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Three strikes for traditional “fixed-point” process validation

Last week’s cold and dreary weather in San Diego did not hinder the casual exchange of information in hallways and seminar rooms, the sharing of technical and business success stories, the launch of new technologies and products, and the input from regulatory authorities that has come to characterize IBC’s annual “BDP Week” conference. The only activity impacted by the weather was the outdoor reception, bravely attended by participants who huddled around the heat lamps while enjoying the food, drink, and camaraderie with colleagues.

This year’s conference contained so many information-packed tracks that it was sometimes a challenge to decide which room to migrate to after the breaks. On one day when I was torn between two or three equally compelling sessions, I fortunately elected to attend a lively session in the Process Validation and Continued Process Verification track. In this session a talk from Genentech on changing the traditional approach to process validation from a “three batches and you’re done” approach to a Lifecycle/continuous review approach was followed by Frank Zettl from Roche Penzberg presenting the underlying details behind Roche’s first FDA approval based on a QbD submission. The astute among you have already realized that these talks were from the same company in two different locations and together these excellent presentations provided the rest of the industry with justification for requesting extra funds to support early development activities based on QbD.

David Reifsnyder of Genentech described a massively parallel effort to align Genentech and Roche Quality Systems, resulting in issuing over 100 new documents in less than two years. Under the unified Quality System, process validation and post-approval monitoring commitments for legacy products that continue to be manufactured at their currently licensed sites would not be changed but for any product that was subject to technology transfer to a new site or even a new scale QbD elements would be implemented that would supersede the “three batches and you’re done” approach. Frank Zettl’s talk focused on Gazyva (obinutuzumab), the recently approved glyco-engineered anti-CD20 antibody that has close to 100X greater antibody-dependent cellular cytotoxicity (ADCC) activity than their current blockbuster product Rituxan. For Gazyva, the critical quality attributes (CQA) were well understood and were those than impacted CD20 binding or ADCC activity. Design space for the product was defined using accurate scale-down models that enabled assessment of the impact of each combination of process parameters on the CQA. With the data to support the design space, Roche proposed a conservative process control strategy and committed to a post-approval lifecycle monitoring plan (PALM) in their submission. Following FDA approval, the PALM became a binding contract and Roche must adhere to the agreed upon testing program. While the pros and cons of lifecycle management versus the three batch process validation approach could be debated, the truth is that lifecycle management provides greater process consistency, earlier warning of a process trending towards the limits of the design space, and improved patient safety. Small companies on lean budgets should learn from the industry leaders and should apply similar strategies throughout their development programs.


Blog article by: Susan Dana Jones