Sourcing, Analyzing, And Ensuring Quality In CGT Raw Materials

By Life Science Connect Editorial Staff

Managing raw material quality is one of the biggest challenges in developing and delivering cell and gene therapies (CGT). Accordingly, phase-appropriate development strategies are vital in CGT, where variability in the cost and quality of raw materials can impact viral capsids, plasma, donor material, and other critical inputs. However, strategies exist for biopharmaceutical sponsors to proactively address potential raw material problems related to quality, viability, regulatory scrutiny, and supply chain security.

Cell & Gene Live recently welcomed Yan Zhi, Ph.D., a director and product manager at CSL Behring, and Lawrence Thompson, Ph.D., an associate research fellow at Pfizer, to examine these preventable issues and to discuss quality, risk, and financial strategies applicable to CGT raw materials.

Research-Grade Materials Offer Utility Alongside Risk

Biopharmaceutical raw materials, often called “ancillary materials,” generally comprise materials used as part of a manufacturing process but not intended to be part of the final product. Sponsors need to understand their supplier’s definition of raw materials and its perception of the difference between research-use-only (RUO)-grade and GMP minimum standards. Since there are enormous differences in cost and quality between RUO and GMP-grade materials, USP recommends classifying raw materials into Tier 1 through 4 categories based on their risk profile. This is helpful, for example, when the sponsor believes its process and product quality can tolerate the difference between grades because the material is low risk.

“To me, segregation, single use, and cross-contamination are the biggest questions that I would have [for a vendor] manufacturing research-grade material,” said Thompson, who insists on an in-person audit of any vendor producing specialized raw materials to ascertain capability and risk.

“It is the toughest thing in the world to make that transition from tox-type animal studies to first-in-human. That is not a cheap step, and it requires a lot of documentation, especially if you're trying to use the same [grade] of materials. [If] you have an R&D material, what controls do you have?”

Determining the raw material’s variability and its potential risks to process, product quality, and patient safety requires a risk assessment based on the drug program’s current phase, as well as regulatory feedback about the sponsor’s planned control strategy. Further, small-scale raw material batches can be used to monitor stability or product CQAs. Introducing lot-to-lot variability can provide insight into an RUO-grade material’s qualities, and consistent monitoring can confirm the effectiveness of vendor controls. Conversely, a large lot-to-lot swing in CQAs may indicate that the sponsor’s process or product cannot tolerate the material.

Material Characterization Guides Risk Analysis And Sourcing

It is not uncommon for a sponsor to create a tailored process to achieve a specific material but then be unable to find a supplier capable of producing the material at the necessary volume and quality. Like biologics, CGT raw materials are inherently complex and are not typically found “off the shelf.” Inconsistent quality and batch-to-batch variability can arise out of poor supply chain documentation, as well as inadequate vendor control over the starting material, manufacturing, or analytical methods.

So, ideally, raw materials used by the sponsor are well-characterized and documented, from critical material attributes (CMAs) to the materials’ impact on the manufacturing process. Providing specialized, GMP-grade material takes significant investment from a CDMO, so it is important for the sponsor to share clinical data showing the product is viable, as well as comprehensive documentation from the development journey.

“Start with good documentation. You may not have a GMP documentation yet, but that does not prevent you writing in a notebook,” advised Zhi. “Document as much [as possible] even though it's R&D material.”  

If dual sourcing is not possible, it becomes even more important to find a vendor that understands the sponsor’s needs and is clear about the capabilities it can provide. Similarly, the sponsor must set clear expectations: for example, is flexibility allowable in raw materials so long as certain CMAs are consistently met? These details can help toward building a comparability study or creating backup plans should the initial supplier be unable to meet the sponsor’s needs.

Upon partnering, a sponsor and its CDMO can collaborate on risk assessment: brainstorm every feasible risk and score each based on likelihood and criticality. If GMP production of the necessary raw materials is not available, this joint assessment can help fill gaps in the sponsor’s awareness of what is needed to achieve it, as well as inform discussions with regulatory authorities.

“If you have unacceptable lead times, you're not going to have the material you need when you need it. If you lack dual sourcing, you could easily not have the material you need. If you have poor documentation, your whole facility can get shut down. All of these are interconnected,” said Thompson.

Align Scientific And Business Goals

Many programs advance quickly utilizing RUO-grade material, only to encounter a bottleneck during scale-up due to lack of enough GMP-grade materials. In many cases, the industry self-corrects. No matter how innovative or complex a product, if it appears commercially viable, vendors will rush to claim their slice of the market, adding or enhancing capacity to produce the necessary raw materials in sufficient volumes and quality. This evolution takes place even faster when a sponsor and CDMO are both vested in a product’s success: perhaps the sponsor negotiates lower up-front cost from the CDMO in exchange for some fraction of the eventual product licensure.

“Innovation is the foundation for industrialization,” remarked Zhi.

As noted above, simultaneously serving scientific and business interests is key to creating a small-scale process that mimics the large scale for purposes of testing material quality and process expectations. This investment helps prevent backend issues, especially those related to comparability assessments and raw material supplier qualifying.

Increased openness to platform technologies by the FDA and other regulators has been helpful to CGT developers since platform processes can significantly de-risk programs, as well as potentially increase early investment in a program, based on the platform’s prior successes. Ideally, each product rewards confidence in the platform used to produce it — justifying buildout of that platform, which can be executed concurrently with product development.

Raw Material Changes: Manage Risk And Establish Comparability

Most biologics developers try to start programs with the end in mind, seeking out partners that can offer different grades of material, which allows the sponsor to use a less-expensive grade for early work (e.g., tox studies) and then switch to a higher grade when GMP quality becomes necessary. This is a basic example of a phased approach. However, it is just as likely that the sponsor has produced a novel raw material in-house or needs to switch or add vendors because of volume or quality needs.

CGT raw materials should be treated almost as a final product. Any changes warrant a comparability study, a risk assessment, and — at the GMP level — a change of control to explain and justify changes. As noted above, differences in a raw material’s testing parameters may necessitate scaling down the production model and performing functional testing to make sure differences in quality will not impact the final product.

The extent of scale-down depends on how well the sponsor understands the material. For example, if the sponsor knows the raw material only requires changes to one problematic step, they can potentially scale that down. But if the raw material is not adequately characterized and there is a risk that changes could impact multiple steps, more product comparability and analytical level compatibility testing are required to determine the new material’s impact.  

Testing and characterization decisions also depend on when changes are executed. Like any process change, earlier is easier, allowing the sponsor to potentially accumulate additional clinical data with the new raw material. Once a product is approved, post-approval changes typically face increased regulatory scrutiny. In either scenario, it is advisable to quickly establish direct communication between upstream and downstream SMEs from both sides to engage the technical personnel, ensuring they are vigilant in spotting differences between facilities, practices, and equipment, as well as gauging whether those differences are minor or major.

Success also depends on the receiving facility, including its experience with the modality or production process and whether it already manufactures similar products that have undergone inspection. These factors can significantly affect the complexity, risk, and timeline for the transfer.

Accordingly, a sponsor’s control strategy should be tailored to the modality and manufacturing process, as well as the specific risks introduced by the new material and vendor. Decisions should be grounded in scientific evidence while also accounting for operational feasibility and cost.

About The Panelists

Yan Zhi, Ph.D., is a director of cell and gene therapy and product owner in process engineering at CSL Behring. She is responsible for the technical performance of Hemgenix to support worldwide markets. Past posts include scientific and analytical leadership roles at WuXi AppTec, Fujifilm, Charles River Laboratories, and Spirovant. She received her undergraduate degree at the University of Science and Technology of China and her Ph.D. in microbiology and molecular genetics at the University of California, Irvine.

Lawrence (Larry) C. Thompson, Ph.D., is a Principal Scientist in Analytical Research and Development within BioTherapeutic Pharmaceutical Sciences at Pfizer. He has been with Pfizer for 3.5 years and is currently analytical lead on viral and plasmid based immunotherapeutics. Previously, he spent three years in small biotech at two different companies as the analytical lead in the development of serum-based cancer diagnostics. He is a graduate of the University of Tennessee (Chattanooga); BS Chemistry in 2001 and Vanderbilt University; PhD Biochemistry 2006. He did his post-doctoral work at the University of Tennessee (Knoxville) from 2006-2010.