FDA publishes Draft Guidance on Stability Testing of Generics

For a long time, the well-known ICH guidelines on stability of pharmaceutical APIs and medicinal products, ICH Q1A - Q1E, have been the basis for the assessment of data submitted for new drug applications (NDA) in the three large economic regions Europe, USA and Japan. Now, the FDA is planning to extend the scope of these guidelines also to abbreviated new drug applications (ANDAs).

The reason for that is based on the fact that the FDA has been receiving more and more inquiries about stability requirements for generics. Up to the present, there has been only one existing guidance document, an "Industry Letter" from 1995, which states that OGD (Office of Generic Drugs) will accept long-term room temperature conditions for stability studies (i.e., 25±2°C, 60±5% RH). With regard to the growing number of complex ANDAs, the FDA felt compelled to harmonise its approach of assessing such applications.

The Agency described in a new draft guideline entitled "ANDAs: Stability Testing of Drug Substances and Products" published on 25 September this year its expectations about the stability data to be submitted by the applicants. Fortunately, not all the complete stability data are required like for applications regarding innovation medicinal products. Fundamentally, the applicant must comply with the following requirements:

  • "Submit data from three pilot scale batches or two pilot batches and one small scale batch. If the size of the pilot does not follow ICH recommendations, the applicant should provide a justification.
  • At the time of submission, provide 6 months of data that include accelerated and long-term conditions. FDA recommends following ICH with respect to utilization of 65 intermediate conditions to support shelf-life.
  • Use multiple lots of drug substance as appropriate.
  • Manufacture and package the drug product using principles that are representative of the commercial process.
  • 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."

Deviations from the above recommendations should be justified.

The requirements apply to both the application itself (ANDA) and the attending Drug Master File for the API (DMF Type II).

These obligations go far beyond the usual scope. Interest groups from the generic industry have therefore already expressed some concerns with regard to the capacity in terms of personnel and space required to be able to cope with the performance of additional stability studies.

Comments to the draft guideline "ANDAs: Stability Testing of Drug Substances and Products" should be submitted within 90 days. The publication can be found in the US Federal Register from 25 September 2012.

Note: The ECA Conference "Setting Specifications and Stability Testing" on 26 - 28 November 2012 will address all the essential aspects of stability testing of APIs and medicinal products.

Dr Gerhard Becker
CONCEPT HEIDELBERG (a service provider entrusted by the ECA Foundation)

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