ANDAs: Impurities in Drug Products
US FDA has issued recommendations In Nov 2010 on what chemistry, manufacturing, and controls (CMC) information sponsors should include regarding the reporting, identification, and qualification of impurities that are classified as degradation products in drug products when submitting:
* Original abbreviated new drug applications (ANDAs)
*ANDA supplements for changes that may affect the quantitative or qualitative degradation product profile
They have also provided recommendations for establishing acceptance criteria for degradation products (specifically, degradation products of the active ingredient or reaction products of the active ingredient with an excipient(s) and/or immediate container/closure system) in generic drug products. The recommendations document replaces on issued in 1998.
FDA in the issued document that it is not establish legally enforceable rather it is a current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited.
US FDA has issued this document for the following reasons:
1. To update information on listing of degradation products, setting acceptance criteria, and qualifying degradation products (thresholds and procedures) in ANDAs in conformance with the revision of the guidance for industry on Q3B(R) Impurities in New Drug Products.
2. To remove those sections of the 1998 document containing recommendations that are no longer needed because they are addressed in the more recent Q3B(R)
The Q3B(R) has been developed by the International Conference on Harmonisation (ICH) to provide guidance on impurities in drug products for new drug applications (NDAs). However, the US FDA believes that many of the recommendations provided on impurities in drug products also apply to ANDAs.
*Lower thresholds can be appropriate if the degradation product is unusually toxic.
For example, do known safety data for this degradation product or its structural class preclude human exposure at the observed level?
A degradation product is considered qualified for ANDAs when one or more of the following conditions are met:
When the observed level and proposed acceptance criterion for the degradation product do not exceed the level justified by the RLD.
When the degradation product is a significant metabolite of the drug substance.
When the observed level and the proposed acceptance criterion for the degradation product are adequately justified by the scientific literature.
When the observed level and proposed acceptance criterion for the degradation product do not exceed the level that has been adequately evaluated in toxicity studies.
*If considered desirable, a minimum screen (e.g.,genotoxic potential) should be conducted. A study to detect point mutations and one to detect chromosomal aberrations, both in vitro, are considered an appropriate minimum screen for genotoxicity.
*If general toxicity studies are appropriate, one or more studies should be designed to allow comparison of unqualified to qualified material. The study duration should be based on available relevant information and performed in the species most likely to maximize the potential for detecting the toxicity of a degradation product. On a case-by-case basis, single-dose studies can be appropriate, especially for single-dose drugs. In general, a minimum duration of 14 days and a maximum duration of 90 days would be considered appropriate.
ANDAs: Impurities in Drug Products:List of the types of degradation products:
ANDAs: Impurities in Drug Products: Setting Acceptance Criteria for Degradation Products
ANDAs: Impurities in Drug Products: Qualification of Degradation Products
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