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DRAFT - Not for Implementation Guidance for Industry · PDF file 2014-11-29 · DRAFT - Not for Implementation J:\!GUIDANC\1707DFT9.WPD 5/27/98 Guidance for Industry Stability Testing

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  • DRAFT - Not for Implementation

    J:\!GUIDANC\1707DFT9.WPD 5/27/98

    Guidance for Industry Stability Testing of Drug Substances and Drug Products

    DRAFT GUIDANCE

    This guidance document is being distributed for comment purposes only.

    Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.

    Copies of this draft guidance are available from the Office of Training and Communications, Division of Communications Management, Drug Information Branch, HFD-210, 5600 Fishers Lane, Rockville, MD 20857 (Phone 301-827-4573) or from the Internet at http://www.fda.gov/cder/guidance/index.htm.

    Copies also are available from the Office of Communication, Training and Manufacturers Assistance, HFM- 40, CBER, FDA, 1401 Rockville Pike, Rockville, MD 20852-1448, or from the Internet at http://www.fda.gov/cber/guidelines.htm. Copies also may be obtained by fax from 1-888-CBERFAX or 301-827-3844 or by mail from the Voice Information System at 800-835-4709 or 301-827-1800.

    For questions on the content of the draft document, contact Kenneth Furnkranz (301) 827-5848.

    U.S. Department of Health and Human Services Food and Drug Administration

    Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

    June 1998

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    TABLE OF CONTENTS

    I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

    II. STABILITY TESTING FOR NEW DRUG APPLICATIONS . . . . . . . . . . . . . . . . . . . . 3 A. Drug Substance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 B. Drug Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 C. New Dosage Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 D. Other NDAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

    III. STABILITY TESTING FOR ABBREVIATED NEW DRUG APPLICATIONS . . . . . 21 A. Drug Substance Stability Data Submission . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 B. Drug Substance Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 C. Drug Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 D. ANDA Data Package Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 E. Exceptions to the ANDA Data Package Recommendations . . . . . . . . . . . . . . . . 23 F. Data Package for Approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 G. Stability Study Acceptance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

    IV. STABILITY TESTING FOR INVESTIGATIONAL NEW DRUG APPLICATIONS . 24 A. Phase 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 B. Phase 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 C. Phase 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

    V. APPROVED STABILITY PROTOCOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

    A. Stability Protocol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 B. Stability Commitment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

    VI. REPORTING STABILITY DATA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 A. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 B. Content of Stability Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 C. Formatting Stability Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

    VII. SPECIFIC STABILITY TOPICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 A. Mean Kinetic Temperature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 B. Container/Closure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 C. Microbiological Control and Quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 D. Stability Sampling Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 E. Statistical Considerations and Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 F. Expiration Dating Period/Retest Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 G. Bracketing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 H. Matrixing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 I. Site-Specific Stability Data For Drug and Biologic Applications. . . . . . . . . . . . 58 J. Photostability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 K. Degradation Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

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    L. Thermal Cycling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 M. Stability Testing in Foreign Laboratory Facilities . . . . . . . . . . . . . . . . . . . . . . . 72 N. Stability Testing of Biotechnology Drug Products . . . . . . . . . . . . . . . . . . . . . . . 73

    VIII. CONSIDERATIONS FOR SPECIFIC DOSAGE FORMS . . . . . . . . . . . . . . . . . . . . . 80 A. Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 B. Capsules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 C. Emulsions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 D. Oral Solutions and Suspensions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 E. Oral Powders for Reconstitution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 F. Metered-Dose Inhalations and Nasal Aerosols . . . . . . . . . . . . . . . . . . . . . . . . . 81 G. Inhalation Solutions and Powders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 H. Nasal Sprays: Solutions and Suspensions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 I. Topical, Ophthalmic and Otic Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 J. Transdermals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 K. Suppositories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 L. Small Volume Parenterals (SVPs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 M. Large Volume Parenterals (LVPs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 N. Drug Additives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 O. Implantable Subdermal, Vaginal and Intrauterine Devices that Deliver Drug

    Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

    IX. STABILITY TESTING FOR POSTAPPROVAL CHANGES . . . . . . . . . . . . . . . . . . . 85 A. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 B. Change in Manufacturing Process of the Drug Substance . . . . . . . . . . . . . . . . . 87 C. Change in Manufacturing Site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 D. Change in Formulation of the Drug Product . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 E. Addition of a New Strength for the Drug Product . . . . . . . . . . . . . . . . . . . . . . . 92 F. Change in Manufacturing Process and/or Equipment for the Drug Product . . . . 93 G. Change in Batch Size of the Drug Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 H. Reprocessing of a Drug Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 I. Change in Container and Closure of the Drug Product . . . . . . . . . . . . . . . . . . . 96 J. Changes in the Stability Protocol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

    BIBLIOGRAPHY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

    GLOSSARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

    LIST OF TABLES

    Table 1: Long-Term/Accelerated Testing Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

    Table 2: Summary of Uniform Storage Statements in Drug Product Labeling . . . . . . . . . .

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