FDA Encourages 'Established Conditions' Use Despite ICH Q12 Uncertainty

Go ahead and list the 'established conditions' in your NDAs, ANDAs and BLAs that require regulatory notification in the event of post-approval changes, which leaves all other CMC changes to be managed internally, FDA tells industry. But the agency wants a heads up if you're planning to do that, as the 'established conditions' paradigm continues to evolve in the context of ICH Q12 deliberations.

Pharmaceutical companies are welcome to rely on last year's "established conditions" draft guidance in crafting applications that say what types of manufacturing changes will be subject to regulatory oversight, an FDA official told the International Society for Pharmaceutical Engineering.

"Submission of established conditions can occur right now," Bob Iser, acting director of the Office of Process and Facilities in FDA's Office of Pharmaceutical Quality, told a Sept. 20 regulatory town hall session at ISPE's annual meeting in Atlanta.

In fact, he said, it's been occurring all along as applicants address "all the pieces of the control strategy when it comes to specifications, when it comes to process parameters and process controls, all of those things."

It's just that before the draft guidance, applicants hadn't been listing the conditions.

The Draft Guidance

Change management regulations at 21 CFR 314.70(a) and 21 CFR 601.12(a) for new and generic drugs and biologics require pharmaceutical companies to notify FDA about any changes in the conditions established in their approved applications for chemistry, manufacturing and controls. (Also see "FDA Would Establish Conditions for Swift Manufacturing Changes" - Pink Sheet, 25 Jun, 2015.)

The draft guidance acknowledges, however, that applications typically also include supportive CMC information that does not constitute an established condition. Such information, it says, should be managed by the company's own quality management system without FDA's involvement.

The draft recommends that applicants provide a summary of proposed established conditions in Module 2, Section 2.3, of the Common Technical Document, Introduction to the Quality Overall Summary, in a tabular format with a brief description or identification of each established condition that references each condition's specific location in Module 3.

Changes to any condition that's not on that list can then be managed internally through the company's quality system.

The Q12 Caveat

However, Iser strongly urged applicants to alert the agency before submitting applications that include a list of established conditions as described in the draft guidance.

The reason is that the agency's approach to established conditions is in flux.

The International Council on Harmonization has incorporated the "established conditions" concept into the Q12 guideline on post-approval changes that it is developing. (Also see "ICH Q12 Experts Develop Four-Tier Scheme For Harmonizing Post-Approval Changes" - Pink Sheet, 8 Aug, 2016.)

The discussion within ICH has very broad participation, with involvement of many countries in the Q12 expert working group, and it could lead to a further evolution of the "established conditions" concept.

Iser alluded to all this at the ISPE meeting when he cautioned that "there's a lot of discussion about what [the list of established conditions] may look like and further clarification that's going to happen within Q12."

Because of the fluid situation, he explained that "it would benefit us as the agency to get a heads up if someone is submitting established conditions in that sort of format in an application, whether it be called out on a cover letter or there'd be some other communication with a project manager or something like that."

Iser noted that the agency has "seen some submissions of some things that kind of fit within that draft guidance already."

While he acknowledged that firms are availing themselves of the opportunity, he cautioned that "it's still a draft and still very much under discussion when it comes to what's going on with Q12."

The Pre-Submission Opportunity

Firms should consider interacting with the agency on the topic of established conditions before they submit new drug applications, suggested Sarah Pope Miksinski, acting director of the Office of New Drug Products in FDA's Office of Pharmaceutical Quality.

The agency has discussed questions about established conditions in pre-submission meetings, which she said "are great opportunities for collaboration between industry and the agency as we move into that paradigm of established conditions in applications."

Miksinski explained that "we're not under a review clock at that point, and we actually have the time to have the discussion and really capture intentions on both sides of the table in a far less compressed framework than what we have once the NDA actually comes through the door."

A Case of Valuable Creativity

Asked to advise ISPE on how to help drive toward the vision of Janet Woodcock, director of FDA's Center for Drug Evaluation and Research, for a maximally efficient, agile, flexible manufacturing sector that reliably produces high quality drugs without extensive regulatory oversight, Miksinski pointed to the effort that led to the "established conditions" draft guidance as a model.

It's easy when someone proposes to do something different for FDA or industry to shoot it down, she said.

But in cases like the movement toward 'established conditions,' "there is evolution that happens based on creative new thinking. So in terms of advice, I would say, 'be creative.' And I would actually say that to the FDA as well."