Regulatory Focus™ > News Articles > FDA Clarifies Stability Testing Requirements for Generics with New Draft Guidance

FDA Clarifies Stability Testing Requirements for Generics with New Draft Guidance

Posted 26 August 2013 | By Alexander Gaffney, RAC

The US Food and Drug Administration (FDA) has released a new draft guidance meant to clarify the agency's expectations about abbreviated new drug applications (ANDAs) and the stability testing used to support those applications.


Under the 1984 Hatch Waxman Act, drug manufacturers were given the ability to compete with innovative drug applications originally filed through the new drug application (NDA) approval pathway. Under the act, innovative products were given a period of market-based exclusivity during which FDA could not approve generic competitors, after which time generic drugs could be approved via the ANDA pathway.

Those ANDAs are principally concerned with showing the equivalence of the generic product to the innovative product, also known as the reference listed drug (RLD). While this includes bioequivalence (BE) testing, it also includes testing to show that its stability-the ability of a product to hold its potency and characteristics over time-is equivalent to the RLD.

The topic was the subject of a September 2012 guidance, ANDAs: Stability Testing of Drug Substances and Products, which explained that sponsors should conform to five standards maintained by the International Conference on Harmonization (ICH):

"Although the ICH stability guidances were developed by ICH to provide guidance on the information that should be provided in NDAs to ensure the stability of new drug substances and drug products, we believe the recommendations should be applied to ANDAs as well," FDA explained in the guidance.

Thus, the new guidance replaces an earlier one released in 1995, and calls on sponsors to do the following:

  • submit stability data from three pilot-scale batches (or two pilot-scale batches and one small-scale batch)
  • provide six months of accelerated and long-term condition data, with the drug being manufactured and stored in conditions representative of the final process
  • use multiple lots of drug substance as appropriate
  • provide a fully packaged primary exhibit batch
  • use three batches when using bracketing and matrixing designs under ICH Q1D
  • provide statistical analysis of the data as appropriate, in accordance with ICH Q1E, Appendix A
  • provide justifications for any deviations from the guidance

New Q&A

Now FDA has released a new question-and-answer guidance document meant to provide clarity to certain common issues.

For example, because ANDAs are popular routes for approving products intended for export through the President's Emergency Plan for AIDS Relief (PEPFAR), manufacturers had inquired whether they would be held to the same standard under the guidance. FDA said the same three-batch standard applies to these products, as well as ANDAs for positron emission tomography (PET) drugs.

FDA also said that with respect to the timing of intermediate, accelerated and long-term stability testing, all studies should begin at the same time "so the data are available at the time of submission, if needed." Some manufacturers had questioned if accelerated study conditions alone would be sufficient for approval.

In another answer, FDA said it would support a proposed expiry period of "two times the available long-term data at the time of approval […] provided the submitted data are satisfactory and data evaluation is provided in accordance with ICH Q1E." Practically speaking, this will allow for a two-year expiration date based on the recommended 12 months of long-term data. Accelerated data will not support 24-month extrapolation.

In addition, FDA said that even if a patent is about to expire for the RLD, a sponsor may not support an ANDA with three months of stability data, even if it supplies a commitment to supply the full six months of data when available. The data must be available at the time of filing the ANDA, FDA explained.

Other parts of the guidance clarify definitions, such as the definition of "small" in "small scale" batches. FDA explains that this definition will vary depending on the physical characteristics of the drug. For example, an oral tablet dosage form should have two batches of "at least" 10% of the proposed production batch or 100,000 finished dosage units (whichever is the larger amount), while the third batch can be smaller, but not less than 25% of the size of the first two tests.

Different definitions of "small" exist for powders, parenterals, transdermal patches, topical creams and inhalation solutions/nasal sprays.

The full draft guidance may be found on FDA's website.

Draft Guidance for Industry: Abbreviated New Drug Applications; Stability Testing of Drug Substances and Products, Questions and Answers

Federal Register

Regulatory Focus newsletters

All the biggest regulatory news and happenings.