Navigating Regulatory Requirements for Critical Starting Materials in Gene and Cell Therapy

Authors: Leslie Rotunno, Marieke Zhao, and Stacy Plum 

When it comes to gene and cell therapy (GCT), few topics spark more debate and demand more precision than the regulatory expectations surrounding Critical Starting Materials (CSMs). Whether you're preparing for a Phase I trial or planning for commercialization, understanding how CSMs are regulated is essential for de-risking your development program and ensuring a smooth regulatory journey.   

What are CSMs?  

CSMs are the foundational raw materials used in the production of CGT products. CSMs are components that are either incorporated into Drug Substance/ Drug Product or directly influence product quality. Each product’s raw material list should be evaluated to determine which materials classify as standard raw materials or as Critical Starting Materials.  

Common CSMs include:  

• Human cells or tissues 
• Plasmids, mRNAs, and mRNA components  
• Synthetic oligonucleotides 
• Growth media and other biological reagents 

Because these materials are biologically derived, they introduce variability and complexity that can challenge standard quality control frameworks.  In addition, they carry a higher inherent risk of contamination with adventitious agents such as viruses, mycoplasma, or prions. Regulatory authorities expect implementation of robust controls to mitigate these risks, particularly when materials are of human or animal origin. 

Raw materials, on the other hand, are materials that are used in the manufacturing process that do not become part of the final product and do not necessarily impact Critical Quality Attributes.  

Common Raw Materials include: 

• Excipients 
• Solvents  
• Buffers 
• Cleaning aids 

GMP, GMP-Like, or Research Use Only: What’s Required and When? 

One of the most frequent questions in GCT development is: “Do we need GMP-grade materials for early-phase trials?” 

The answer isn’t one-size-fits-all. The grade of starting materials—whether GMP, GMP-like, or Research Use Only (RUO)—depends on both the development phase and the intended use of the material in the process. 

A risk-based assessment should be conducted to evaluate: 

• How the material is used in manufacturing 
• Its potential exposure to the Drug Substance/Drug Product 
• The likelihood that it impacts critical quality attributes (CQAs) 
• The phase of clinical development 

To make this determination, it is important to understand how raw materials are categorized.   

GMP (Good Manufacturing Practice)  

Materials manufactured in full compliance with current Good Manufacturing Practices (cGMP), as defined by regulatory authorities. This includes: 

• Comprehensive quality systems 
• Validated manufacturing processes 
• Full traceability, documentation, and change control 
• Qualified personnel and facilities 

GMP-grade materials are generally required for late-stage development and commercial manufacturing. 

GMP-like 

“GMP-like” refers to materials that are manufactured with many GMP principles in mind, but that may not meet the full regulatory definition of GMP. This can be acceptable especially in early-phase programs if there are: 

• A well-controlled production environment (including environmental and process controls)  
• Robust quality systems 
• Adequate documentation and traceability 

Understanding whether your supplier’s processes meet these expectations is critical when justifying the use of GMP-like materials in regulatory filings. For many earlier phase programs, this GMP-like material grade may be deemed acceptable, especially when certain GMP principles are adhered to during production of the material.  

RUO (Research Use Only) 

Materials labeled as not intended for use in human therapeutic applications. RUO materials: 

• Are generally not appropriate for manufacturing clinical products 
• Lack GMP controls and traceability 
• May be acceptable only in very early discovery research or preclinical development 

Use of RUO materials in clinical manufacturing is discouraged and must be scientifically justified with a strong risk mitigation strategy. However, use of RUO material in early and pre-clinical development is often beneficial from a cost and timing perspective. It is typically much faster to source RUO grade materials than GMP or GMP-like grade materials.  

A Tale of Two Agencies: FDA vs EMA 

While both the FDA and EMA align in principle on the importance of controlling CSMs, there are nuanced differences in how each agency approaches oversight.  

FDA Expectations 

The FDA focuses heavily on supply chain control and traceability, particularly for materials of human or animal origin. Regulatory submissions should include: 

• Source and qualification data 
• Testing results 
• Change control documentation 
• Risk assessments for each CSM 

Several FDA guidance documents (Q11) address these expectations, and early engagement through pre-IND meetings is encouraged.  

EMA Expectations 

Under its Advanced Therapy Medicinal Products (ATMP) framework, the EMA has historically held stricter GMP requirements for starting materials, even in early development phases. However, the agency does offer flexibility through a risk-based approach, allowing GMP-like starting materials if a comprehensive scientific justification is provided. This risk-based flexibility can be invaluable, but only when backed by solid documentation and a proactive regulatory strategy.  

Be Proactive: Strategies for Compliance   

Delays or surprises in your development program can be avoided if you take a proactive approach. Things to keep in mind include:  

• Define and assess CSMs early in development 
• Map out GMP expectations by region and phase 
• Align cross-functional teams including Regulatory, CMC, and Quality on sourcing and qualification plans for CSMs 
• Document everything: source, testing, traceability, risk, and rationale 

CSM compliance isn’t just a box to check—it’s a key pillar of successful gene and cell therapy development. Getting it right from the start can save time, reduce risk, and bring life-changing therapies to patients faster. 

How Syner-G Biopharma Group can help 

At Syner-G BioPharma Group, we specialize in helping GCT developers navigate the evolving regulatory landscape for Critical Starting Materials. Whether you're building a preclinical strategy or preparing for commercialization, our team can help you: 

• Conduct phase-appropriate risk assessments 
• Draft robust documentation for regulatory filings 
• Develop sourcing strategies aligned with FDA and EMA expectations 
• Prepare for and lead effective regulatory interactions 

Connect now to learn more .