Phase-appropriate Compliance for Cell and Gene Therapies

Cell and gene therapies (CGTs) offer the potential to revolutionize healthcare by addressing unmet medical needs. However, the science is advancing at a pace faster than regulatory authorities can issue relevant laws, regulations, and guidance documents. Therefore, it is imperative that the industry apply appropriate compliance controls in the manufacturing of CGT products. These products pose unique manufacturing and compliance challenges due to their inherent nature (i.e., originating from living organisms, being used in the treatment of only one or a limited number of persons, extremely small batch sizes, and challenging contamination control). There is limited manufacturing and regulatory experience with CGTs, as only few products have yet obtained marketing authorization; 31 CGTs were approved by FDA (1) by mid-2023 and 25 by the European Medicines Agency (EMA) (2). CGTs are termed advanced therapy medicinal products (ATMP) in Europe. Yet, the pipeline is still growing, with more than 2000 CGTs/ATMPs in clinical pipelines (3). These products are at the forefront of research and, as a consequence, many companies involved in their discovery are small and medium-sized enterprises, often with staff who are inexperienced or unfamiliar with regulatory expectations and/or spin-offs from academic research centers.

The importance of applying the appropriate level of compliance in the respective phases of the product’s lifecycle cannot be over-emphasized. The chemistry, manufacturing, and controls (CMC) for these products will be scrutinized by the approving regulatory authorities, such as FDA and EMA. Any delay to the approval of clinical trials or license to market the CGT will not only be costly, but it will also delay essential therapies, often without any alternative, for patients. For instance, some sponsors have experienced delays with FDA at key trial milestones for reasons 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 afterthought, 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 implies that, at this point, a pharmaceutical quality system (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 quality target product profile [QTPP], the process, material, and environmental properties impacting the QTPP, and the necessary controls to achieve the desired product quality, safety, and efficacy).

How much GMP is needed?

The recommended and anticipated regulatory expected level of GMP is illustrated using the example of chimeric antigen receptor T-cell (CAR-T) productscell products, which are cell therapy drugs. There are generally two components for manufacturing CAR-T drug products: a vector carrying well-characterize genes, and T cells from the patient or a donor. The 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 modified T cells are then introduced back to the patient for therapeutic purpose.

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About the authors

Zhongren Wu, PhD, is principal consultant at Parexel; Siegfried Schmitt, PhD, is vice president, Technical, at Parexel; and Lynne Ensor, PhD, is senior director, Pharma Biotech and Dietary Supplements Consulting at NSF.

Article details

BioPharm International®
Quality and Regulatory Sourcebook 2024
March 2024
Pages: 4-6

Citation

When referring to this article, please cite it as, Zhongren, W.; Schmitt, S.; Ensor, L. Phase-appropriate Compliance for Cell and Gene Therapies. BioPharm International Quality and Regulatory Sourcebook March 2024.