Ensuring Quality Of CGT Materials
By Erin Harris, Editor-In-Chief, Cell & Gene
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This month’s Cell & Gene Live, “Materials Matter: Ensuring Quality of CGT Materials,” covered one of the most critical yet often overlooked aspects of cell and gene therapy development: raw, starting, and ancillary materials. I had the pleasure of moderating a conversation with two experts deeply embedded in this space, Anthony Blaszczyk, Ph.D., Senior Scientist at the U.S. Pharmacopeia, and Basak Clements, Ph.D., Founder and Senior Advisor at biomatria. Together, we explored why clearly defining, controlling, and understanding these materials is foundational to successful CGT programs, and why missteps early on can ripple throughout development.
Understanding the Complexity of Materials
We began by discussing the complexity of materials themselves. Blaszczyk highlighted plasmid DNA as a prime example. At first glance, plasmid DNA may seem straightforward, but small variations, whether sequence differences or changes in topology like supercoiling, can dramatically influence the final product. The stakes are high: even one or two nucleic acid differences can impact a viral vector’s potency or safety profile. Yet, current analytical tools often struggle to fully characterize these materials. Conventional sequencing or other physicochemical assays may not capture the full picture, leaving developers with incomplete or inconsistent data. He stressed that these analytical gaps are not just academic; they translate into real-world risks, including batch variability, comparability challenges, and regulatory scrutiny.
Clements reinforced this point, emphasizing that materials are not interchangeable and require a nuanced, risk-based control strategy. She noted that companies often underestimate the effort required to manage biologically derived materials like serum or human- and animal-derived components. While chemically defined or recombinant alternatives may come at a higher upfront cost, they can significantly reduce variability, simplify regulatory interactions, and minimize downstream challenges. Both experts underscored that the choices made at the materials stage cascade through the entire development process: poor alignment here can lead to rework, delays, and increased costs.
Why Regulatory Expectations Are on the Rise
Our conversation naturally shifted to regulatory expectations, and our panelists were aligned on one point: regulators are paying attention. Blaszczyk noted that recent FDA, EMA, and other international guidances emphasize science-and risk-based control over raw and starting materials. Sponsors are expected to deeply understand each material’s function, impact on critical quality attributes (CQAs), and potential variability. Clements added that this means more than just documentation; it requires a structured, phased risk assessment and ongoing oversight. In early-phase development, a high-level evaluation of material safety, supplier qualifications, and potential red flags can suffice, but as programs move toward pivotal studies and commercialization, more detailed analytics and rigorous control strategies become essential.
We also discussed the role of USP and its expert committees in providing guidance to the industry. Blaszczyk highlighted USP General Chapter 1043, which has become a widely referenced resource for ancillary materials in CGT. While it is not a compendial requirement, regulators and developers alike treat it as a benchmark for best practices. Clements shared insights from her work with the USP Cell and Gene Therapy Expert Committee, noting that the committee’s goal is to make guidance such as 1043 more actionable and to clarify responsibilities across the supply chain, from suppliers to CDMOs to sponsors. They are also exploring updates to other chapters, such as 1040 on plasmid manufacturing, to provide practical frameworks that support risk-based control and standardization across the field.
Supplier Selection Impacts Material Selection
A major theme of the conversation was supplier selection and collaboration. Clements framed this as the “trifecta:” technical fit, quality, and supply chain reliability. Blaszczyk emphasized that cost alone should never drive material selection. Cutting corners early may save money initially, but it often leads to rework, additional testing, and regulatory complications. Both experts encouraged early engagement with suppliers to align on testing approaches, change controls, and documentation. Transparency is key, and the most reliable suppliers are often those who openly share their processes and limitations, helping sponsors understand and mitigate risks from the start.
We also dug into particulates and other CQAs, a growing focus in the CGT space. Blaszczyk explained that visible or sub-visible particulates in raw materials can impact both safety and process performance. For example, a particulate in a raw material may disrupt cell growth or viral vector production, creating a cascade effect that influences final product quality. Clements noted that these risks underscore the need for a phased, risk-based approach: early assessments should identify high-risk materials, with more in-depth characterization and testing introduced as programs progress.
Finally, we tackled analytics and standardization, which Blaszczyk called a persistent challenge. For complex materials such as lentivirus, plasmids, or cytokines, existing methods often fail to measure the full spectrum of attributes reliably. Different labs may report inconsistent results, making comparability difficult. Both experts emphasized that aligning analytical methods with suppliers, investing in fit-for-purpose assays early, and prioritizing metrology and residual testing are essential strategies to prevent costly downstream failures.
Advice for Early-Stage CMC Leaders
As we wrapped up, I asked both experts for their advice to CMC leaders entering Phase 1 today. Clements advised developer companies to start with early risk assessments, prioritize chemically defined or recombinant materials where possible, and consider the long-term cost of quality over upfront price. Blaszczyk’s takeaway was equally practical: don’t take shortcuts. Investing time and resources upfront (e.g., in supplier qualification, analytics, and risk management) pays dividends in program stability, regulatory confidence, and overall development efficiency.
In short, materials are a foundation, not just a starting point. By understanding the complexity, aligning with regulatory expectations, collaborating closely with suppliers, and prioritizing robust analytics and risk-based strategies, CGT developers can mitigate downstream challenges and set themselves up for long-term success. As our experts reminded us, a disciplined approach to materials isn’t optional; it’s mission critical.
Check out the full-length on-demand version of this Cell & Gene Live to capture the complete nuance, real-world examples, and in-depth guidance our experts shared.