Big Pharma Pushes FDA To Decouple Inspections From Drug Approval Applications

 

Representatives of companies including AbbVie, Eli Lilly, Johnson & Johnson and Merck have voiced concerns about the FDA’s approach to pre-approval inspections.

When the FDA asked manufacturers about the biggest regulatory hurdles to reshoring drug production this year, the branded medicine industry spoke with one voice. Leading drugmakers including AbbVie, Eli Lilly, Johnson & Johnson and Merck told the FDA that pre-approval inspections are among their biggest challenges—and shared a vision for how the agency can alleviate the problem of complete response letters (CRLs) tied to these inspections.

The FDA consulted with the industry about manufacturing challenges, first in person and then in writing, as part of the development of its PreCheck program. While the agency designed the program to support the construction of new facilities in the U.S., drugmakers used the consultation to call for changes to the pre-approval inspection (PAI) process for existing production plants.

Currently, a manufacturing facility undergoes an FDA inspection when it is used to make a medicine that has been submitted for approval. Kevin Fitzpatrick, senior vice president for quality assurance at AbbVie, cited an example to explain the challenges created by that model.

“We brought on a new U.S. manufacturing facility two years ago and the PAI for that facility was weeks prior to our PDUFA date,” Fitzpatrick said at the FDA’s PreCheck meeting in September. “At that point, we’re under a lot of pressure. Any questions or comments or observations that come up [during the PAI] are very difficult to resolve in that time frame.”

Other attendees made similar points. Miguelina Matthews, head of quality intelligence, advocacy and pharmacopoeia affairs at Sanofi, told the FDA that the unpredictability of inspections is a factor that can lead to CRLs. Drugmakers reiterated the concerns in their written feedback to the FDA.

Many of the verbal and written responses to the FDA proposed addressing the problems by decoupling inspections from the review of drug approval applications. Rather than only inspect sites when they are included in filings for approval, the drugmakers said the FDA could check whether plants are compliant before authorization applications are filed to give companies time to fix issues before they cause CRLs.

Aligning Inspection Timings

Establishing clearer inspection timelines is one of the ways the PreCheck program could benefit the industry, Guggenheim Securities analysts said in a note to investors. Under the current process, manufacturers can lack the forewarning they require to ensure a production run is active when the FDA visits. Karen Wolfrom, global head of regulatory affairs at Lonza, told the FDA the alignment problem has a particular impact on contract manufacturers because they commonly make batches of different products for different clients at different times.

Lonza and a client will predict the point in the approval review process that the FDA will inspect a site. “In the meantime, we have other important medicines that are coming into the suite. Do we delay them going into the suite so that we can keep it open and idle to do an inspection for this particular product? There’s that dance,” Wolfrom said at the September meeting. “It’s terrible to have a submission delayed because we have to be in active manufacturing at the time.”

Aligning manufacturing runs with FDA inspections is particularly challenging when a company only needs a small quantity of drug product—for example, because it is targeting a rare disease. Christopher Shilling, chief regulatory officer at Forge Biologics, told BioSpace that gene therapy clients may only need a few batches. That means “jumping through hoops” to align inspections with the manufacturing of those batches, he said.

The Alliance for Regenerative Medicine (ARM), a trade group that represents Forge and other cell and gene therapy companies, used its written feedback to the FDA to add to the calls for decoupling inspections from approval timelines.

ARM paired the request with the suggestion that the FDA inspect different parts of a facility, such as a vector suite and cleanroom, as they become ready rather than waiting to inspect the entire facility at once. The trade group said the move to phased or modular inspections could help identify issues earlier. Johnson & Johnson proposed a similar idea in its written feedback to the FDA.

While branded drugmakers led the calls for changes to PAIs, the generics industry has its own inspection challenges. A spokesperson for the Association for Accessible Medicines, a trade group that represents generic and biosimilar manufacturers, told BioSpace that off-patent drugmakers undergo inspections by both the FDA and state-level authorities. Manufacturers must assign staff to host inspectors and manage document requests for each of these inspections.

Cooperation between the FDA and state authorities could reduce this redundancy, the spokesperson said. They added that the mutual recognition agreements that allow the FDA to use the inspections of certain overseas regulatory agencies provide a potential model for how agencies within the U.S. could share workloads to reduce burdens on their own teams and the companies they inspect.

The FDA stopped accepting written feedback on the PreCheck program in late October. With hours of verbal testimony and 74 written submissions to review, the agency has yet to respond publicly to the feedback or to finalize the PreCheck program.

https://www.biospace.com/fda/big-pharma-pushes-fda-to-decouple-inspections-from-drug-approval-applications