Understanding FDA complete response letters: Why CMC readiness must become a strategic priority

In September 2025, the US Food and Drug Administration (FDA) announced that it would begin publicly posting newly issued complete response letters (CRLs) along with historically issued CRLs tied to both approved and unapproved applications. FDA CRLs typically stem from gaps in efficacy, safety, manufacturing processes or control systems. CRLs will describe the deficiencies or inadequate data and the recommended actions to appropriately address the issues thereby best placing the application in a state for approval. One of the goals for publicly posting CRLs is to guide the biopharmaceutical industry in minimizing the number of deficiencies to their applications by avoiding the most common deficiencies cited in the publicly posted CRLs. 

How CMC deficiencies are leading to CRLs 

Although studies of FDA Complete Response decisions that were performed prior to September 2025 have shown that CMC deficiencies are a leading reason for non-approval, granular detail about the types of deficiencies was lacking since the CRLs were not public information.^1,2 Consequently, drug developers had limited insights into the kinds of CMC issues that would preclude drug approval. When the FDA first proposed to post CRLs publicly, this was initially opposed by the biopharmaceutical industry for fear of revealing companies’ trade secrets and proprietary information.³ However, in its 2025 announcement, the FDA confirmed that all confidential information would be redacted.⁴ Because much of CMC information is considered proprietary, unlike most clinical data, many CMC-related deficiencies in the posted CRLs are heavily redacted.   

Nevertheless, the CRLs do provide valuable information.  An analysis conducted on the first batch of CRLs released (more than 200 CRLs issued between 2020 and 2024) revealed that the combined deficiencies of facilities and quality (i.e. CMC) related issues were more frequent (29.1%) than clinical safety (13.4%) and efficacy (10.9%) related issues combined.⁵ A similar trend was observed in another study where the analysis was conducted on CRLs issued for the same timeframe but limited to 43 applications containing only new chemical entities (NCE), either as a single agent or in a drug-drug combination. The CMC and facility related issues were still the most prevalent deficiencies (23% and 29% of all 97 deficiencies reported, respectively).⁶ 

An analysis conducted on the first batch of CRLs released (more than 200 CRLs issued between 2020 and 2024) revealed that the combined deficiencies of facilities and quality (i.e. CMC) related issues were more frequent (29.1%) than clinical safety (13.4%) and efficacy (10.9%) related issues combined.⁵

Late-phase CMC changes are a major driver of CMC deficiencies, making them one of the leading causes of CRLs  

Because the success of a new drug development program ultimately depends on clinical safety and efficacy outcomes, sponsors tend to focus more heavily on clinical development than on CMC during the investigational phases. Consequently, the clinical program is typically stress-tested and undergoes substantial FDA regulatory assessment. In contrast, the CMC strategy, including manufacturing process and final formulation, in most cases, is not fully defined until late phases of development. In addition, clinical trial material is usually manufactured at a smaller scale than intended commercial scale, or at a facility different from the proposed commercial manufacturing site. Consequently, many CMC features of a drug product that are related to overall quality, and not just the safety-related aspects, do not get reviewed in-depth before submission of a marketing application. The step wise development of the CMC aspects of drug products helps to explain the higher frequency of CMC-related issues in CRLs compared to safety or efficacy issues.   

Understanding the types of CMC deficiencies mitigates the risk of a CRL 

Anticipating potential CMC deficiencies and addressing them proactively during product development and prior to submission of the marketing application can reduce the potential for a CRL. Below we outline CMC issues that, in our experience, can pose challenges during FDA’s review of a marketing application.   

Strategies to strengthen CMC data package prior to Marketing Application submission 

Careful CMC planning early on in drug development can prevent or alleviate some of the challenges faced during the marketing application review stage and that lead to CRLs.  

1. Contract Development and Manufacturing Organization (CDMO) selection 

Since issues related to manufacturing facilities are the most common CRL deficiencies, companies interested in outsourcing part or all of their development and/or manufacturing activities should carefully select their CMO/CDMO partner. This is important because PAIs and PLIs are often conducted late in the review cycle, giving the facilities insufficient time to address any inspection-related concerns. Therefore, when selecting a CMO/CDMO, it is important to establish a strong unequivocal agreement, clearly defining the CGMP roles, manufacturing operations and activities of each of the parties involved in the contract manufacturing operations, ideally based on FDA guidance recommendations.¹³ In addition, given the number of deficiencies associated with facilities companies should consider the following key pillars for evaluating CMO/CDMO partners.  

• Technical capabilities: Process development and scale up ability and experience with similar products (similar molecules and/or dosage form). 
• Regulatory readiness: Track record of successful inspections by the FDA and other regulatory agencies (such as EMA). Ensure readiness by performing mock audits.   
• Quality Control (QC) system: Strong quality control structure (for example through management of audit findings).   
• Quality Management System (QMS): QMS robustness. Review sites documentation practices, recent audit findings and corrective actions.   
• Communications: Responsiveness and transparency in sharing data and resolving issues. 
• Supply chain management: Network robustness (i.e. reliability of their network of raw material suppliers and contingency plans verification).   
• External validation: Feedback received from current/former clients on their experience with CDMO.   

2. Regulatory intelligence  

Sponsors should be aware from an early stage of the CMC content potentially needed later in development. Familiarization with the content included in publicly available CRL letters is therefore an important part of a company’s regulatory CMC strategy. Although much CRL content is redacted and publicly available information is limited, familiarity with CMC deficiency trends, where possible, can help ensure product CMC is aligned with state-of-the-art developments and Agency expectations. This approach can inform drug development and may consequently reduce the number of review cycles and expedite the drug product approval process.   

In addition, engagement with the FDA via Type B or C meetings can help also ensure companies remain up to date with any evolving or novel regulatory expectations and thereby ensure appropriate CMC content will be available on time for submission. Partnering with a CRO who maintain regulatory intelligence databases informed by previous CRLs and the engagement experience with the FDA is also an excellent option.   

3. Engaging consultants to mitigate FDA CMC deficiency risk 

Early engagement with regulatory strategy consultants who offer deep CMC expertise and direct regulatory agency experience enables sponsors to: 

• Develop a forward-looking risk mitigation strategy. Identifying high-risk gaps (e.g., scale-up, aseptic processing, comparability) early; and integrating regulatory, technical, and operational inputs into mitigation plans.   
• Align with FDA expectations. Because misalignment with FDA expectations can lead to avoidable deficiencies or delay, consider using experienced consultants to shape your CMC positioning and messaging, particularly for those issues that may require FDA interactions. 
• Ensure inspection readiness of manufacturing sites through independent compliance evaluations and mock inspections of QMS, analytical and QC infrastructures, and alignment of systems and documentation practices with current GMP and regulatory best practices.   

Parexel's CMC, compliance and regulatory experts provide deep insights into how to avoid the CMC challenges that lead to non-approval decisions and CRLs. Our team includes former regulators from the FDA, EMA, MHRA, NMPA, and PDA, as well as senior industry professionals, and bring our extensive CMC and compliance expertise and tailor this to the unique needs of your development program. Together with you, we will strengthen your CMC strategy and improve quality of regulatory submissions.  

Please contact us; we are always available for a conversation.  

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References: 

1. Sacks et al., (2014) Scientific and Regulatory Reasons for Delay and Denial of FDA Approval of Initial Applications for New Drugs, 2000-2012.  JAMA. 311(4):378–384.  
2. Lurie et al., (2015) Comparison of content of FDA letters not approving applications for new drugs and associated public announcements from sponsors: cross sectional study. BMJ 350:h2758  
3. FDA Transparency Initiative: Draft Proposals for Public Comment Regarding Disclosure Policies of the U.S. Food and Drug Administration; Availability, FDA Federal Register (Docket No. FDA-2009-N-0247), May 2010. 
4. FDA News Release – FDA Announces Real-Time Release of Complete Response Letters, Posts Previously Unpublished Batch of 89, September 2025. 
5. Anatomy of a Rejection: A Data-Driven Analysis of 202 FDA Complete Response Letters, July 2025. 
6. Dilek et al (2026). Deficiencies Delaying Prescription Drug Approvals by the U.S. Food and Drug Administration, 2020–2024, Ther Innov Regul Sci 60, 837–846 .   
7. FDA Guidance – Control of Nitrosamine Impurities in Human Drugs, September 2024. 
8. FDA Guidance – Recommended Acceptable Intake Limits for Nitrosamine Drug Substance Related Impurities (NDSRIs), August 2023. 
9. ICH Q3D(R1) – Guideline for Elemental Impurities, March 2019. 
10. USP General Chapter <232> – Elemental Impurities Limits, Official as of May 2024. 
11. USP General Chapter <233> – Elemental Impurities Procedures, Official as of May 2026. 
12. ICH M7(R2) – Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, April 2023. 
13. FDA Guidance – Contract Manufacturing Arrangements for Drugs: Quality Agreements, November 2016. 

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