PDA Letter Article

Next Steps in ATMPs and Beyond

by Renske ten Ham, PhD, UMC Utrecht and Richard Denk, Skan AG

As an increasing number of advanced therapy medicinal products (ATMPs) (also known as cell and gene therapies) are approved by regulatory bodies across the globe, large-scale and commercial manufacturing is becoming increasingly important. However, manufacturing strategy and requirements must be considered in early product development, as they are often complex, and large changes are difficult, timely, and costly to make in more advanced stages. Many of the therapies are also very labor intensive. Therefore, how certain processes can be automated in an early stage should be considered.

In addition to the manufacturing requirements, the regulatory requirements must also be considered. On a global view, these are currently very heterogeneous and may have different requirements in different regions. The most discussed regulatory guidelines at the moment are the European Union GMP Annex 1: Manufacture of Sterile Medicinal Products, PIC/s Annex1, and WHO Annex 2 (PIC/s Annex 1 and WHO Annex 2 are very similar in content with small adjustments to the Annex 1) for the production of sterile products and the PIC/s Annex 2A for ATMPs. It is important to note that the PIC/s Annex 1 references the PIC/s Annex 2A and, therefore, also influences the requirements for the production of ATMPs. It should also be noted that PIC/s documents are not mandatory unless they are incorporated into national requirements, as is the case in Switzerland and the United Kingdom. These requirements must be considered when implementing production for the global market.

Other important factors include the issue of cross-contamination when producing different therapies in a room or multi-purpose facility, as well as the handling of cells from people who may already be contaminated due to the patient's current illnesses or previous therapies. Employee protection also plays an increasingly important role, especially when the therapies involve targeted reproduction in the body or when processing viral vectors. These products often require a higher biosafety level. Since there is no acceptable exposure level for employees for most therapies, high safety factors must be taken into account here, which are implemented, for example, using closed single-used systems or isolators or a combination of both technologies. On top of this, sustainability during production is another factor of increasing societal importance.

In addition to technical and manufacturing advancements, societal, economic, and organizational considerations and capabilities are increasingly important to achieving and maintaining patient access to ATMPs. This is emphasized by the observed contrast between high clinical development activity and the relatively low number of products reaching regulatory and market access milestones, with 18 ATMPs currently approved in Europe and even fewer reimbursed. Although regulatory challenges are still flagged in the assessment of ATMPs, concerns around pricing and affordability are becoming more vocal. In Europe, recent reimbursement decisions for the same product have led to inequity, but more so disappointment and disbelief among patients and physicians.

Research has highlighted that ATMPs experience several clinical, regulatory, and economic challenges more than conventional medicinal products. It is also observed that most ATMP developers are not companies but hospitals, academic facilities, and small and medium enterprises, which is higher compared to the small-molecule and biotechnology industry. This change in the developer landscape implies other stakeholders, such as regulatory and reimbursement authorities, who introduced new and additional support to help academic and non-profit organizations meet regulatory requirements. Also, this change in the landscape amongst developers asks for new interactions via new or extended public-private partnerships, international infrastructures, and knowledge exchange. Time will tell how these trends will develop.

All of these points, and more, will be presented and discussed at the 2024 Advanced Therapy Medicinal Products Conference in Amsterdam, the Netherlands on June 24-25. We look forward to welcoming you to join us in advancing the promising and dynamic ATMP field.