The special role of raw materials in Cell Therapy Products

High quality raw materials play important role in pharmaceutical and biopharmaceutical production, in particular if they are used in downstream processing and come into contact with the final drug substance or the drug product (e.g., excipients, primary packaging materials etc.). However, in Cell Therapy manufacturing, the need for sterile, highest quality materials (reagents, consumables and single use plastics, and intermediate or long-term packaging materials) practically applies to all stages of manufacturing as the typical cell therapy process does not include any true purification or filtration steps. Cell washing steps may have limitations in clearing out unwanted contaminations such as particulates that may have been introduced through the addition or use of certain raw materials. For many materials, a thorough E & L (Extractables & Leachables) assessments is necessary, in some cases with time-consuming in-house studies to check for Leachables. In addition, the understanding of variations in raw material critical material attributes presents an essential aspect of pharmaceutical product development [1].Furthermore, Vial Safety and TSE risk assessments are needed for certain materials that are human- or animal-derived or are made with such raw materials.

The regulatory authorities are paying increasing attention to proper raw material qualification during their audits and inspections; up to one third of recent Cell Therapy product deficiency letter questions were raw material-related, which can cause unwanted delays on the road to commercial launch.

Over the last 5+ years, ProDeMaCon Consulting has successfully helped several Cell & Gene Therapy clients by implementing risk-based, phase-appropriate raw material qualification and testing strategies, covering important aspects (such as particulates, viral safety etc.), and by providing hands-on operational support with raw material assessments, writing SOPs, streamlining internal company processes etc. Our simple, risk-based process for raw material onboarding considers the requirements for the different phases of development from preclinical to early stage clinical to late stage clinical to commercial and is customizable to each individual company's needs. This process follows the philosophy of the well-written PDA report TR 81 [2] and also covers formal Supplier assessment and qualification that has to occur in tandem with the raw material onboarding [3]. This has helped our clients meet the requirements of USP, e.g., [4] and [5], and their EP equivalents.

[1] A Rational Hierarchy to Capture Raw Material Attribute Variability in the Pharmaceutical Drug Product Development and Manufacturing Lifecycle. Conway SL et al. Journal of Pharmaceutical Sciences, 113 (2024) 523−538

[2] PDA Technical Report No. 81 (TR 81) Cell-Based Therapy Control Strategy. 

ISBN Number: 9781945584060

[3] Best Practices For Raw Material And Supplier Management For Cell & Gene Therapy Manufacturing. A.M. Beckhaus, D.J. Cady. https://www.cellandgene.com/doc/best-practices-for-raw-material-and-supplier-management-for-cell-gene-therapy-manufacturing-0001

[4] USP <1043> Ancillary materials for cell, gene, and tissue-engineered products

[5] USP <1046> Cellular and tissue-based products

A fundamental problem in healthcare R&D is that the development of new products is very expensive: failures and delays are frequent and each one is costly. In fact, the number of new drugs approved per billion US dollars spent on R&D has halved roughly every 9 years since 1950, falling around 80-fold in inflation-adjusted terms [6]. In addition, finding the right pricing and reimbursement strategy has become increasingly difficult on a global level. Bottomline: not every launch is as successful as it could be if there is no overarching product strategy.

Another example for potential failure in late stage development can include underestimated activities such as proper raw material onboarding and qualification, especially in case of ATMPs (Advanced therapy medicinal products) such as cell and gene therapy products. Companies must work with their suppliers and regulators to qualify each raw material (reagents, excipients, buffers, single-use plastics or primary containers) to assess source, purity, identity, safety, and suitability in a given application [7]. ProDeMaCon LLC has recently worked with several clients in the field and has supported them to build a process for this assessment from the ground up.

If you are still looking for the optimal strategy for your product or portfolio or simply want your project to get back on track, ProDeMaCon LLC can provide strategic and executional advice, given its unique setup:

• Unparalleled ability to discover, analyze, and solve complex problems based on a unique combination of experiences that covers all aspects of product development
• Strong marketing and project management capabilities to enhance pre-launch and launch plans as well as lifecycle activities
• Extensive upstream and downstream marketing experience
• Solid scientific background combined with excellent business acumen that helps identify and weigh all risks and opportunities
• Cost-effective through optimal use of resources and time based on individual project customization
• Flexible, fast, and efficient

[6] J.W. Scannell et al.: Diagnosing the decline in pharmaceutical R&D efficiency. Nature Reviews Drug Discovery 11, 191-200 (2012)

[7] J. Solomon et al.: Current perspectives on the use of ancillary materials for the manufacture of cellular therapies. Cytotherapy 18, 1-12 (2016) ProDeMaCon Consulting boutique consulting