FDA药品稳定指导大纲

Guidance for Industry
Q1A Stability Testing of New Drug SubstancesProducts

U.S. Department of HealthHuman Services
FoodDrug Administration
Center for Drug EvaluationResearch (CDER)
Center for Biologics EvaluationResearch (CBER)
ICH
August 2001
Revision 1
Additional copies of this guidance are available from:

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FoodDrug Administration
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Guidance for Industry Q1A Stability Testing of New Drug SubstancesProducts

This guidance represents the FoodDrug Administration”s (FDA”s) current thinking on this topic. It does not create or confer any rights for or on any persondoes not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutesregulations.
This guidance is a revision of Q1A Stability Testing of New Drug SubstancesProducts (September 1994). The purpose of the revision is to add information to certain sectionsto provide clarification to other sections of the guidance

I. INTRODUCTION (1)
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,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 substancesproducts, but leaves sufficient flexibility to encompass the variety of different practical situations that may be encountered due to specific scientific considerationscharacteristics of the materials being evaluated. Alternative approaches can be used when there are scientifically justifiable reasons.
B. Scope of the Guidance (1.2)
The guidance addresses the information to be submitted in registration applications for new molecular entitiesassociated 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 samplingtesting for particular dosage forms in their proposed container closures are not covered in this guidance.
Further guidance on new dosage formson biotechnological/biological products can be found in ICH guidances Q1CQ5C, 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,light,to establish a retest period for the drug substance or a shelf life for the drug productrecommended 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,the United States. The mean kinetic temperature in any part of the world can be derived from climatic data,the world can be divided into four climatic zones, I-IV. This guidance addresses climatic zones III. The principle has been established that stability information generated in any one of the three regions of the EU, Japan,the United States would be mutually acceptable to the other two regions, provided the information is consistent with this guidancethe labeling is in accord with national/regional requirements.
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.
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 pathwaysthe intrinsic stability of the moleculevalidate the stability indicating power of the analytical procedures used. The nature of the stress testing will depend on the individual drug substancethe 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% relative humidity or greater) where appropriate, oxidation,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.
Examining degradation products under stress conditions is useful in establishing degradation pathwaysdevelopingvalidating 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 batchesusing a method of manufactureprocedure 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 storagedistribution.
5. Specification (2.1.5)
Specification, which is a list of tests, references to analytical procedures,proposed acceptance criteria, is addressed in ICH Q6AQ6B. In addition, specification for degradation products in a drug substance is discussed in Q3A.
Stability studies should include testing of those attributes of the drug substance that are susceptible to change during storageare likely to influence quality, safety, and/or efficacy. The testing should cover, as appropriate, the physical, chemical, biological,microbiological attributes. Validated stability-indicating analytical procedures should be applied. Whetherto 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,annually thereafter through the proposed retest period.
At the accelerated storage condition, a minimum of three time points, including the initialfinal time points (e.g., 0, 3,6 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 initialfinal 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 conditionsthe lengths of studies chosen should be sufficient to cover storage, shipment,subsequent use.
The long-term testing should cover a minimum of 12 months” duration on at least three primary batches at the time of submissionshould 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 is not specifically covered by a subsequent section. Alternative storage conditions can be used if justified.
a. General case (2.1.7.1)

When significant change occurs at any time during 6 months” testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conductedevaluated 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)