Most of the clinical trials in which eyetec is involved are called 'immunotherapies' for cancer. This method trains the patient's own immune system to fight against cancer cells. In addition to cancer we are also involved in trials for treating other degenerative neural diseases, such as Multiple Sclerosis. In practice, manufacturing ATMPs is a complex and challenging process. In this article, we will provide an overview of ATMP manufacturing, and the challenges faced by the industry.
ATMPs are a class of therapies that are developed using gene therapy, cell therapy, and tissue engineering. They offer innovative treatment options for a variety of diseases, including genetic disorders, cancer, and autoimmune diseases. ATMPs can be used to replace or regenerate damaged tissues or cells, modify gene expression, or introduce new genes.
In addition, eyetec is often consulted during regulatory discussions regarding the categorisation of an ATMP within a specific sub-category. These discussions may involve determining whether a particular treatment should be classified as cell therapy or gene therapy. The classification can have major implications on the entire lifecycle of the ATMP, so it's better to determine the correct classification early, preferably during the clinical trial phase.
eyetec actively participates in ongoing regulatory discussions concerning the precise classification of Advanced Therapy Medicinal Products (ATMPs) within specific sub-categories. These discussions are crucial as they for example determine whether a treatment falls under the classification of cell therapy or gene therapy, which holds substantial implications throughout the entire lifecycle of the ATMP. To mitigate any potential issues, it is of utmost importance to establish the accurate classification during the early stages of clinical trials.
Challenges in ATMP manufacturing
One of the biggest challenges in ATMP manufacturing is the complexity of the process. ATMPs are often personalised therapies, therefore each batch must be tailored to the specific patient. This requires a high degree of precision and consistency in manufacturing, while the starting materials are intrinsically variable (one patient’s cells differ from those of another patient, also depending on previous treatments). The idea of variable starting materials goes against one of the most fundamental requirements in Good Manufacturing Practices (GMPs), the regulations that prescribe how medicinal products should be produced by law.
Another challenge is the regulatory environment for ATMPs. For the last 12 years, it has become mandatory in Europe to produce ATMPs under GMP. Initially, when eyetec pioneered the ATMP landscape in Belgium, there were no written GMPs for ATMPs. Fortunately, since November 2017 the European Commission came out with a set of requirements specific to ATMP manufacturing.
Further, there are challenges related to the scalability of ATMP manufacturing. Currently most processes are performed manually in Laminar Air Flow (LAF) hoods. This implies an increased risk for human error and microbial contamination. However, automating these processes in closed systems would be an impossible feat due the huge variety of processes. It’s hard to imagine a single solution that would fit everybody’s needs.
The Importance of GMP Compliance in ATMP Manufacturing
GMP (Good Manufacturing Practices) compliance is crucial in the manufacturing of ATMPs to ensure patient safety, regulatory compliance, quality control, product consistency, and cost-effectiveness. Adherence to GMP guidelines can help ensure that ATMPs are produced in a controlled and consistent manner, with rigorous testing and quality control measures to ensure that they are safe and effective for patients. On the other hand, producing ATMPs under GMP can pose real challenges. Some considerations include:
Divided responsibilities between production and Quality Assurance: Often, very small teams are involved, making it difficult to achieve independence.
Testing of incoming materials: Most starting materials are sterile, frozen, and highly expensive. Taking samples often requires sacrificing an entire container. Alternatively, more emphasis can be placed on material and vendor qualification, but this option has its own challenges.
Data Integrity: The systems are often designed for R&D purposes without considering the necessary GMP requirements. Additionally, the obligations of patient data protection and the need for full traceability between the donor and acceptor make the process very challenging.
Aseptic Process Validation: a small team working in a multi-product and multi-process facility, requires a balanced Media Fill approach for manufacturing products that have a very low frequency. Meeting all legal requirements while minimising unnecessary burden on production resources is also crucial.
Freshly administered products: These products are delivered to the patient immediately after production. The process of testing, batch certification, sponsor release, and transportation to the hospital must take place within hours, if not minutes. This demands a Pharmaceutical Quality System optimised for efficiency.
Cryopreservation: As soon as cells come in contact with most commonly used cryopreservatives, they begin to lose viability. Therefore, all GMP manufacturing steps that take place after formulation and filling must be completed in the shortest timeframe possible. This challenge also applies to Visual Inspection.
eyetec’s services for the ATMP industry
eyetec is a specialized provider of quality assurance (QA) and contract qualified person (QP) services for the biotech and ATMP industries. Bram Keymolen, co-founder and QP at eyetec, played a pioneering role in ATMP manufacturing in Belgium under GMP. He was one of the first QPs involved in the field and collaborated closely with the Federal Agency for Medicines and Health Products (FAMHP) to establish a framework for manufacturing ATMPs under GMP guidelines. This was accomplished by interpreting existing GMP regulations, as the GMP for ATMP (Part IV) did not yet exist at that time.
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