The FDA initially rejected nearly half of all biologics applications received last year, many for quality-related CMC issues that need to be improved upon, according to CDER Director Patrizia Cavazzoni.
“Our standards have not changed,” she said Monday at a Duke University and FDA event at the National Press Club in Washington, DC. “We have exactly the same standards as we had in 2018 and 2019.”
What CDER is seeing is quality-related issues, Cavazzoni said — “and we really need to work on this.”
She said the deficiencies spotted in facilities are typically fundamental ones, like contamination, overall oversight, manufacturing controls or insufficient quality management systems. “These are not things where we can exercise regulatory flexibility,” Cavazzoni said.
She offered the example of a manufacturer that recently delayed a CMC supplement submission for a drug that’s in shortage, with the company saying it had to address certain issues.
“That’s a good decision,” Cavazzoni said, “rather than counting on FDA and our investigators to invariably uncover the issues and then having even longer delays than what might be a month or a couple of months’ delay in filing and potentially avoiding a complete response.”
While noting that the agency couldn’t access sites in China until 2023 because of the pandemic, inspections are now increasing there, she said, including sites with no inspection histories. Typically, those sites have more findings than sites with prior inspections.
Max Van Tassell, senior pharmaceutical quality assessor in CDER’s Office of Pharmaceutical Quality, offered some insights gleaned from a review of 100 complete response letters for BLAs from 2014 to 2024.
In particular, he said facility-related deficiencies are up, especially when compared to microbiology or product quality issues, Van Tassell said.
“Facility deficiencies generally result from a failure to demonstrate that proposed corrective and preventive actions would be sufficient to address risks identified on site,” he wrote on one of his presentation slides.
Van Tassell also said that the majority of products receiving multiple CRLs were for biosimilars, more foreign manufacturing sites were identified in complete responses, and about half of all facility deficiencies are for contract manufacturing organizations.