Considering Cell Therapy Product "Good Manufacturing Practice" Status.

Abstract

The promise of cell therapies is beginning to be recognized internationally. Cell therapy products (CTPs) are different from other drug products because many aim to be curative, and they are less comprehensively characterizable and more variable, sometimes being manufactured one lot at a time. They have complex mechanisms of action that remain incompletely understood. These unique features have led some regulators to take different approaches to cell therapy regulation in the form of special guidance for navigating regulatory frameworks that were originally intended for pharmaceutical drugs. A consideration for CTP developers is where to manufacture them, and under what circumstances. With few regulators developing manufacturing requirements specifically for CTPs, highly harmonized regulatory principles of Good Manufacturing Practice (GMP) for pharmaceuticals and biologics apply. However, what people mean when they say they make “GMP grade” CTPs remains ambiguous, and this confusion is exacerbated because most CTPs in early stage development are processed in whole or in part in academic hospital-based settings instead of industrial facilities. Since GMP guidelines were not originally written with CTPs in mind, the regulatory landscape has been influenced by “multi-level model of practice-driven institutional change” (1). That is to say that, in the absence of prescriptive regulations, the regulated party improvises to meet what they think the regulator expects, and then reorient approaches based on what others can be seen doing. The resulting practices evolve into basic standards of practice that regulators expect the field to follow. This situation compounds confusion about “GMP grade” CTPs because it presents a moving target and creates uncertainty for manufacturing CTPs emerging at the investigational stage of development. To inject some clarity, stating that GMP is a grade of material is overly simplistic. Instead, GMP should be considered a product-specific assertion based on what is known about a product’s relevant characteristics and a system of ensuring its quality and must be determined on a case-by-case, product-specific basis. This assertion can be substantiated, which may or may not include direct or indirect evidence of third party (e.g., regulator) review. Others have identified the need for CTP GMP and noted jurisdictional and study phase differences (2–5). From a review of regulatory documents, here we take a basic look at approaches taken in three full ICH member jurisdictions (Canada, the United States, and the European Union) to briefly summarize in (Table ​(Table1)1) similar but different approaches to assessing GMP throughout clinical trial development, and to suggest potential strategies for cell therapy clinical trial product manufacturers. Table 1 Summary table.