By Andreas M. Beckhaus and David J. Cady, ProDeMaCon LLC Consulting
Despite the recent progress made with new regulatory approvals, the cell & gene therapy (CGT) space is still in its infancy. Actual category experience is relatively limited for all parties involved (pharmaceutical companies, CDMOs, raw material suppliers, and regulatory authorities). One aspect of the complex manufacturing process is often neglected or underestimated: the sources and quality of the materials used in the GMP manufacturing process for CGT products, or advanced therapy medicinal products (ATMPs), as they are referred to in Europe.
While the actual definitions vary slightly between the EU and the U.S., such critical materials typically include starting materials (such as donor cells, viral vectors, mRNA), excipients, primary and secondary packaging materials (e.g., cryo vials or bags, labels), raw or ancillary materials (such as reagents and culture media components), and consumables (single-use plastics and other process aids).
In this article, we will focus on best practices for ensuring supply continuity of the specialty materials used to manufacture and test CGT products and offer strategies for ensuring the phase-appropriate qualification of materials critical to the CGT manufacturing process(es).
Sourcing And Supply Continuity
Typically, cell and gene therapy product manufacturing and testing materials are initially sourced by academic researchers who pioneered the specific CGT target manufacturing process for the drug of interest. At this stage of early development, scientists will use what they find technically appropriate with limited regard for the ability of the supplier to meet the myriad of phase-dependent requirements of the customer throughout the future life cycle of the CGT product.
Due to the need to quickly advance the preclinical and early-stage clinical studies, the CGT process development team has little ability to source and qualify more ideal raw material options. In addition, few process development teams have the bandwidth to take on the work needed to establish and execute against a materials qualification program that can span multiple years. Unfortunately, this gap often extends into the mid- and late-stage of the clinical program, further increasing the risk of an improper transition from simple receipt and use to qualification and quality control testing of incoming lots of materials. This could lead to delays in later stages due to regulators’ concerns about the lack of proper key material qualification (see details on that topic under section 2 below).
Suppliers’ ongoing capacity to supply can be strained as demand scales for their products and related technical, quality, and regulatory support needs. In addition, the 20 to 30 most critical raw materials and quality testing materials of any CGT program are usually sole-sourced (only one supplier option) or single-sourced (only one supplier option currently in use/qualified) from one provider which usually only has manufacturing capability in a single location. In our experience to date, >95% of the critical raw materials and quality testing materials are sole- or single-sourced within any given program.1 The time required to qualify an alternative in the event of supply disruption is typically well over six months and may require expensive and time-consuming comparability studies or even repeated clinical work.
To complicate the current situation further, many suppliers of key CGT materials are new to providing their materials and the critical phase-appropriate information needed for proper qualification to their customers. That requires the CGT customer to bring together the many internal functions needed to define specific cross-functional requirements, processes, and procedures for supplier and material onboarding, qualification and quality testing, and effective supplier management. In our experience, most CGT startup entities do not have the expertise and bandwidth needed to develop and execute a supplier and material management plan. Therefore, they fail to plan for the two-years-plus duration effort and the expertise and costs needed for qualification strategy development and execution.
Finally, the primary interface between material suppliers and early-stage startup CGT customers is typically between a CGT company scientist or purchasing agent and a supplier’s customer service representative. In most cases, neither entity fully understands how critical the supplier’s material is to the clinical lot and patient, and they do not take a strategic approach to developing the deep relationship needed to ensure supply continuity. We argue that these key suppliers are just as strategically important to the success of the CGT customer as the generation of clinical data, and the relationship between the supplier and CGT customer should extend accordingly to the CGT company leadership level.
Suppliers also differ significantly in their ability to present a rational and robust supply risk and mitigation management strategy for their own supply chain(s) and a useful and ongoing reporting capability to their customers. Major supply interruptions are not uncommon and key risk factors can continue to go unnoticed and may need to be managed reactively.
Best practices to understand and mitigate potential supply continuity risk include:
- Approach raw materials and supplier program management as a strategic critical success factor to the CGT business and anticipate a dramatic increase in the time and expertise required, and in the costs your firm will incur, regarding ongoing program management. This will involve defining supply continuity risk mitigation levers and a proper qualification program, especially in anticipation of pivotal study and market filing application (commercial) readiness. In our experience, CGT clients can incur $3 million to $5 million in unplanned costs to acquire talent, set up a robust supplier management process, and acquire the necessary analytical capabilities to execute basic material qualification and quality control testing of incoming new lots of materials.
- Form an appropriate cross-functional raw materials team and governance process with key objectives of prioritizing materials and suppliers. These objectives will need to be based on the technical risk of supplied materials and an assessment of supply continuity risk factors.
- Engage suppliers based on their risk profile outcome to begin development of supplier relationship management. Do so by sharing and evaluating your current sense of supply continuity risk with them. Assess key factors such as the supplier’s strategic fit to CGT requirements, ongoing capacity and demand assessment, financial stability, quality and regulatory maturity, and technical services capabilities. A collaborative effort to drive actions to update your risk model and partner on the mitigation options available will be necessary. Consider specifically how you plan to interface with key suppliers and if there is a sponsorship role senior leadership can take with strategic suppliers.
- “Market” your company’s goals to your critical suppliers. Do they know who you are? What patients are you serving? Where are you in your clinical program(s)? How are their products being used? Which critical quality attributes of their products are key to your intended use? What specific process controls are in place for critical quality attributes? How much of their product do you project you may need in the next quarter, year, two-year outlook? How can you most effectively maintain ongoing engagement together? How do they currently approach supporting CGT customers for material qualification support through the clinical stages into commercial market filing readiness?
- Organize your firm to speak with one voice when communicating with key suppliers and avoid a siloed approach to supplier engagement. Establish a defined communications lead and issue escalation pathway for key suppliers and your firm. You want your suppliers to be absolutely certain what your key priorities are on an ongoing basis and how best to interact with you given all of their other options/priorities with other customers. A key best practice to include will be bi-annual or quarterly business review meetings with key suppliers.
Raw Material Qualification
The impact of the GMP materials on the quality, safety, and efficacy of the cell-based/gene therapy medicinal product should be evaluated using a risk-based approach and considering quality by design (QbD) principles. Compared to a typical biotech process (e.g., for a recombinant antibody), even higher quality requirements must be applied for materials used in CGT manufacturing, given that there are no true purification steps, limited clearance/wash steps, and no terminal sterile filtration step for the drug product. Raw materials must be sterile and produced under aseptic conditions and/or subject to terminal sterilization, unless otherwise justified. If a raw material is not sterile, the level of microbial contamination must be known. Detailed risk assessments are particularly necessary for all materials used toward the end of the production, i.e., excipients, primary containers, and consumables used in formulation and filling (such as interim storage bags and fill line tubing).
However, per EP 5.2.12,2 all materials used require risk assessments that must consider the following:
- the production steps applied to the raw material and the ability of the drug product manufacturing process to control or remove it from the final medicinal product,
- in the case of vectors or recombinant proteins, the traceability to the master cell bank/virus seed, and
- the biological origin, traceability, and risks related to the sourcing (including pooling) of the substances used for the production of the raw material.
- For all raw materials of human or animal origin, or raw materials produced using substances of human or animal origin, a viral risk assessment must be performed for Europe according to the requirements of general chapter EP 220.127.116.11 In addition, a TSE risk assessment is also required for such materials.
USP <1043>4 gives guidance on how to apply one of four risk tiers to ancillary materials and what actions to take dependent on the resulting risk tier. While raw materials should be of pharmaceutical grade (i.e., produced under cGMP conditions), the EC GMP guideline for ATMPs5 acknowledges that “in some cases, only materials of research grade are available. The risks of using research grade materials should be understood (including the risks to the continuity of supply when larger amounts of product are manufactured). Additionally, the suitability of such raw materials for the intended use should be ensured, including – where appropriate – by means of testing (e.g., functional test, safety test).” However, USP<1046>6 states that “In the later stages, material qualification activities … should comply with cGMP.”
Material onboarding and qualification activities should be phase-appropriate and should be carefully planned, depending on the development phase. In the early stages of product development, safety concerns are the primary focus in a material qualification plan. For pivotal trials, the material risk assessments and resulting qualification activities “should be completely developed,” per USP.6 Further guidance on the material criticality assessment can be found in the well-written PDA Technical report on Cell-Based Therapy Control Strategy.7
Specific attention should be paid to the risk of potentially introducing particulates into the cell process via reagents, buffers, single-use plastics, and other components. As the majority of CGT products are administered intravenously, they need to comply with USP<1>8 and, therefore, indirectly with the requirements for visible9 and subvisible10 particulate matter. Unfortunately, testing of final cell therapy drug products for particulates has strong limitations given the presence of cells and cell debris. Thus, the material risk assessments need to take this aspect into account and testing of certain materials may be required to ensure appropriate quality. For many materials, a thorough E&L (extractables & leachables) assessment is necessary, in some cases with time-consuming in-house studies to check for leachables.
In its draft guidance for CGT products development,11 the FDA recommends that "sponsors qualify ancillary materials for quality, safety, and potency through vendor qualification programs and incoming material qualification programs, including quarantine, Certificate of Analysis (COA) and Certificate of Origin (COO) assessment, visual inspection, and testing, as appropriate.” Such vendor qualification programs are not only important from a material quality perspective but also from a business perspective to ensure continuity of supply.
In conclusion, failure to recognize the strategic importance and complexities of carefully managing your raw materials and suppliers can quickly result in delays, costs, and failures in your CGT program. A cross-functional raw materials team with senior operational leadership governance can be established to own raw material program management holistically and throughout your firm’s life cycle. This will allow you to effectively manage the myriad of risks and the qualification program(s) needed to set your firm up for success at the critical pivotal study and BLA stages of your clinical program(s).
- ProDeMaCon LLC internal analysis
- Ph.Eur. 5.2.12. Raw Materials of Biological Origin for the Production of Cell-Based and Gene Therapy Medicinal Products
- Ph.Eur. 5.1.7. Viral Safety
- USP <1043> Ancillary materials for cell, gene, and tissue-engineered products
- EudraLex: The Rules Governing Medicinal Products in the European Union Volume 4. Good Manufacturing Practice. Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products
- USP <1046> Cell-Based Advanced Therapies and Tissue-Based Products
- PDA Technical Report No. 81 (TR 81) Cell-Based Therapy Control Strategy. ISBN Number: 9781945584060
- USP<1> Injections
- USP<790> Visible particulates in injections
- USP<788> Particulate matter in injections
- Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products. FDA Draft Guidance for Industry. Center for Biologics Evaluation and Research March 2022
About The Authors:
Andreas M. Beckhaus is the president of ProDeMaCon LLC. He started his international career in the regulatory affairs department of a large German healthcare company and later worked in a number of different functions (project management, lifecycle management, portfolio management, and marketing) with increasing responsibility, particularly focusing on biotech products and rare diseases. He further broadened his scope into medical devices at a global wound-healing company. In 2014, Beckhaus started ProDeMaCon as an independent consulting business. Over the last several years, he worked with several clients in the CGT space (small and large pharmaceutical companies and CDMOs), particularly focusing on material qualification and management. He has a background in pharmacy and a Ph.D. in toxicology.
David J. Cady is a principal consultant at ProDeMaCon LLC and has over 30 years of experience in progressive leadership roles in R&D, manufacturing, quality, marketing, sales, customer service, and strategic sourcing functions, including 20 years at a global material supplier and 10 years as head of global strategic sourcing at a leading biotech company. Over the past six years, Cady has been working with a variety of cell therapy-based startup organizations to develop and execute strategies to ensure effective material and supplier sourcing, onboarding, and qualification, and has successfully supported development and regulatory filing preparation for pivotal trial and commercial Biological License Applications. He has a BS in biotechnology and an MBA.