Key Considerations For Materials And Components Used In CGT Manufacturing

By Alyssa Colon, Amanda Cinquin, Donnie Beers, Morven McAlister, and Rebecca Govier, members of BioPhorum

The field of cell and gene therapy (CGT) has ushered in a new era of medical treatments, offering hope for conditions once deemed incurable. However, the journey from groundbreaking research to practical application is fraught with complexities, particularly in the manufacturing processes.

In this article, we delve into the critical role of raw materials in CGT manufacturing, with a special focus on ancillary materials and single-use systems (SUS), which are pivotal in ensuring the flexibility and sterility required in CGT production. The diverse array of raw materials used introduces various challenges that necessitate a thorough regulatory overview and meticulous examination.

Here, we shed light on the complexities and regulatory intricacies of ancillary materials and SUS, and discuss the significance of materials such as resins, bags, filters, and electroporation cartridges and their impact on product quality and process efficiency. We also highlight the often-overlooked ancillary materials, categorizing the material grades and outlining their qualification and testing requirements. The discussion covers the critical aspect of sterility in CGT products, exploring their validation and implications for the manufacturing process.

By drawing on industry practices and regulatory frameworks, this article serves as a comprehensive guide for manufacturers and researchers. It aims to enhance the overall quality, safety, and efficiency of CGT manufacturing processes, ultimately advancing the accessibility and effectiveness of these revolutionary therapies.

The Complexities Of Raw Materials In The CGT Industry

When investigating this area, it quickly became apparent to us at BioPhorum that there is a lack of a common vocabulary around raw materials and their classifications or suitability for different phases of development in CGTs. Raw materials for cell therapies, gene therapies, and genetically modified cell therapies are drastically different and have vastly different scales compared to those used in other therapies, such as vaccines made from monoclonal antibodies.

For other biologics, the industry is mature with defined processes, clear regulations, and standards. There is less heterogeneity in manufacturing procedures, scale-up poses fewer challenges, and the finished drug product can be purified and sterilized. Research and development of new products typically occurs in pharmaceutical companies with experienced staff and standard operating procedures in place.

In CGTs, products often start R&D at academic institutes or translational centers with expertise in science and medicine but not necessarily in quality and regulatory affairs. Although regulations and standards exist for biologics, translating these requirements for CGTs is challenging due to the breadth of processes and products. Raw materials are crucial for consistent product manufacturing, requiring GMP compliance, appropriate quality attributes, and contamination risk mitigation.

What Industry Practices Influence Material Research For CGT?

University-based laboratories and clinicians have significantly influenced CGT development, leveraging experience in blood separation and fractionation. Academia often relies on familiar tools used by researchers. Traditional biopharma, with extensive experience in GMP-ready tools and tech transfer, also shapes the space. The fragmented manufacturing landscape draws on a wide range of raw materials and tools, making standardization challenging. We want to create a baseline framework for selecting and interacting with raw materials, especially ancillary materials or research-use-only grade materials.

The Main Challenges Of Using A Diverse Range Of Raw Materials In CGT Manufacturing

The main challenges stem from variability in the source, quality, and consistency of raw materials. In CGT, materials often come from different suppliers and may not always be available in therapeutic or medical grades. This diversity can introduce risks such as contamination, inconsistent performance, or regulatory noncompliance. Managing these risks requires robust sourcing strategies, supplier qualification, and thorough material characterization.

Material Grades In The CGT Manufacturing Process

While medical or therapeutic grade materials are ideal, they are not always necessary or practical due to cost and availability. A risk-based approach helps determine when lower-grade materials can be used without compromising product safety or quality. This involves assessing the material’s role in the process, potential impact on the final product, and whether risks can be mitigated through controls like incoming testing or additional purification steps.

Key Regulatory Considerations For Ancillary Materials And SUS, And How They Affect Product Quality, Process Efficiency, And Associated Risks

Regulatory guidance on ancillary materials for CGTs is limited due to diverse manufacturing processes. A risk-based approach is recommended to address the closeness of ancillary materials to the finished product, lot-to-lot consistency, and likelihood of residuals.

Single-use systems have become a cornerstone of modern biomanufacturing, offering streamlined operations, reduced cleaning requirements, and faster turnaround times. These systems, composed primarily of presterilized plastic and polymer components, are designed to support the production of complex biologics without compromising the identity, strength, quality, purity, or potency of the final drug product. Their integration into manufacturing processes is often supported by comprehensive quality documentation, which facilitates regulatory submissions and accelerates development timelines.

Despite these advantages, the adoption of SUS is not without challenges. A primary concern is the potential for contamination, particularly in processes where open handling or fragile components increase the risk of leaks or breakage. Regulatory expectations also demand that SUS materials be nonadditive, nonreactive, and nonabsorptive to ensure product safety and efficacy. The risk of leachables and extractables — chemical substances that can migrate from SUS materials into the drug product — is especially critical. These substances can compromise product stability or introduce safety concerns, particularly in therapies with long contact times or large surface area exposure.

Cell therapy products, which often lack a final sterile filtration step, are especially vulnerable to contamination risks. In such cases, additional safeguards must be implemented to ensure product integrity. While cold storage can mitigate some risks associated with extractables and adsorption, many CGT products are not stored at reduced temperatures, limiting the effectiveness of this strategy. As the industry continues to innovate, careful validation and risk assessment of SUS and ancillary materials for specific applications remain essential to ensure both regulatory compliance and patient safety.

The Significance Of SUS In CGT Manufacturing And How They Minimize Cross-Contamination Risks

Single-use systems significantly reduce the risk of cross-contamination, which is critical in CGTs due to the small volumes of therapeutic products, where every drop counts. SUS eliminates the need for engineers to develop and validate clean-in-place procedures by using components made from virgin polymers. Manufacturers of SUS typically perform rigorous cleanliness testing to ensure their products do not introduce contaminants into the process. Since components like tubing, connectors, bags, and filters are used only once, cross-contamination from other processes is minimized. Additionally, SUS enables a closed system, further mitigating the risk of extraneous contamination.

Although virgin polymers are currently preferred due to their consistency and regulatory familiarity, the biopharmaceutical industry is increasingly exploring more sustainable alternatives. As the sector moves toward greener practices, there may be opportunities to adopt equivalent scientific standards for recovered or second-life polymers. With appropriate validation and risk mitigation strategies, these materials could offer a viable path toward reducing environmental impacts without compromising product safety or quality in CGT manufacturing.

Resins, Bags, Filters, And Electroporation Cartridges In CGTs Compared To General Biologics

Bags, tubing, and connectors must be inert and unreactive to the product inside them, while providing a protective barrier from the exterior environment. Bags are exposed to extreme conditions during cryopreservation, and tubing must be robust enough for use in peristaltic pumps. This has led to advances in bag designs and ultra-pure polymers. Filters in CGTs should minimize nonspecific adsorption of critical product components while allowing maximum product recovery, which is especially important for gene therapies with very low batch volumes. Consideration must also be given to potential extractables and leachables.

Sterility In CGT Raw Materials

For liquid cell culture media, sterilization is typically achieved by aseptic filling and sterile filtration. It is crucial that suppliers have routine validation protocols for aseptic filling and perform re-validation if significant changes occur in the manufacturing process. Stability and transportation studies are essential to ensure that container integrity supports maintaining product sterility.

Ensuring sterility in CGT products is both paramount and challenging. Critical measures include sterility assurance, aseptic techniques, and closed manufacturing processes to minimize patient safety risks. Additionally, understanding and controlling bioburden through supplier specifications is vital. The complexity of this landscape is further compounded by difficulties in sterility testing due to short shelf lives and small batch sizes. Validation of sterility depends on the supplier’s internal procedures, encompassing initial validation via a risk-based approach and routine re-validation activities. These validations may apply to the product formulation and supporting methods or equipment used in CGT material production.

How Do Material Choices Impact Functional And Supplier Risks In CGT?

In CGT development, clearing the chemistry, manufacturing, and controls requirements for IND filing and ensuring a solid regulatory approval path are crucial. Material choices dictate development, gap assessment, and risk assessment discussions from R&D through tech transfer and commercial manufacturing and are essential. Selecting the right collaborative partners for CDMOs and suppliers is inherently tied to material choices, impacting safety, efficacy, and critical quality attributes. During process development and scaling, it is advised to select materials that are certified as fit for pharmaceutical manufacturing.

The Most Significant Advances In CGT Manufacturing From A Supply Perspective

Significant advances include aligning suppliers to scales relevant for individualized medicines or rare diseases with small patient populations. The availability of raw materials can be scarce, such as T cells from patients with low white blood cell counts or bone marrow from small children. Suppliers are adapting to these new scale requirements to eliminate waste. Increased collaboration among end users, CDMOs, and suppliers is also notable, as they recognize the benefits of cooperation in reducing risk and investment while competing in areas of strength. The desire for chemically defined media and raw materials, free from xenogenic components, is growing. However, balancing this with the efficacy of animal-derived materials remains a challenge. Scalability and consistency are critical, with new analytical methods being developed to ensure safety and efficacy across different production scales and locations.

Moving Into The Future For Success

Advances in CGTs represent a monumental leap in medical science, offering unprecedented treatment possibilities. However, the complexity of manufacturing processes, particularly concerning raw materials, poses significant challenges. This article has explored the critical aspects of ancillary materials and SUS, highlighting their pivotal roles in ensuring the quality, safety, and efficiency of CGT products. 

By delving into the regulatory landscape and examining the intricacies of material grades, manufacturing requirements, and sterility considerations, we aim to provide a comprehensive guide for industry professionals. These insights underscore the importance of meticulous material selection and robust quality management systems in overcoming the hurdles of CGT manufacturing.

For more information, read the full paper, Materials and components in CGT: a consensus approach.

About The Authors:

The authors, all members of BioPhorum, are: Alyssa Colon (Thermo Fisher Scientific), Amanda Cinquin (FUJIFILM Biosciences), Donnie Beers (Entegris, Inc.), Morven McAlister (Cytiva), and Rebecca Govier (Watson-Marlow Fluid Technology Solutions).