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Guidance for Industry Q1A(R2) Stability Testing of New Drug Substances and Products 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) November 2003 ICH Revision 2 Guidance for Industry Q1A(R2) Stability Testing of New Drug Substances and Products Additional copies are available from: Office of Training and Communication Division of Drug Information, HFD-240 Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 (Tel) 301-827-4573 http://www.fda.gov/cder/guidance/index.htm or Office of Communication, Training and Manufacturers Assistance, HFM-40 Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike, Rockville, MD 20852-1448 http://www.fda.gov/cber/guidelines.htm. (Tel) Voice Information System at 800-835-4709 or 301-827-1800 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) November 2003 ICH Revision 2 Contains Nonbinding Recommendations i TABLE OF CONTENTS I. INTRODUCTION (1) ................................................................................................1 A. Objectives of the Guidance (1.1).............................................................................................................1 B. Scope of the Guidance (1.2) .....................................................................................................................2 C. General Principles (1.3)............................................................................................................................2 II. GUIDANCE (2)..........................................................................................................2 A. Drug Substance (2.1) .................................................................................................................................2 1. General (2.1.1)..............................................................................................................................................2 2. Stress Testing (2.1.2)...................................................................................................................................3 3. Selection of Batches (2.1.3) ........................................................................................................................3 4. Container Closure System (2.1.4)..............................................................................................................3 5. Specification (2.1.5).....................................................................................................................................3 6. Testing Frequency (2.1.6)...........................................................................................................................4 7. Storage Conditions (2.1.7)..........................................................................................................................4 8. Stability Commitment (2.1.8)......................................................................................................................6 9. Evaluation (2.1.9).........................................................................................................................................7 B. Drug Product (2.2) .....................................................................................................................................8 1. General (2.2.1)..............................................................................................................................................8 2. Photostability Testing (2.2.2) .....................................................................................................................8 3. Selection of Batches (2.2.3) .......................................................................................................................8 4. Container Closure System (2.2.4)..............................................................................................................8 5. Specification (2.2.5).....................................................................................................................................9 6. Testing Frequency (2.2.6)...........................................................................................................................9 7. Storage Conditions (2.2.7)........................................................................................................................10 8. Stability Commitment (2.2.8)....................................................................................................................14 9. Evaluation (2.2.9).......................................................................................................................................15 10. Statements/Labeling (2.2.10) .................................................................................................................16 GLOSSARY (3) .............................................................................................................. 17 REFERENCES (4) .......................................................................................................... 21 ATTACHMENT List Of Revision 2 Changes.................................................................. 22 Contains Nonbinding Recommendations 1 Guidance for Industry1 Q1A(R2) Stability Testing of New Drug Substances and Products This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. I. INTRODUCTION (1) 2 This guidance is the second revision of Q1A Stability Testing of New Drug Substances and Products, which was first published in September 1994 and revised in August 2001. The purpose of this revision is to harmonize the intermediate storage condition for zones I and II with the long-term condition for zones III and IV recommended in the ICH guidance Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV. The changes made in this second revision are listed in the attachment to this guidance. A. Objectives of the Guidance (1.1) This guidance is intended to define what stability data package for a new drug substance or drug product is sufficient for a registration application within the three regions of the European Union (EU), Japan, and the United States. It does not seek to address the testing for registration in or export to other areas of the world. The guidance exemplifies the core stability data package for new drug substances and products, but leaves sufficient flexibility to encompass the variety of different practical situations that may be encountered due to specific scientific considerations and characteristics of the materials being evaluated. Alternative approaches can be used when there are scientifically justifiable reasons. 1 This guidance was developed within the Expert Working Group (Quality) of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been subject to consultation by the regulatory parties, in accordance with the ICH process. This document was endorsed by the ICH Steering Committee at Step 4 of the ICH process, February 2003. At Step 4 of the process, the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States. 2 Arabic numbers reflect the organizational breakdown in the document endorsed by the ICH Steering Committee at Step 4 of the ICH process. Contains Nonbinding Recommendations 2 B. Scope of the Guidance (1.2) The guidance addresses the information to be submitted in registration applications for new molecular entities and associated drug products. This guidance does not currently seek to cover the information to be submitted for abbreviated or abridged applications, variations, or clinical trial applications. Specific details of the sampling and testing for particular dosage forms in their proposed container closures are not covered in this guidance. Further guidance on new dosage forms and on biotechnological/biological products can be found in ICH guidances Q1C Stability Testing for New Dosage Forms and Q5C Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products, respectively. C. General Principles (1.3) The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors, such as temperature, humidity, and light, and to establish a retest period for the drug substance or a shelf life for the drug product and recommended storage conditions. The choice of test conditions defined in this guidance is based on an analysis of the effects of climatic conditions in the three regions of the EU, Japan, and the United States. The mean kinetic temperature in any part of the world can be derived from climatic data, and the world can be divided into four climatic zones, I-IV. This guidance addresses climatic zones I and II. The principle has been established that stability information generated in any one of the three regions of the EU, Japan, and the United States would be mutually acceptable to the other two regions, provided the information is consistent with this guidance and the labeling is in accord with national/regional requirements. FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. II. GUIDANCE (2) A. Drug Substance (2.1) 1. General (2.1.1) Information on the stability of the drug substance is an integral part of the systematic approach to stability evaluation. Contains Nonbinding Recommendations 3 2. Stress Testing (2.1.2) Stress testing of the drug substance can help identify the likely degradation products, which can in turn help establish the degradation pathways and the intrinsic stability of the molecule and validate the stability indicating power of the analytical procedures used. The nature of the stress testing will depend on the individual drug substance and the type of drug product involved. Stress testing is likely to be carried out on a single batch of the drug substance. The testing should include the effect of temperatures (in 10°C increments (e.g., 50°C, 60°C) above that for accelerated testing), humidity (e.g., 75 percent relative humidity or greater) where appropriate, oxidation, and photolysis on the drug substance. The testing should also evaluate the susceptibility of the drug substance to hydrolysis across a wide range of pH values when in solution or suspension. Photostability testing should be an integral part of stress testing. The standard conditions for photostability testing are described in ICH Q1B Photostability Testing of New Drug Substances and Products. Examining degradation products under stress conditions is useful in establishing degradation pathways and developing and validating suitable analytical procedures. However, such examination may not be necessary for certain degradation products if it has been demonstrated that they are not formed under accelerated or long-term storage conditions. Results from these studies will form an integral part of the information provided to regulatory authorities. 3. Selection of Batches (2.1.3) Data from formal stability studies should be provided on at least three primary batches of the drug substance. The batches should be manufactured to a minimum of pilot scale by the same synthetic route as production batches and using a method of manufacture and procedure that simulates the final process to be used for production batches. The overall quality of the batches of drug substance placed on formal stability studies should be representative of the quality of the material to be made on a production scale. Other supporting data can be provided. 4. Container Closure System (2.1.4) The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution. 5. Specification (2.1.5) Specification, which is a list of tests, references to analytical procedures, and proposed acceptance criteria, is addressed in ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances and Q6B Contains Nonbinding Recommendations 4 Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Biotechnological/Biological Products. In addition, specification for degradation products in a drug substance is discussed in ICH Q3A Impurities in New Drug Substances. Stability studies should include testing of those attributes of the drug substance that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy. The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes. Validated stability-indicating analytical procedures should be applied. Whether and to what extent replication should be performed should depend on the results from validation studies. 6. Testing Frequency (2.1.6) For long-term studies, frequency of testing should be sufficient to establish the stability profile of the drug substance. For drug substances with a proposed retest period of at least 12 months, the frequency of testing at the long-term storage condition should normally be every 3 months over the first year, every 6 months over the second year, and annually thereafter through the proposed retest period. At the accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study is recommended. Where an expectation (based on development experience) exists that the results from accelerated studies are likely to approach significant change criteria, increased testing should be conducted either by adding samples at the final time point or including a fourth time point in the study design. When testing at the intermediate storage condition is called for as a result of significant change at the accelerated storage condition, a minimum of four time points, including the initial and final time points (e.g., 0, 6, 9, 12 months), from a 12-month study is recommended. 7. Storage Conditions (2.1.7) In general, a drug substance should be evaluated under storage conditions (with appropriate tolerances) that test its thermal stability and, if applicable, its sensitivity to moisture. The storage conditions and the lengths of studies chosen should be sufficient to cover storage, shipment, and subsequent use. The long-term testing should cover a minimum of 12 months’ duration on at least three primary batches at the time of submission and should be continued for a period of time sufficient to cover the proposed retest period. Additional data accumulated during the assessment period of the registration application should be submitted to the authorities if requested. Data from the accelerated storage condition and, if appropriate, from the intermediate storage condition can be used to evaluate the effect of short-term excursions outside the label storage conditions (such as might occur during shipping). Long-term, accelerated, and, where appropriate, intermediate storage conditions for drug substances are detailed in the sections below. The general case should apply if the drug substance Contains Nonbinding Recommendations 5 is not specifically covered by a subsequent section. Alternative storage conditions can be used if justified. a. General case (2.1.7.1) Study Storage condition Minimum time period covered by data at submission Long-term* 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH 12 months Intermediate** 30°C ± 2°C/65% RH ± 5% RH 6 months Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 months * It is up to the applicant to decide whether long-term stability sturdies are performed at 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH. ** If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition. If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5% RH and significant change occurs at any time during 6 months’ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria. Testing at the intermediate storage condition should include all tests, unless otherwise justified. The initial application should include a minimum of 6 months’ data from a 12-month study at the intermediate storage condition. Significant change for a drug substance is defined as failure to meet its specification. b. Drug substances intended for storage in a refrigerator (2.1.7.2) Study Storage condition Minimum time period covered by data at submission Long-term 5°C ± 3°C 12 months Accelerated 25°C ± 2°C/60% RH ± 5% RH 6 months Data from refrigerated storage should be assessed according to the evaluation section of this guidance, except where explicitly noted below. If significant change occurs between 3 and 6 months’ testing at the accelerated storage condition, the proposed retest period should be based on the real time data available at the long-term storage condition. If significant change occurs within the first 3 months’ testing at the accelerated storage condition, a discussion should be provided to address the effect of short-term excursions outside the label storage condition (e.g., during shipping or handling). This discussion can be supported, if appropriate, by further testing on a single batch of the drug substance for a period shorter than Contains Nonbinding Recommendations 6 3 months but with more frequent testing than usual. It is considered unnecessary to continue to test a drug substance through 6 months when a significant change has occurred within the first 3 months. c. Drug substances intended for storage in a freezer (2.1.7.3) Study Storage condition Minimum time period covered by data at submission Long-term -20°C ± 5°C 12 months For drug substances intended for storage in a freezer, the retest period should be based on the real time data obtained at the long-term storage cond