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www.biopharminternational.com Quality and Regulatory Sourcebook eBook March 2024 BioPharm International ® 5 Cell and Gene Therapies Cell and Gene Therapies including failure to agree on the required potency assays to fully define a specific therapy. These types of setbacks illustrate that proactive planning for CMC compliance is a significant contributor to ultimate success of a product. Where compliance may be an af- terthought, there are often regulatory delays, which are exacerbated by the growing pipeline of therapies and under-resourced regulatory agencies. Therefore, going to the back of the queue at later stages because of preventable compliance mistakes is costly and can jeopardize a highly valuable first-to-market position. The product lifecycle Good manufacturing practices (GMPs) apply from clinical Phase I onwards (4) (see Figure 1). This im- plies that, at this point, a pharmaceutical quality sys- tem (PQS) in accordance with International Council for Harmonisation (ICH) Q12 (5) must be in place. Knowledge about the product increases along the lifecycle (i.e., knowledge about the qualit y target product profile [QTPP], the process, material and en- vironment properties impacting the QTPP, and the necessar y controls to achieve the desired product quality, safety, and efficacy). How much GMP is needed? The recommended and anticipated regulator y ex- pected level of GMP is illustrated using the example of chimeric antigen receptor T (CAR-T) cell products, which are cell therapy drugs. There are generally t wo components for ma nufact ur i ng CA R-T d r ug product: a vector carrying well-characterized genes, and T cells from the patient. A patient's T cells are genetically modified ex vivo with a vector to enable recognition of a desired target antigen on the surface of tumor cells. The T cells are then reintroduced back into the same patient (this is known as autologous) for therapeutic purpose. Due to their unique nature, it is challenging, if not impossible, to apply the traditional phases of develop- ment, manufacture, testing, and clinical assessment to CAR-T cells. The definitions of drug substance and drug product no longer apply with that clarity of dis- tinctiveness as generally there are no intermediates from the leukapheresis (the removal of white blood cells from the donor blood) to the finished CAR-T product. Equally, traditional GMP concepts are diffi- cult to apply to CAR-T cell products because of their inherent biological complexity and variability. Unlike traditional biologic drugs, the bioburden reduction procedure using filtration or any other ster- ilization measures cannot be used during the manu- facturing process with T cells, thus the entire manufac- turing process must be conducted aseptically from the point when the apheresis blood bag is prepared. This is a small-scale operation over a period of a few weeks, involving much manual handling, prefer- ably close to the location of patient treatment to min- imize cell transport. Commonly, a working cell bank is used to grow a sufficient number of cells, typically requiring the handling of large volumes (5–10 litres) of potentially microbial growth-promoting media. Given these circumstances, single-use systems (SUS) are widely used to maintain contamination control, thereby eliminating the need for equipment cleaning and sterilization. Data integrit y compliance requirements apply from the moment of leukapheresis. Full traceability is paramount because each lot of autologous CAR-T product is made for one patient only. Plastic SUS bag use is common, and labels are pasted directly onto the bag. Labels must be correct, unique, and com- plete. Label reconciliation is mandatory. Companies must have procedures for label issuance (including label printing), use (including placing more than one label onto a bag), and reconciliation. Handwritten la- bels should be avoided, if possible, not least because of the risk of ink leaching issues, or legibility of the handwriting. There is no difference whether this pro- cedure is for clinical development or for commercial manufacture. This traceability, which also equates to prevention of mix-ups between patient lots, also requires strict production line clearance protocols. In this case, the line is normally in a biosafety cabinet (BSC). Standard operating procedures (SOPs) for the line clearance and the subsequent cleaning of the BSC surfaces must be in place. A PQS must be established, irrespective FIGURE 1. The cell and gene therapy development and regulatory lifecycle. Pre-IND IND/CTA Phase I Phase II Phase IIb Phase III BLA/NDA/ MAA (CTD) Peri-approval/ Phase IV Commercialized product FIGURES COURTESY OF THE AUTHORS