FDA, Industry Discuss the Fine Points of QbD

In a rare Summit Meeting hosted by FDA and Conformia (whose CRADA team won a 2008 Team of the Year award for initiating these programs), FDA officials, academics and senior level professionals from both Big Pharma and generic drug manufacturers, debated the finer points of Quality by Design and ICH Q10.  Industry participants represented manufacturing, R&D, quality assurance and control, regulatory and senior management functions.

Catalyzing much of the discussion was a case study designed to provide a real world example of ICH implementations, quality systems and Quality by Design, and to offer an opportunity for cross-functional dialogue. Due to be released later this Spring, the case study is the second developed as part of Conformia’s CRADA with FDA.

Among the topics discussed were the “design space” and the “control strategy.”  Participants agreed that any control strategy should be a living thing and should change, post filing, to reflect process experience and new manufacturing information.  Although it should be part of a QbD submission, attendees agreed, a number of different documents would be needed to outline the control strategy.

Change management was also discussed, and the importance of having a module encompassing multivariate analysis, that would be updated using new batch data and become part of a change management system. This information could be filed in annual reports.

Also discussed was the design space.  Concerns were voiced about making changes to formulation components, given regulatory concerns about potential impact of changes on bioavailability.  Attendees noted the need to ensure clear linkage between clinical trials and manufacturing, an area where it would be too challenging to apply the Design Space concept.  They also noted the need to translate the Design Space into target operating parameters that would allow operators to make educated decisions about operating ranges based on where a product was in the design space.

Scaleup and its impact on the Design Space generated some debate. Simply extrapolating from small to large scale based on material attributes would be treating the manufacturing process like a “black box,” some attendees argued. Knowledge of material attributes should be coupled with some understanding of how they relate with input parameters.

“The question is, when you file it, does it look like a black box to the regulators?” asked Purdue professor Ken Morris.

One common question from industry is” What happens if changes are made to operating parameters.  Is that a change to the design space?  Nasr said, “Industry wants to be able to change the Design Space as long as the quality of materials doesn’t change.  I have no problem with an applicant, at the time of submission, stating that they would like to expand the design space upon learning of additional facts during manufacturing, but there must be some framework established.

The question thus becomes, Morris said, how do you create the Design Space.  Should you use parameters that can be scaled up?  You don’t want to design a whole new DS, you can establish that youre adding knowledge from experience….

FDA’s Joe Famulare said, “The way we’ve defined DS is as interaction with materials, but the dilemma is that a certain set of process parameters may produce specific attributes but as you scale up, it may turn out to be different….may also be different as you develop experience and produce more batches.

The Design space was designed to have flexibility, it should be presented so that you’re not locked into a particular parameter but understand the relationships so that you should be able to change a parameter, Famulare said. Overall goal of DS is to have a company understand and be able to adjust parameters based on principles laid down in the first place.  

If one changes specific equipment to achieve an endpoint, this may be a Quality Systems question rather than a Design Space question, Nasr commented.

Also discussed was applying QbD to biologics, the basis for an upcoming CRADA Case study. For this case study, attendees agreed, mechanism of action will be extremely important as will immunogenicity. Parametric release will be more challenging, attendees agreed and will require more robust quality systems.

The next Summit is planned for the Spring.  For more information, visit www.conformia.com

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