Guideline No. 5
Drug Stability Guidelines
Revised 12/01/1990 (Fourth Revision)
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
CENTER FOR VETERINARY MEDICINE
Original Nov. 2, 1976
First Revision Feb. 1, 1978
Second Revision July 1, 1979
Third Revision Dec. 1, 1987
Fourth Revision Dec. 1, 1990
[Note: The following is an editor's Table of Contents--it is not part of printed version of guidance]
Corrections Changes--Fourth Revision
Use of Drug Stability Guideline
New Animal Drug Stability Requirements
21 C.F.R. § 514.1(b)(5)(x)
21 C.F.R. § 211.137
21 C.F.R. § 211.166
21 C.F.R. § 225.58
21 C.F.R. § 226.58
Elements of a Stability Program
Section 1: General Considerations
Section 2: Specific Considerations
This document contains the Fourth Revision of the Drug Stability Guideline developed by the Center for Veterinary Medicine in the Food and Drug Administration.
Notice of the original publication of the guideline was made in the FEDERAL REGISTER, Vol. 41, No. 212, 41850, November 2, 1976. The first and second revisions provided for corrections, certain section changes and clarifications of various issues.
The third revision of the guideline contained editorial revisions and corrections, an updated section on containers, method format for analytical methods, stability references, new sections on medicated premixes and feeds and liquid feed supplements and the addition of a reference to rDNA derived products.
The fourth revision provides for changes based on comments received from on interested person, viz., the Animal Health Institute. A copy of the comments are on display in the Docket Management Branch. The major changes or revisions in the fourth revision of the guideline includes the following:
A specific list of changes is provided below.
An alphabetical list of major stability topics is provided at the end of section 3 of the guideline.
The guideline is not copyrighted. Agency approval is not required to reproduce them.
A list of the additions, changes or corrections made in this
revision of the guideline is provided below for quick reference.
Room/Elevated Temperatures - Medicated Products
Freezing: Precipitate
Ambient Temperature
Information on Decomposition Testing: Product Stress
Control Blank
Calculations
Multiple Dose Container
Addition of Definitions
Ambient Temperature of Type C Medicated Products
Elevated Temperature Study of Type C Medicated Products
Paragraph on Testing of Mash and Pellet
Clarification of Homogeneity Studies
Deletion of Note Section 3, part D.
Correction of Paragraphs 4 and 5
Soluble Powder: (1) Addition of Solution Studies
(2) Addition of Note Concerning
Type of Water for studies
Drinking Water: (1) Addition of Use of Ambient
Temperature
(2) Addition of Note Concerning
Type of Water for Studies
Oral Drenches: Addition of Note Concerning Type
of Water for Studies
Milk Replacers: Addition of Note Concerning Type
of Water for Studies
Addition of Paragraph on Drug Substances Stability
Alphabetical Listing of Stability Topics
DRUG STABILITY GUIDELINE
CENTER FOR VETERINARY MEDICINE
The guideline is to be used as an aid in designing and conducting studies to establish drug stability in support of original, abbreviated or supplements to new animal drug applications (NADAs/ANADAs). The guideline will provide a framework within which stability studies can be conducted to provide meaningful and sufficient data. The concept of the guidelines is applicable to studies on drug substances and the actual dosage form. The guideline is not intended to restrict experimentation. The guideline applys to pharmaceutical dosage forms and medicated feed products.
Section 512(b) of the Federal Food, Drug and Cosmetic Act (21 U.S.C. 360b) establishes the requirements for new animal drug approval. 21 CFR 514.1 specifies the proper form and the information required to be submitted. Included is a requirement under section 514.1(b)(5)(x) that an applicant submit data from stability studies completed as well as information about studies that are underway to substantiate the request for a specific expiration date and provide information on the stability of the drug products.
CGMP regulations under 21 CFR Part 200 also require stability testing for pharmaceutical dosage forms (21 CFR 211) and Type A Medicated Articles (medicated premixes) (21 CFR 226). This guideline can be used as an aid to conduct the required stability testing.
The agency advises that this final guideline represents its current position on the development of stability studies to meet the requirements of the submission of original or abbreviated new animal drug applications and the corresponding CGMP regulations. The guideline may be useful to manufacturers of new animal drug products. A person may follow the guideline or may choose to use alternate procedures even though they are not provided for in the guideline. If a person chooses to use alternate procedures, that person may wish to discuss the matter further with the agency to prevent an expenditure of money and effort on activities that may later be determined to be unacceptable by FDA. This guideline does not bind the agency, and it does not create or confer any rights, privileges, or benefits for or on any person.
Interested persons may submit written comments on the guideline to the Docket management Branch (HFA-305), Food and Drug Administration, Rm. 4-62, 5600 Fishers Lane, Rockville, MD 20857. Such comments will be considered in determining whether amendments to or revisions of the guidelines are warranted.
Original Nov. 2, 1976
First revision Feb. 1, 1978
Second Revision July 1, 1979
Third Revision Dec. 1, 1987
Fourth Revision Dec. 1, 1990
°514.1. Applications
[X] A complete description of, and
data derived from, studies of the <-------- STABILITY PROGRAM
stability of the new animal drug in the
final dosage form, including information
showing the suitability of the analytical<-------- METHOD SUITABILITY
methods used. A description of any
additional stability studies underway or
planned. Stability data for the finished
dosage form of the new animal drug in
the container in which it is to be <----------- MARKET CONTAINER
marketed, including any proposed
multiple dose container, and, if it is to
be put into solution at the time of
dispensing, for the solution prepared as <----------- RECONSTITUTED PRODUCTS
directed. If the new animal drug is
intended for use in the manufacture of
Type C medicated feed as defined in
Sec. 558.3 of this chapter, stability data
derived from studies in which
representative formulations of the
medicated feed articles are used. Similar
data may be required for Type B
medicated feeds as determined by the
Food and Drug Administration on a
case-by-case basis. Expiration dates
shall be proposed for finished <----------- EXPIRATION DATE NEED
pharmaceutical dosage forms and Type Finished Pharmaceuticals
A medicated articles. If the data Medicated Premixes
indicate that an expiration date is (Type A Article)
needed for Type B or Type C medicated <-----------
feeds, the applicant shall propose such |
expiration date. If no expiration date is < Medicated Feed Products
proposed for Type B or Type C | Type B
medicated feeds, the applicant shall | Type C
justify its absence with data.<------------------
Title 21--Food and Drugs Sec. 211.137 Expiration dating.
(a) To assure that a drug product
meets applicable standards of identity,<-------GENERAL REQUIREMENT
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 <-------STORAGE CONDITIONS/LABEL
labeling, as determined by stability
studies described in Sec. 211.166.
(c) If the drug products is to be
reconstituted at the time of dispensing,<-------RECONSTITUTED PRODUCTS
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 <------------DATE ON LABEL
requirements of Sec. 201.17 of this chapter.
(e) Homeopathic drug products shall <------------
be exempt from the requirements of |
this section I11(f) Allergenic extracts |
that are labeled "No U.S. Standard of |
Potency" are exempt form the requirements |
of this section. |-------EXEMPTIONS:
(f) Allergenic extracts that are | - Homeopathic Products
labeled "No U.S. Standard of Potency" are | - Human OTC Products
exempt from the requirements of this section. |
(g) 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. <----------------------
Title 21--Food and Drugs
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 <----------- WRITTEN PROGRAM
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 <----------- SAMPLES/TEST INTERVALS
based on statistical criteria for each
attribute examined to assure valid
estimates of stability;
(2) Storage conditions for samples
retained for testing; <----------- STORAGE CONDITIONS
(3) Reliable, meaningful, and
specific test methods; <----------- TESTS
(4) Testing of the drug product in
the same container-closure system as <----------- MARKET CONTAINER SYSTEM
that in which the drug products is
marketed;
(5) Testing of drug products for
reconstitution at the time of dispensing
(as directed in the labeling) as well as <----------- RECONSTITUTED PRODUCTS
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 <----------- BATCH SELECTION
maintained. Accelerated studies,
combined with basic stability information
on the components, drug products, <----------- ACCELERATED TESTING
and container-closure system, may be (Tentative Date)
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 <----------- TESTING COMMITMENT
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, <----------- HOMEOPATHIC 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 products is
being marketed.
(d) Allergenic extracts that are
labeled "No U.S. Standard of Potency"
are exempt from the requirements of
this section.
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.
Sec. 226.58 Laboratory controls.
Laboratory controls shall include
the establishment of adequate
specifications and test procedures to
assure that the drug components and the
Type A medicated article(s) conform to
appropriate standards of identity,
strength, quality, and purity.
Laboratory controls shall include:
(a) The establishment of master
records containing appropriate
specifications and a description of the
test procedures used to check them for
each kind of drug component used in the
manufacture of Type A medicated
article(s). This may consist of the
manufacturer's or supplier's statement
of specifications and methods of
analyses.
(b) The establishment of
specifications for Type A medicated
article(s) and a description of necessary
laboratory test procedures to check such
specifications.
(c) Assays which shall be made of
representative samples of finished Type
A medicated article(s) in accordance
with the following schedule:
(1) Each batch of a Type A medicated
article(s) manufactured from an undiluted
drug shall be assayed for its drug
component(s).
(2) In the case of Type A medicated
article(s) which are manufactured by
dilution of Type A medicated article(s)
assayed in accordance with paragraph
(c)(1) of this section, each batch shall
be assayed for its drug component(s)
with the first five consecutive batches
assaying within the limitations, followed
thereafter by assay of representative
samples of not less than 5 percent of all
batches produced. When any batch does
not assay within limitations, each batch
should again be assayed until five
consecutive batches are within
limitations.
(d) A determination establishing
that the drug components remain uniformly
dispersed and stable in the Type A <------- HOMOGENEITY
medicated article(s) under ordinary
conditions of shipment, storage, and use. <------- STABILITY
This may consist of a determination on a
Type A medicated article(s) of
substantially the same formula and
characteristics. Suitable expiration <------- EXPIRATION DATE
dates shall appear on the labels of the
Type A medicated article(s) to
assure that the articles meet the
appropriate standards of identity,
strength, quality, and purity at the time
of use.
(e) Adequate provision to check the
reliability, accuracy, and precision of
any laboratory test procedure used. The
official methods in "Methods of Analysis
of the Association of Official Analytical
Chemists", (see footnote *) methods
described in an official compendium, and
any method submitted as a part of a
food additive petition or new-drug
application that has been accepted by
the Food and Drug Administration shall be
regarded as meeting this provision.
(f) Provisions for the maintenance
of the results of any assays, including
dates and endorsement of analysts. Such
records shall be retained in the
possession of the manufacturer and shall
be maintained for a period of at least 2
years after distribution by the
manufacturer of the Type A medicated
article(s) has been completed.
* Footnote - [40 FR 14031, Mar. 27, 1975, as amended
at 55 FR 11577, Mar. 29, 1990]
* End footnote.
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