Improving CMC Review for Breakthrough Therapies

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FDA and industry seek a more consistent, flexible CMC review process for breakthrough therapies.

The development of more complex biotech therapies that merit accelerated evaluation and approval has put pressure on FDA to speed up its review process without compromising objectivity and standards. Greater flexibility about when manufacturers have to submit chemistry, manufacturing, and controls (CMC) data and how extensive that information should be prior to approval are key issues for speeding up the development of critical new drugs.

Manufacturers of breakthroughs and other innovative therapies need to plan for manufacturing with the same forethought as for clinical, commented Steven Kozlowski, director of the Office of Biotechnology Products (OBP) in the year-old Office of Pharmaceutical Quality (OPQ) in the Center for Drug Evaluation and Research (CDER). Sponsors should assess how much product will be needed at launch, how they are going to supply the patient population, whether sites are ready, and how to validate the production process. Talk early with the agency on how to make that happen and have “a real plan for bringing the new product forward,” he advised quality experts at the WCBP symposium in Washington, D.C. in January 2016, noting that complications can arise from a sponsor’s use of multiple testing and manufacturing sites.

Agency flexibility
Manufacturers and FDA staffers further discussed the challenges of providing sufficient quality information on breakthrough therapies in market applications and at time of launch at a workshop at the WCBP meeting. Agency reviewers emphasized that they are trying to be more flexible in accepting less complete data in applications on product specifications, process validation, and stability to avoid delaying patient access to needed therapies. Critical product attributes may be set broadly in an application and then tightened down as more experience is gained with a product. FDA says it’s open to retrospective assessment of process validation and has approved several breakthroughs based on manufacturing data from a clinical site, with additional information filed following transfer to commercial production.

Manufacturers, however, expressed concern and confusion over just how much process validation needs to be done during development, and what can be confirmed after approval. FDA officials emphasized that the old standard of three validation runs no longer holds, but that manufacturers have to provide sufficient indication that they fully understand the potential for product changes. Ashley Boam, acting director of OPQ’s Office of Policy for Pharmaceutical Quality (OPPQ), noted that CDER is looking to adopt a more formalized risk assessment process for the “quality space,” similar to how it has examined risk-benefit assessment for safety and efficacy. This involves looking closer at clinically relevant specifications and evaluating quality issues in terms of product performance.

Seeking consistency
Consistent and efficient reviews depend considerably on the quality of the manufacturing process, particularly for breakthrough products, Kozlowski noted. He has seen considerable variation in breakthroughs-some for tiny orphan populations and developed very quickly, others in development for several years. His four review divisions can assess these applications quickly, but “it’s a resource issue,” he noted, as a breakthrough application often needs twice as many people to split up and coordinate the review and to participate in multiple meetings with sponsors on CMC issues.


Kozlowski also observed that some complaints about inconsistent regulatory decisions may arise when a sponsor has limited access to the detailed information about the specific product and its review scenario. Just what is a “good quality review” often is hard to define, he said: There is “no magic formula.”

Despite pressure on FDA to accelerate development and review of breakthrough therapies, this is not altering the agency’s basic requirement for high quality product. FDA staffers see many cases where products and processes fail and want assurance from sponsors that the commercial process is reasonably well controlled and that the company can scale up to manufacture the product to meet quality standards.

There was agreement among the participants that certain practices that were unacceptable a few years ago, “now are possible.” Less extensive experience with breakthrough products is “not a license to give FDA less information,” explained agency staffers at the workshop. It’s more a commitment to provide certain information later. Even without extensive validation runs, a manufacturer should be clear about its planned validation approach and how it will leverage information from small development runs and link that to the commercial process.

Yet agency efforts to do things in new ways may appear confusing initially. Some sponsors may feel they’re getting a break, while others complain about being overburdened. Companies with extensive manufacturing experience on similar products at the same site may be able to tap that knowledge to provide confidence to the agency of being able to meet quality objectives.