Continuous learning isn’t just a professional development checkbox for me — it’s a mindset. At SynerG, we make learning part of our culture, and one of the most valuable ways to learn is by studying the challenges others have faced.
On July 10th, 2025, the FDA published 202 Complete Response Letters (CRLs) issued between 2020-2024. This was followed up with the release of another 89 CRLs on September 4, 2025. These publications are a goldmine for anyone interested in regulatory strategy and CMC risk management. A CRL is issued when FDA has reviewed a submitted NDA or BLA and determined that it cannot be approved in its present form. It marks the end of the current review cycle and outlines why the application was not approved. Importantly, the CRLs published in July relate to applications that have since gone on to approval. In contrast, the CRLs released in September remained tied to applications that are still pending approval.
While most of the industry buzz following this unusual publication focused on the sheer number of CRLs, I wanted to take a closer look at what these letters could teach us specifically about biologics development. The CRLs were issued against both New Drug Applications (NDA) and Biologics License Applications (BLAs). As NDAs are for small molecule drugs and BLAs are for biological products, I focused my deep dive into the BLAs. Out of the 202 CRLs published in July:
- 156 were linked to NDAs (77%)
- 46 were tied to BLAs (23%)
Out of the 89 CRLs made public in September,
- 58 were linked to NDAs (65%)
- 31 were linked to BLAs (35%)
That ratio didn’t surprise me — BLAs typically make up only about 20-30% of total NDA/BLA approvals over similar timeframes (NDA and BLA Calendar Year Approvals | FDA and Biological Approvals by Year | FDA). Digging further into the total of 77 CRLs issued against BLAs, the reasons for the CLRs are as follows:
- 7 were issued solely for clinical-data concerns (3 from July, 4 from September)
- 70 had product quality, facility, or regulatory issues worth digging into (43 from July, 27 from September)
Further breaking down the 70 BLA CMC-relevant CRLs, here’s where the real learning starts.
Regulatory issues
- 4 letters fell into this category, all from the July publications. 3 were biosimilars where the reference product had already received interchangeability and FDA cannot make a new interchangeability determination until exclusivity period has expired. The fourth letter was because product was no longer deemed to qualify for accelerated approval, and a different approval pathway should be considered.
Facility inspection issues
Under 21CFR § 601.20, a BLA cannot be approved until a Pre-Approval Inspection has been satisfactorily completed.
- 25 of the 43 CMC related CRLs from July cited facility inspections.
- All 27 CRLs from September publication cited facility inspection deficiencies.
4 cited inspection timing challenges — 3 from COVID-related travel restrictions and 1 from late inclusion of a manufacturing site in the filing. 1 cited data management concerns. For the remainder 47 facility inspection related deficiencies, there were not many specifics to be gleaned.
Microbiology issues
- 8 letters flagged gaps such as:
- Insufficient bioburden and endotoxin testing/limits
- Growth promotion test issues
- No low endotoxin recovery (LER) study
Notably, for the 4 CRLs from the September release that cited microbiology gaps, all details were redacted, leaving no specifics to analyze.
Product quality deficiencies
- 27 letters from the July release cited product quality issues, with recurring themes:
- Control strategy (11)
- Transport validation (5)
- Drug Product media fill (4)
- Drug Product sterile filtration/microbial retention (4)
- Reference standard programs (4)
- Cell bank characterization/stability and LIVCA studies (4)
- Container closure integrity testing method (4)
- Extractables & leachables (3)
- Other one-off deficiencies noted: analytical similarity assessment, identity testing, extractable volume, and clinical-in-use study deficiencies
- In the September CRL release, 13 letters cited product quality issues. However, due to extensive redactions, no additional details could be gleaned, leaving the specific nature of these quality concerns unknown.
The themes observed in the July release highlight opportunities to evaluate specific deficiencies and map to regulatory expectations to strengthen control strategies, validation protocols, and CMC Quality System components.
The Takeaway
The September CLR tranche was heavily redacted, making it difficult to extract meaningful insights. In contrast, the July tranche revealed several key patterns, showing that many sponsors continue to stumble on well-known CMC fundamentals that could be addressed proactively with the right planning and quality mindset.
If FDA continues its radical transparency initiative, relaxing redactions for pending applications could make these CRLs far more useful for learning and risk mitigation across the biologics industry.
For those willing to dig in, the July tranche was a free masterclass in what not to do when aiming for first-cycle approval.
