Why ‘Established Conditions’ CMC Approach Could Generate More Supporting Information, Not Less
Executive Summary
The ‘established conditions’ concept enshrined in the ICH Q12 draft guideline was the US FDA’s answer to the background information that has cluttered new drug applications in the quality-by-design era. But early indications are that it will amass information clutter of its own.
It turns out that as sponsors begin submitting drug applications that describe the "established conditions" of their manufacturing process that are subject to regulatory review per US Food and Drug Administration guidance, the agency may be more focused instead on the non-established conditions.
It is reminiscent of the situation a decade ago as the quality-by-design paradigm took hold, when FDA reviewers paid special attention to quality attributes and process parameters that applicants claimed to be non-critical. After all, those claims would have to carefully assessed to ensure applicants had not mischaracterized critical factors as non-critical.
But the reams of supporting information applicants submitted in large part to demonstrate non-criticality created new problems by leaving the sponsors saddled with increasingly complex, detailed regulatory commitments on matters of dubious criticality that the “established conditions” concept is supposed to rectify.
An effort led by a Pharmaceutical Research and Manufacturers of America team four years ago convinced the FDA to give industry a new opportunity to begin sorting actual regulatory commitments, which the agency dubbed established conditions, from mere supporting information, which firms would manage within their internal quality management systems. (Also see "Industry’s ‘Regulatory Commitments’ Concept Draws FDA’s Interest" - Pink Sheet, 29 Sep, 2014.)
The FDA issued draft guidance on established conditions in May 2015 and later helped lead the effort to incorporate the concept into the International Conference on Harmonization’s Q12 guideline on pharmaceutical product lifecycle management, now in consultation. (Also see "FDA Would Establish Conditions for Swift Manufacturing Changes" - Pink Sheet, 25 Jun, 2015.)
The Revival Of Supporting Information
However, in initial interactions with industry on established conditions, much of the agency’s attention has been focused on what applicants assert to be non-established conditions, Hasmukh Patel of the FDA’s Office of Pharmaceutical Quality on 26 June told the Drug Information Association annual meeting in San Diego, CA.
The agency trained CMC review staff last year on established conditions, anticipating that they would begin to appear in CMC regulatory submissions, noted Patel, who is a division director in OPQ’s Office of Lifecycle Drug Products. Agency officials have been encouraging such submissions for a couple of years. (Also see "FDA Encourages 'Established Conditions' Use Despite ICH Q12 Uncertainty" - Pink Sheet, 4 Oct, 2016.)
So far, Patel said, applicants have discussed their intentions regarding established conditions in Type C meetings and one has even submitted a new drug application that references established conditions.
“Established conditions are not that difficult for us to figure out,” he said. “But non-established conditions invariably need more information – because you want to manage them under your pharmaceutical quality system.”
A Laser Focus On Purported Non-Issues
Naturally, the agency will be laser-focused on anything industry claims should be beneath its attention, whether it’s a non-critical quality attribute, a non-critical process parameter or a non-established condition.
“I highly recommend you [schedule] a Type C meeting to discuss your plan for established conditions,” Patel said. “Because that will save a lot of time for both you and us. Because it’s new and we are learning. We are learning with you.”
Patel went on to say that the shortened review timelines for designated breakthrough therapies do not allow for discussions about established conditions.
“In those cases, probably I recommend that you think about coming post-approval for a meeting … and then we can provide you our guidance that will help both of us to take care of an approval of established conditions.”
Patel noted that an established conditions pilot announced 15 February should be getting underway soon, now that the pilot’s 30 May application deadline has passed. (Also see "FDA Launches Pilot To Gain Practical Experience With 'Established Conditions' In Quality Assessments" - Pink Sheet, 15 Feb, 2019.)
The pilot will provide the agency and the industry an opportunity to work out the issues of trust inherent in the “established conditions” discussion, much as they did with the FDA’s quality-by-design pilot more than a decade ago. (Also see "FDA QUALITY-BY-DESIGN PILOT PROGRAMS" - Pink Sheet, 15 Aug, 2006.)
An Opportunity For Regulatory Engagement
In 24 June remarks at the DIA meeting, Sarah Pope Miksinski, senior director for global regulatory affairs at AstraZeneca PLC, expressed optimism about the regulatory interactions the pilot will bring.
“The exciting thing about the pilot in our minds is it's a way of seeking engagement and having engagement as a way of having a better understanding across the table of how agency and industry can actually work together to implement Q12 effectively.”
Miksinski, who also advocated for such interactions while at the agency, where she was director of OPQ’s Office of New Drug Products until February 2018, explained that it will help industry “have a view on the agency's thinking on red lines, maybe they could be blue lines, around the topic, and being in a position to really validate what we as a company think about Q12 implementation as we see it."
As with the QbD pilot, the most important outcome of the established conditions pilot may well be the detailed regulatory interactions that result.