Chapter 4 - Human Drugs
CONTENTS
Sub Chapter 400 - General
400.100 Drugs, Human - Failure to Register
400.200 Consistent Application of CGMP Determinations
400.325 Candy "Pills" Representation as Drug
400.335 Fructose-Containing Drugs
400.400 Conditions Under Which Homeopathic
Drugs May be Marketed
400.500 Identical or Similar Product Names
400.600 Drugs - Declaration of Quantity of Active
400.700 Drug Product Entries in Periodic Publications
400.800 Collection and Charitable Distribution of Drugs
400.900 Class I Recalls of Prescription Drugs
Sub Chapter 405 - Antibiotics
405.100 Prescriptions Prepared from Certified Antibiotics
405.200 Export of Uncertified Antibiotics
405.210 Returned Antibiotics Exported Under 80(d) of the Act
Sub Chapter 410 - Bulk Drugs
410.100 *Finished Dosage Form Drug Products in Bulk
Containers - Applications of Current Good
Manufacturing Practice Regulations*
Sub Chapter 420 - Compendial /Test Requirements
420.100 Adulteration of Drugs Under Section 501(b) and
501(c) of the Act. *Direct Reference Seizure Authority
for Adulterated Drugs Under Section 501(b)*
400.200 Compendium Revisions and Deletions
420.300 Changes in Compendial Specifications and NDA
420.400 Performance of Tests for Compendial
Requirements on Compendial Products
420.500 Interference with Compendial Tests
Sub Chapter 425 - Computerized Drug Processing
425.100 Computerized Drug Processing; CGMP Applicability
to Hardware and Software
425.200 Computerized Drug Processing; Vendor Responsibility
425.300 Computerized Drug Processinor
Process Control Application Programs
425.400 Computerized Drug Processing; Input/Output
Checking
425.500 Computerized Drug Processing; Identification
of "Persons" on Batch Production and Control
Records
Sub Chapter 430 - Labeling and Repackaging
430.100 Unit Dose labeling for Solid and Liquid Oral Dosage
Forms
430.200 Repacking of Drug Products - Testing/Examination
under CGMPs
430.300 Labeling Shipping Containers of Drugs
430.400 Urinary Preparations - Misbranding - Lack of
Rx Legend and Claims
Sub Chapter 435 - Medical Gases
435.100 Compressed Medical Gases - *Warning Letters for
Specific Violations Covering Liquid and Gaseous
Oxygen*
Sub Chapter 440 - 448 New Drugs
440.100 Marketed New Drugs Without Approved NDAs
442.100 New Drugs - Export
444.100 Recovery of Investigational New Drugs from
Clinical Investigators
446.100 Regulatory Action Regarding Approved New
Drug and Antibiotic Drug Products Subjected to
Additional Processing or other Manipulations
448.100 Reconditioning of New Drugs Which Do Not
Have Approved NDAs/ANDAs
Sub Chapter 450 - 457 OTC
450.100 CGMP Enforcement Policy - OTC vs Rx Drugs
450.200 Drugs - General Provisions and Administrative
Procedures for Recognition as Safe and Effective
450.300 OTC Drugs - General Provisions and Administrative
Procedures for Marketing Combination Products
450.400 Labeling and Distribution of OTC Drugs in Vending
Machines
450.500 Tamper-Resistant Packing Requirements for Certain
Over-the-Counter (OTC) Human Drug Products
450.550 Control and Accountability of Labeling Associated
with Tamper-Resistant Packaging of Over-the-Counter
Drug Products
454.100 OTC Ear Drop Preparations
455.100 Inert Glandular Preparations *(OTC)*,
Inadequate Full Disclosure and Claims
456.100 Non-Rx Drugs Anti-Obesity Preparations
457.100 Pangamic Acid and Pangamic Acid Products
afe for Food and Drug Use
Sub Chapter 460 - Pharmacy Issues
460.100 Hospital Pharmacies - Status as Drug Manufacturer
460.200 Manufacture, Distribution, and Promotion
of Adulterated, Misbranded, or Unapproved New Drugs
for Human Use by State-Licensed Pharmacies
460.300 Return of Unused Prescription Drugs to Pharmacy
Stock
460.400 Computerized Prescription Recordkeeping by
Pharmacies
460.425 Prescription Status when Telephoned to Recording
Machine
460.450 Status of Mail-Order Filling of Prescriptions
460.500 Prescription Drugs for Ship's Medicine Chests
460.600 Content Uniformity Testing of Tablets and Capsules
460.700 Controlled Release Dosage Form Drugs - Rate
of Release of Active Ingredients
460.800 Paramedic Release - Terminally Heat Sterilized
Drug Products
Sub Chapter 470 - Post Approval Issues
470.100 Orders for Post-Approval Record Reviews
Sub Chapter 480 - Stability/Expiration
480.100 Requirements for Expiration Dating and Stability
Testing
480.200 Expiration Dating of Unit Dose Repackaged Drugs
480.300 Lack of Expiration Date of Stability Data
Sub Chapter 490 - Validation
490.100 Process Validation Requirements for Drug
Products Subject to Pre-Market Approval
___________________________________________________________
Sub Chapter 400
General
Sec. 400.100 Drugs, Human - Failure to
Register (CPG 7132.07)
BACKGROUND:
Sections 510(b)&(c) of the Act requires the registration of all
producers of drugs and devices. When the legislation amending the Act was
passed, Congress found and declared that in order to make the regulation
of interstate commerce in drugs effective, it was necessary to provide
for the registration and inspection of all establishments in which drugs
were manufactured, prepared, propagated, compounded, or processed; as the
products of such establishments were likely to enter interstate commerce;
and that the regulation of interstate commerce in drugs without provision
for registration and inspection of establishments engaged only intrastate
commerce of drugs would discriminate against and depress interstate commerce
of such drugs, and adversely burden, obstruct, and affect such interstate
commerce. Section 510(h) requires that each registrant be inspected for
compliance every two years.
REGULATORY ACTION GUIDANCE:
If an establishment is required to register and has failed to do so,
then every reasonable effort should be made to convince management to register
the establishment on a voluntary basis during the initial inspection. If
this effort is unsuccessful then an informal discussion between the District
Director and the establishment's management should be held. if registration
is not accomplished after these initial steps then the issuance of a *warning*
letter will be considered by the *CDER*.
*Material between asterisks is new or revised*
Issued: 10/1/80
Revised: 3/95
Sec. 400.200 Consistent Application of
CGMP Determinations (CPG 7132.12)
BACKGROUND:
In recent years there has been a growing number of commitments made
by FDA to various programs and systems designed to ensure the quality of
drug products by carefully monitoring drug manufacturers' compliance with
the Current Good Manufacturing Practice (CGMP) regulations. FDA has for
many years enforced CGMP as part of its overall drug quality assurance
program. The approval process for drug marketing applications (original
and abbreviated new drug applications and antibiotic Forms 5 and 6) includes
a review of the manufacturer's compliance with the CGMP. More recently,
FDA has assumed additional roles in the area of assurance of drug quality
involving good manufacturing practice through such programs as the Government-Wide
Quality Assurance Programs for drug purchase contracts by the Department
of Defense and the Veterans Administration, and the Maximum Allowable Cost
program of HHS. Decisions regarding compliance with CGMP regulations are
based upon inspection of the facilities, sample analyses, and compliance
history of the firm. These data are summarized in profiles which represent
several years of history of the firms. In consideration of the growing
number of programs dependent upon CGMP assessment, Agency policy must be
consolidated in regard to approval or disapproval of drug marketing applications,
government purchasing contracts, etc., and the relation of such determinations
to regulatory action.
POLICY:
CGMP deficiencies supporting a regulatory action also support decisions
regarding non-approval of drug marketing applications, government purchasing
contracts, candidates for MAC, etc. Therefore, the issuance of a *warning*
letter or initiation of other regulatory action based upon CGMP deficiencies
must be accompanied by disapproval of any pending drug marketing application,
or government contract for a product produced under the same deficiencies.
Similarly, disapproval of any drug marketing application, government
contract, etc., based upon CGMP deficiencies must be accompanied by regulatory
and/or administrative action against any other product produced under the
same conditions.
*Material between asterisks is new or revised*
Issued: 4/1/81
Revised: 3/95
Sec. 400.325 Candy "Pills" -
Representation as Drug (CPG 7132.04)
BACKGROUND:
From time to time persons question whether or not candy pills should
be subjected to regulatory action based on misbranding under Section 403(a)
in that they are represented as pills which they are not.
POLICY:
We are not prepared to take regulatory action against these products
solely on the basis that they are labeled as "candy pills".
Issued: 10/1/80
Sec. 400.335 Fructose-Containing Drugs
(CPG 7132b.02)
BACKGROUND:
Hereditary fructose intolerance is a metabolic error due to the deficiency
of fructose 1-phosphate aldolase in the liver. It is thought to be inherited
as an autosomal recessive trait. The condition is characterized by symptomatic
hypoglycemia and vomiting. Prolonged fructose ingestion in young children
results in their failure to thrive and in jaundice, liver damage, renal
impairment, and sometimes cachexia. <> There have been deaths involving
the administration of IV solutions containing "Invert Sugar"
to patients with hereditary fructose intolerance.
There are many drug products which contain fructose. In many cases,
fructose has been identified on the product label as either levulose or
invert sugar. FDA has learned that the public and many professionals are
not always aware of the fact that levulose is a synonym for fructose, or
that "invert sugar" is a mixture of glucose and fructose. Clearly
identifying *the* presence of fructose in drugs which may be used by persons
with hereditary fructose intolerance would help insure that they are not
unknowingly being treated with such drugs.
POLICY:
All oral dosage form drugs and all parenteral drugs which contain fructose
should clearly identify this ingredient as "fructose" on labels
and labeling. The words "Fructose/Dextrose" should immediately
follow the words "Invert Sugar" whenever they appear. The word
"Fructose" should immediately follow the word "Levulose"
whenever it appears.
*Material between asterisks is new or revised*
<> Indicates material has been deleted
Issued: 1/21/75
Revised: 10/1/80, 5/22/87
Sec. 400.400 Conditions Under Which Homeopathic
Drugs May be Marketed (CPG 7132.15)
BACKGROUND:
The term "homeopathy" is derived from the Greek words homeo
(similar) and pathos (suffering or disease). The first basic principles
of homeopathy were formulated by Samuel Hahnemann in the late 1700's. The
practice of homeopathy is based on the belief that disease symptoms can
be cured by small doses of substances which produce similar symptoms in
healthy people.
The Federal Food, Drug, and Cosmetic Act (the Act) recognizes as official
the drugs and standards in the Homeopathic Pharmacopeia of the United
States and its supplements (Sections 201 (g)(1) and 501 (b), respectively).
Until recently, homeopathic drugs have been marketed on a limited scale
by a few manufacturers who have been in business for many years and have
predominantly served the needs of a limited number of licensed practitioners.
In conjunction with this, homeopathic drug products historically have borne
little or no labeling for the consumer.
Today the homeopathic drug market has grown to become a multimillion
dollar industry in the United States, with a significant increase shown
in the importation and domestic marketing of homeopathic drug products.
Those products that are offered for treatment of serious disease conditions,
must be dispensed under the care of a licensed practitioner. Other products,
offered for use in self-limiting conditions recognizable by consumers,
may be marketed OTC.
This document provides guidance on the regulation of OTC and prescription
homeopathic drugs and delineates those conditions under which homeopathic
drugs may ordinarily be marketed in the U.S. Agency compliance personnel
should particularly consider whether a homeopathic drug is being offered
for use (or promoted) significantly beyond recognized or customary practice
of homeopathy. If so, priorities and procedures concerning the agency's
policy on health fraud would apply. (See CPG 7150.10 "Health Fraud-Factors
in Considering Regulatory Action" 6/5/87).
DEFINITIONS:
The following terms are used in this document and are defined as follows:
1. Homeopathy: The practice of treating the syndromes and conditions
which constitute disease with remedies that have produced similar syndromes
and conditions in healthy subjects.
2. Homeopathic Drug: Any drug labeled as being homeopathic which
is listed in the Homeopathic Pharmacopeia of the United States (HPUS),
an addendum to it, or its supplements. The potencies of homeopathic drugs
are specified in terms of dilution, i.e., 1x (1/10 dilution), 2x (1/100
dilution), etc. Homeopathic drug products must contain diluents commonly
used in homeopathic pharmaceutics. Drug products containing homeopathic
ingredients in combination with non-homeopathic active ingredients are
not homeopathic drug products.
3. Homeotherapeutics: Involves therapy which utilizes drugs that
are selected and administered in accordance with the tenets of homeopathy.
4. Homeopathic Pharmacopeia of the United States (HPUS): A compilation
of standards for source, composition, and preparation of homeopathic drugs.
HPUS contains monographs of drug ingredients used in homeopathic treatment.
It is recognized as an official compendium under Section 201(j) of the
Act.
5. Compendium of Homeotherapeutics: An addendum to the HPUS which
contains basic premises and concepts of homeopathy and homeotherapeutics;
specifications and standards of preparation, content, and dosage of homeopathic
drugs; a description of the proving* process used to determine the eligibility
of drugs for inclusion in HPUS; the technique of prescribing the therapeutic
application of homeopathic drugs; and a partial list of drugs which meet
the criteria of the proving process and are eligible for inclusion in HPUS
and other homeopathic texts.
6. Extemporaneously Compounded OTC Products: Those homeopathic
drug products which are often prepared by dilution to many variations of
potency from stock preparations, and which: (1) have at least one OTC indication;
(2) are prepared pursuant to consumers' oral or written requests; and (3)
are not generally sold from retail shelves. Those products which are prescription
drugs only cannot be provided to consumers as extemporaneously compounded
OTC products but, may only be prepared pursuant to a prescription order.
*7 Health Fraud: The deceptive promotion, advertisement, distribution
or sale of articles, intended for human or animal use, that are represented
as being effective to diagnose, prevent, cure, treat, or mitigate disease
(or other conditions), or provide a beneficial effect on health, but which
have not been scientifically proven safe and effective for such purposes.
Such practices may be deliberate, or done without adequate knowledge or
understanding of the article.*
*A proving is synonymous with the homeopathic procedure (identified
in HPUS as a "Research Procedure") which is employed in healthy
individuals to determine the dose of a drug sufficient to produce symptoms.
DISCUSSION:
Section 201(g)(1) of the Act defines the term "drug" to mean
articles recognized in the official United States Pharmacopeia (USP),
the official Homeopathic Pharmacopeia of the United States (HPUS),
or official National Formulary (NF) or any supplement to them; and
articles intended for use in the diagnosis, cure, mitigation, treatment,
or the prevention of disease in man or other animals; articles (other than
food) intended to affect the structure or any function of the body of man
or other animals; and articles intended for use as a component of any articles
specified in the above. Whether or not they are official homeopathic remedies,
those products offered for the cure, mitigation, prevention, or treatment
of disease conditions are regarded as drugs within the meaning of Section
201(g)(l) of the Act.
Homeopathic drugs generally must meet the standards for strength, quality,
and purity set forth in the Homeopathic Pharmacopeia. Section 501(b) of
the Act (21 U.S.C. 351) provides in relevant part:
Whenever a drug is recognized in both the United States Pharmacopeia
and the Homeopathic Pharmacopeia of the United States it shall be subject
to the requirements of the United States Pharmacopeia unless it is labeled
and offered for sale as a homeopathic drug, in which case it shall be subject
to the provisions of the Homeopathic Pharmacopeia of the United States
and not to those of the United States Pharmacopeia.
A product's compliance with requirements of the HPUS, USP, or NF does
not establish that it has been shown by appropriate means to be safe, effective,
and not misbranded for its intended use.
A guide to the use of homeopathic drugs (including potencies, dosing,
and other parameters) may be found by referring to the following texts:
A Dictionary of Practical Materia Medica by John Henry Clarke, M.D.,
(3 volumes; Health Science Press) and A Clinical Repertory to the Dictionary
of Materia Medica by John Henry Clarke, M.D. (Health Science Press).
These references must be reviewed in conjunction with other available literature
on these drug substances.
POLICY:
LABELING
Homeopathic drug product labeling must comply with the labeling provisions
of Sections 502 and 503 of the Act and Part 201 Title 21 of the Code of
Federal Regulations (CFR), as discussed below, with certain provisions
applicable to extemporaneously compounded OTC products. Those drugs in
bulk packages intended for manufacture or preparation of products, including
those subsequently diluted to various potencies, must also comply with
the provisions of Section 502 of the Act and Part 201 (21 CFR 201).
General Labeling Provisions
Name and Place of Business: Each product must bear the name and
place of business of the manufacturer, packer, or distributor in conformance
with Section 502(b) of the Act and 21 CFR 201.1.
Directions for Use: Each drug product offered for retail sale
must bear adequate directions for use in conformance with Section 502(f)
of the Act and 21 CFR 201.5. An exemption from adequate directions for
use under Section 503 is applicable only to prescription drugs.
Statement of Ingredients: Ingredient information shall appear
in accord with Section 502(e) of the Act and 21 CFR 201.10. Labeling must
bear a statement of the quantity and amount of ingredient(s) in the product
in conformance with Section 502(b) of the Act, as well as 21 CFR 201.10,
expressed in homeopathic terms, e.g., lx, 2x.
Documentation must be provided to support that those products or ingredients
which are not recognized officially in the HPUS, an addendum to it, or
its supplements are generally recognized as homeopathic products or ingredients.
Established Name: The product must be in conformance with Section
502(e)(1) of the Act and must bear an established name in accord with Section
502(e)(3) of the Act and 21 CFR 201.10. Many homeopathic products bear
Latin names which correspond to listings in the HPUS. Since Section 502(c)
of the Act and 21 CFR 201.15(c)(1) require that all labeling be in English,
the industry is required to translate these names from Latin to their common
English names as current labeling stocks are depleted, or by June 11, 1990,
whichever occurs first. It is permissible for industry to include in the
labeling both English and Latin names.
Container Size - Labeling Exemption: For those products packaged
in containers too small to accommodate a label bearing the required information,
the labeling requirements provided under Section 502 of the Act and 21
CFR 201 may be met by placing information on the carton or outer container,
or in a leaflet with the package, as designated in 21 CFR 201.10(i) for
OTC drugs and in 21 CFR 201.100(b)(7) for prescription drugs. However,
as a minimum, each product must also bear a label containing a statement
of identity and potency, and the name and place of business of the manufacturer,
packer, or distributor.
Language: The label and labeling must be in the English language
as described and provided for under 21 CFR 201.15(c)(1), although it is
permissible for industry to include foreign language in the labeling, as
well.
Prescription Drugs
The products must comply with the General Labeling Provisions above,
as well as the provisions for prescription drugs below.
Prescription Drug Legend: All prescription homeopathic drug products
must bear the prescription legend, "Caution: Federal law prohibits
dispensing without prescription," in conformance with Section 503(b)(1)
of the Act.
Statement of Identity: The label shall bear a statement of identity
as provided for under 21 CFR 201.50.
Declaration of Net Quantity of Contents and Statement of Dosage:
The label shall bear a declaration of net quantity of contents as provided
in 21 CFR 201.51 and a statement of the recommended or usual dosage as
described under 21 CFR 201.55.
General Labeling Requirements: The labeling shall contain the
information described under 21 CFR 201.56 and 21 CFR 201.57. For all prescription
homeopathic products, a package insert bearing complete labeling information
for the homeopathic practitioner must accompany the product.
OTC Drugs
Product labeling must comply with the General Labeling Provisions above
and the provisions for OTC drugs below, as current labeling stocks are
depleted or by June 11, 1990, whichever occurs first.
Principal display Panel: The labeling must comply with the principal
display panel provision under 21 CFR 201.62.
Statement of Identity: The label shall contain a statement of
identity as described in 21 CFR 201.61.
Declaration of Net Quantity of Contents: The label shall conform
to the provisions for declaring net quantity of contents under 21 CFR 201.62.
Indications for Use: The labeling for those products offered
for OTC retail sale must bear at least one major OTC indication for use,
stated in terms likely to be understood by lay persons. For extemporaneously
compounded OTC products, the labeling must bear at least one major OTC
indication for use, stated in terms likely to be understood by lay persons.
For combination products, the labeling must bear appropriate indications(s)
common to the respective ingredients. Industry must comply with the provisions
concerning indications for use as current labeling stocks are depleted,
or by June 11, 1990, whichever occurs first.
Directions for Use: See the General Labeling Provisions above.
Warnings: OTC homeopathic drugs intended for systemic absorption,
unless specifically exempted, must bear a warning statement in conformance
with 21 CFR 201.63(a). Other warnings, such as those for indications conforming
to those in OTC drug final regulations, are required as appropriate.
Prescription/OTC Status
The criteria specified in Section 503(b) of the Act apply to the determination
of prescription status for all drug products, including homeopathic drug
products. If the HPUS specifies a distinction between nonprescription (over-the-counter
(OTC)) and prescription status of products which is based on strength (e.g.,
30x) - and which is more restrictive than Section 503(b) of the Act - the
more stringent criteria will apply. Homeopathic products intended solely
for self-limiting disease conditions amenable to self-diagnosis (of symptoms)
and treatment may be marketed OTC. Homeopathic products offered for conditions
not amenable to OTC use must be marketed as prescription products.
Home Remedy Kits Homeopathic home remedy kits may contain several
products used for a wide range of conditions amenable to OTC use. When
limited space does not allow for a list of those conditions on the labels
of the products, the required labeling must appear in a pamphlet or similar
informational piece which is enclosed in the kits. However, as a minimum,
each product must also bear a label containing a statement of identity
and potency.
Other Requirements
All firms which manufacture, prepare, propagate, compound, or otherwise
process homeopathic drugs must register as drug establishments in conformance
with Section 510 of the Act and 21 CFR 207. Further, homeopathic drug products
must be listed in conformance with the sections above. (Note: For
a given product, variations in package size and potency are not required
to be listed on separate forms 2657 but instead, may be listed on the same
form). Homeopathic drug products must be packaged in accordance with Section
502(g) of the Act. Homeopathic drug products must be manufactured in conformance
with current good manufacturing practice, Section 501(a)(2)(B) of the Act
and 21 CFR 211. However, due to the unique nature of these drug products,
some requirements of 21 CFR 211 are not applicable, as follows:
1. Section 211.137 (Expiration dating) specifically exempts homeopathic
drug products from expiration dating requirements.
2. Section 211.165 (Testing and release for distribution): In the Federal
Register of April 1, 1983 (48 FR 14003), the Agency proposed to amend 21
CFR 211.165 to exempt homeopathic drug products from the requirement for
laboratory determination of identity and strength of each active ingredient
prior to release for distribution.
Pending a final rule on this exemption, this testing requirement will
not be enforced for homeopathic drug products.
REGULATORY ACTION GUIDANCE:
Those firms marketing homeopathic drugs which are not in compliance
with the conditions described above will be considered for regulatory follow-up.
<> The Office of Compliance, HFD-304, Center for Drug Evaluation
and Research, should be consulted before *warning* letters are issued.
Recommendations for the issuance of *warning* letters or other regulatory
sanctions must be submitted in conformity with the Regulatory Procedures
Manual and other Agency guidance concerning the review of regulatory actions.
*Material between asterisks is new or revised*
<> Indicates material has been deleted
Issued: 5/31/88
Revised: 3/95
Sec. 400.500 Identical or Similar Product
Names (CPG 7132b.14)
BACKGROUND:
*Periodically different drugs, or drugs and other products, are marketed
under identical brand names similar enough to cause confusion. It is apparent
that a serious danger to health could exist if a relatively mild drug or
other product was dispensed in the place of a vitally needed antibiotic
or vice versa. Other situations, equally serious could also be imagined.
We investigated a complaint where a prescription drug was dispensed in
the place of the prescribed vitamin with a similar name.
POLICY:
All instances of drugs of different composition including different
dosage strengths being marketed under identical or similar brand names
are regarded as serious violations of the Act due to the inherent potential
health hazards. Regulatory action will normally be authorized*
REGULATORY ACTION GUIDANCE:
The following represents criteria for recommending legal action to the
*Division of Drug Labeling Compliance, HFD-310*.
1. Identical Brand Names for Drugs of Different Composition. Section
502(i)(3) of the Act specifies that a drug shall be deemed to be misbranded
if it is offered for sale under the name of another drug. This charge is
to be used when regulatory action is recommended in this situation..
2. Similar Brand Names for Drugs of Different Composition. Section 502(a)
of the Act specifies that a drug shall be deemed to be misbranded if its
labeling is false or misleading in any particular. This charge is to be
used when regulatory action is recommended in this situation.
The initial action of choice where no direct health hazard is involved
is a *warning* letter. Recall is the initial action of choice in situations
involving a hazard to health.
*Material between asterisks is new or revised*
Issued: 10/1/80
Revised: 5/22/87, 3/95
Sec. 400.600 Drugs - Declaration of Quantity
of Active Ingredient by Both Metric and Apothecary Systems (CPG 7132.03)
BACKGROUND:
The USP and NF allow the simultaneous use of both the metric and apothecary
systems to declare the quantity of active ingredients present in drug product
labeling. Prior to USP XX and NF XV, the official compendia allowed the
approximate equivalent of the exact quantity to be enclosed in parenthesis;
such as Quinidine Sulfate 200 mg. (3 grains).
On July 1, 1980 the USP XX and NF XV became official and requires that
"Where expressed in both the metric and apothecary systems, statements
of quantity or strength in the labeling of drug products shall utilize
the exact equivalent." (See inside back cover USP XX and NF XV). Therefore
the above example would now have to be modified to read Quinidine Sulfate
200 mg (3.086 grains).
POLICY:
USP and NF products shipped after 7/1/80 bearing a dual declaration
will be considered misbranded if the exact equivalents are not used. However,
as a general rule we are not prepared to initiate regulatory action of
this violation alone. It may be included as a 502(g) charge only when other
violations exist or it may serve as the basis for a Notice of Adverse Findings
letter.
Issued: 10/1/80
Sec. 400.700 Drug Product Entries in Periodic
Publications (CPG 7132b.17)
BACKGROUND:
On June 3, 1986, an attorney wrote to the Food and Drug Administration
("FDA") on behalf of the publisher of a monthly publication distributed
to physicians that contains entries describing prescribing information
for certain drug products. The attorney requested an advisory opinion on
whether FDA would deem the product entries labeling under section 201(m)
or advertising under section 502(n) of the Federal Food, Drug, and Cosmetic
Act ("the Act") for those products that were the subject of a
paid advertisement in the same publication. In response to this request,
FDA issued an advisory opinion in accordance with 21 C.F.R. 10.85 which
stated that the agency would not seek to regulate drug product entries
in question as advertising or labeling under the Act. This guide describes
the agency's enforcement policy reflected in that advisory opinion.
POLICY:
FDA generally will not seek to regulate drug product entries as labeling
or advertising under the sections of the Act cited above, when in publications
intended for distribution to physicians and other health professionals,
unless the publications are intended for use in promoting drug products.
In judging whether a publication that contains drug product entries
or reports may be subject to regulatory action as promotional, agency compliance
personnel should consider the following factors:
1. Whether the publication is published by an entity that is owned by,
controlled by, or otherwise affiliated with a drug company.
2. Whether the publication is primarily a compilation of factual, informative,
and educational data on a variety of drug products.
3. Whether the publication has been prepared solely for educational
and informational use, rather than promotional purposes.
4. Whether the publication determines which products will be included,
and has final, complete editorial control over all product entries and
other reports.
5. Whether the publication promotes the use of particular drugs or the
drugs of particular firms other than by providing space for advertising.
6. Whether the publication accepts advertising and other promotional
material from a variety of drug firms.
7. Whether the product entries cover a wide variety of drugs from a
wide variety of drug firms.
Promotional messages that appear in the publication as advertisements
are the manufacturer's responsibility and are subject to the requirements
of 21 C.F.R. 202.1. The publisher's product entry or report cannot serve
as a "brief summary" for an advertisement since it is not produced
by the promoter. In addition, if a manufacturer uses a product entry or
report for promotional purposes, the manufacturer's use of that entry or
report must comply with the Act's labeling or advertising requirements.
Issued: 8/15/89
Sec. 400.800 Collection and Charitable
Distribution of Drugs. (CPG 7132.08)
BACKGROUND:
A significant proportion of the prescription drugs distributed in the
United States is in the form of free physicians samples. Not all of these
samples are used by the physicians to whom they are given. As a result,
many religious, philanthropic and charitable organizations conceived the
idea of collecting and distributing these and drugs from other sources
for charitable purposes, especially overseas - a worthy undertaking fraught
with many pitfalls and hazards. Practically all of the protective provisions
of the Federal Food, Drug, and Cosmetic Act were being nullified by some
of these operations.
FDA's experience showed that many of the drug samples collected from
physicians and other sources were of questionable quality because of:
1. Age.
2. Adverse storage conditions such as excessive temperature or moisture.
3. Detached labeling.
4. Products that had been recalled from the U.S. market for various
reasons.
5. The presence of investigational drugs that are not approved for use
in general medical practice, and
6. Other factors.
From the legal point of view, the Federal Food, Drug, and Cosmetic Act
requires that a drug distributed through charitable channels be in compliance
with the applicable legal provisions in the same manner as a drug distributed
commercially. Initially, the Food and Drug Administration took the position
that samples of drugs intended for physicians should be used only under
their professional supervision and that any other disposition of physicians
samples was illegal. The courts ruled, however, that so long as the samples
are held in their original packages, and not repacked they are not in violation
per se, by being collected and held for sale or distribution for uses other
than as "physicians samples."
The controlling decision was given in an opinion by the U.S. Court of
Appeals for the Third Circuit in:
U.S. vs Various Articles of Drugs (Stanack Sales Co., Inc; Kaybel, Inc.;
William B. Mandell, T/a Mandell Pharmaceutcials; claimants), 3 circ., 1964
332 F.2d 286.
Following the above decision the FDA felt constrained to change its
position; at the same time recommending a procedure to eliminate or minimize
the risks involved in such collection programs. Questions also arose concerning
the division and repacking of large bulk contributions of pharmaceuticals.
POLICY:
To comply with the meaning and intent of the Federal Food, Drug, and
Cosmetic Act, and to insure the safety and integrity of drugs, FDA recommends
the following guidelines:
1. The sample drugs should be collected from the physician's office
in their original unopened packages only by authorized collectors. The
unopened samples should be placed in a carton, sealed, and sent to the
responsible collection agency. (A responsible collection agency is one
which is registered with the Food and Drug Administration; licensed by
the appropriate health agency, if required, in the State in which it operates;
and maintains its operations under the supervision of a registered pharmacist
or licensed physician.) The drugs so collected should not be sent directly
overseas.
2. The responsible collection agency should, under the supervision of
a registered pharmacist or licensed physician at the agency's place of
business, sort and screen all samples to eliminate all recalled, outdated
and investigational drugs.
3. Sample drugs, after having been screened and sorted, should be sent
in the original, unopened package by the agency to physicians and hospitals
overseas.
4. Large bulk contributions of pharmaceuticals intended for overseas
shipment may be subdivided, repackaged and labeled under the supervision
of a registered pharmacist or licensed physician as indicated in (1 and
2) provided proper control procedures are observed and the repackaged product
complies with the Food, Drug, and Cosmetic Act.
5. State laws which prohibit the operations provided for in these guidelines
will take precedence - thus if a State's law prohibits the collection of
physicians samples these guidelines would be inapplicable in that State.
Issued: 10/1/80
Sec. 400.900 Class I Recalls of Prescription
Drugs (CPG 7132.01)
BACKGROUND:
A Class I recall is an emergency situation involving removal from the
market of a product in which the consequences are immediate or long-range,
life threatening, and involve a direct cause-effect relationship. Class
I recalls can, if necessary, require retrieval of the recalled article
from consumers (users). The pattern of distribution of prescription drugs
to consumers is different from that of other articles. Retrieval of drugs
when in the possession of consumers must take into consideration the doctor/patient
relationship.
POLICY:
When there is a Class I recall of a prescription drug, retail level
consignees (retail, hospital, nursing home pharmacists) will be required
to review their prescription files for the appropriate time period consistent
with the period of distribution of the drug, in order to identify all customers
to whom the recalled drug was dispensed. The pharmacist must notify those
customers' physicians of the specific problem, and keep a record of the
physician notifications. The physician will be responsible for deciding
whether his patients are to be contacted.
If the pharmacist cannot distinguish in his prescription records between
those customers to whom the lot(s) of recalled drug was dispensed, and
those who received the same drug from a lot not under recall, or from a
different manufacturer, then the pharmacist, as a precautionary measure,
must notify the physicians of all customers who received the drug.
If retail level consignees (pharmacists, hospitals, dispensing physicians)
cannot identify persons to whom a drug under Class I recall was dispensed,
there must be a warning issued by FDA to the general public.
Issued: 10/1/80
Sub Chapter 405
Antibiotics
Sec. 405.100 Prescriptions Prepared from
Certified Antibiotics (CPG 7122.01)
BACKGROUND:
FDA Policy was requested concerning the situation in which a pharmacist
receives a prescription calling for an antibiotic preparation which is
not commercially available but which could be prepared on an extemporaneous
basis by the pharmacist, using an antibiotic preparation commercially available
to him in a certified package.
POLICY:
There is no objection under the FD&C Act if a pharmacist uses packages
of commercially available antibiotic products which he receives in certified
form for mixing with other components in order to prepare the particular
product called for in the physician's prescription. Our reply would be
the same if it was necessary for the pharmacist to use two or more certified
antibiotics in preparing the article called for in the physician's prescription.
The views expressed in the preceding paragraph are based on the situation
in which the pharmacist merely responds to the physician's request that
a noncertified antibiotic preparation be prepared for an individual case.
If a pharmacist should develop an antibiotic formula and induce physicians
to prescribe the article, the operation would then assume the nature of
a manufacturing operation. The resulting product would require batch certification
by FDA.
Issued: 10/1/80
Sec. 405.200 Export of Uncertified Antibiotics
(CPG 7122.02)
BACKGROUND:
Questions have arisen as to whether antibiotics which have not been
certified in accordance with Section 507 of the Act may be exported. In
addition, there is also some disagreement as to what antibiotic drugs are
subject to Section 505 instead of Section 507 and what the conditions for
export are for these drugs.
POLICY:
A certifiable antibiotic drug subject to Section 507 of the Act is not
subject to any provision of Section 505 and can be exported even if the
lot is uncertified if it is in conformance with Section 801(d) of the Act.
This is elaborated upon in 21 CFR 433.25.
A new antibiotic drug, exempted under Section 507(e) is a new drug subject
to Section 505. As such, it may not be introduced or delivered for introduction
into interstate commerce including export in the absence of an approved
new drug application.
When a new drug application is approved for a new antibiotic, it is
regarded as a certifiable antibiotic subject to Sections 507 and 502(l)
and may be exported provided that it is in conformance with Section 801(d)
of the Act.
NOTE: Legislation presently pending before both houses of Congress would
discontinue the disparate requirements for the export of antibiotic and
non-antibiotic drugs. Export of unapproved antibiotic drugs will be more
restrictive if this legislation is passed.
Issued: 10/1/80
Sec. 405.210 Returned Antibiotics Exported
Under 801(d) of the Act (CPG 7122.03)
BACKGROUND:
From time-to-time situations have occurred where uncertified antibiotics
exported under 801(d) of the Act, have been returned to the United States
for a variety of reasons such as being in surplus or failure to meet the
foreign consignee's specifications, container or product damage, etc.
Returned pharmaceuticals, including uncertified finished antibiotics
are considered to be imports and, as such, are held by U.S. Customs for
FDA examination. Generally, due to their U.S. origin, returned pharmaceuticals
have been allowed entry by the FDA without examination. However, a problem
exists regarding uncertified finished antibiotics (bulks and dosage forms)
in that since they are not from a certified batch they must be refused
entry except under the conditions set forth in 801(b) of the Act.
POLICY:
Uncertified antibiotics exported from the U.S. and subsequently returned
are considered to be imports by the FDA. If such returns would require
certification for domestic distribution, they must be detained because
they are misbranded under 502(l) of the Act due to their uncertified status.
They may be released only to the original U.S. exporter for reconditioning
under Section 801(b) of the Act if we are provided with an acceptable written
plan (FD-766, Application to Relabel or Perform other Action) to bring
the uncertified antibiotics into compliance. In general, uncertified antibiotics
may be brought into compliance by either:
1. Conversion into a chemical entity of possible use in the production
of another antibiotic product or chemical precursor, or
2. Reworking to resolve the problem that caused its return. In this
instance the product may be released for export under 801(d), or, if subsequently
certified, released unconditionally.
In lieu of the above options the product may be converted into a product
or substance not subject to the Act or destroyed in a manner acceptable
to FDA and released from import status.
Complete records must be kept which show the receipt, examination, handling,
storage, and ultimate disposition of the material as required by the CGMP
regulations (21 CFR 211).
Issued: 7/1/81
Sub Chapter 410
Bulk Drugs
Sec. 410.100 *Finished Dosage Form Drug
Products In Bulk Containers - Applications Of Current Good Manufacturing
Practice Regulations* (CPG 7132a.06)
BACKGROUND:
*Questions have arisen concerning the application of the "umbrella"
CGMP regulations, 21 CFR Parts 210 and 211 to firms which prepare dosage
form drug products in bulk containers, such as tablets in fiber drums,
and sterile antibiotic powders in bulk containers. Drug products in such
bulk quantities are usually intended for further repacking into conventional
retail packages such as bottles of 100 tablets each or vials of an antibiotic
powder for reconstitution. These questions of application have, on occasion
mistakenly expanded the term "bulk drug" to mean not only ingredients
of drug products but also finished dosage forms in large quantities. However,
in order to apply Parts 210 and 211 it is important to distinguish drug
products in finished dosage forms in bulk containers from bulk drug components
(i.e. ingredients intended for use in manufacturing or processing of a
drug product.)*
POLICY:
The CGMP regulations set forth in 21 CFR Parts 210 and 211 apply to
the preparation of finished dosage forms regardless of whether such drug
products are in bulk containers or retail packaged form. This is set forth
in 21 CFR 210.3(b)(4) and 211.3(a).
The CGMP regulations do not apply as binding regulations to bulk drug
components. They are to be used as guidelines during the inspection of
facilities manufacturing drug components (43 FR 45026, TP 42a, 9-29-78).
*Material between asterisks is new or revised*
Issued: 2/9/81
Revised: 9/4/87
Sub Chapter 420 Compendial/Test Requirements
Sec. 420.100 Adulteration of Drugs Under
Section 501(b) and 501(c) of the Act. *Direct Reference Seizure Authority
for Adulterated Drugs Under Section 501(b)* (CPG 7132a.03)
BACKGROUND:
Section 501(b) of the Food, Drug, and Cosmetic Act (the Act) deems an
official drug (i.e., a drug purported to be or represented as a drug the
name of which is recognized in an official compendium) to be adulterated
if it fails to conform to compendial standards of quality, strength or
purity. Compendial tests or assay methods are used when determining such
conformance under 501(b); the standards are stated in individual monographs
as well as portions of the General Notices section of the USP/NF. Standards
and test methods have been established for such characteristics as potency,
sterility, *dissolution*, weight variation and content uniformity.
If an official drug fails to conform to one or more compendial standards
of strength, quality or purity, but plainly states on the label how it
differs from the standard, then the drug is not deemed to be adulterated
under Section 501(b).
Section 501(c) of the Act deems *a drug that is not recognized in an
official compendium to be adulterated if it fails to meet the strength,
purity or quality which it purports or is represented to possess. The applicable
quality standards for a drug not recognized in an official compendium can
be determined from such sources as the labeling of the drug (or drug product),
the manufacturer's written specifications, and new drug applications. (Test
methods are usually contained in the written specifications or new drug
application).*
POLICY:
Any official drug which, when tested by compendial methods, fails to
conform to compendial standards for quality, strength, or purity, is adulterated
unless the differences from such standards are plainly stated on the drug's
label.
Any *drug which is not recognized in an official compendium is adulterated
if its strength differs from, or its purity or quality falls below that
which it purports or is represented to possess, when tested by scientifically
sound methods.*
REGULATORY ACTION GUIDANCE:
Recommendations for regulatory action will be considered in the above
instances of adulteration. The regulatory action of choice will depend
upon the circumstances of each case.
In cases where there is a health hazard, the first choice of action
should be recall, particularly for drugs found to be non-sterile, and for
narrow therapeutic range drugs that fail potency or dissolution tests.
However, where the district office has advised the firm of such a defective
product, and the firm fails to recall, seizure should be considered. Seizure
recommendations charging adulteration under section 501(c) should be submitted
to the Office of Compliance, Center for Drug Evaluation and Research (HFD-300)
(CDER).
District offices are authorized to submit seizure recommendations, charging
adulteration under section 501(b), directly to the Office of Enforcement
without CDER review under the following circumstances, provided introduction
or delivery for introduction into interstate commerce has been documented:
1. An official sample of either a compendial bulk pharmaceutical chemical
or a compendial finished dosage form has been analyzed using the compendial
methods without modification and found to fail both the original and check
analyses.
2. The analyzing laboratory has certified in the transmittal memorandum
that an unmodified compendial method was used.
Note: No tolerance need be applied beyond that provided by the official
compendium.
3. For sterile products, no check analysis is needed provided the compendial
sterility test was utilized without modification, the product is one that
is required to be sterile, and all relevant laboratory controls (including
positive and negative) are satisfactory.
Where the analyzing laboratory deviates from the official compendial
analytical method(s), a detailed description of the deviation(s) and justification
for such deviation(s) can be submitted to CDER for review. In such cases,
CDER will review only the deviation(s) and not the choice of regulatory
action or other documentation.
For seizure actions, the charges may be drafted as follows:
That the article of drug was adulterated, when introduced into and while
in interstate commerce and is adulterated while held for sale after shipment
in interstate commerce within the meaning of 21 U.S.C. 351(b), in that
it purports to be and is represented as a drug, the name of which is recognized
in an official compendium (United States Pharmacopeia) and its strength
differs from, and its quality and purity falls below the standard set forth
in such compendium because it fails the official (INSERT TYPE OF TEST)
test.
or
That the article of drug was adulterated, when introduced into and while
in interstate commerce and is adulterated while held for sale after shipment
in interstate commerce within the meaning of 21 U.S.C. 351(c), in that
it is a drug not subject to the provisions of 21 U.S.C. 351(b) and its
strength differs from, and its purity and quality falls below that which
it purports or is represented to possess because (e.g., the drug contains
less than the amount of (INSERT NAME OF INGREDIENT) on the label).
It should be kept in mind that the types of adulteration found under
501(b) and 501(c) may be indicative of a wider problem involving failure
of the manufacturer to adhere to current good manufacturing practice that
should be addressed.
Issued: 10/1/80
Revised: 5/1/92
Sec. 420.200 Compendium Revisions and
Deletions (CPG 7132.02)
BACKGROUND:
The USP and NF are continually being revised to keep pace with advances
in new drugs, analytical methods, changes in governmental regulations,
etc. The revisions are put into effect through periodic publication of
supplements and publication of new editions of the compendia every five
years. The revisions may, among other things, add monographs for new drugs,
delete monographs for others, change analytical procedures, or alter specific
requirements affecting strength, quality, and purity of the article. The
official article may be a drug product, an active ingredient, or a pharmaceutical
necessity.
On 7/1/80, when the combined USP XX/NF XV became official a major change
occurred. All monographs for dosage forms and active ingredients were placed
in the USP whereas all monographs for pharmaceutical necessities were placed
in the NF. It is anticipated that because of these changes that many more
articles, transferred from one compendium to the other, will have to be
relabeled than would normally be expected when a new compendium becomes
official. However, our basic policy will remain unchanged.
POLICY:
1. Articles shipped prior to and after the official date of the current
USP or NF.
A. All official articles shipped after the current USP/NF became official
should be in compliance with the current compendia.
B. All official articles shipped prior to the date that the current
USP/NF became official should be in compliance with the official compendia
in effect at the time of shipment.
2. Articles that have been dropped from the USP or NF.
Articles which at one time or another were recognized in either the
USP or NF, but are no longer recognized in the current edition of either
compendium should, if they are labeled as conforming to a superseded USP
or NF, bear a statement that the article is no longer official.
3. Articles that differ in strength, quality, or purity from the current
USP or NF.
Under Section 501(b) of the Act, a drug defined in an official compendium
shall not be deemed to be adulterated if it differs from the compendial
standard of strength, quality, or purity if the difference is plainly stated
on the label. 21 CFR 299.5(c) further clarifies this by requiring that
the label statement show all the respects in which such drug so differs,
and the extent of each such difference.
4. Articles that differ in identity from the USP or NF standard.
Both the USP and NF under "OFFICIAL" and "OFFICIAL ARTICLES"
in the General Notices section specify that where a product fails to comply
with the identity prescribed in the compendia, such product shall be designated
by a name that is clearly distinguishing and differentiating from any name
recognized in the compendia. This is also stated in 21 CFR 299.5(a).
REGULATORY ACTION GUIDANCE:
Regulatory action is not indicated based solely on the continued use
of existing stocks of old labels bearing the old USP or NF designation
provided that the firm makes arrangements to revise labels in a reasonable
period of time, and the drug meets the monograph requirements of the current
compendium.
Issued: 10/1/80
Sec. 420.300 Changes in Compendial Specifications
and NDA Supplements (CPG 7132c.04)
BACKGROUND:
Periodically due to advances in technology, methodology, etc., the compendial
specifications for a NDA drug will be changed. The question then arises
as to whether the NDA and ANDA holder(s) are required to supplement their
application(s).
POLICY:
Any change in the compendial specifications for an NDA drug will normally
require the submission of an NDA supplement as set forth in 21 CFR 314.8
and the supplement must normally be approved before the changes can be
effected by the NDA holder. However certain changes, as set forth in 21
CFR 314.8(a)(5), may be placed into effect without the approval of a supplement
under the conditions described in that section. Such changes included:
1. A change to more stringent specifications without altering the method
described in the approved application.
2. Inclusion of additional specifications and methods without deletion
of those described in the approved application.
3. The alteration of specifications or methods for inactive ingredients
to bring them into compliance with new or revised specification or methods
in an official compendium.
Issued: 10/1/80
Sec. 420.400 Performance of Tests for
Compendial Requirements on Compendial Products (CPG 7132.05)
BACKGROUND:
There have been inquiries from the field and industry concerning the
following four items as they apply to the manufacture of compendial (USP/NF)
drug products.
1. Does a firm have to use the compendial methodology on a batch release
basis, to determine whether its product meets the requirements of the monograph?
2. Does the word, "specifications" as used in 21 CFR 211.165
refer to compendial specifications or those set up by the firm's quality
control unit?
3. Does a firm have to test for all requirements listed in the monograph
for a compendial product?
4. Are the compendial testing requirements the same for products destined
for the commercial market and the military?
POLICY:
1. Compendial methods need only be applied, as a batch release test,
where a firm has made specific commitments to do so (as in a new drug application),
or where the official method is the only appropriate test. It should be
noted that neither the USP/NF nor the CGMP regulations necessarily require
a firm to utilize, as a batch release test, the methods and procedures
stated in the official compendia.
What is required is that official drug products conform to the appropriate
compendial standards. This conformance must be assured by suitable means,
including adequate manufacturing process validation and control. Scientifically
sound alternative test methods may be acceptable for the purpose of batch
release testing. However, in the event of a dispute as to whether or not
a drug product meets the standard, the compendial method will be applied
as the referee test.
2. The term "specifications" as used in 21 CFR 211.165 refers
to the criteria established by manufacturers to assure that their products
have the properties they purport to possess. Typically, these specifications
are identical to, or more stringent than those contained in the compendia
themselves. However, the manufacturer's specifications for standards of
strength, quality and purity may be less stringent in those cases in which
the differences from the official standards are stated on the product label;
such alternate standards must not adversely affect the product's safety
or efficacy.
3. Where an official product purports to conform to the standards of
the USP/NF the manufacturer must assure that each batch conforms to each
monograph requirement. This assurance must be achieved by appropriate means,
including process validation and controls and end product testing. However,
the nature and extent of end product testing which is needed will depend
upon the circumstances. Factors to consider in determining the need to
test each batch for a given monograph requirement include: the adequacy
of the manufacturer's process validation, adequacy of in-process manufacturing
controls, and the nature of the particular product characteristic which
is the subject of the specification (e.g. potency, sterility, content uniformity).
Therefore, in some cases it may not be necessary for a manufacturer to
test each batch for each monograph requirement.
4. Compendial testing requirements are the same for products destined
for commercial and military use unless the Defense Personnel Support Center
(DPSC) insists upon certain requirements as part of military contracts.
For example, DPSC can insist that only compendial methods be used and that
each batch be tested for every monograph specification, whereas, as explained
above, FDA considers that alternative procedures may sometimes be acceptable.
Under the Government Wide Quality Assurance Program FDA must assure that
the drug manufacturer abides by the terms of the military contract, including
testing requirements.
Issued: 10/1/80
Sec. 420.500 Interference with Compendial
Tests (CPG 7132a.01)
BACKGROUND:
The recurring question is: What is the legal status of a compendial
drug in which an added substance interferes with the compendial assay of
the product, even though the product may be fully potent as shown by other
methods of analysis?
Section 501(b) of the Federal Food, Drug, and Cosmetic Act states that
a drug is deemed to be adulterated if it is recognized in an official compendium
and its strength differs from, or its quality or purity falls below the
standards set forth in the compendium. Determination as to strength, quality,
or purity shall be made in accordance with tests or methods of assay set
forth in such compendium.
The USP XX in the section on Added Substances (p. 4) states that suitable
substances such as bases, carriers, coatings, colors, flavors, preservatives,
stabilizers, vehicles may be added to a pharmacopeial dosage form to enhance
its stability, usefulness, or elegance, or to facilitate its preparation.
The USP restrictions on the use of such added substances include "if
they do not interfere with the assays and tests prescribed for determining
compliance with the pharmacopeial standards."
POLICY:
A compendial drug product containing an added substance which interferes
with the compendial assay of the product would be adulterated under 501(b)
of the Act.
Issued: 10/1/80
Sub Chapter 425
Computerized Drug Processing
Sec. 425.100 Computerized Drug Processing;
CGMP Applicability To Hardware and Software* (CPG 7132a.11)
BACKGROUND:
The use of computers in the production and control of drug products
is quickly increasing. Questions have been raised as to the applicability
of various sections of the Current Good Manufacturing Practice Regulations
to the physical devices (hardware) which constitute the computer systems
and to the instructions (software) which make them function.
POLICY:
Where a computer system is performing a function covered by the CGMP
regulations then, in general, hardware will be regarded as equipment and
applications software1 will be regarded as records. The kind
of record (e.g., standard operating procedure, master production record)
that the software constitutes and the kind of equipment (e.g., process
controller, laboratory instrument) that the hardware constitutes will be
governed by how the hardware and software are used in the manufacture,
processing, packing, or holding of the drug product. Their exact use will
then be used to determine and apply the appropriate sections of the regulations
that address equipment and records.
1Applications software consists of programs written to specified
user requirements for the purpose of performing a designated task such
as process control, laboratory analyses, and acquisition/processing/storage
of information required by the CGMP regulations.
*Material between asterisks is new or revised*
Issued: 10/19/84
Revised: 9/4/87
Sec. 425.200 Computerized Drug Processing;
Vendor Responsibility (CPG 7132a.12)
BACKGROUND:
Computer systems used in the production and control of drug products
can consist of various devices (hardware) and programs (software) supplied
by different vendors, or in some cases by a single vendor. It is important
that such computer systems perform accurately and reliably, *and* that
they are suitable for their intended use.
Questions have arisen as to the vendor's responsibility in assuring
computer systems performance and suitability. When an integrated system,
composed of elements from several different vendors, fails, it can be especially
difficult to attribute the cause of a problem to one particular vendor.
POLICY:
The end user is responsible for the suitability of computer systems
(hardware and software) used in manufacture, processing or holding of a
drug product.
*The vendor may also be liable, under the FD&C Act, for causing
the introduction of adulterated or misbranded drug products into interstate
commerce, where the causative factors for the violation are attributable
to intrinsic defects in the vendor's hardware and software. In addition
vendors may incur liability for validation, as well as hardware/software
maintenance performed on behalf of users.*
*Material between asterisks is new or revised*
Issued: 1/18/85
Revised: 9/4/87
Sec. 425.300 Computerized Drug Processing;
Source Code for Process Control Application Programs (CPG 7132a.15)
BACKGROUND:
An increasing number of pharmaceuticals are being manufactured under
the control of computer systems. The manufacturing procedures, control,
instructions, specifications and precautions to be followed within such
automated systems are embodied in the computer program(s) which drive the
computer. Depending of the complexity of the programs, they may also contain
controlling data on product formulation, batch size, yields and automated
in-process sampling/testing procedures. In a manual system such procedures,
instructions, specifications, precautions and other controlling data would
be embodied in master production records which must be reviewed and approved
before implementation and which must be maintained, as required by the
current good manufacturing practice regulations (CGMP's). Such manual records
are, of course, prepared in human readable form.
In the case of computerized drug process control, certain information
required by CGMP's to be in a master production record is contained in
the source code for the application program. (An application program is
software written to specified user requirements for the purpose of performing
a designated task.) Source code is the human readable form of the program,
written in its original (source) programming language. Source code must
be compiled, assembled, or interpreted before it can be executed by a computer.
Because the source code ultimately has a direct and significant bearing
on drug product quality as manual master records, it is vital that source
code and supporting documentation be reviewed and approved by the drug
manufacturer prior to implementation, and be maintained as the CGMP's require
for master production and control records. (E.g., see 21 CFR 211.100, 211.180,
and 211.186.) Careful review of source code and its documentation is especially
important for assuring that process specifications, conditions, sequencing,
decision criteria, and formulas have been properly incorporated into the
computer program; source code should also be reviewed to detect and remove
dead code--non-executable instructions which are usually artifacts of earlier
versions of the program.
Supportive program documentation, such as flow diagrams and explanatory
narratives, can be useful in understanding and reviewing source code. However,
such documentation is not an acceptable substitute for source code itself.
POLICY:
We regard source code and its supporting documentation for application
programs used in drug process control to be part of master production and
control records, within the meaning of 21 CFR Parts 210 and 211.
Accordingly, those sections of the current good manufacturing practice
regulations which pertain to master production and control records will
be applied to source code.
Issued: 4/16/87
Sec. 425.400 Computerized Drug Processing;
Input/Output Checking (CPG 7132a.07)
BACKGROUND:
Section 211.68 (automatic, mechanical, and electronic equipment) of
the Current Good Manufacturing Practice Regulations requires, in part,
that input to and output from the computer or related system of formulas
or other records or data be checked for accuracy. This requirement has
generated questions as to the need for and extent of checking a computer's
input and output.
The agency received several petitions to delete or modify the requirement
on the grounds that a validated computer system need not have its input/output
routinely checked. The request to delete or modify the requirement was
denied because our experience has shown that input/output error can occur,
even in validated systems. Printouts, for example, can contain errors as
a result of faulty input, programming, or equipment malfunction. More significantly,
there is the human element which can induce errors. At worst, input/output
errors can result in serious production errors and distribution of adulterated
or misbranded products. Several recalls have, in fact, been conducted because
of insufficient input/output checks.
Despite the general need for input/output checks, not all input and
output need be checked. The regulation is, in fact, deliberately silent
on the required frequency and extent of data checking to afford firms the
necessary flexibility. Also, the use of efficient input edits, for example,
could mitigate the need for more detailed manual data checks.
POLICY:
Input/Output checks of data for computer systems, as required by 21
CFR 211.68, are necessary to assure the quality of a drug product processed
using such systems. The extent and frequency of input/output checking will
be assessed on an individual basis, and should be determined based upon
the complexity of the computer system and built in controls.
Issued: 9/20/82
Reissued: 9/4/87
Sec. 425.500 Computerized Drug Processing;
Identification of "Persons" on Batch Production and Control Records
(CPG 7132a.08)
BACKGROUND:
Section 211.188(b)(11) of the Current Good Manufacturing Practice Regulations
requires that batch production and control records include documentation
that each significant step in the manufacture, processing, packing, or
holding of a batch was accomplished, including identification of the persons
performing, directly supervising or checking each significant step in the
operation.
Questions have been raised as to acceptable ways of complying with this
requirement when the "person" performing, supervising or checking
each step is, in fact, not a human being, but rather an automated piece
of equipment, such as a computer system.
The intent of the regulation is to assure that each significant step
in a process was, in fact, performed properly and that there is some record
to show this. It is quite possible that a computerized system can achieve
the same or higher degree of assurance. In this case it may not be necessary
to specifically record the checks made on each of a series of steps in
the production of the product.
POLICY:
When the significant steps in the manufacturing, processing, packing
or holding of a batch are performed, supervised or checked by a computerized
system an acceptable means of complying with the identification requirements
of 21 CFR 211.188(b)(11) would consist of conformance to all of the following:
1. Documentation that the computer program controlling step execution
contains adequate checks, and documentation of the performance of the program
itself.
2. Validation of the performance of the computer program controlling
the execution of the steps.
3. Recording specific checks in batch production and control records
of the initial step, any branching steps and the final step.
NOTE: In assessing how well a computer system checks a process step
it is necessary to demonstrate that the computer system examines the same
conditions that a human being would look for, and that the degree of accuracy
in the examination is at least equivalent.
Issued: 11/2/82
Reissued: 9/4/87
Sub Chapter 430
Labeling and Repackaging
Sec. 430.100 Unit Dose Labeling for Solid
and Liquid Oral Dosage Forms (CPG 7132b.10)
BACKGROUND:
In recent years the pharmaceutical industry has responded to an increased
demand for drug products which are packaged for "unit dose" dispensing,
i.e. the delivery of a single dose of a drug to the patient at the time
of administration for institutional use, e.g., hospitals. The drug product
is dispensed in a unit dose container--a non-reusable container designed
to hold a quantity of drug intended for administration (other than the
parenteral route) as a single dose, directly from the container, employed
generally in a hospital unit dose system. The advantages of unit dose dispensing
are that the drug is fully identifiable and the integrity of the dosage
form is protected until the actual moment of administration. If the drug
is not used and the container is intact, the drug may be retrieved and
redispensed without compromising its integrity.
In view of the intended use of unit dose packaging, each unit dose container
is regarded as a drug in package form subject to all requirements of the
Act and implementing regulations. However, the pertinent labeling regulations
[21 CFR 201.10(i) and 201.100] present problems in interpretation in that
they are inconsistent with respect to exemptions for containers too small
or otherwise unable to accommodate a label with sufficient space to bear
all mandatory information. As a result of several recent regulatory actions
emphasizing these inconsistencies, the regulations will be rewritten in
the future to clarify the requirements.
Because of the general lack of uniformity in the labeling for unit dose
containers due to inconsistent interpretations of the regulations, or to
a lack of knowledge of unit dose labeling requirements, we are issuing
this Compliance Policy Guide (CPG).
This CPG does not encompass "Unit of Use" packaging which
is defined as a method of preparing a legend medication in an original
container, sealed and labeled, prelabeled by the manufacturer, and containing
sufficient medication for one normal course of therapy. (Reference: Proceedings
Unit of Use Packaging Conference, January 24-26, 1979).
POLICY:
Until the regulations are revised, the attached document describes the
labeling requirements for oral solid and liquid dosage forms packaged in
unit dose containers. The requirements apply to all firms which package
drugs into unit dose containers.
Since unit dosage forms are primarily intended for institutional use
rather than sale to the general public, we will not require the warnings
described in 21 CFR, Part 369 or the statements described under item 6.b.
(Section I and II) of Attachment A to be on the label; however, this information
must appear elsewhere in the labeling.
Where unit dose repacking is performed by a single facility for a closed
membership or group (e.g. "shared services") a current package
insert, bearing adequate directions for use, located on the premises of
each member to whom the repacked goods are shipped is regarded as satisfying
this requirement. The absence of such a current package insert on the premises
of a member to which a drug product is shipped will cause that drug product
to be misbranded.
Solid and liquid oral dosage forms in unit dose containers shall be
deemed misbranded under Section 502 of the Act if they deviate from the
attached list of requirements.
Other unit dose forms, e.g., topical ointments/creams, ophthalmic, etc.
are not included in this document. They will be considered at a future
date should circumstances warrant.
ATTACHMENT A
UNIT DOSE LABELING
I. PRESCRIPTION DRUGS (Solid and Liquid Oral Dosage Forms, e.g., Capsules,
Tablets, Solutions, Elixirs, Suspensions, etc.)
The label of the actual unit dose container must bear all of the following
information (except item 9).
NOTE: A firm may not claim an exemption on the basis that the label
is too small to accommodate all mandatory information if all available
space is not utilized or the label size can readily be made larger, or
if the type size on the label can readily be made smaller without affecting
the legibility of the information.
1. The established name of the drug and the quantity of the active ingredient
per dosage unit, if a single active ingredient product; if a combination
drug, the established name and quantity of each active ingredient per dosage
unit. In each case, the label must bear the established name and quantity
or proportion of any ingredient named in Section 502(e) whether active
or not. For solid dosage forms, a declaration of potency per tablet/capsule
will suffice; for liquid dosage forms, the total volume shall be declared
as well as the quantity or proportion of active ingredient contained therein,
e.g., Cimetadine HCL Liquid 5 ml, 300 mg/5 ml or 300 mg per 5 ml; or Septra/Bactrim
Suspension 5 ml, contains Trimethoprim 40 mg and Sulfamethoxazole 200 mg
per 5 ml; or each 5 ml. contains...
2. The expiration date (see Attachment B). (Ref. 21 CFR 201.17, 211.137).
3. The lot or control number. [Ref. 21 CFR 201.100(b), 211.130].
4. The name and place of business of the manufacturer, packer, or distributor
as provided for in 21 CFR 201.1.
5. For a drug recognized in an official compendium, the subject of an
approved new drug application (NDA/ANDA) or as provided by regulation:
A. Required statements such as "Refrigerate", "Protect
From Light", "Dilute Before Using", etc., [Ref.: FD&C
Act 502(f)(1), 502(g), and 505].
B. Any pertinent Statement bearing on the special characteristics of
the dosage form, e.g., sustained release, enteric coated, chewable, suspension,
etc.; [Ref. FD&C Act 502(e), 502(a), 201(n)].
6. For any drug product, not subject to 5:
A. Any pertinent statement bearing on special characteristics of the
dosage form, e.g., sustained release, enteric coated, sublingual, chewable,
solution, elixir, suspension, etc.; [Ref. FD&C Act 502(e), 502(a),
201(n)].
B. While not required to be on the label per se, it is strongly recommended
that:
(1) Any pertinent statement bearing on the need for special storage
conditions, e.g., "Refrigerate", "Do not Refrigerate",
"Protect from Light", etc., [Ref. FD&C Act 502(f)(1)] appear
on the label, and
(2) Any information needed to alert the health professional that a procedure(s)
is necessary prior to patient administration to prepare the product as
a finished dosage form, e.g., "Shake Before Using" [Ref: FD&C
Act 502(f)(1)].
7. If more than one dosage unit is contained within the unit dose container
(solid dosage form), the number of dosage units per container and the strength
per dosage unit should be specified (e.g., two capsules; each capsule contains
300 mg. Rifampin).
8. The statement "Warning: May be habit forming" where applicable,
the controlled drug substances symbol required by Drug Enforcement Administration
(DEA), and the name and quantity or proportion of any substance as required
by Section 502(d).
9. The National Drug Code designation is recommended, although this
is not mandatory.
In addition to all of the above (except item 9), the following information
must appear on the outer package from which the unit dose container is
dispensed:
1. The number of unit dose containers in the package, e.g., 100 unit
doses. If more than one dosage unit is within each unit dose container
this should also be stated (e.g., "100 packets; each packet contains
two tablets," or "100 packets of two tablets each.").
2. Full disclosure information, as detailed in 21 CFR 201.100. Where
unit dose repacking is performed by a single facility for a closed membership
or group (e.g., "shared services") a current package insert bearing
adequate directions for use, located on the premises of each member to
whom the repacked goods are shipped is sufficient to satisfy this requirement.
The absence of such a current package insert on the premises of a member
to which a drug is shipped will cause that drug to be misbranded.
3. The prescription legend.
II. OVER THE COUNTER DRUGS (Solid and Liquid Oral Dosage Forms, e.g.
Capsules, Tablets, Elixirs, Suspension, etc.)
The label of the actual unit dose container must bear all of the following
information (except item 9).
NOTE: A firm may not claim an exemption on the basis that the label
is too small to accommodate all mandatory information if all available
space is not utilized, the label size can be made larger, or if the type
size on the label can readily be made smaller without affecting the legibility
of the information.
1. The established name of the drug if it contains a single active ingredient;
if a combination drug, the established name of each active ingredient.
If a compendial drug, the label must express the quantity of each therapeutically
active ingredient contained in each dosage unit, e.g., Aspirin Tablets,
325 mg., (USP -General Notices), and the quantity or proportion of any
ingredient, whether active or not, as required by Section 502(e).
2. The expiration date (see attachment B).
3. The lot or control number.
4. The name and place of business of the manufacturer, packer, or distributor
as provided for in 21 CFR 201.1.
5. For a drug recognized in an official compendium, the subject of an
approved new drug application (NDA/ANDA) or as provided by regulation:
A. Required statements such as "Refrigerate", "Protect
from Light", "Dilute Before Using", etc.; [Ref. FD&C
Act 502(f)(1), 502(g), and 505].
B. Any pertinent statement bearing on special characteristics of the
dosage form, e.g., sustained release, enteric coated, chewable, suspension,
etc.; [Ref. FD&C Act 502(e), 502(a), 201(n)].
6. For any drug product not subject to 5:
A. Any pertinent statement bearing on special characteristics of the
dosage form, e.g., sustained release, enteric coated, sublingual, chewable,
solution, elixir, suspension, etc.; [Ref. FD&C Act 502(e), 502(a),
201(n)].
B. While not required to be on the label per se, it is strongly recommended
that:
(1) Any pertinent statement bearing on the need for special storage
conditions, e.g., "Refrigerate", "Do not Refrigerate",
"Protect from Light", etc., [Ref. FD&C Act 502(f)(1)], appear
on the label, and
(2) Any information needed to alert the user that a procedure(s) is
necessary prior to patient administration to prepare the product for use,
e.g., "Shake Well", "Dilute Before Using" [Ref: FD&C
Act 502(f)(1), 21 CFR 201.5].
7. If more than one dosage unit is contained within the unit dose container,
the number of dosage units per container should be specified (e.g., two
tablets aspirin; each tablet contains 325 mg).
8. The statement "Warning: May be habit forming" where applicable,
the controlled drug substances symbol required by DEA, and the name and
quantity or proportion of any substance required by Section 502(d).
9. The National Drug Code designation is recommended, although this
is not mandatory.
In addition to all of the above (except item 9), the following information
must appear on the outer package from which the unit dose container is
dispensed:
1. The number of unit dose containers in the package. If more than one
dosage unit is within each unit dose container this should also be stated
(e.g., "100 packets; each packet contains two tablets," or "100
packets of two tablets each.")
2. The labeling, i.e., the outer carton or a leaflet enclosed within
the package must bear adequate directions for use as specified in 21 CFR
201.5 and should include:
A. Statement of all conditions, purposes, or uses for which the drug
product is intended.
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 conditions.
C. Frequency of administration.
D. Duration of administration.
E. Time of administration (in relation to time of meals, time of onset
of symptoms, or other time factors).
ATTACHMENT B
EXPIRATION DATING OF SOLID AND LIQUID ORAL DOSAGE FORMS IN UNIT DOSE
CONTAINERS. (See CPG 7132b.11).
No action will be initiated against any unit dose repackaging firm,
including shared services, or drug product in unit dose container meeting
all other conditions of FDA's repackaging requirements, solely on the basis
of the failure of the repacking firm to have stability studies supporting
the expiration dates used provided:
1. The unit dose container complies with the Class A or Class B standard
described in the Twentieth Edition of the United States Pharmacopeia, General
Tests, Single-Unit Containers and Unit-Dose Containers for Capsules and
Tablets (page 955); and
2. The expiration date does not exceed six months; and
3. The six month expiration period does not exceed 25 per cent of the
remaining time between the date of repackaging and the expiration date
shown on the original manufacturer's bulk container of the drug repackaged,
and the bulk container has not been previously opened.
This policy does not apply to antibiotics or to nitroglycerin sublingual
tablets which are known to have stability problems that preclude them from
being repackaged.
Issued: 2/1/84
Sec. 430.200 Repacking of Drug Products
- Testing/Examination under CGMPs (CPG 7132.13)
BACKGROUND:
Questions have periodically arisen regarding how various testing and/or
examination requirements under the CGMP regulations (21 CFR Parts 210 and
211) are to be applied to repackers of finished dosage form drugs. In particular,
there have been questions regarding whether it is appropriate to apply
various "component" requirements in the CGMPRs (such as those
under Section 211.84 concerning identity testing and analysis or receipt
of a report of analysis for purity, strength, and quality) to finished
dosage form drugs which an establishment receives and repackages. It has
also been questioned how the requirements under 211.165 are to be applied
to repackers, insofar as the requirements for appropriate laboratory determination
for identity and strength of each active ingredient prior to release are
concerned.
We have carefully considered the suitability of applying the requirements
concerning "components" in the CGMPRs to repackers of finished
dosage form drugs. Due to the definitions of "component" under
210.3(b)(3) and "drug product" under 210.3(b)(4), we have concluded
that the requirements for "components" under Part 211 cannot
be suitably applied to finished dosage form drugs which are received by
an establishment and repackaged without alteration to the "drug product"
itself.
In the preamble to the final order for the CGMP regulations, it is pointed
out in regards to a manufacturer that there is no intent under 211.165(a),
once the product is in its finished dosage form, to require potency testing
of both the bulk and packaged drug product phases, and that manufacturers
could choose to do potency assays at either phase (43 FR 45062, paragraph
389). We believe a similar principle is applicable to drug product repackers;
where the manufacturer of the finished dosage form in a bulk container
is required to perform appropriate analytical testing for all appropriate
specifications, including the identity and strength of each active ingredient,
we do not consider it necessary for the repacker to repeat such testing
upon such drug products he receives and repacks with label declarations
consistent with those on the bulk container and without altering the properties
of the finished dosage form product.
POLICY:
Generally, we do not consider the CGMP regulations (21 CFR Parts 210
and 211) to require repackers of finished dosage form drugs to perform
analytical testing such as chemical identity tests or assays, or to require
receipt of reports of analysis, on a batch-by-batch basis for drug products
which are repacked under the following circumstances:
1. The incoming bulk containers of finished dosage form drug products
are received in intact, undamaged containers which are completely and properly
labeled as received, and there is no reason to suspect they have been subjected
to improper storage or transit conditions prior to receipt;
2. The repacking operations are conducted under conditions which assure
that the properties of the incoming drug product are not altered;
3. The repackaged containers are labeled with the same substantive labeling
declarations (e.g. identity, strength, and directions for use) concerning
the properties and use of the drug product which are consistent with the
labeling on the incoming bulk containers.
Under such circumstances we consider that requirements for appropriate
specifications and testing/examination procedures for repacked drug products
will be met by an appropriate system involving examination of the labeling
and sufficient organoleptic examination of the drug product to confirm
its identity in accordance with corresponding specifications established
by the repacker.
The policy in this Compliance Policy Guide applies only to the question
of adequate batch-to-batch testing/examination criteria for routine acceptance
and release of drug products which are repacked. It does not alter any
testing which repackers may be required to perform on drug products from
other standpoints, such as any stability testing required in order to establish
appropriate expiration dates in the container-closure system used by the
repacker, testing which may be required to determine the suitability of
the repacker's drug product containers and closures, testing which may
be necessary to establish appropriate time limits for the completion of
each phase of production, or
testing which may be required on non-penicillin drug products for the
presence of penicillin.
Issued: 7/1/81
Sec. 430.300 Labeling Shipping Containers
of Drugs (CPG 7132b.13)
BACKGROUND:
Because of the pilferage problem, some firms prefer not to name the
drugs on shipping containers, so that *their contents are not easily determined*.
Questions have been raised as to whether or not the FDC Act requires mandatory
label information on such shipping containers.
POLICY:
If the outer carton is used only to protect the goods during shipment
and is stripped away by the consignee, then the FDC Act does not require
any information to be stated on such shipping carton.
*Material between asterisks is new or revised*
Issued:7/12/76 as 7132b.12
Revised: 10/1/80, 5/22/87
Sec. 430.400 Urinary Preparations - Misbranding
- Lack of Rx Legend and Claims (CPG 7132b.04)
POLICY:
We are not prepared to take regulatory action against the following
class of products, particularly those which have been on the market for
a significant period of time:
Products offered as urinary antiseptics, urinary analgesics, acidifiers,
or diuretics; which are botanical mixtures, botanical with sodium biphosphate,
ammonium chloride, phenazopyridine hydrochloride, or these chemicals alone
or in combination.
Generally, we would prefer not to initiate regulatory action on such
products based on misbranding charges (lack of Rx legend or inadequate
full disclosure) until our medical position has been clarified.
If the product contains ingredients which may cause the drug to be dangerous
to health when used as directed or if its labeling makes direct claims
for more serious conditions, we might want to consider action. If you encounter
such products which you believe warrant action, submit full labeling and
formulation to Division of Drug Labeling Compliance, *HFD-310* for advice
before collecting samples for regulatory consideration.
*Material between asterisks is new or revised*
Issued: 10/1/80
Revised: 5/22/87, 3/95
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