Optimize your CMC strategy: Five steps to avoid regulatory setbacks

This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.

Published May 12, 2025 

Chemistry, Manufacturing and Control (CMC) data provide assurance that every medicinal product, from active ingredient manufacture through to the final formulation, meets regulatory standards. Serious CMC deficiencies can, and do, lead to regulatory agencies suspending clinical trials or rejecting drug approval applications. For example, FDA data reveals that for oncology INDs placed on clinical hold, CMC-related quality concerns rank as the second most common reason, surpassed only by clinical considerations. In addition, CMC deficiencies account for approximately 20% of non-approval decisions for marketing applications.^1,2    

Serious CMC issues result in delayed product development, and patient access to new drugs. Therefore, in today’s evolving regulatory landscape, a proactive approach to ensuring drug quality is more crucial than ever. Building on the seven actions we recently shared, to navigate changes at FDA, we focus here on five CMC areas that can pose challenges, and provide practical advice to manage them effectively.   

1. Understand and strategize to avoid CMC deficiencies in marketing applications    

CMC information is a key focus area during regulatory review of marketing applications. In our experience, companies need to be well-prepared from the pre-clinical phase onwards to provide this essential data to avoid potential setbacks.   

• For biologics, commonly seen deficiencies are about process characterization and control strategy, knowledge of product mechanism of action and specifications, as well as adventitious agents’ safety.   
• For biosimilars, matching a complex and potentially evolving innovator product is critical, but also a substantial challenge.  
• For small molecules, companies must be careful to adequately specify and characterize the regulatory starting materials³ and demonstrate a control strategy that is based on drug characterization and process knowledge. In our experience, aspects that are common hurdles to the approval of applications include inadequate specifications or when appropriate extractable and leachable studies have not been performed. In addition, companies should ensure that stability studies are designed to meet regulatory requirements and that any trends in stability data are addressed.   

2. Be prepared to meet regional CMC regulatory requirements and expectations   

Companies pursuing global marketing approval must also understand and prepare for nuanced regional differences in CMC regulatory standards and expectations. Compliance with key requirements of regional pharmacopeias is a baseline regulatory expectation. While there has been some harmonization between the EU and US, other pharmacopeias cannot simply be substituted into these regions, and testing equivalence must instead be demonstrated.  

For example, the ICH Q4B guideline (pharmacopeial harmonization) has not been fully implemented in China, as the China Medical Culture Collection (CMCC)‌ and American Type Culture Collection (ATCC) did not reach mutual recognition. Consequently, any microbiology test (e.g. sterility) should be repeated using test cells recommended by the local authority; otherwise, the BLA/NDA may be delayed as China’s National Medical Products Administration (NMPA) may consider the product does not meet its national/area requirements. In addition, in the EU, there are specific requirements for Certification of Suitability (CEP) and Active Substance Master Files (ASMFs).   

Effective strategies to pre-empt regulators’ findings of serious CMC deficiencies in marketing applications include: 

• Plan a risk assessment and control strategy that is in line with each regulatory agency’s guidance and expectations. For instance, US and EU regulators recently updated guidance on appropriate control of nitrosamine impurities. 
• For sterile product types, understand each regulatory agency’s approach to the microbiology data review. These reviews are often very detailed technically, and each agency can have unique data requirements, such as the FDA’s requirements on endotoxin levels and demonstration of low endotoxin recovery. 
• Stability studies should be designed considering regional climatic zones.   
• Companies must ensure that their GMP systems meet the requirements of the local agencies and are aligned with the proposed manufacturing process. Additionally, they need to satisfy local importation and batch release requirements for each market they enter. For example, China has banned the import of certain pharmaceutical products because of a failure to prove compliance with the country’s GMP requirements. These requirements include adherence to the Chinese pharmacopoeia and specific management protocols for highly toxic products.  

3. Focus on product quality to maximize likelihood of FIH study approval and participant safety    

At the first-in-human (FIH) phase, the safety of trial participants is the most important consideration, and this begins with the quality of the investigational product. There are several actions companies should take to avoid regulators’ decisions against the initiation of the FIH trial.  

• For biologics, appropriate cell substrate characterization and relevant release specifications are essential as adventitious agent control is largely based on the quality of the raw and starting materials (including the cell substrate). Additionally, for biotech and plasma-derived products, viral clearance study design is critical to ensure viral safety of the investigational product. Based on agency guidance and IND/CTA rejection root cause analysis, sterility concerns are also a major reason of IND on-hold or rejection.  
• For small molecules, drug substance genotoxic structural alerts and the potential risk of having genotoxic process impurities or degradation products may be a concern. The information about genotoxic assessment and findings provided in the CTA and IND application should align with ICH M7 guidance.   
• Non-clinical batches demonstrate the first level of safety of the drug. In order for the clinical lot to be considered representative of those findings, companies must demonstrate comparability between the non-clinical and clinical drug product batches. For example, careful justification for any dosage form changes during development (e.g. from a vial to a pre-filled syringe) will be required and likely need support from comparability data. Early planning on CMC changes during development is recommended.  
• Even in early stages, regulators are looking for the prospect of efficacy from strength and potency assay data. Therefore, to ensure a safe starting dose of an active compound, and to link to non-clinical data, it is important to test with relevant and reliable assays.   
• For drug-device combination products or products to be delivered via a device, companies must confirm compatibility and assess the effect of the delivery device on dosing. For certain drugs and treatment indications (e.g., long-acting/extended release opioids for treatment of moderate to severe pain), regulators have concerns about the potential of overdosing, and residual drug in the administration device should be addressed. 

4. Demonstrate product comparability when making manufacturing changes   

During the drug lifecycle, changes in the manufacturing process are inevitable. Companies must therefore proactively consider different approaches for post-approval changes, including the creation of change management protocols.  It is essential to demonstrate comparability during development and post-licensure/approval to ensure continued safety and efficacy and the relevance of all prior clinical data with the previous product to the new one.  

• Comparability requires specific approaches throughout dug development, with early phase approaches differing from considerations for the commercial process. For example, a much more comprehensive CMC comparability study is required in later stages because the safety and efficacy profiles have been built. There is more flexibility in the early stage because the primary focus is on ensuring that the drug is safe for FIH testing.  
• Regulators require evidence that manufacturing changes will not negatively impact product quality, safety, or efficacy. This evidence can be developed through a robust comparability protocol that considers the effects of the changes and risks to Critical Quality Attributes (CQAs), including appropriate testing strategies.   
  
  For cell and gene therapy products, changes to manufacturing present several challenges regarding demonstrating comparability. It is important to statistically justify the number of batches included in the exercise. When using surrogate material, consideration should be given to including some patient batches.    

Due to the complexities involved, companies should seek early regulatory agency feedback on the planned comparability protocol, to ensure alignment with agency expectations and prevent any missteps that could prevent or delay future approval.   

Related to the issue of manufacturing changes for an individual drug product is the development of a biosimilar to an original innovator product.  For a biosimilar developer, demonstration of analytical comparability in support of biosimilarity is crucial and may pave the way for potentially supporting the waiver of some clinical studies. 

5. Carefully select a CDMO that can meet your manufacturing objectives    

Contract Development and Manufacturing Organizations (CDMOs) are foundational to ensuring clinical supply of investigational medicinal product and commercial manufacturing of approved drug. Technical know-how and a good working relationship are key for successful product development. Considerations to inform CDMO selection include: 

• Quality: A quality agreement is a formal contract that defines and establishes the quality responsibilities of both the CDMO and the sponsor. It's crucial because it ensures both parties understand their role in maintaining product quality and compliance with regulatory standards, which can help avoid future pitfalls during regulatory review. Ensuring that current Good Manufacturing (cGMP) activities and change control are covered in this agreement is vital to prevent quality issues and ensure smooth operations throughout the manufacturing process.  
• Compliance: GMP audits assess whether the CDMO adheres to regulatory standards for safe and effective drug production. Ensuring a site's inspection readiness is important as it indicates its ability to pass future and potentially unannounced regulatory inspections, which is critical for avoiding delays or rejections.  
• Communication: Flexibility in contracts is essential, especially for novel modalities, as it allows for necessary adjustments during process development and scale-up. Scalability determines whether the CDMO can meet increasing demand as the drug progresses from clinical to commercial production. A robust communication plan ensures timely and effective information exchange between the sponsor and CDMO on these matters. This is crucial for addressing issues promptly, making informed decisions, and maintaining alignment throughout the project and may ultimately help avoid delays in patient access to the product.  
• Excellence: High-quality data collection and detailed process characterization are fundamental for understanding and optimizing the manufacturing process. Efficient data transfer and client ownership of data are important for maintaining control over the product and for facilitating regulatory submissions. Clear practices for data and process transfer are crucial for ensuring continuity of manufacturing, whether for scaling up or moving to a different site, without compromising product quality or consistency. A defined process for data transfer is also important in supporting the preparation of the regulatory submission dossier.   

In an era of increasing regulatory scrutiny and evolving agency structures, a forward-thinking approach to CMC is not just beneficial, it's essential. By anticipating potential CMC challenges and addressing them proactively, sponsors can significantly reduce development delays, minimize costly setbacks, and ultimately accelerate patient access to innovative therapies. This strategic foresight is particularly crucial given that CMC issues are a leading cause of clinical holds and non-approval decisions, making it a critical factor in the success of drug development programs. 

With a team of 1,300+ regulatory specialists, including former regulators from agencies across the world, Parexel has the knowledge, insights, and technology-enabled processes to accelerate and streamline your drug development journey by proactively mitigating and managing CMC challenges. With experience in more than 110 countries, we provide strategic regulatory advice, identify and mitigate risks and navigate the ever-evolving regulatory landscape – including managing the implications of regulatory agency changes. Please get in touch, we’re always available for a conversation.  

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References 

1. Michael L. Manning, et al. An FDA analysis of clinical hold deficiencies affecting investigational new drug applications for oncology products. Regulatory Toxicology and Pharmacology. Volume 110, 2020.  
2. Sacks LV, Shamsuddin HH, Yasinskaya YI, Bouri K, Lanthier ML, Sherman RE. Scientific and Regulatory Reasons for Delay and Denial of FDA Approval of Initial Applications for New Drugs, 2000-2012. JAMA. 2014;311(4):378–384. doi:10.1001/jama.2013.282542 
3. Craig, M and Ferrarese, A. The subjectivity of starting materials in the era of harmonization. RAPS. 2023, November 8.   

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