and other packaging
materials shall be destroyed.
(f) Use of gang-printed labeling for different drug products, or
different strengths or net contents of the same drug product, is
prohibited unless the labeling from gang-printed sheets is adequately
differentiated by size, shape, or color.
(g) If cut labeling is used, packaging and labeling operations shall
include one of the following special control procedures:
(1) Dedication of labeling and packaging lines to each different
strength of each different drug product;
(2) Use of appropriate electronic or electromechanical equipment to
conduct a 100-percent examination for correct labeling during or after
completion of finishing operations; or
(3) Use of visual inspection to conduct a 100-percent examination
for correct labeling during or after completion of finishing operations
for hand-applied labeling. Such examination shall be performed by one
person and independently verified by a second person.
(h) Printing devices on, or associated with, manufacturing lines
used to imprint labeling upon the drug product unit label or case shall
be monitored to assure that all imprinting conforms to the print
specified in the batch production record.
[43 FR 45077, Sept. 29, 1978, as amended at 58 FR 41353, Aug. 3, 1993]
Sec. 211.125 Labeling issuance.
(a) Strict control shall be exercised over labeling issued for use
in drug product labeling operations.
(b) Labeling materials issued for a batch shall be carefully
examined for identity and conformity to the labeling specified in the
master or batch production records.
(c) Procedures shall be used to reconcile the quantities of labeling
issued, used, and returned, and shall require evaluation of
discrepancies found between the quantity of drug product finished and
the quantity of labeling issued when such discrepancies are outside
narrow preset limits based on historical operating data. Such
discrepancies shall be investigated in accordance with Sec. 211.192.
Labeling reconciliation is waived for cut or roll labeling if a 100-
percent examination for correct labeling is performed in accordance with
Sec. 211.122(g)(2).
(d) All excess labeling bearing lot or control numbers shall be
destroyed.
(e) Returned labeling shall be maintained and stored in a manner to
prevent mixups and provide proper identification.
(f) Procedures shall be written describing in sufficient detail the
control procedures employed for the issuance of labeling; such written
procedures shall be followed.
[43 FR 45077, Sept. 29, 1978, as amended at 58 FR 41354, Aug. 3, 1993]
Sec. 211.130 Packaging and labeling operations.
There shall be written procedures designed to assure that correct
labels, labeling, and packaging materials are used for drug products;
such written procedures shall be followed. These procedures shall
incorporate the following features:
(a) Prevention of mixups and cross-contamination by physical or
spatial separation from operations on other drug products.
(b) Identification and handling of filled drug product containers
that are set aside and held in unlabeled condition for future labeling
operations to preclude mislabeling of individual containers, lots, or
portions of lots. Identification need not be applied to each individual
container but shall be sufficient to determine name, strength, quantity
of contents, and lot or control number of each container.
(c) Identification of the drug product with a lot or control number
that permits determination of the history of the manufacture and control
of the batch.
(d) Examination of packaging and labeling materials for suitability
and correctness before packaging operations, and documentation of such
examination in the batch production record.
(e) Inspection of the packaging and labeling facilities immediately
before use to assure that all drug products have been removed from
previous operations. Inspection shall also be made to
[[Page 115]]
assure that packaging and labeling materials not suitable for subsequent
operations have been removed. Results of inspection shall be documented
in the batch production records.
[43 FR 45077, Sept. 29, 1978, as amended at 58 FR 41354, Aug. 3, 1993]
Sec. 211.132 Tamper-evident packaging requirements for over-the-counter (OTC) human drug products.
(a) General. The Food and Drug Administration has the authority
under the Federal Food, Drug, and Cosmetic Act (the act) to establish a
uniform national requirement for tamper-evident packaging of OTC drug
products that will improve the security of OTC drug packaging and help
assure the safety and effectiveness of OTC drug products. An OTC drug
product (except a dermatological, dentifrice, insulin, or lozenge
product) for retail sale that is not packaged in a tamper-resistant
package or that is not properly labeled under this section is
adulterated under section 501 of the act or misbranded under section 502
of the act, or both.
(b) Requirements for tamper-evident package. (1) Each manufacturer
and packer who packages an OTC drug product (except a dermatological,
dentifrice, insulin, or lozenge product) for retail sale shall package
the product in a tamper-evident package, if this product is accessible
to the public while held for sale. A tamper-evident package is one
having one or more indicators or barriers to entry which, if breached or
missing, can reasonably be expected to provide visible evidence to
consumers that tampering has occurred. To reduce the likelihood of
successful tampering and to increase the likelihood that consumers will
discover if a product has been tampered with, the package is required to
be distinctive by design or by the use of one or more indicators or
barriers to entry that employ an identifying characteristic (e.g., a
pattern, name, registered trademark, logo, or picture). For purposes of
this section, the term ``distinctive by design'' means the packaging
cannot be duplicated with commonly available materials or through
commonly available processes. A tamper-evident package may involve an
immediate-container and closure system or secondary-container or carton
system or any combination of systems intended to provide a visual
indication of package integrity. The tamper-evident feature shall be
designed to and shall remain intact when handled in a reasonable manner
during manufacture, distribution, and retail display.
(2) In addition to the tamper-evident packaging feature described in
paragraph (b)(1) of this section, any two-piece, hard gelatin capsule
covered by this section must be sealed using an acceptable tamper-
evident technology.
(c) Labeling. (1) In order to alert consumers to the specific
tamper-evident feature(s) used, each retail package of an OTC drug
product covered by this section (except ammonia inhalant in crushable
glass ampules, containers of compressed medical oxygen, or aerosol
products that depend upon the power of a liquefied or compressed gas to
expel the contents from the container) is required to bear a statement
that:
(i) Identifies all tamper-evident feature(s) and any capsule sealing
technologies used to comply with paragraph (b) of this section;
(ii) Is prominently placed on the package; and
(iii) Is so placed that it will be unaffected if the tamper-evident
feature of the package is breached or missing.
(2) If the tamper-evident feature chosen to meet the requirements in
paragraph (b) of this section uses an identifying characteristic, that
characteristic is required to be referred to in the labeling statement.
For example, the labeling statement on a bottle with a shrink band could
say ``For your protection, this bottle has an imprinted seal around the
neck.''
(d) Request for exemptions from packaging and labeling requirements.
A manufacturer or packer may request an exemption from the packaging and
labeling requirements of this section. A request for an exemption is
required to be submitted in the form of a citizen petition under
Sec. 10.30 of this chapter and should be clearly identified on the
envelope as a ``Request for Exemption from the Tamper-Evident Packaging
Rule.'' The petition is required to contain the following:
[[Page 116]]
(1) The name of the drug product or, if the petition seeks an
exemption for a drug class, the name of the drug class, and a list of
products within that class.
(2) The reasons that the drug product's compliance with the tamper-
evident packaging or labeling requirements of this section is
unnecessary or cannot be achieved.
(3) A description of alternative steps that are available, or that
the petitioner has already taken, to reduce the likelihood that the
product or drug class will be the subject of malicious adulteration.
(4) Other information justifying an exemption.
(e) OTC drug products subject to approved new drug applications.
Holders of approved new drug applications for OTC drug products are
required under Sec. 314.70 of this chapter to provide the agency with
notification of changes in packaging and labeling to comply with the
requirements of this section. Changes in packaging and labeling required
by this regulation may be made before FDA approval, as provided under
Sec. 314.70(c) of this chapter. Manufacturing changes by which capsules
are to be sealed require prior FDA approval under Sec. 314.70(b) of this
chapter.
(f) Poison Prevention Packaging Act of 1970. This section does not
affect any requirements for ``special packaging'' as defined under
Sec. 310.3(l) of this chapter and required under the Poison Prevention
Packaging Act of 1970.
(Approved by the Office of Management and Budget under OMB control
number 0910-0149)
[54 FR 5228, Feb. 2, 1989, as amended at 63 FR 59470, Nov. 4, 1998]
Sec. 211.134 Drug product inspection.
(a) Packaged and labeled products shall be examined during finishing
operations to provide assurance that containers and packages in the lot
have the correct label.
(b) A representative sample of units shall be collected at the
completion of finishing operations and shall be visually examined for
correct labeling.
(c) Results of these examinations shall be recorded in the batch
production or control records.
Sec. 211.137 Expiration dating.
(a) To assure that a drug product meets applicable standards of
identity, strength, quality, and purity at the time of use, it shall
bear an expiration date determined by appropriate stability testing
described in Sec. 211.166.
(b) Expiration dates shall be related to any storage conditions
stated on the labeling, as determined by stability studies described in
Sec. 211.166.
(c) If the drug product is to be reconstituted at the time of
dispensing, its labeling shall bear expiration information for both the
reconstituted and unreconstituted drug products.
(d) Expiration dates shall appear on labeling in accordance with the
requirements of Sec. 201.17 of this chapter.
(e) Homeopathic drug products shall be exempt from the requirements
of this section.
(f) Allergenic extracts that are labeled ``No U.S. Standard of
Potency'' are exempt from the requirements of this section.
(g) New drug products for investigational use are exempt from the
requirements of this section, provided that they meet appropriate
standards or specifications as demonstrated by stability studies during
their use in clinical investigations. Where new drug products for
investigational use are to be reconstituted at the time of dispensing,
their labeling shall bear expiration information for the reconstituted
drug product.
(h) Pending consideration of a proposed exemption, published in the
Federal Register of September 29, 1978, the requirements in this section
shall not be enforced for human OTC drug products if their labeling does
not bear dosage limitations and they are stable for at least 3 years as
supported by appropriate stability data.
[43 FR 45077, Sept. 29, 1978, as amended at 46 FR 56412, Nov. 17, 1981;
60 FR 4091, Jan. 20, 1995]
Subpart H--Holding and Distribution
Sec. 211.142 Warehousing procedures.
Written procedures describing the warehousing of drug products shall
be
[[Page 117]]
established and followed. They shall include:
(a) Quarantine of drug products before release by the quality
control unit.
(b) Storage of drug products under appropriate conditions of
temperature, humidity, and light so that the identity, strength,
quality, and purity of the drug products are not affected.
Sec. 211.150 Distribution procedures.
Written procedures shall be established, and followed, describing
the distribution of drug products. They shall include:
(a) A procedure whereby the oldest approved stock of a drug product
is distributed first. Deviation from this requirement is permitted if
such deviation is temporary and appropriate.
(b) A system by which the distribution of each lot of drug product
can be readily determined to facilitate its recall if necessary.
Subpart I--Laboratory Controls
Sec. 211.160 General requirements.
(a) The establishment of any specifications, standards, sampling
plans, test procedures, or other laboratory control mechanisms required
by this subpart, including any change in such specifications, standards,
sampling plans, test procedures, or other laboratory control mechanisms,
shall be drafted by the appropriate organizational unit and reviewed and
approved by the quality control unit. The requirements in this subpart
shall be followed and shall be documented at the time of performance.
Any deviation from the written specifications, standards, sampling
plans, test procedures, or other laboratory control mechanisms shall be
recorded and justified.
(b) Laboratory controls shall include the establishment of
scientifically sound and appropriate specifications, standards, sampling
plans, and test procedures designed to assure that components, drug
product containers, closures, in-process materials, labeling, and drug
products conform to appropriate standards of identity, strength,
quality, and purity. Laboratory controls shall include:
(1) Determination of conformance to appropriate written
specifications for the acceptance of each lot within each shipment of
components, drug product containers, closures, and labeling used in the
manufacture, processing, packing, or holding of drug products. The
specifications shall include a description of the sampling and testing
procedures used. Samples shall be representative and adequately
identified. Such procedures shall also require appropriate retesting of
any component, drug product container, or closure that is subject to
deterioration.
(2) Determination of conformance to written specifications and a
description of sampling and testing procedures for in-process materials.
Such samples shall be representative and properly identified.
(3) Determination of conformance to written descriptions of sampling
procedures and appropriate specifications for drug products. Such
samples shall be representative and properly identified.
(4) The calibration of instruments, apparatus, gauges, and recording
devices at suitable intervals in accordance with an established written
program containing specific directions, schedules, limits for accuracy
and precision, and provisions for remedial action in the event accuracy
and/or precision limits are not met. Instruments, apparatus, gauges, and
recording devices not meeting established specifications shall not be
used.
Sec. 211.165 Testing and release for distribution.
(a) For each batch of drug product, there shall be appropriate
laboratory determination of satisfactory conformance to final
specifications for the drug product, including the identity and strength
of each active ingredient, prior to release. Where sterility and/or
pyrogen testing are conducted on specific batches of shortlived
radiopharmaceuticals, such batches may be released prior to completion
of sterility and/or pyrogen testing, provided such testing is completed
as soon as possible.
(b) There shall be appropriate laboratory testing, as necessary, of
each
[[Page 118]]
batch of drug product required to be free of objectionable
microorganisms.
(c) Any sampling and testing plans shall be described in written
procedures that shall include the method of sampling and the number of
units per batch to be tested; such written procedure shall be followed.
(d) Acceptance criteria for the sampling and testing conducted by
the quality control unit shall be adequate to assure that batches of
drug products meet each appropriate specification and appropriate
statistical quality control criteria as a condition for their approval
and release. The statistical quality control criteria shall include
appropriate acceptance levels and/or appropriate rejection levels.
(e) The accuracy, sensitivity, specificity, and reproducibility of
test methods employed by the firm shall be established and documented.
Such validation and documentation may be accomplished in accordance with
Sec. 211.194(a)(2).
(f) Drug products failing to meet established standards or
specifications and any other relevant quality control criteria shall be
rejected. Reprocessing may be performed. Prior to acceptance and use,
reprocessed material must meet appropriate standards, specifications,
and any other relevant critieria.
Sec. 211.166 Stability testing.
(a) There shall be a written testing program designed to assess the
stability characteristics of drug products. The results of such
stability testing shall be used in determining appropriate storage
conditions and expiration dates. The written program shall be followed
and shall include:
(1) Sample size and test intervals based on statistical criteria for
each attribute examined to assure valid estimates of stability;
(2) Storage conditions for samples retained for testing;
(3) Reliable, meaningful, and specific test methods;
(4) Testing of the drug product in the same container-closure system
as that in which the drug product is marketed;
(5) Testing of drug products for reconstitution at the time of
dispensing (as directed in the labeling) as well as after they are
reconstituted.
(b) An adequate number of batches of each drug product shall be
tested to determine an appropriate expiration date and a record of such
data shall be maintained. Accelerated studies, combined with basic
stability information on the components, drug products, and container-
closure system, may be used to support tentative expiration dates
provided full shelf life studies are not available and are being
conducted. Where data from accelerated studies are used to project a
tentative expiration date that is beyond a date supported by actual
shelf life studies, there must be stability studies conducted, including
drug product testing at appropriate intervals, until the tentative
expiration date is verified or the appropriate expiration date
determined.
(c) For homeopathic drug products, the requirements of this section
are as follows:
(1) There shall be a written assessment of stability based at least
on testing or examination of the drug product for compatibility of the
ingredients, and based on marketing experience with the drug product to
indicate that there is no degradation of the product for the normal or
expected period of use.
(2) Evaluation of stability shall be based on the same container-
closure system in which the drug product is being marketed.
(d) Allergenic extracts that are labeled ``No U.S. Standard of
Potency'' are exempt from the requirements of this section.
[43 FR 45077, Sept. 29, 1978, as amended at 46 FR 56412, Nov. 17, 1981]
Sec. 211.167 Special testing requirements.
(a) For each batch of drug product purporting to be sterile and/or
pyrogen-free, there shall be appropriate laboratory testing to determine
conformance to such requirements. The test procedures shall be in
writing and shall be followed.
(b) For each batch of ophthalmic ointment, there shall be
appropriate testing to determine conformance to specifications regarding
the presence of foreign particles and harsh or abrasive substances. The
test procedures shall be in writing and shall be followed.
[[Page 119]]
(c) For each batch of controlled-release dosage form, there shall be
appropriate laboratory testing to determine conformance to the
specifications for the rate of release of each active ingredient. The
test procedures shall be in writing and shall be followed.
Sec. 211.170 Reserve samples.
(a) An appropriately identified reserve sample that is
representative of each lot in each shipment of each active ingredient
shall be retained. The reserve sample consists of at least twice the
quantity necessary for all tests required to determine whether the
active ingredient meets its established specifications, except for
sterility and pyrogen testing. The retention time is as follows:
(1) For an active ingredient in a drug product other than those
described in paragraphs (a) (2) and (3) of this section, the reserve
sample shall be retained for 1 year after the expiration date of the
last lot of the drug product containing the active ingredient.
(2) For an active ingredient in a radioactive drug product, except
for nonradioactive reagent kits, the reserve sample shall be retained
for:
(i) Three months after the expiration date of the last lot of the
drug product containing the active ingredient if the expiration dating
period of the drug product is 30 days or less; or
(ii) Six months after the expiration date of the last lot of the
drug product containing the active ingredient if the expiration dating
period of the drug product is more than 30 days.
(3) For an active ingredient in an OTC drug product that is exempt
from bearing an expiration date under Sec. 211.137, the reserve sample
shall be retained for 3 years after distribution of the last lot of the
drug product containing the active ingredient.
(b) An appropriately identified reserve sample that is
representative of each lot or batch of drug product shall be retained
and stored under conditions consistent with product labeling. The
reserve sample shall be stored in the same immediate container-closure
system in which the drug product is marketed or in one that has
essentially the same characteristics. The reserve sample consists of at
least twice the quantity necessary to perform all the required tests,
except those for sterility and pyrogens. Except for those for drug
products described in paragraph (b)(2) of this section, reserve samples
from representative sample lots or batches selected by acceptable
statistical procedures shall be examined visually at least once a year
for evidence of deterioration unless visual examination would affect the
integrity of the reserve sample. Any evidence of reserve sample
deterioration shall be investigated in accordance with Sec. 211.192. The
results of the examination shall be recorded and maintained with other
stability data on the drug product. Reserve samples of compressed
medical gases need not be retained. The retention time is as follows:
(1) For a drug product other than those described in paragraphs (b)
(2) and (3) of this section, the reserve sample shall be retained for 1
year after the expiration date of the drug product.
(2) For a radioactive drug product, except for nonradioactive
reagent kits, the reserve sample shall be retained for:
(i) Three months after the expiration date of the drug product if
the expiration dating period of the drug product is 30 days or less; or
(ii) Six months after the expiration date of the drug product if the
expiration dating period of the drug product is more than 30 days.
(3) For an OTC drug product that is exempt for bearing an expiration
date under Sec. 211.137, the reserve sample must be retained for 3 years
after the lot or batch of drug product is distributed.
[48 FR 13025, Mar. 29, 1983, as amended at 60 FR 4091, Jan. 20, 1995]
Sec. 211.173 Laboratory animals.
Animals used in testing components, in-process materials, or drug
products for compliance with established specifications shall be
maintained and controlled in a manner that assures their suitability for
their intended use. They shall be identified, and adequate records shall
be maintained showing the history of their use.
[[Page 120]]
Sec. 211.176 Penicillin contamination.
If a reasonable possibility exists that a non-penicillin drug
product has been exposed to cross-contamination with penicillin, the
non-penicillin drug product shall be tested for the presence of
penicillin. Such drug product shall not be marketed if detectable levels
are found when tested according to procedures specified in `Procedures
for Detecting and Measuring Penicillin Contamination in Drugs,' which is
incorporated by reference. Copies are available from the Division of
Research and Testing (HFD-470), Center for Drug Evaluation and Research,
Food and Drug Administration, 200 C St. SW., Washington, DC 20204, or
available for inspection at the Office of the Federal Register, 800
North Capitol Street, NW., suite 700, Washington, DC 20408.
[43 FR 45077, Sept. 29, 1978, as amended at 47 FR 9396, Mar. 5, 1982; 50
FR 8996, Mar. 6, 1985; 55 FR 11577, Mar. 29, 1990]
Subpart J--Records and Reports
Sec. 211.180 General requirements.
(a) Any production, control, or distribution record that is required
to be maintained in compliance with this part and is specifically
associated with a batch of a drug product shall be retained for at least
1 year after the expiration date of the batch or, in the case of certain
OTC drug products lacking expiration dating because they meet the
criteria for exemption under Sec. 211.137, 3 years after distribution of
the batch.
(b) Records shall be maintained for all components, drug product
containers, closures, and labeling for at least 1 year after the
expiration date or, in the case of certain OTC drug products lacking
expiration dating because they meet the criteria for exemption under
Sec. 211.137, 3 years after distribution of the last lot of drug product
incorporating the component or using the container, closure, or
labeling.
(c) All records required under this part, or copies of such records,
shall be readily available for authorized inspection during the
retention period at the establishment where the activities described in
such records occurred. These records or copies thereof shall be subject
to photocopying or other means of reproduction as part of such
inspection. Records that can be immediately retrieved from another
location by computer or other electronic means shall be considered as
meeting the requirements of this paragraph.
(d) Records required under this part may be retained either as
original records or as true copies such as photocopies, microfilm,
microfiche, or other accurate reproductions of the original records.
Where reduction techniques, such as microfilming, are used, suitable
reader and photocopying equipment shall be readily available.
(e) Written records required by this part shall be maintained so
that data therein can be used for evaluating, at least annually, the
quality standards of each drug product to determine the need for changes
in drug product specifications or manufacturing or control procedures.
Written procedures shall be established and followed for such
evaluations and shall include provisions for:
(1) A review of a representative number of batches, whether approved
or rejected, and, where applicable, records associated with the batch.
(2) A review of complaints, recalls, returned or salvaged drug
products, and investigations conducted under Sec. 211.192 for each drug
product.
(f) Procedures shall be established to assure that the responsible
officials of the firm, if they are not personally involved in or
immediately aware of such actions, are notified in writing of any
investigations conducted under Secs. 211.198, 211.204, or 211.208 of
these regulations, any recalls, reports of inspectional observations
issued by the Food and Drug Administration, or any regulatory actions
relating to good manufacturing practices brought by the Food and Drug
Administration.
[43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091, Jan. 20, 1995]
Sec. 211.182 Equipment cleaning and use log.
A written record of major equipment cleaning, maintenance (except
routine maintenance such as lubrication and adjustments), and use shall
be included in individual equipment logs that show the date, time,
product, and lot number
[[Page 121]]
of each batch processed. If equipment is dedicated to manufacture of one
product, then individual equipment logs are not required, provided that
lots or batches of such product follow in numerical order and are
manufactured in numerical sequence. In cases where dedicated equipment
is employed, the records of cleaning, maintenance, and use shall be part
of the batch record. The persons performing and double-checking the
cleaning and maintenance shall date and sign or initial the log
indicating that the work was performed. Entries in the log shall be in
chronological order.
Sec. 211.184 Component, drug product container, closure, and labeling records.
These records shall include the following:
(a) The identity and quantity of each shipment of each lot of
components, drug product containers, closures, and labeling; the name of
the supplier; the supplier's lot number(s) if known; the receiving code
as specified in Sec. 211.80; and the date of receipt. The name and
location of the prime manufacturer, if different from the supplier,
shall be listed if known.
(b) The results of any test or examination performed (including
those performed as required by Sec. 211.82(a), Sec. 211.84(d), or
Sec. 211.122(a)) and the conclusions derived therefrom.
(c) An individual inventory record of each component, drug product
container, and closure and, for each component, a reconciliation of the
use of each lot of such component. The inventory record shall contain
sufficient information to allow determination of any batch or lot of
drug product associated with the use of each component, drug product
container, and closure.
(d) Documentation of the examination and review of labels and
labeling for conformity with established specifications in accord with
Secs. 211.122(c) and 211.130(c).
(e) The disposition of rejected components, drug product containers,
closure, and labeling.
Sec. 211.186 Master production and control records.
(a) To assure uniformity from batch to batch, master production and
control records for each drug product, including each batch size
thereof, shall be prepared, dated, and signed (full signature,
handwritten) by one person and independently checked, dated, and signed
by a second person. The preparation of master production and control
records shall be described in a written procedure and such written
procedure shall be followed.
(b) Master production and control records shall include:
(1) The name and strength of the product and a description of the
dosage form;
(2) The name and weight or measure of each active ingredient per
dosage unit or per unit of weight or measure of the drug product, and a
statement of the total weight or measure of any dosage unit;
(3) A complete list of components designated by names or codes
sufficiently specific to indicate any special quality characteristic;
(4) An accurate statement of the weight or measure of each
component, using the same weight system (metric, avoirdupois, or
apothecary) for each component. Reasonable variations may be permitted,
however, in the amount of components necessary for the preparation in
the dosage form, provided they are justified in the master production
and control records;
(5) A statement concerning any calculated excess of component;
(6) A statement of theoretical weight or measure at appropriate
phases of processing;
(7) A statement of theoretical yield, including the maximum and
minimum percentages of theoretical yield beyond which investigation
according to Sec. 211.192 is required;
(8) A description of the drug product containers, closures, and
packaging materials, including a specimen or copy of each label and all
other labeling signed and dated by the person or persons responsible for
approval of such labeling;
[[Page 122]]
(9) Complete manufacturing and control instructions, sampling and
testing procedures, specifications, special notations, and precautions
to be followed.
Sec. 211.188 Batch production and control records.
Batch production and control records shall be prepared for each
batch of drug product produced and shall include complete information
relating to the production and control of each batch. These records
shall include:
(a) An accurate reproduction of the appropriate master production or
control record, checked for accuracy, dated, and signed;
(b) Documentation that each significant step in the manufacture,
processing, packing, or holding of the batch was accomplished,
including:
(1) Dates;
(2) Identity of individual major equipment and lines used;
(3) Specific identification of each batch of component or in-process
material used;
(4) Weights and measures of components used in the course of
processing;
(5) In-process and laboratory control results;
(6) Inspection of the packaging and labeling area before and after
use;
(7) A statement of the actual yield and a statement of the
percentage of theoretical yield at appropriate phases of processing;
(8) Complete labeling control records, including specimens or copies
of all labeling used;
(9) Description of drug product containers and closures;
(10) Any sampling performed;
(11) Identification of the persons performing and directly
supervising or checking each significant step in the operation;
(12) Any investigation made according to Sec. 211.192.
(13) Results of examinations made in accordance with Sec. 211.134.
Sec. 211.192 Production record review.
All drug product production and control records, including those for
packaging and labeling, shall be reviewed and approved by the quality
control unit to determine compliance with all established, approved
written procedures before a batch is released or distributed. Any
unexplained discrepancy (including a percentage of theoretical yield
exceeding the maximum or minimum percentages established in master
production and control records) or the failure of a batch or any of its
components to meet any of its specifications shall be thoroughly
investigated, whether or not the batch has already been distributed. The
investigation shall extend to other batches of the same drug product and
other drug products that may have been associated with the specific
failure or discrepancy. A written record of the investigation shall be
made and shall include the conclusions and followup.
Sec. 211.194 Laboratory records.
(a) Laboratory records shall include complete data derived from all
tests necessary to assure compliance with established specifications and
standards, including examinations and assays, as follows:
(1) A description of the sample received for testing with
identification of source (that is, location from where sample was
obtained), quantity, lot number or other distinctive code, date sample
was taken, and date sample was received for testing.
(2) A statement of each method used in the testing of the sample.
The statement shall indicate the location of data that establish that
the methods used in the testing of the sample meet proper standards of
accuracy and reliability as applied to the product tested. (If the
method employed is in the current revision of the United States
Pharmacopeia, National Formulary, Association of Official Analytical
Chemists, Book of Methods,\2\ or in other recognized standard
references, or is detailed in an approved new drug application and the
referenced method is not modified, a statement indicating the method and
reference will suffice). The suitability of all testing methods used
shall be verified under actual conditions of use.
---------------------------------------------------------------------------
\2\ Copies may be obtained from: Association of Official Analytical
Chemists, 2200 Wilson Blvd., Suite 400, Arlington, VA 22201-3301.
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[[Page 123]]
(3) A statement of the weight or measure of sample used for each
test, where appropriate.
(4) A complete record of all data secured in the course of each
test, including all graphs, charts, and spectra from laboratory
instrumentation, properly identified to show the specific component,
drug product container, closure, in-process material, or drug product,
and lot tested.
(5) A record of all calculations performed in connection with the
test, including units of measure, conversion factors, and equivalency
factors.
(6) A statement of the results of tests and how the results compare
with established standards of identity, strength, quality, and purity
for the component, drug product container, closure, in-process material,
or drug product tested.
(7) The initials or signature of the person who performs each test
and the date(s) the tests were performed.
(8) The initials or signature of a second person showing that the
original records have been reviewed for accuracy, completeness, and
compliance with established standards.
(b) Complete records shall be maintained of any modification of an
established method employed in testing. Such records shall include the
reason for the modification and data to verify that the modification
produced results that are at least as accurate and reliable for the
material being tested as the established method.
(c) Complete records shall be maintained of any testing and
standardization of laboratory reference standards, reagents, and
standard solutions.
(d) Complete records shall be maintained of the periodic calibration
of laboratory instruments, apparatus, gauges, and recording devices
required by Sec. 211.160(b)(4).
(e) Complete records shall be maintained of all stability testing
performed in accordance with Sec. 211.166.
[43 FR 45077, Sept. 29, 1978, as amended at 55 FR 11577, Mar. 29, 1990]
Sec. 211.196 Distribution records.
Distribution records shall contain the name and strength of the
product and description of the dosage form, name and address of the
consignee, date and quantity shipped, and lot or control number of the
drug product. For compressed medical gas products, distribution records
are not required to contain lot or control numbers.
(Approved by the Office of Management and Budget under control number
0910-0139)
[49 FR 9865, Mar. 16, 1984]
Sec. 211.198 Complaint files.
(a) Written procedures describing the handling of all written and
oral complaints regarding a drug product shall be established and
followed. Such procedures shall include provisions for review by the
quality control unit, of any complaint involving the possible failure of
a drug product to meet any of its specifications and, for such drug
products, a determination as to the need for an investigation in
accordance with Sec. 211.192. Such procedures shall include provisions
for review to determine whether the complaint represents a serious and
unexpected adverse drug experience which is required to be reported to
the Food and Drug Administration in accordance with Sec. 310.305 of this
chapter.
(b) A written record of each complaint shall be maintained in a file
designated for drug product complaints. The file regarding such drug
product complaints shall be maintained at the establishment where the
drug product involved was manufactured, processed, or packed, or such
file may be maintained at another facility if the written records in
such files are readily available for inspection at that other facility.
Written records involving a drug product shall be maintained until at
least 1 year after the expiration date of the drug product, or 1 year
after the date that the complaint was received, whichever is longer. In
the case of certain OTC drug products lacking expiration dating because
they meet the criteria for exemption under Sec. 211.137, such written
records shall be maintained for 3 years after distribution of the drug
product.
(1) The written record shall include the following information,
where known: the name and strength of the drug product, lot number, name
of complainant, nature of complaint, and reply to complainant.
[[Page 124]]
(2) Where an investigation under Sec. 211.192 is conducted, the
written record shall include the findings of the investigation and
followup. The record or copy of the record of the investigation shall be
maintained at the establishment where the investigation occurred in
accordance with Sec. 211.180(c).
(3) Where an investigation under Sec. 211.192 is not conducted, the
written record shall include the reason that an investigation was found
not to be necessary and the name of the responsible person making such a
determination.
[43 FR 45077, Sept. 29, 1978, as amended at 51 FR 24479, July 3, 1986]
Subpart K--Returned and Salvaged Drug Products
Sec. 211.204 Returned drug products.
Returned drug products shall be identified as such and held. If the
conditions under which returned drug products have been held, stored, or
shipped before or during their return, or if the condition of the drug
product, its container, carton, or labeling, as a result of storage or
shipping, casts doubt on the safety, identity, strength, quality or
purity of the drug product, the returned drug product shall be destroyed
unless examination, testing, or other investigations prove the drug
product meets appropriate standards of safety, identity, strength,
quality, or purity. A drug product may be reprocessed provided the
subsequent drug product meets appropriate standards, specifications, and
characteristics. Records of returned drug products shall be maintained
and shall include the name and label potency of the drug product dosage
form, lot number (or control number or batch number), reason for the
return, quantity returned, date of disposition, and ultimate disposition
of the returned drug product. If the reason for a drug product being
returned implicates associated batches, an appropriate investigation
shall be conducted in accordance with the requirements of Sec. 211.192.
Procedures for the holding, testing, and reprocessing of returned drug
products shall be in writing and shall be followed.
Sec. 211.208 Drug product salvaging.
Drug products that have been subjected to improper storage
conditions including extremes in temperature, humidity, smoke, fumes,
pressure, age, or radiation due to natural disasters, fires, accidents,
or equipment failures shall not be salvaged and returned to the
marketplace. Whenever there is a question whether drug products have
been subjected to such conditions, salvaging operations may be conducted
only if there is (a) evidence from laboratory tests and assays
(including animal feeding studies where applicable) that the drug
products meet all applicable standards of identity, strength, quality,
and purity and (b) evidence from inspection of the premises that the
drug products and their associated packaging were not subjected to
improper storage conditions as a result of the disaster or accident.
Organoleptic examinations shall be acceptable only as supplemental
evidence that the drug products meet appropriate standards of identity,
strength, quality, and purity. Records including name, lot number, and
disposition shall be maintained for drug products subject to this
section.
PART 216--PHARMACY COMPOUNDING--Table of Contents
Subpart A--General Provisions [Reserved]
Subpart B--Compounded Drug Products
Sec.
216.23 [Reserved]
216.24 Drug products withdrawn or removed from the market for reasons
of safety or effectiveness.
Authority: 21 U.S.C. 351, 352, 353a, 355, and 371.
Source: 64 FR 10944, Mar. 8, 1999, unless otherwise noted.
Effective Date Note: At 64 FR 10944, Mar. 8, 1999, part 216 was
added, effective Apr. 7, 1999.
[[Page 125]]
Subpart A--General Provisions [Reserved]
Subpart B--Compounded Drug Products
Sec. 216.23 [Reserved]
Sec. 216.24 Drug products withdrawn or removed from the market for reasons of safety or effectiveness.
The following drug products were withdrawn or removed from the
market because such drug products or components of such drug products
were found to be unsafe or not effective. The following drug products
may not be compounded under the exemptions provided by section 503A(a)
of the Federal Food, Drug, and Cosmetic Act:
Adenosine phosphate: All drug products containing adenosine phosphate.
Adrenal cortex: All drug products containing adrenal cortex.
Azaribine: All drug products containing azaribine.
Benoxaprofen: All drug products containing benoxaprofen.
Bithionol: All drug products containing bithionol.
Bromfenac sodium: All drug products containing bromfenac sodium.
Butamben: All parenteral drug products containing butamben.
Camphorated oil: All drug products containing camphorated oil.
Carbetapentane citrate: All oral gel drug products containing
carbetapentane citrate.
Casein, iodinated: All drug products containing iodinated casein.
Chlorhexidine gluconate: All tinctures of chlorhexidine gluconate
formulated for use as a patient preoperative skin preparation.
Chlormadinone acetate: All drug products containing chlormadinone
acetate.
Chloroform: All drug products containing chloroform.
Cobalt: All drug products containing cobalt salts (except radioactive
forms of cobalt and its salts and cobalamin and its derivatives).
Dexfenfluramine hydrochloride: All drug products containing
dexfenfluramine hydrochloride.
Diamthazole dihydrochloride: All drug products containing diamthazole
dihydrochloride.
Dibromsalan: All drug products containing dibromsalan.
Diethylstilbestrol: All oral and parenteral drug products containing 25
milligrams or more of diethylstilbestrol per unit dose.
Dihydrostreptomycin sulfate: All drug products containing
dihydrostreptomycin sulfate.
Dipyrone: All drug products containing dipyrone.
Encainide hydrochloride: All drug products containing encainide
hydrochloride.
Fenfluramine hydrochloride: All drug products containing fenfluramine
hydrochloride.
Flosequinan: All drug products containing flosequinan.
Gelatin: All intravenous drug products containing gelatin.
Glycerol, iodinated: All drug products containing iodinated glycerol.
Gonadotropin, chorionic: All drug products containing chorionic
gonadotropins of animal origin.
Mepazine: All drug products containing mepazine hydrochloride or
mepazine acetate.
Metabromsalan: All drug products containing metabromsalan.
Methamphetamine hydrochloride: All parenteral drug products containing
methamphetamine hydrochloride.
Methapyrilene: All drug products containing methapyrilene.
Methopholine: All drug products containing methopholine.
Mibefradil dihydrochloride: All drug products containing mibefradil
dihydrochloride.
Nitrofurazone: All drug products containing nitrofurazone (except
topical drug products formulated for dermatalogic application).
Nomifensine maleate: All drug products containing nomifensine maleate.
Oxyphenisatin: All drug products containing oxyphenisatin.
Oxyphenisatin acetate: All drug products containing oxyphenisatin
acetate.
Phenacetin: All drug products containing phenacetin.
Phenformin hydrochloride: All drug products containing phenformin
hydrochloride.
Pipamazine: All drug products containing pipamazine.
Potassium arsenite: All drug products containing potassium arsenite.
Potassium chloride: All solid oral dosage form drug products containing
potassium chloride that supply 100 milligrams or more of potassium per
dosage unit (except for controlled-release dosage forms and those
products formulated for preparation of solution prior to ingestion).
Povidone: All intravenous drug products containing povidone.
Reserpine: All oral dosage form drug products containing more than 1
milligram of reserpine.
Sparteine sulfate: All drug products containing sparteine sulfate.
Sulfadimethoxine: All drug products containing sulfadimethoxine.
Sulfathiazole: All drug products containing sulfathiazole (except those
formulated for vaginal use).
[[Page 126]]
Suprofen: All drug products containing suprofen (except ophthalmic
solutions).
Sweet spirits of nitre: All drug products containing sweet spirits of
nitre.
Temafloxacin hydrochloride: All drug products containing temafloxacin.
Terfenadine: All drug products containing terfenadine.
3,3',4',5-tetrachlorosalicylanilide: All drug products containing
3,3',4',5-tetrachlorosalicylanilide.
Tetracycline: All liquid oral drug products formulated for pediatric use
containing tetracycline in a concentration greater than 25 milligrams/
milliliter.
Ticrynafen: All drug products containing ticrynafen.
Tribromsalan: All drug products containing tribromsalan.
Trichloroethane: All aerosol drug products intended for inhalation
containing trichloroethane.
Urethane: All drug products containing urethane.
Vinyl chloride: All aerosol drug products containing vinyl chloride.
Zirconium: All aerosol drug products containing zirconium.
Zomepirac sodium: All drug products containing zomepirac sodium.
PART 225--CURRENT GOOD MANUFACTURING PRACTICE FOR MEDICATED FEEDS--Table of Contents
Subpart A--General Provisions
Sec.
225.1 Current good manufacturing practice.
225.10 Personnel.
Subpart B--Construction and Maintenance of Facilities and Equipment
225.20 Buildings.
225.30 Equipment.
225.35 Use of work areas, equipment, and storage areas for other
manufacturing and storage purpose.
Subpart C--Product Quality Control
225.42 Components.
225.58 Laboratory controls.
225.65 Equipment cleanout procedures.
Subpart D--Packaging and Labeling
225.80 Labeling.
Subpart E--Records and Reports
225.102 Master record file and production records.
225.110 Distribution records.
225.115 Complaint files.
Subpart F--Facilities and Equipment
225.120 Buildings and grounds.
225.130 Equipment.
225.135 Work and storage areas.
Subpart G--Product Quality Assurance
225.142 Components.
225.158 Laboratory assays.
225.165 Equipment cleanout procedures.
Subpart H--Labeling
225.180 Labeling.
Subpart I--Records
225.202 Formula, production, and distribution records.
Authority: 21 U.S.C. 351, 352, 360b, 371, 374.
Source: 41 FR 52618, Nov. 30, 1976, unless otherwise noted.
Subpart A--General Provisions
Sec. 225.1 Current good manufacturing practice.
(a) Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act
provides that a drug (including a drug contained in a medicated feed)
shall be deemed to be adulterated if the methods used in, or the
facilities or controls used for, its manufacture, processing, packing,
or holding do not conform to or are not operated or administered in
conformity with current good manufacturing practice to assure that such
drug meets the requirement of the act as to safety and has the identity
and strength, and meets the quality and purity characteristics, which it
purports or is represented to possess.
(b)(1) The provisions of this part set forth the criteria for
determining whether the manufacture of a medicated feed is in compliance
with current good manufacturing practice. These regulations shall apply
to all types of facilities and equipment used in the production of
medicated feeds, and they shall also govern those instances in which
failure to adhere to the regulations has caused nonmedicated feeds that
are manufactured, processed, packed, or held to be adulterated. In such
cases, the medicated feed shall be deemed to be adulterated within the
meaning of section
[[Page 127]]
501(a)(2)(B) of the act, and the nonmedicated feed shall be deemed to be
adulterated within the meaning of section 402(a)(2)(D) of the act.
(2) The regulations in Secs. 225.10 through 225.115 apply to
facilities manufacturing one or more medicated feeds for which an
approved medicated feed application is required. The regulations in
Secs. 225.120 through 225.202 apply to facilities manufacturing solely
medicated feeds for which approved medicated feed applications are not
required.
[41 FR 52618, Nov. 30, 1976, as amended at 51 FR 7389, Mar. 3, 1986]
Sec. 225.10 Personnel.
(a) Qualified personnel and adequate personnel training and
supervision are essential for the proper formulation, manufacture, and
control of medicated feeds. Training and experience leads to proper use
of equipment, maintenance of accurate records, and detection and
prevention of possible deviations from current good manufacturing
practices.
(b)(1) All employees involved in the manufacture of medicated feeds
shall have an understanding of the manufacturing or control operation(s)
which they perform, including the location and proper use of equipment.
(2) The manufacturer shall provide an on-going program of evaluation
and supervision of employees in the manufacture of medicated feeds.
[41 FR 52618, Nov. 30, 1976, as amended at 42 FR 12426, Mar. 4, 1977]
Subpart B--Construction and Maintenance of Facilities and Equipment
Sec. 225.20 Buildings.
(a) The location, design, construction, and physical size of the
buildings and other production facilities are factors important to the
manufacture of medicated feed. The features of facilities necessary for
the proper manufacture of medicated feed include provision for ease of
access to structures and equipment in need of routine maintenance; ease
of cleaning of equipment and work areas; facilities to promote personnel
hygiene; structural conditions for control and prevention of vermin and
pest infestation; adequate space for the orderly receipt and storage of
drugs and feed ingredients and the controlled flow of these materials
through the processing and manufacturing operations; and the equipment
for the accurate packaging and delivery of a medicated feed of specified
labeling and composition.
(b) The construction and maintenance of buildings in which medicated
feeds are manufactured, processed, packaged, labeled, or held shall
conform to the following:
(1) The building grounds shall be adequately drained and routinely
maintained so that they are reasonably free from litter, waste, refuse,
uncut weeds or grass, standing water, and improperly stored equipment.
(2) The building(s) shall be maintained in a reasonably clean and
orderly manner.
(3) The building(s) shall be of suitable construction to minimize
access by rodents, birds, insects, and other pests.
(4) The buildings shall provide adequate space and lighting for the
proper performance of the following medicated feed manufacturing
operations:
(i) The receipt, control, and storage of components.
(ii) Component processing.
(iii) Medicated feed manufacturing.
(iv) Packaging and labeling.
(v) Storage of containers, packaging materials, labeling and
finished products.
(vi) Routine maintenance of equipment.
Sec. 225.30 Equipment.
(a) Equipment which is designed to perform its intended function and
is properly installed and used is essential to the manufacture of
medicated feeds. Such equipment permits production of feeds of uniform
quality, facilitates cleaning, and minimizes spillage of drug components
and finished product.
(b)(1) All equipment shall possess the capability to produce a
medicated feed of intended potency, safety, and purity.
(2) All equipment shall be maintained in a reasonably clean and
orderly manner.
(3) All equipment, including scales and liquid metering devices,
shall be of
[[Page 128]]
suitable size, design, construction, precision, and accuracy for its
intended purpose.
(4) All scales and metering devices shall be tested for accuracy
upon installation and at least once a year thereafter, or more
frequently as may be necessary to insure their accuracy.
(5) All equipment shall be so constructed and maintained as to
prevent lubricants and coolants from becoming unsafe additives in feed
components or medicated feed.
(6) All equipment shall be designed, constructed, installed and
maintained so as to facilitate inspection and use of cleanout
procedure(s).
Sec. 225.35 Use of work areas, equipment, and storage areas for other manufacturing and storage purpose.
(a) Many manufacturers of medicated feeds are also involved in the
manufacture, storage, or handling of products which are not intended for
animal feed use, such as fertilizers, herbicides, insecticides,
fungicides, rodenticides, and other pesticides. Manufacturing, storage,
or handling of nonfeed and feed products in the same facilities may
cause adulteration of feed products with toxic or otherwise unapproved
feed additives.
(b) Work areas and equipment used for the manufacture or storage of
medicated feeds or components thereof shall not be used for, and shall
be physically separated from, work areas and equipment used for the
manufacture of fertilizers, herbicides, insecticides, fungicides,
rodenticides, and other pesticides unless such articles are approved
drugs or approved food additives intended for use in the manufacture of
medicated feed.
Subpart C--Product Quality Control
Sec. 225.42 Components.
(a) A medicated feed, in addition to providing nutrients, is a
vehicle for the administration of a drug, or drugs, to animals. To
ensure proper safety and effectiveness, such medicated feeds must
contain the labeled amounts of drugs. It is necessary that adequate
procedures be established for the receipt, storage, and inventory
control for all such drugs to aid in assuring their identity, strength,
quality, and purity when incorporated into products.
(b) The receipt, storage, and inventory of drugs, including
undiluted drug components, medicated premixes, and semiprocessed (i.e.,
intermediate premixes, inplant premixes and concentrates) intermediate
mixes containing drugs, which are used in the manufacture and processing
of medicated feeds shall conform to the following:
(1) Incoming shipments of drugs shall be visually examined for
identity and damage. Drugs which have been subjected to conditions which
may have adversely affected their identity, strength, quality, or purity
shall not be accepted for use.
(2) Packaged drugs in the storage areas shall be stored in their
original closed containers.
(3) Bulk drugs shall be identified and stored in a manner such that
their identity, strength, quality, and purity will be maintained.
(4) Drugs in the mixing areas shall be properly identified, stored,
handled, and controlled to maintain their integrity and identity.
Sufficient space shall be provided for the location of each drug.
(5) A receipt record shall be prepared and maintained for each lot
of drug received. The receipt record shall accurately indicate the
identity and quantity of the drug, the name of the supplier, the
supplier's lot number or an identifying number assigned by the feed
manufacturer upon receipt which relates to the particular shipment, the
date of receipt, the condition of the drug when received, and the return
of any damaged drugs.
(6) A daily inventory record for each drug used shall be maintained
and shall list by manufacturer's lot number or the feed manufacturer's
shipment identification number at least the following information:
(i) The quantity of drug on hand at the beginning and end of the
work day (the beginning amount being the same as the previous day's
closing inventory if this amount has been established to
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be correct); the quantity shall be determined by weighing, counting, or
measuring, as appropriate.
(ii) The amount of each drug used, sold, or otherwise disposed of.
(iii) The batches or production runs of medicated feed in which each
drug was used.
(iv) When the drug is used in the preparation of a semiprocessed
intermediate mix intended for use in the manufacture of medicated feed,
any additional information which may be required for the purpose of
paragraph (b)(7) of this section.
(v) Action taken to reconcile any discrepancies in the daily
inventory record.
(7) Drug inventory shall be maintained of each lot or shipment of
drug by means of a daily comparison of the actual amount of drug used
with the theoretical drug usage in terms of the semiprocessed,
intermediate and finished medicated feeds manufactured. Any significant
discrepancy shall be investigated and corrective action taken. The
medicated feed(s) remaining on the premises which are affected by this
discrepancy shall be detained until the discrepancy is reconciled.
(8) All records required by this section shall be maintained on the
premises for at least one year after complete use of a drug component of
a specific lot number or feed manufacturer's shipment identification
number.
Sec. 225.58 Laboratory controls.
(a) The periodic assay of medicated feeds for drug components
provides a measure of performance of the manufacturing process in
manufacturing a uniform product of intended potency.
(b) The following assay requirements shall apply to medicated feeds:
(1) For feeds requiring approved Medicated Feed Applications (Form
FDA 1900) for their manufacture and marketing, at least three
representative samples of medicated feed containing each drug or drug
combination used in the establishment shall be collected and assayed by
approved official methods, at periodic intervals during the calendar
year, unless otherwise specified in this chapter. At least one of these
assays shall be performed on the first batch using the drug. If a
medicated feed contains a combination of drugs, only one of the drugs
need be subject to analysis each time, provided the one tested is
different from the one(s) previously tested.
(2) [Reserved]
(c) The originals or copies of all results of assays, including
those from State feed control officials and any other governmental
agency, shall be maintained on the premises for a period of not less
than 1 year after distribution of the medicated feed. The results of
assays performed by State feed control officials may be considered
toward fulfillment of the periodic assay requirements of this section.
(d) Where the results of assays indicate that the medicated feed is
not in accord with label specifications or is not within permissible
assay limits as specified in this chapter, investigation and corrective
action shall be implemented and an original or copy of the record of
such action maintained on the premises.
(e) Corrective action shall include provisions for discontinuing
distribution where the medicated feed fails to meet the labeled drug
potency. Distribution of subsequent production of the particular feed
shall not begin until it has been determined that proper control
procedures have been established.
[41 FR 52618, Nov. 30, 1976, as amended at 51 FR 7390, Mar. 3, 1986; 55
FR 11577, Mar. 29, 1990]
Sec. 225.65 Equipment cleanout procedures.
(a) Adequate cleanout procedures for all equipment used in the
manufacture and distribution of medicated feeds are essential to
maintain proper drug potency and avoid unsafe contamination of feeds
with drugs. Such procedures may consist of cleaning by physical means,
e.g., vacuuming, sweeping, washing, etc. Alternatively, flushing or
sequencing or other equally effective techniques may be used whereby the
equipment is cleaned either through use of a feed containing the same
drug(s) or through use of drug free feedstuffs.
(b) All equipment, including that used for storage, processing,
mixing, conveying, and distribution that comes
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in contact with the active drug component, feeds in process, or finished
medicated feed shall be subject to all reasonable and effective
procedures to prevent unsafe contamination of manufactured feed. The
steps used to prevent unsafe contamination of feeds shall include one or
more of the following, or other equally effective procedures:
(1) Such procedures shall, where appropriate, consist of physical
means (vacuuming, sweeping, or washing), flushing, and/or sequential
production of feeds.
(2) If flushing is utilized, the flush material shall be properly
identified, stored, and used in a manner to prevent unsafe contamination
of other feeds.
(3) If sequential production of medicated feeds is utilized, it
shall be on a predetermined basis designed to prevent unsafe
contamination of feeds with residual drugs.
Subpart D--Packaging and Labeling
Sec. 225.80 Labeling.
(a) Appropriate labeling identifies the medicated feed, and provides
the user with directions for use which, if adhered to, will assure that
the article is safe and effective for its intended purposes.
(b)(1) Labels and labeling, including placards, shall be received,
handled, and stored in a manner that prevents labeling mixups and
assures that correct labeling is employed for the medicated feed.
(2) Labels and labeling, including placards, upon receipt from the
printer shall be proofread against the Master Record File to verify
their suitability and accuracy. The proofread label shall be dated,
initialed by a responsible individual, and kept for 1 year after all the
labels from that batch have been used.
(3) In those instances where medicated feeds are distributed in
bulk, complete labeling shall accompany the shipment and be supplied to
the consignee at the time of delivery. Such labeling may consist of a
placard or other labels attached to the invoice or delivery ticket, or
manufacturer's invoice that identifies the medicated feed and includes
adequate information for the safe and effective use of the medicated
feed.
(4) Label stock shall be reviewed periodically and discontinued
labels shall be discarded.
Subpart E--Records and Reports
Sec. 225.102 Master record file and production records.
(a) The Master Record File provides the complete procedure for
manufacturing a specific product, setting forth the formulation,
theoretical yield, manufacturing procedures, assay requirements, and
labeling of batches or production runs. The production record(s)
includes the complete history of a batch or production run. This record
includes the amounts of drugs used, the amount of medicated feed
manufactured, and provides a check for the daily inventory record of
drug components.
(b) The Master Record File and production records shall comply with
the following provisions:
(1) A Master Record File shall be prepared, checked, dated, and
signed or initialed by a qualified person and shall be retained for not
less than 1 year after production of the last batch or production run of
medicated feed to which it pertains. The Master Record File or card
shall include at least the following:
(i) The name of the medicated feed.
(ii) The name and weight percentage or measure of each drug or drug
combination and each nondrug ingredient to be used in manufacturing a
stated weight of the medicated feed.
(iii) A copy or description of the label or labeling that will
accompany the medicated feed.
(iv) Manufacturing instructions or reference thereto that have been
determined to yield a properly mixed medicated feed of the specified
formula for each medicated feed produced on a batch or continuous
operation basis, including mixing steps, mixing times and, in the case
of medicated feeds produced by continuous production run, any additional
manufacturing directions including, when indicated, the settings of
equipment.
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(v) Appropriate control directions or reference thereto, including
the manner and frequency of collecting the required number of samples
for specified laboratory assay.
(2) The original production record or copy thereof shall be prepared
by qualified personnel for each batch or run of medicated feed produced
and shall be retained on the premises for not less than 1 year. The
production record shall include at least the following:
(i) Product identification, date of production, and a written
endorsement in the form of a signature or initials by a responsible
individual.
(ii) The quantity and name of drug components used.
(iii) The theoretical quantity of medicated feed to be produced.
(iv) The actual quantity of medicated feed produced. In those
instances where the finished feed is stored in bulk and actual yield
cannot be accurately determined, the firm shall estimate the quantity
produced and provide the basis for such estimate in the Master Record
File.
(3) In the case of a custom formula feed made to the specifications
of a customer, the Master Record File and production records required by
this section shall consist either of such records or of copies of the
customer's purchase orders and the manufacturer's invoices bearing the
information required by this section. When a custom order is received by
telephone, the manufacturer shall prepare the required production
records.
(4) Batch production records shall be checked by a responsible
individual at the end of the working day in which the product was
manufactured to determine whether all required production steps have
been performed. If significant discrepancies are noted, an investigation
shall be instituted immediately, and the production record shall
describe the corrective action taken.
(5) Each batch or production run of medicated feed shall be
identified with its own individual batch or production run number, code,
date, or other suitable identification applied to the label, package,
invoice or shipping document. This identification shall permit the
tracing of the complete and accurate manufacturing history of the
product by the manufacturer.
Sec. 225.110 Distribution records.
(a) Distribution records permit the manufacturer to relate
complaints to specific batches and/or production runs of medicated feed.
This information may be helpful in instituting a recall.
(b) Distribution records for each shipment of a medicated feed shall
comply with the following provisions:
(1) Each distribution record shall include the date of shipment, the
name and address of purchaser, the quantity shipped, and the name of the
medicated feed. A lot or control number, or date of manufacture or other
suitable identification shall appear on the distribution record or the
label issued with each shipment.
(2) The originals or copies of the distribution records shall be
retained on the premises for not less than one year after the date of
shipment of the medicated feed.
Sec. 225.115 Complaint files.
(a) Complaints and reports of experiences of product defects
relative to the drug's efficacy or safety may provide an indicator as to
whether or not medicated feeds have been manufactured in conformity with
current good manufacturing practices. These complaints and experiences
may reveal the existence of manufacturing problems not otherwise
detected through the normal quality control procedures. Timely and
appropriate follow-up action can serve to correct a problem and minimize
future problems.
(b) The medicated feed manufacturer shall maintain on the premises a
file which contains the following information:
(1) The original or copy of a record of each oral and written
complaint received relating to the safety and effectiveness of the
product produced. The record shall include the date of the complaint,
the complainant's name and address, name and lot or control number or
date of manufacture of the medicated feed involved, and the specific
details of the complaint. This record shall also include all
correspondence
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from the complainant and/or memoranda of conversations with the
complainant, and a description of all investigations made by the
manufacturer and of the method of disposition of the complaint.
(2) For medicated feeds requiring an approved Medicated Feed
Application (Form FDA 1900), records and reports of clinical and other
experience with the drug shall be maintained and reported, appropriately
identified with the number(s) of the Form FDA 1900 to which they relate,
to the Center for Veterinary Medicine, 7500 Standish Pl., Rockville, MD
20855, in duplicate, pursuant to Sec. 510.301 of this chapter.
[41 FR 52618, Nov. 30, 1976, as amended at 51 FR 7390, Mar. 3, 1986; 57
FR 6475, Feb. 25, 1992]
Subpart F--Facilities and Equipment
Source: 51 FR 7390, Mar. 3, 1986, unless otherwise noted.
Sec. 225.120 Buildings and grounds.
Buildings used for production of medicated feed shall provide
adequate space for equipment, processing, and orderly receipt and
storage of medicated feed. Areas shall include access for routine
maintenance and cleaning of equipment. Buildings and grounds shall be
constructed and maintained in a manner to minimize vermin and pest
infestation.