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# Biologic Manufacturing Quality Deteriorating: Cavazzoni
- URL: https://www.fdaweb.com/biologic-manufacturing-quality-deteriorating-cavazzoni/
- Published: 2024-08-23T12:00:00.000Z
- Updated: 2026-09-14T14:39:27.000Z
- Author: David McFarland
- Tags: Drugs, #legacy-id-D5157642

CDER director **Patrizia Cavazzoni** says agency inspectors and reviewers are seeing deteriorating manufacturing quality in the facilities where biologics and biosimilars are made, and industry needs to address this. Speaking at a [Duke Margolis Institute for Health Policy program](https://youtu.be/On1bhwvXWRc?si=idQcCS8m1hiKUG6x&ref=fdaweb.com) in Washington, DC 8/20, Cavazzoni noted that BLA and biosimilar applications and approvals are on the rise, but so are complete response letters (CRLs) for these submissions. This is concerning because the advances in technologies that the agency is seeing in manufacturing should also translate into advances in manufacturing quality controls, she said.

Cavazzoni’s talk specifically addressed the manufacturing component and chemistry, manufacturing and controls (CMC) elements that are driving the uptick in CRLs. “I just want to make it very clear, because it seems to be a bit of a narrative out there that FDA standards have changed,” she told the audience. “Our standards have not changed. 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, however what we are seeing is lesser quality in the facilities where these products are manufactured, and we really need to work on this.”

In 2023, nearly half of CRLs with facility deficiencies were for BLAs with manufacturing proposed at contract manufacturing organizations (CMOs), she said, adding that facility and CMC deficiencies are now a more common CRL driver than biosimilarity is for biosimilar applications (351(k)s). And there is an additional problem on top of this because there’s an increasing use of CMOs as industry rushes to expand manufacturing capacity, which produces a snowball effect when a facility is found not to be GMP compliant during a pre-licensure inspection because other unrelated BLAs in the queue that also reference the facility automatically get a CRL too.

Cavazzoni said the manufacturing problems being found at the facilities are not “trivial issues,” and include “microbiology issues, contamination, overall quality oversight, manufacturing controls, insufficient quality management systems in the facility, and so on. So these are not things that we can exercise regulatory flexibility \[on\], even in situations where we’re dealing with applications for drugs that would address a high unmet need.”

One of the most fundamental ways to address the issues is communication, according to Cavazzoni. “It is extremely important that you take advantage of the meetings during the review cycle, or even ideally before an application is submitted, to discuss issues with FDA,” she emphasized. It is also very important to not only think about the facility from a GMP perspective, but also from the application-readiness standpoint.

“It's also very important,” she continued, that there be very strong communication with the CMOs, and by that, I mean, you’ve got to make sure that the contracts embed an exchange of information about the inspections, even if they’re not related to the product that is the subject of the contract. ” She said it is also important to have an ongoing dialog with CMOs because they also need that engagement from BLA holders to continue to understand the expectations. “The best situations that we have seen, are those where we have the BLA holder working very closely with the CMO and viewing their sort of quality management system oversight as being fully integrated and working hand in hand…,” she said.

The Duke Margolis program also featured a more in-depth analysis from CDER Office of Pharmaceutical Assessment senior quality assessor **Maxwell Van Tassell**. He said facility deficiencies “generally result from a failure to demonstrate that proposed corrective and preventive actions (CAPAs) would be sufficient to address risks identified on-site,” adding that outstanding deficiencies in CAPAs are most often due to one or more of the following reasons:

- Failure to conduct a comprehensive root cause analysis
- Failure to assess product impact
- Insufficient CAPA details
- Recurrent observations or expansive issues that require CAPA verification

Van Tassell said CAPA root cause analyses “should include an assessment of all relevant manufacturing and laboratory systems to determine where existing practices might be deficient. The investigation should be extended to other processes, equipment, batches, etc., that could potentially be informative for the resolution of the subject issue. Furthermore, impact assessments ensure that CAPA have an appropriate scope and monitoring strategies are looking in the right places.”

Additionally, he said a CAPA root cause analysis should include a summary of data evaluated to assess the potential impact on product quality. This should also include all relevant testing and monitoring performed, including but not limited to in-process and release testing, environmental monitoring complaints, data from media fills or examination of reserve samples, the batches and dates of manufacture that are covered by this assessment and the disposition of potentially affected lots should be both specified and justified.