Regulatory Focus™ > News Articles > Regulators Ask: Is FDA's Generic Drug Submission Process Broken?

Regulators Ask: Is FDA's Generic Drug Submission Process Broken?

Posted 22 January 2014 | By Alexander Gaffney, RAC

Can the quality of generic drug applications to the US Food and Drug Administration (FDA) be improved, and if so, what can regulators do to improve it?

So asks FDA in a new Federal Register notice published on 22 January 2014, in which the agency notes that the completeness and quality of abbreviated new drug applications (ANDA)-the application used by generic drugs-has left something to be desired by regulators as of late.

Common Problems

"The Office of Generic Drug's (OGD) review is often hindered by the quality of the ANDA submissions," FDA states in the notice.

Some problems have seemingly come up time and again. Regulators listed dozens of common deficiencies, grouped into six major categories:

  1. Filing: Failure to provide a completed Form FDA 356h; unjustified inactive ingredient levels; inadequate dissolution data; packaging less than the recommended threshold amount without justification; inadequate or insufficient stability data; submissions of non-qualitative and non-quantitative (not Q/Q) same formulations; electronic submission and formatting deficiencies; applications containing an incorrect or unfounded basis of submission.
  2. Chemistry: Poor or inadequate justification of impurities limits; failure to provide a list of potential impurities and their origins; failure to provide adequate verification of analytical procedures for active pharmaceutical ingredient and finished dosage forms, where appropriate; failure to identify the critical manufacturing process parameters or to link in-process controls to development studies; failure to provide appropriate acceptance criteria of manufacturing yields for the critical steps, or providing yield values varying without adequate rationale or explanation.
  3. Sterilityassurance for sterile drug product applications manufactured by aseptic processing: Failure to describe sterilization and/or depyrogenation of relevant equipment and components that may come in contact with the sterile drug; failure to provide relevant validation data for sterilization and/or depyrogenation of relevant equipment and components that may come in contact with the sterile drug; failure to provide validation data for sterilizing grade filters, if needed; failure to provide process simulation data for the proposed aseptic filling process/line/room.
  4. Bioequivalence: Inaccurate and/or incomplete information contained in electronic tables; submission of pharmacokinetic repeats; inaccurate and/or incomplete biowaiver requests (e.g., inappropriate method of solubility determination, lack of dissolution data for all strengths, missing standard operating procedures for analytical methods).
  5. Fatal flaws: Significant flaws in the design of a drug product such that the proposed product will not be able to meet all conditions of use of the reference listed drug.
  6. Drug master files: Submission contains more than a single drug substance or more than a single drug manufacturing process; failure to update the drug master file following a large number of amendments or time lapse since the original submission; failure to provide a complete description of manufacturing process and controls; failure to justify appropriate starting materials.

A Process of Improvement: Four Questions

The good news for both regulators and industry is that FDA is now flush with money thanks to the Generic Drug User Fee Act (GDUFA) of 2012 and has committed to making fixes to the process where it can. The goal, FDA said, is to reform the process to allow for more predictable reviews and approval decision timelines.

And the process of improvement starts now, and it starts with industry and the public.

FDA's Register notice explains that it's soliciting input from stakeholders on "how to improve the completeness and quality of ANDA submissions to OND," and is interested in "hearing about any difficulties sponsors are having developing and preparing their applications for submission that FDA could help address."

FDA said it is specifically interested in hearing industry's response to four specific questions:

  1. What aspects of the ANDA application process are confusing or not well defined?
  2. What problems do ANDA applicants encounter when developing a submission that FDA could help address? 
  3. Prior to GDUFA, were ANDA submissions consistently slowed or stalled at certain recurring review points post-filing? If so, why?
  4. How should FDA share suggestions for improving ANDA submissions with industry, beyond issuing regulatory guidance?

Regulators said they are also interested in hearing about how they can best disseminate their eventual findings, such as in a guidance, a dedicated webpage, a question-and-answer document, or other forms of assistance.

Comments on the ANDA process are due in 60 days and may be submitted to FDA's federal docket citing document number FDA-2014-N-0032.


Federal Register

Regulatory Focus newsletters

All the biggest regulatory news and happenings.