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ANDA Regulatory Pathway: Stability Testing FAQs

Do you have questions about FDA’s guidance for industry regarding Abbreviated New Drug Application (ANDA) stability requirements? We caught up with Avomeen’s CMC expert, Neelam Varshney, to answer the most frequently asked questions about ANDAs: Stability Testing of Drug Substances and Products.

Does FDA’s ANDA stability testing guidance apply to post approval changes?

No, it does not apply to post approval changes. The ANDA stability testing guidance applies to all new ANDAs, and drug master files (DMFs) (type II for drug substances that support the ANDAs).

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

In short, yes. 6 months of accelerated stability data as well as 6 months of long-term stability data should be provided at the time of submission. However, if 6 months of accelerated data show a significant change or failure of any attribute, 6 months of intermediate data should also be included in the ANDA submission.

Can you define significant change?

Significant change is defined in the International Conference on Harmonisation (ICH) guidance to industry on Q1A(R2) Stability Testing of New Drug Substances and Products, section

  • 5% change in assay from its initial value, or failure to meet the acceptance criteria for potency when using biological or immunological procedures;
  • Any degradation product’s exceeding its acceptance criterion;
  • Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, resuspendibility, 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

  • Failure to meet the acceptance criterion for pH; or
  • Failure to meet the acceptance criteria for dissolution for 12 dosage units

One of the three batches that were tested under accelerated conditions shows a significant change. How should this be handled?

If there is a significant change or failure for any attribute in one or more batches, intermediate data for all 3 batches should be submitted. Additionally, a discussion concerning the observed failure(s) should be included in the submission.

For an original ANDA, can stability bracketing and/or matrixing be used to establish packaging configurations to be placed on stability without first obtaining approval from the Office of Generic Drugs (OGD)?

Yes. ICH guidance for industry on Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products and its example tables should be referenced and followed.

For simple dosage forms, is there an instance where only two lots of finished product at pilot scale batch size would be considered sufficient to support the stability of an ANDA?

According to FDA stability guidance, for all dosage forms, data should be submitted from three pilot scale batches or the applicant should submit data from two pilot scale batches and one small scale batch.

How should I reference stability timeframes in my submission? Months or weeks?

You should reference stability timeframes in months, not weeks. FDA, following the recommendations of ICH stability guidances, refers to timeframes in terms of months, not weeks. For example, 6 months accelerated data should not be referred to as 24 weeks.

A patent is going to expire soon, and there are no approved ANDAs. Can the ANDA be filed with 3 months of stability data, along with a commitment to provide 6 month data when it’s available?

FDA stability guidance needs to be followed regardless of the status of a patent.

How long do the three pilot scale batches that are submitted as part of an ANDA need to be stored before they can be disposed of or destroyed?

Generally, ANDA submission batch samples should be stored for 1 year after approval. Samples of drug product used for bioequivalence (BE) studies need to be stored according to the requirements listed in 21 CFR 320.38 and 21 CFR 320.63.

Can different lots of APIs and/or packaging materials be used to manufacture drug product? When manufacturing finished product lots to support the ANDA, how many API lots should be used?

A minimum of two lots of the API should be used to prepare the three primary batches of drug product to be placed on stability. However, if nasal aerosols or sprays are being manufactured, three different lots of API should be used. It’s only necessary to use different lots of packaging material in cases where packaging material could affect drug product performance and/or delivery.

Should the final proposed packaging be used to store all three batches?

Yes. The same container-closure system that’s been proposed for marketing should be used for the three batches.

Is it acceptable to package small scale batches by hand or with research equipment, or should they be packaged with commercial equipment?

FDA doesn’t recommend packaging small scale batches by hand or using research equipment. According to FDA guidance, small scale batches should be packaged with equipment that’s similar to what’s been proposed for use prior to market distribution, or by commercial equipment.

Does all relevant CMC batch information for the three stability batches need to be included in the application?

Yes. The corresponding section in Module 3 should be complete with appropriate CMC information when more than one lot of API or excipients are used.

I’m still looking for more information. Where do I go?

Get in touch with one of our regulatory and scientific experts.


Our expert blogger is Neelam Varshney, Avomeen’s Sr. Technical Director, Pharmaceutical Sciences. Neelam’s diligence and intellect brings incredible value to Avomeen and to our clients. She has extensive experience in all CMC aspects of pharmaceutical products from preclinical testing and submission to IND/NDA modules to post-approval regulatory requirements. Neelam’s great wealth of regulatory knowledge of all CMC aspects include expertise in E&L for all product types, including drug-device combination products, and Avomeen’s clients benefit greatly from her insight and expertise in cleaning validation. To all of this, Neelam brings 22 years of pharmaceutical industry experience, primarily applying ICH and other regulatory guidance to build compliant products.