Manufacturing and control strategies for Cell and Gene Therapy products: Navigating EU and US regulatory requirements

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 June 12, 2025

With recent changes at the US Food and Drug Administration (FDA), companies are seeking effective navigation strategies that allow their development programs to advance. One such strategy is pursuing global development or leveraging global guidance to inform a region-specific program. 

For developers targeting Cell and Gene Therapy (CGT) approvals in both the United States (US) and the European Union (EU), it is vital to develop strategies that align with the regulatory frameworks on both sides of the Atlantic. This is particularly important for chemistry, manufacturing and control (CMC) activities, as early decisions made on process, analytical and manufacturing approaches can impact licensure and commercialization.  

By highlighting two main focus areas of regulatory nuance, we aim to provide CGT sponsors with actionable insights to inform region-specific CMC strategies, while identifying opportunities for harmonization to streamline development for global access. 

Focus area 1: Starting materials/raw materials 

Regulatory definitions and testing requirements differ for raw and starting materials: 

• EMA: The European Medicines Agency (EMA) defines ‘starting materials’ as those that will become part of the drug substance ¹, such as vectors used to modify cells, gene editing components and cells. Therefore, vectors to be used as precursors for product manufacture must be prepared in accordance with Good Manufacturing Practices (GMP) principles. While regulatory inspections of manufacturing sites for starting materials of CGT are uncommon, the drug substance/drug product manufacturer must ensure the quality of the starting material via their qualified person.
• FDA: The FDA does not have a regulatory definition of starting materials. Instead, the term ‘critical raw materials’ is often used to encompass most substances listed above. FDA expects an enhanced material control approach, aligned with the risk of the material and the stage of development, mirroring EMA expectations. 

There are also regulatory distinctions regarding viral vectors:

The FDA classifies in vitro viral vectors used to modify cell therapy products as a drug substance, but the EMA considers these to be starting materials. The level of potency verification required for in vitro viral vectors also differs, with the FDA expecting more functional assays. 

Regarding replication competent virus (RCV) testing, the EMA considers that once absence has been demonstrated on the in vitro vector, the resulting genetically modified (GM) cells do not require further RCV testing. However, the FDA requires that the cell-based drug product also needs to be tested. 

CGT products that require human material in their manufacture, such as patient cells, are subject to regional donor testing requirements by both agencies. Additionally, the EMA requires some donor testing even for autologous material. 

Focus area 2: Demonstrating comparability 

Currently, CGTs are considered outside the scope of the ICH Q5E guideline on comparability of biotechnological/biological products.² However, a new Annex to ICH Q5E is in development, which will address CGT-specific compatibility challenges. In the meantime, there are regional guidances and documentation that CGT developers can employ:

• EU: 
  • EMA ‘Questions and Answers’ document on comparability considerations for these product types³ (effective December 2019)
  • For medicinal products containing GM cells, multidisciplinary EMA guidance including content on expectations for comparability⁴ (effective November 2012, updated June 2021) 
  • For demonstrating comparability for CGTs undergoing clinical development, a multidisciplinary EU guideline⁵ (effective July 2025) 
• US: FDA has issued draft guidance on comparability for CGT products⁶ (July 2023), reflecting current FDA thinking on CGT comparability. A future draft could benefit from addressing comparability requirements following changes related to recombinant starting materials.

Both EMA and FDA stress the importance of including testing for potency, however some differences exist in the requirements for stability data and in the use of supportive development data. In terms of comparability exercise design, and the testing/quality attributes included, both agencies agree that the extent of testing increases with the stage of clinical and product development and that characterization tests should be added if appropriate.^{5, 6} Overall, both the EMA and FDA also align on the extent of quality attributes included should be driven by a risk-based approach to evaluate the impact of the changes.^{3, 6} In addition to release and characterization testing, there is consensus on including stability testing and recognition that accelerated or stress studies can be useful for identifying differences in stability indicating attributes.^{3, 6} 

EMA guidance for GM cells outlines specific attributes to evaluate when changing the manufacturing process for recombinant starting materials. For the starting material, these include full vector sequencing, confirming the absence of RCV, comparing impurities and assessing stability. The guidance also specifies tests for the finished product, such as transduction efficiency, vector copy number and transgene expression.¹ There is no equivalent in the FDA guidance. 

Other requirements to support CMC planning for CGT products

Defining the raw/starting materials and demonstrating comparability are just two key CMC aspects of CGT development. Table 1 shows other important CMC considerations, and where the EMA and FDA converge or diverge in their requirements. Understanding these comparisons can support decision-making for CGT CMC development plans.  

Table 1. Comparison of FDA and EMA regulatory requirements for key CMC aspects of CGT

Conclusions 

Manufacturing of CGT products is highly complex. To be successful in their global CGT development programs, it is essential that companies understand the FDA and EMA region-specific requirements and be aware of where harmonization can be leveraged to streamline and possibly even accelerate CMC development.  

Our team of CMC experts, including former FDA and EMA regulators, has direct experience with advising on and critically assessing global programs for CGT products. We provide strategic advice in the areas that lack streamlined global regulatory guidance to help navigate the evolving landscape. With experience gained from industry, and global agencies, we develop and implement solutions that help bring therapies to patients quicker, and with lower risk.   

References

1. EMA/CAT/22473/2025 Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials - Scientific guideline 
2. EMA/CHMP/BWP/QWP/IWG/694114/2019, Toolbox guidance on scientific elements and regulatory tools to support quality data packages for PRIME and certain marketing authorisation applications targeting an unmet medical need - Scientific guideline 
3. EMA/CAT/499821/2019, Questions and answers on comparability considerations for advanced therapy medicinal products (ATMP) - Scientific guideline
4. EMA/CAT/GTWP/671639/2008, Quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells - Scientific guideline
5. EMA/CAT/22473/2025, Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials - Scientific guideline
6. Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products

Disclaimer:
Parexel provides the information contained in this document for educational purposes only. The information does not constitute legal or regulatory advice. Readers should not act upon this information without seeking advice from professional adviser 
 

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