Developing breakthrough products requires a new approach to process development and commercial launch, said Earl Dye of Genentech at the CASSS forum, in describing the company’s program to develop CMC/GMP strategies and “manufacturing readiness plans” for both large- and small-molecule breakthrough products. This involves assessing timelines around formulation and process validation and ensuring that all manufacturing sites are GMP compliant. If there are no changes in formulation, it may be easier to leverage stability data from early development, Nye noted, adding that it’s important to determine as early as possible if the clinical manufacturing facility can produce drug substance and drug product for launch. If no transfer of production is needed, that will save a lot of time, he observed, but all facilities have to meet standards.
Seeking flexibility
FDA has established many standards and requirements to ensure quality manufacturing, but often allows for variation in how a firm demonstrates a product’s “fitness for use,” Woodcock pointed out at the CASSS symposium. She noted that a patient facing only a few months life expectancy is not that worried about a product’s expiration date. And if a companion diagnostic is not fully tested, FDA may decide to approve a drug without the test product. “We have to think about what’s necessary,” she observed.
FDA officials acknowledge ongoing discussions at the agency on ways to exercise flexibility in terms of quality requirements for products demonstrating high clinical benefits. The regulator understands that evaluations based on limited stability data and provisional specifications could mask safety issues and that permitting manufacturers to shift more CMC analysis and final stability testing to the postmarketing timeframe raises concerns about ensuring that a quality product is available to patients on a reliable basis. FDA is intent on avoiding situations where it approves a high-demand breakthrough, only to see the firm unable to scale up sufficiently to meet demand, or to run into quality problems that require a recall or production halt. Treatment followed by product withdrawal can be devastating to patients with life-threatening conditions, and availability to patients is a crucial concern, Lacana emphasized.
Nye of Genentech looks to work with FDA to assess the risks of providing less CMC information at time of filing vs. the benefits of early access to a needed medicine. But he and others understand that it’s important to assess whether delays in process validation would compromise patient safety and to commit to providing more confirmatory data during review and post approval.
For the long term, FDA would like to see companies adopt innovative manufacturing strategies that can accelerate quality production, such as continuous manufacturing systems. Agency officials note that there can be advantages in using a clinical manufacturing site for initial commercial production or producing clinical supplies at a commercial site.
FDA reviewers are “doing triple backwards somersaults to facilitate development of breakthrough products,” Shacter commented. They are looking to be flexible whenever possible, provided that quality is assured. To do this, manufacturers need to demonstrate control over the process and product, to justify specifications, to ensure that sterile products are free of adventitious agents, and that there is adequate stability data to ensure product quality on the market.
Reference
1. FDA, Expedited Programs for Serious Conditions-Drug and Biologics, Draft Guidance(June 2013), accessed Feb. 7, 2014.
About the Author
Jill Wechsler is Pharmaceutical Technology’s Washington editor. [email protected].