Any modification to the drug substance manufacturing process such as facility / equipment changes, synthetic route changes etc. has the potential to affect the final drug product’s quality / efficacy / safety. To avoid such risks and keep the industry informed about the best practices, as part of the reauthorization of the Generic Drug User Fee Amendments (GDUFA II), the United States Food and Drug Administration (US FDA) has recently issued a guidance on post-approval changes to Type II API Drug Master Files (DMFs) and submission mechanisms for Abbreviated New Drug Application (ANDA) holders who reference such DMFs. Though the guidance is only for comment purpose, it clearly laid out information for drug manufacturers looking to make post-approval changes to the drug substance manufacturing process and pointed out how should they report the change and provide required information about the change to CDER, CMER or CVM.

Is the guidance applicable to all types of drug product applications?

The guidance applies only to the holders of the application types listed below.

  • New Drug Application (NDA)
  • Abbreviated New Drug Application (ANDA)
  • New Animal Drug Application (NADA)
  • Abbreviated New Animal Drug Application (ANADA)
  • Drug Master File (DMF)
  • Veterinary Master File (VMF)

The guidance does not apply to the holders of biologics license applications (BLAs) or master files cross-referenced in the BLAs. Also, it does not address complex active ingredient and it does not address post-approval changes to,

  • Peptides, oligonucleotides and radiopharmaceuticals  
  • Drug substances isolated from natural sources  
  • Drug substances produced by procedures involving biotechnology
  • Non-synthetic steps (such as fermentation) for semi-synthetic drug substances

What Does It Emphasize?

The guidance referred only to synthetic drug substances and the synthetic steps involved in preparing semi-synthetic drug substances. The exact nature of changes to which the guidance applies to are as follows:

  • Facility, scale, and equipment changes associated with all steps of drug substance manufacturing
  • Specification changes to starting materials, raw materials, intermediates, and the unfinished and final drug substance
  • Synthetic manufacturing process changes
  • Changes in the source of the drug substance
  • Changes to the container closure system for the drug substance

The guidance also covers Regulatory aspects about risk assessment, the routeway of notification of the change and the reporting responsibilities and the documentation requirements. For manufacturers with post-approval changes to the drug substance manufacture, the need of the hour is to consult a proven Regulatory expert for a professional change evaluation and compliant notification of the change as per the proposed recommendations. Be informed right from the first step. Be compliant throughout product life cycle. 


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