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Guidelines for Stability Testing of Pharmaceutical Products

Stability testing of pharmaceutical products provide an 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 re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions.

Stability guidelines for pharmaceutical products addresses the information to be submitted in registration applications for drug products. Where include –

Stress testing

Photo-stability testing

Selection of batches

Testing frequency

Storage conditions

Container closure system

Significant Changes in Stability Testing of Pharmaceutical Product

As per ICH stability testing guidelines, significant change for a drug product is defined as:

1. A 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures;

2. Any degradation product’s exceeding its acceptance criterion;

3. Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, re-suspendibility, caking, hardness, dose delivery per actuation); however, some changes in physical attributes (e.g., softening of suppositories, melting of creams) may be expected under accelerated conditions; and, as appropriate for the dosage form:

4. Failure to meet the acceptance criterion for pH; or

5. Failure to meet the acceptance criteria for dissolution for 12 dosage units.

Read also: Basic Knowledge on Stability Study

Statistical Approaches for Evaluation of Stability Data

Where applicable, an appropriate statistical method should be employed to analyze the long-term primary stability data in an original application. The purpose of this analysis is to establish, with a high degree of confidence, a retest period or shelf life during which a quantitative attribute will remain within acceptance criteria for all future batches manufactured, packaged, and stored under similar circumstances.

Read also: Shelf Life Determination of Pharmaceutical Products

FDA Stability Guidance Question and Answer

1. Can an ANDA be submitted with 6 months of accelerated stability and 6 months of long-term stability data?

Yes. An ANDA applicant should submit 6 months of accelerated stability data and 6 months of long-term stability data at the time of submission. However, if 6 months of accelerated data show a significant change or failure of any attribute, the applicant should also submit 6 months of intermediate data at the time of submission.

2. When do intermediate stability studies need to be initiated in the event of failure at accelerated condition?

An ANDA applicant should start accelerated, intermediate, and long-term stability studies at the same time so the data are available at the time of submission if the accelerated stability study fails.

3. If one among the three batches in accelerated conditions shows a significant change, what should be done?

If accelerated data show a significant change or failure of any attribute in one or more batches, an applicant should submit intermediate data for all three batches. In addition, the submission should contain a failure analysis (i.e., discussion concerning the observed failure(s)).

4. Can stability bracketing and/or matrixing be used to determine the packaging configurations to be placed on stability for an original ANDA without prior approval from the Office of Generic Drugs (OGD)?

Yes. You should follow the International Conference on Harmonization (ICH) guidance for industry on Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products and its example tables.

5. During the review cycle, will the application need to be updated with 12 months of long-term data?

FDA will grant a shelf life period of two times the available long-term data at the time of approval (up to 24 months) following the recommendation of the ICH Q1E Evaluation of Stability Data (ICH Q1E) guidance, provided the submitted data are satisfactory, and data evaluation and appropriate commitments are provided in accordance with ICH Q1E. Please refer to the decision tree (Appendix A) in ICH Q1E. The ANDA should be updated with 12 months of long-term data during the review cycle.

6. Can only two lots of finished product at pilot scale batch size ever be considered sufficient to support the stability of an ANDA for simple dosage forms?

According to the FDA stability guidance, the applicant should submit data from three pilot scale batches or should submit data from two pilot scale batches and one small scale batch. This applies to all dosage forms. If the size of the pilot scale batch does not follow ICH recommendations, the applicant should provide a justification.

7. How is the proposed shelf life supposed to be calculated? Will 6 months of accelerated data equal 24 months at long-term?

ICH Q1E principles will help in the calculation of shelf life. Data from the three ANDA submission batches (i.e., 6 months), accelerated data meeting all criteria (without significant change per ICH Q1A(R2)), and 12 months long-term data without variability will not need statistical evaluation, and with appropriate post approval stability commitments, can be used to support extrapolation to a 24 months shelf life.

8. When a patent is due to shortly expire and there are no approved ANDAs, can we file with 3 months stability data with a commitment to supply 6 months data when available?

No. Data recommendations in the FDA stability guidance should be followed irrespective of patent status.

9. How long do the three pilot scale batches, submitted as a part of an ANDA, need to be stored before destruction?

Sample storage times are discussed in 21 CFR 320.38 and 21 CFR 320.63 in connection with bioequivalence study samples. 

In general, ANDA submission batch samples should be stored for 1 year after approval of the

ANDA, and samples of the drug product used for bioequivalence studies must be stored following the requirements listed in 21 CFR 320.38 and 21 CFR 320.63. 

In addition, the guidance for industry on Handling and Retention of BA and BE Testing Samples may be helpful regarding the procedure for handling reserve samples from relevant bioavailability and bioequivalence studies. Additional information on sample quantities (for retention purposes) is discussed in 21 CFR 211.170 (a) and (b), Reserve Samples.

Read also: Bracketing and Matrixing in Stability Study

Reference Guidelines for Stability Study of Pharmaceutical Products

1. ICH Q 1 A (R2) Stability Testing of new Drug Substances and Products

2. ICH Q 1 E Evaluation of Stability Data

3. World Health Organization (WHO) Technical Report Series, No. 953, 2009 (1)

4. Guidance for Industry ANDAs: Stability Testing of Drug Substances and Products

Read also: Forced Degradation Study in Pharmaceutical Industry

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