Cavazzoni urges proactive measures to avoid CRLs for biologics manufacturing issues

Updated on 21 August 2024 to clarify Patricia Cavazzoni’s statements about complete response letters.

WASHINGTON, DC – Coinciding with a jump in biologic licensing applications (BLA) in recent years, the US Food and Drug Administration’s Center for Drug Evaluation and Research (CDER) has handed out an increasing number of complete response letters (CRL) to facilities related to manufacturing issues.

Speaking at a meeting on biologics and biosimilars chemistry, manufacturing, and controls (CMC) hosted by the Duke Margolis Institute for Health Policy at the National Press Club on Tuesday, CDER Director Patrizia Cavazzoni, said it’s in everyone’s best interest to be proactive and address manufacturing deficiencies early on. She noted that 20 years ago, there were much fewer biologics in drugmakers’ portfolios, but today, they represent a significant portion of the market.

However, with the increasing number of biological products under development, Cavazzoni said they have also seen an increasing number of complete response letters (CRL) to manufacturing facilities for not meeting FDA’s regulatory requirements, which could delay a product coming to market by six months or more. She emphasized that by statute, the agency cannot approve products unless they meet its requirements for current good manufacturing practices (cGMP).

“I want to make it very clear, because there seems to be a bit of a narrative out there that FDA standards have changed, our standards have not changed,” said Cavazzoni. “Nothing happened during the pandemic that led to our standards having changed. We have exactly the same standards as we had in 2018 and 2019.”

“What we are, however, seeing is lesser quality in the facilities where these products are manufactured and we really need to work on this,” she added.

During the pandemic, FDA inspectors could not easily visit foreign manufacturing facilities, and there has also been a significant increase in new BLA manufacturing facilities in general. As regulators are now able to inspect the facilities, they are also finding that many of them are not in compliance with complying with all cGMP requirements.

Cavazzoni lamented that it’s unfortunate that CRLs have increased, especially considering the technological advancements made in manufacturing quality controls. She noted that 2023 saw the highest number of BLA approvals, but about half of the applications the center issued a decision on that year received a CRL.

“What we’re seeing is that facility issues represent an increasing proportion of CRLs,” said Cavazzoni.

On top of this, Cavazzoni said that companies are rushing to increase manufacturing for certain promising drugs by relying more on contract manufacturing organizations (CMOs) and contract development and manufacturing organizations (CDMOs). However, she said that half the CRLs linked to facility deficiencies are given to CMOs and CDMOs.

The CDER director said that handing sponsors CRLs related to CMOs and CDMOs can create a backlog of applications because the agency can’t approve other applications related to the CMO or CDMO if there is an issue at the facility that would impact other applications.

“We cannot approve the applications that are in the queue, and this has a domino effect on multiple programs and ultimately has a domino effect on more and more patients,” said Cavazzoni.

Cavazzoni said that the violations they’ve found during facility inspections are not trivial matters where the agency can exercise regulatory flexibility. They include issues with potential contaminations, quality oversight, manufacturing controls, and insufficient quality management systems.

To address the facility problems, Cavazzoni recommended that sponsors take advantage of FDA’s various communication channels, especially meetings with regulators during the product review cycle, and ideally before the application is submitted to the agency.

“It’s very important that you not only think about the facility from a cGMP standpoint but also an application readiness standpoint,” said Cavazzoni.

Cavazzoni praised a manufacturer who, she said, recently came to FDA and voluntarily delayed CMC supplement submission after discovering manufacturing issues even though their drug was in shortage. She noted that agency inspectors would have invariably discovered those issues on their own, and the manufacturer would have faced an even longer delay after getting a CRL.

Cavazzoni advised BLA holders to maintain good communication with their CMOs and CDMOs and receive updates on any inspection issues, even if the inspection is unrelated to their product.

“CDMOs and CMOs need that engagement from the BLA holders to continue to understand what their expectations are,” said Cavazzoni. She added that it’s better to be proactive to prevent deficiencies rather than resolve deficiencies only after FDA inspectors discover them.

Cavazzoni urges proactive measures to avoid CRLs for biologics manufacturing issues

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