FDA’s CRLs reveal 74% of applications rejected for quality, manufacturing issues
In an effort to increase transparency, the U.S. Food and Drug Administration (FDA) last week published more than 200 Complete Response Letters issued in response to since-approved applications submitted to the agency for drugs and biological products.
“These records include Complete Response Letters (CRL) issued in response to approved new drug applications (NDAs) and biologics license applications (BLAs) between 2020 and 2024,” states the openFDA archive. “This is the first ever centralized database of past CRLs.”
While the CRLs were redacted for trade secrets and confidential commercial information, the FDA contends that “the public now has significantly greater insight into the FDA’s decision-making and the most common deficiencies cited that sponsors must address before their application is approved.”
Pharma Manufacturing analyzed the published CRLs and out of a total of 202 decision letters issued between 2020 and 2024, 150 (74%) involved quality/manufacturing issues — including problems with manufacturing processes, facility inspections, or chemical, manufacturing and controls (CMC) — according to the FDA’s newly released documents.
Several companies were hit with multiple CRLs over those years, including Alvotech, Azurity Pharmaceuticals, Celltrion, Coherus BioSciences, Dr. Reddy’s Laboratories, Eli Lilly, Pfizer, Sun Pharma, and Teva Pharmaceuticals.
Jefferies analysts in a July 11 note to investors wrote that although most of the CRLs have already been made public as part of drug approval packages, the release of the agency’s documents “sheds light on where the FDA pushed back in the past and could have readthrough to current drugs on file.”
Below are nine “of interest” applications initially rejected for CMC issues, according to Jefferies:
Ascendis Pharma Yorvipath (palopegteriparatide) for PTH: CMC deficiencies. Concern that amount of delivered drug could vary between pens of different manufacturing lots or even for a single pen. This variability could lead to dosing inaccuracy which could lead to potential efficacy and safety concerns (such as hypo/hypercalcemia).
Eli Lilly Ebglyss (lebrikizumab) for atopic dermatitis: Manufacturing facility issues. Concerns about comparability between commercial and clinical materials and therefore ability to achieve expected clinical outcome with commercial material. “The adequacy of the proposed lebrikizumab drug substance (DS) manufacturing process and overall control strategy cannot be determined at this time to support the licensure of lebrikizumab,” stated a CRL.
Eli Lilly Omvoh (mirikizumab) for ulcerative colitis (UC): Manufacturing facility issues. “Following pre-license inspection of the Eli Lilly and Company, Indianapolis, Indiana (FEI 1819470), manufacturing facility listed in this application, FDA conveyed deficiencies to the representative of the facility,” according to a CRL. “Satisfactory resolution of these deficiencies is required before this application may be approved.”
Gilead Sciences Sunlenca (lenacapavir) for HIV treatment: Possible incompatibility between the drug product solution and the proposed commercial glass vials. “As evidenced by your data and glass particles found in the clinical batches, glass containers are generally incompatible with highly alkaline solutions,” wrote the FDA in a CRL. “In order to resolve this deficiency, we require a comprehensive study report with unambiguous data and fully validated methods to demonstrate the compatibility of the drug product solution with your proposed primary container closure system.”
GSK Vocabria (cabotegravir) for HIV treatment: CMC issue with Cabenuva NDA. CRL issued for Vocabria because Vocabria approval is dependent on Cabenuva approval. “Deficiencies must be adequately addressed before this application can be approved,” the FDA said.
Novartis Leqvio (inclisiran) for lowering LDL cholesterol: Objectionable conditions at manufacturing facility. “Satisfactory resolution of these objectionable conditions is required (e.g., preapproval inspection and/or adequate facility responses addressing these conditions) before this application may be approved,” the FDA wrote in a CRL.
Regeneron Eylea HD (aflibercept) for wAMD, DME, DR: Manufacturing facility issues. “The methods to be used in, and the facilities and controls used for, the manufacture, processing, packing, or holding of the drug substance or the drug product do not comply with the current good manufacturing practice regulations in parts 210 and 211,” according to a CRL.
Takeda Entyvio prefilled pen (vedolizumab) for UC & Crohn’s: Numerous use-related issues (use errors, close calls, use difficulties) with device. FDA issued recommendations for revising the user interface (device design, device labeling, and instructions for use).
UCB Bimzelx (bimekizumab) for plaque psoriasis: Manufacturing facility issues. “Satisfactory resolution of these deficiencies is required before this application may be approved,” the FDA said in a CRL.
