FDA Needs to Step Up As Use of Third-Party Manufacturers Leads to Rejections

It was a tough week for biopharma companies that rely on contract manufacturing, which is pretty much all the major industry players these days. The FDA on Tuesday again issued a Complete Response Letter (CRL) to AbbVie rejecting ABBV-951, a proposed treatment for motor fluctuations in adults with advanced Parkinson’s disease. Then on Thursday, the agency declined to approve Merck and Daiichi Sankyo’s HER3-targeted antibody-drug conjugate patritumab deruxtecan for lung cancer. In both cases, the FDA cited issues with third-party manufacturers.

While some might argue that the rise in outsourcing of manufacturing is helping biopharma companies to focus on their core capabilities, it’s also an Achilles’ heel. Out of a total of 238 CRLs issued between 2017 and 2023, 30% involved quality/manufacturing issues—particularly problems with manufacturing processes, facility inspections, or chemical, manufacturing and controls (CMC).  

AbbVie and Merck/Daiichi did not provide details about the problems identified by the regulator in their respective CRLs. In its letter, AbbVie said the FDA cited “observations” that were identified during inspection of a third-party manufacturer, but hastened to add that it did not involve ABBV-951. Merck and Daiichi only reported that their CRL “results from findings pertaining to an inspection of a third-party manufacturing facility.”

I’m one of those industry observers who believes it is time for the FDA to publicly release CRLs, or at least some kind of summary. It’s critical because biopharma companies are not being transparent. One study concluded: “Press releases are incomplete substitutes for the detailed information contained in Complete Response Letters.”

The details of the manufacturing issues aside, just the fact that these CRLs focused on them over any clinical issues is cause for concern. At the same time, the FDA itself has been struggling for years with its inspection program.

A December 2023 study in Health Affairs revealed that FDA inspections of drug manufacturing facilities in the U.S. and especially abroad dropped well below pre-pandemic levels between 2020 and 2022 and have not yet bounced back. As the agency begins to pick up the pace of foreign inspections, the import of several drugs from these facilities has been halted, leading to a spike in drug shortages. India-based Intas Pharmaceuticals, for example, has received warning letters from the FDA and is on the agency’s import alert list due to failures to comply with Current Good Manufacturing Practice (CGMP) regulations and poor data integrity.

India’s own regulator has also been cracking down on manufacturing problems in the country. Reuters on Thursday reported that more than 36% of the 400 drug manufacturing units inspected since last year in India were ordered to be shut by the country’s drug regulator, after deaths linked to substandard cough syrups prompted an increase in scrutiny.

While India is responding on some level, a ProPublica investigation last year of FDA oversight following deaths from bacteria-tainted eyedrops made in an Indian plant showed “the agency’s inspections of overseas drug manufacturers, located mostly in India and China, has dropped precipitously even as the number of manufacturers has remained relatively steady.”

Neither AbbVie or Merck/Daiichi gave any indication of whether their CRLs involved foreign third-party manufacturers, but it wouldn’t be a surprise. More than 50% of manufacturers supplying the U.S. market are located overseas—mainly in India and China. With biopharma companies relying on the outsourcing of manufacturing, especially overseas, the FDA must do more to ensure quality controls are being implemented by third-party manufacturers.

I’m not alone in this belief. A letter last week to FDA Commissioner Robert Califf from the chairs of the House Energy and Commerce Committee and two subcommittees pressed the agency for more information regarding “large variations” in its foreign drug inspection program. And in February, Mary Denigan-Macauley, the director of healthcare at the Government Accountability Office, testified before a congressional subcommittee that the FDA continues to face “persistent challenges” overseeing foreign drug manufacturing.

That same month, the FDA said it planned to increase inspections of Indian manufacturing facilities this year. Whether that is happening remains to be seen.

https://www.biospace.com/article/fda-needs-to-step-up-as-third-party-manufacturers-lead-to-rejections/