Interview with: Peter Calcott, Ph.D.
President, Calcott Consulting

1. What are your takeaways from FDA's New Validation Guidance and what are the areas that you are asking your team to focus on?

There are several takeaways from the guidance. Firstly, there is the point that process validation is not a one time activity. Once you begin, you continue until the product stops being marketed. This is really the conversion of an activity that is reactive (the agencies tell us to do it), to one that is proactive (the beginning of continuous improvement). In this way the activity becomes value added rather than a cost liability. The second is that the activity relies heavily on the foundations of a robust process development activity. You can call it Quality by Design or just a strong process development program. Thirdly, there will be more up front development activity to build this foundation prior to performing any process validation. In fact this activity is paramount to assure there is value added in performing the continuous process validation confirmation during the lifecycle.

2. In your view, what are some of the biggest challenges/obstacles to implementing the new guidance?

A major potential obstacle or challenge is to convince the agency to go from the classical 3 or 5 runs to zero versus to 20-30. It is clear that 3 or 5 runs does not tell you or give you data to assure the process has translated from the bench to the plant. In the present mind set, 20-30 runs would give you more data at the large scale to assure that the process is operating as predicted. Thus it is logical that agencies might want to require these runs prior to approval. However, I feel industry will challenge this from an economic perspective with tremendous push back - and rightfully so. Rather with the new paradigm, the robust process development program with QbD will lay the foundation for design space, which, with a validated scale down model for the commercial process, will deliver the assurance that the commercial process is rugged. Thus logically, the number of process validation runs pre-approval should decrease to zero with a commitment to perform formal review and adjustment initially with the first 20-30 or so and then afterwards continuously as you move into the verification phase. Thus we will get out of the pre-submission rush to get the PV work done. With this continuous verification, it will enable you to truly move into a value added arena.

Another area of challenge is to determine when all this "added" activity is performed. No senior manage is going to allow the submission to be pushed back to accommodate the extra studies and they will also be reluctant to start much before the phase 3 process is being developed. Rather, there needs to added resources during the classic process development phase for the phase 3 process to accommodate the work. This, together with more intelligent experimental design using Q9 Quality Risk Management, will allow an efficient building of the process framework that will pay off in the future.

3. What are your next steps towards aligning your validation strategies with the guidance?

For the new paradigm to take hold requires several elements. Firstly, we must develop and assure that our process development programs are robust and meet the requirements for QbD. Secondly, we have a validated scaled down process model to test all the parameters for impact. Thirdly, we truly understand our design space and the impact of inputs, control points and control strategies that lead to our outputs, which we can clearly define with respect to attributes. Fourthly, we must negotiate with the agency with respect to the number of PV runs needed prior to approval moving forward, prior to making the submission. Fifthly, we recognise that QbD and the PV guidance apply to certain drugs, biologics and devices. But there maybe other areas or products where this strategy will add value. While it may not be required today, if there is a business advantage to apply it, it will add value. Progressive companies that are looking into the future will see the writing on the wall and begin to move in this direction to create a competitive advantage.