BRIEF FROM THE PDA WORKSHOP ON FDA’S NEW GUIDANCE ON PROCESS VALIDATION “THE SHIFTING PARADIGM IN PROCESS VALIDATION” OCTOBER 26-27, 2009 (10/31/2009)

Background:

  1. The FDA’s Draft Guidance on Process Validation is nearing approval stage.  It has been circulating within the industry for comments for a year and FDA is committed to finalizing by the end of 2009.
  2. This was the fourth of five workshops to discuss the new guidance document and to solicit feedback from the industry.  Consequently, the focus of discussions at the PDA workshops has shifted over the course of the year from review to implementation.

Introduction:

  1. The concepts contained in the draft guidance document are not revolutionary.  In many ways, they reinforce what we (BioTechLogic) are already doing.
  2. What we sense as different is a renewed focus on Stage 1 (Process Design) and Stage 3 (Continued Process Verification) during PAI and CMC review.
  3. While we already knew this, “Process Validation” is now being considered as a progressive sequence of activities rather than as an event.  Three consecutive successful full-scale batches is now a minimalistic approach.

Stage 1 (Process Design):

  1. Design of Experiment (DOE) during process development is now a must.  Single variable experiments that lack an evaluation of interacting parameters are not sufficient for gaining process knowledge and defining Critical Operating Parameters.
  2. Process Characterization Reports should include a full discussion of both “design space” and interacting parameters.  Statistical evaluation of experimental data is crucial.

Stage 2 (Process Qualification):

  1. Overall, this stage is very much the same.  The biggest change is that FDA is very hesitant to use the term “three consecutive batches” to describe Process Qualification (PQ).  “As many as it takes to demonstrate process control” is the new mantra.
  2. Additional sampling throughout PQ was emphasized.  It was also noted that additional sampling should continue after PQ and into Continued Process Verification (CPV) until the appropriate process knowledge is gained.

Stage 3 (Continued Process Verification):

  1. There is a strong emphasis on Statistical Process Control (SPC) for this stage.
  2. Whereas commercial data evaluation in the form of an annual report was previously expected, more frequent monitoring and formal internal reporting will be expected.
  3. Investigators are now being trained to inspect commercial sites one to two years post-approval to specifically evaluate: (1) maintenance of a validated process (i.e., CPV), (2) stability data, and (3) quality of incoming materials and components.
  4. The agency strongly recommends a formal protocol for CPV.