Cell therapy has rapidly expanded what’s possible in medicine. Groundbreaking treatments are emerging for cancer, genetic conditions, and more. However, manufacturing cell therapies is complex, and the success of these therapies relies heavily on the raw materials used during the manufacturing process.  

What are raw materials in cell therapy? 

Raw materials, also called ancillary materials in U.S. regulations, are used in manufacturing cell therapies but are not intended to be present in the final product. Together with excipients—administered as part of the product to maintain cell quality—they make up the input materials for cell therapy manufacturing.  

Several types of raw materials are used in cell therapy, including: 

• Cell culture components: Antibiotics, cell culture media, serum for culture media, enzymes, and more 

• Components used to stimulate cells: Cytokines, growth factors, and other supplements 

• Materials used for cell selection/depletion: Monoclonal antibodies coupled to microbeads 

• Substrates/scaffolds that support cell expansion and differentiation 

• Disposables: Plasticware, bioprocessing bags, and more 

Each of these components is vital to the ultimate success of cell therapy manufacturing. It’s crucial to use raw materials that are traceable, consistent, safe, pure, and effective as new therapies progress through clinical development toward commercialization. 

Why raw materials matter 

The quality and consistency of the raw materials may impact the downstream therapeutic. Any variability in these components can create variability in the end product—which could affect its safety or efficacy.  

Take cytokines, for example—a material used to expand cells for a variety of cell therapy products. Unfortunately, the industry lacks standardized methods for measuring cytokine activity and analyzing results, which means each vendor develops its own internal standards. While lot-specific activities values are reported on each manufacturer’s certificate of analysis (CoA), this variation in methodology makes it harder for developers to compare cytokine activity across manufacturers.  

As a result, cell therapy developers may have to take additional steps to ensure consistent cytokine activity when switching raw materials. If they don’t, they risk failing to meet critical product attributes like cell number, transduction frequency, and cell function.  

Unfortunately, cell therapy manufacturers still face key challenges around raw material selection 

Raw materials can be a significant step to scaling manufacturing successfully. 

The raw materials often first selected in an R&D environment are research use only (RUO). These are often relatively lower cost and have shorter lead times. While RUO materials are suitable for R&D, they’re typically produced using less defined, controlled, and validated processes than GMP-grade (good manufacturing practices) materials. They also undergo less rigorous testing, which often requires retesting many parameters independently. 

Such inconsistencies create roadblocks later in development, when developers must switch to GMP materials to meet heightened regulatory standards. Not only do manufacturers need to find a consistent supply of GMP materials, but they also face significant costs and delays in conducting clinical comparability studies. They could avoid this step entirely by using preclinical-grade raw materials from the start. 

How cell therapy manufacturers can enact effective controls for raw materials 

Not all raw materials pose the same risk to the quality, consistency, and safety of the final product. Developers can lay the foundation for consistency by understanding the level of risk for each raw material. 

To help, the United States and European Pharmacopoeia have sorted materials into four risk categories, depending on the quality and state at which each raw material is introduced: 

• Tier 1: Low-risk, highly qualified materials such as licensed biologics, approved drugs or medical devices used off-label in manufacturing. 

• Tier 2: Low-risk, well-characterized materials intended for drug, biologic or medical device manufacture, produced under GMP conditions. Excludes most animal-derived materials. 

• Tier 3: Moderate-risk materials requiring higher qualification, often produced for in vitro diagnostics and not initially intended for cell, gene or tissue-engineered products. May need process upgrades. 

• Tier 4: Highest-risk materials needing extensive qualification, not produced under GMP conditions, and not intended for cell, gene or tissue-engineered products. Includes highly toxic substances and complex animal-derived materials without viral removal or inactivation. 

Cell therapy developers and manufacturers should have a risk management strategy for their raw materials. This could include in-house testing of critical raw materials and those not sufficiently qualified by the supplier. It also could mean finding new suppliers for materials that fail to meet specifications—and a strategy re-evaluation when switching materials or changing processes.  

How a CDMO partner can help 

Ultimately, selecting the optimal raw materials and managing risk require deep, specialized expertise—one that many developers may need an external partner to provide.  

Creating a risk management plan 

A CDMO partner can help early developers implement a risk-reduction approach that identifies the most important characteristics for each raw material. The CDMO can help develop a raw material qualification program, which includes performing a risk assessment, evaluating each material’s attributes and associated risk, and implementing a mitigation plan.  

Providing support to source materials 

CDMOs can also work closely with raw material suppliers to assess the suitability of specific raw materials. This includes leveraging technical expertise to streamline raw material and vendor qualification, as well as gathering and evaluating data to establish the source, identity, purity, and biological safety. The result: Developers have the information they need to select the optimal raw materials.  

What’s involved in qualifying raw materials for cell and gene therapy production? 

1. Verifying the vendor’s CoA to ensure the material meets acceptance criteria

2. Performing audits of suppliers and partners 

3. Ensuring that material purification does not involve untested components or those that could risk the end-user 

4. Verifying that adequate viral inactivation/removal techniques are used to ensure the material is free of adventitious agents

5. Verifying the CoA to determine human- or animal-derived components and confirm BSE-free countries of origin 

6. Analyzing and verifying the identity, purity and performance of crucial raw materials in manufacturing procedures 

Offering end-to-end support

A CDMO partner can anticipate how developers’ needs might change during clinical development and commercialization—and offer support to match. This includes preparing a well-designed qualification framework that becomes more comprehensive throughout clinical development. A partner will also regularly update the framework as new scientific insights and analytical capabilities emerge. 

The bottom line

Raw materials play a critical role in cell therapy manufacturing. Choosing suboptimal materials at any stage of development hurts downstream processes, increases development costs, and delays time to market.  

As cell therapies continue to evolve, the right CDMO partner can help developers source high-quality materials—ones that ensure consistency, safety, efficacy, and regulatory compliance. Having a partner to manage the risks can streamline development and commercialization—and make it economically feasible to reach patients who need these life-saving treatments the most.  

Catalent, Inc. is a leading global contract development and manufacturing organization (CDMO) championing the missions that help people live better and healthier lives. Every product that Catalent helps develop, manufacture and launch reflects its commitment to improve health outcomes around the world through its Patient First approach. Catalent provides unparalleled service to pharma, biotech and consumer health customers, delivering on their missions to transform lives. Catalent tailors end-to-end solutions to meet customers’ needs in all phases of development and manufacturing. With thousands of scientists and technicians and the latest technology platforms at more than 40 global sites, Catalent supplies billions of doses of life-enhancing and life-saving treatments for patients annually. For more information, visit www.catalent.com.