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.