Development of modern pharmaceuticals, vaccines and more
ATMPs (Advanced Therapy Medicinal Products) are an essential part of any discussion of innovative, personalized medical products. They are at the forefront of biomedical research and offer revolutionary approaches to treating a range of serious and often incurable diseases. These therapeutic approaches represent an innovative area of medicine based on advances in genetics, molecular biology and cell biology. These therapies include CAR-T cell therapies, stem cell therapies, adeno-associated viruses (AAVs), lentiviruses, adenoviruses such as Ad5, plasmid DNA technologies and tissue engineering. The need for innovative drugs based on cell and gene therapies has increased significantly in recent years. The summary of this need can be summarized in several key points:
1. Precision medicine/patient-specific therapy: Cell and gene therapies enable customized treatment at the genetic level.
2. Treatment of rare diseases: Many cell and gene therapy approaches focus on the treatment of rare genetic diseases for which there are currently no targeted therapies.
3. Cancer therapy: The development of CAR-T cell therapies represents a significant advance in cancer treatment. The CAR-T cells attach specifically to the cancer cells and destroy them. As long as they find "targets", i.e. corresponding cancer cells, they multiply and attack them.
4. Regenerative medicine: Cell therapies have the potential to regenerate or replace damaged tissue. This is particularly relevant for diseases such as heart attacks, strokes or degenerative diseases, where the restoration of tissues and organs is crucial.
5. Overcoming challenges: Despite the enormous potential, cell and gene therapies also face challenges such as safety, scalability, low shelf life and cost. These are based on external fac tors such as low patient numbers for certain diseases, lack of healthcare systems in many countries, but also on product and process-related factors such as difficulty in ensuring quality, consistent efficacy, difficult upscaling, handling and testing of small and very small batches, etc. The Research is focused on overcoming these obstacles so that these therapeutic approaches can be produced commercially with consistent quality.
Overall, the increasing demand for new drugs based on cell and gene therapies reflects the growing recognition of these innovative technologies and their potential transformative impact on modern medicine. It remains to be seen how these developments will influence clinical practice in the coming years. But the first approval of a CRISPR gene therapy in the UK to treat the blood disorders sickle cell anemia and beta-thalassemia shows that progress is being made. But even in this case, the price hurdle still poses a problem. The first recombinant gene therapy was also approved by the FDA in 2023 for the treatment of Duchenne Muscular Dystrophy (DMD) in children aged 4 to 5 years.
Progress is also being made at other levels. In few other fields are so many efforts being made by the authorities to support development, approval and manufacturing with updated or new (draft) guidelines and scientific advice approaches. On the one hand, there are a number of basic guidelines from the most important international approval and regulatory authorities, e.g. the EMA.
Recommendation
Berlin, Germany5-7 November 2024
Contamination Control Strategies
The European Medicines Agency (EMA) has published various guidelines and directives dealing specifically with the manufacture of ATMPs. Some of the most important EMA guidelines for ATMPs are
1. Guideline on Good Manufacturing Practice for Advanced Therapy Medicinal Products: This guideline sets out the requirements for the manufacture of ATMPs in accordance with the principles of good manufacturing practice (GMP). It contains detailed requirements for manufacturing processes, quality control, validation of procedures, storage and transportation of ATMPs.
2. Guideline on Human Cell-Based Medicinal Products: This guideline contains specific requirements for the development and manufacture of somatic cell therapy products. It covers topics such as the selection and characterization of cells, the manufacturing process, contamination and stability.
3. Guideline on the Quality, Non-clinical and Clinical Aspects of Gene Therapy Medicinal Products: This guideline contains requirements for the development, manufacture and clinical testing of gene therapy products. It covers topics such as the construction and characterization of the vector, the expression of the gene, the safety and efficacy of gene therapy products.
4. Reflection Paper on Classification of Advanced Therapy Medicinal Products: This document provides guidance on the classification of ATMPs as defined in Regulation (EC) No 1394/2007 and helps manufacturers to determine whether their product is classified as an ATMP and therefore subject to the specific requirements
In addition, there are also the EMA (PRIME) and FDA (Breakthrough Therapy) programs to support accelerated approval of urgently needed drugs.
This progress is also reflected in the revisions of existing guidelines, such as the planned revision of ICH Q6. The Q6(R1) working group has only been in existence since February 2024 and the concept paper is still being worked on. It remains to be seen to what extent the guideline on specifications will be adapted and what impact this will have on the test procedures and acceptance criteria for ATMPs. Progress can also be seen in the new harmonized guideline ICH Q5A(R2). This refers to guidelines on the quality of biological medicinal products, in particular the quality of recombinant DNA products, including recombinant proteins and monoclonal antibodies. Such new documents are of particular importance with regard to the application of modern analytics and control methods such as Next Generation Sequencing (NGS).
The guideline provides an overview of the development and manufacture of recombinant DNA products and applies to the various phases of development through to approval and marketing. It emphasizes the importance of characterization of cell lines and DNA constructs for product quality and safety. This includes aspects such as the identity, stability and purity of the cells and DNA. The guideline also sets standards for process development and validation to ensure that the manufacturing process is consistent and reproducible. This includes the selection of suitable production methods, the monitoring of process parameters and the validation of manufacturing processes. The topic of stability testing is also covered. The stability of recombinant DNA products is an important aspect of quality assurance. The guideline describes the requirements for stability studies to ensure that the product retains its quality over a defined period of time.
It specifies requirements for the control of impurities in recombinant DNA products, including host cell proteins, DNA residues and other potential impurities.
Overall, ICH Q5A(R2) aims to improve the quality and safety of recombinant DNA products by providing clear guidance for their development, manufacture and control.
On the positive side, there are already a number of approved products on the market, e.g.
1. Glybera (Alipogentiparvovec): Glybera was the first gene therapy drug to be approved by the European Medicines Agency (EMA). It was used to treat a rare genetic disorder called lipoprotein lipase deficiency (LPLD). However, the approval was later withdrawn due to commercial and regulatory reasons.
2. Strimvelis: Strimvelis is a gene therapy for the treatment of the rare genetic disorder adenosine deaminase deficiency (ADA-SCID), a severe form of combined immunodeficiency. It has been approved by the EMA and is one of the few approved gene therapies.
3. Yescarta (Axicabtagene Ciloleucel): Yescarta is a CAR-T cell therapy used to treat certain forms of non-Hodgkin's lymphoma. It has been approved by the Food and Drug Administration (FDA) in the USA and has also been approved in Europe.
4. Kymriah (Tisagenlecleucel): Kymriah is another CAR-T cell therapy approved for the treatment of acute lymphoblastic leukemia (ALL) and certain forms of non-Hodgkin's lymphoma. It has been approved by the FDA and EMA.
5. Luxturna (Voretigene Neparvovec): Luxturna is a gene therapy to treat a rare inherited retinal disease that can lead to severe visual impairment or blindness. It has been approved by the FDA and the EMA.
Recommendation
Berlin, Germany8 November 2024
Risk Assessment in Contamination Control
However, we are constantly learning in these fields, also with regard to the risks of side effects or long-term effects mentioned above. The FDA's publication in November 23 "FDA Investigating Serious Risk of T-cell Malignancy Following BCMA-Directed or CD19-Directed Autologous Chimeric Antigen Receptor (CAR) T cell Immunotherapies" also shows us that new knowledge is still being gained. The approvals of such gene therapies with integrating vectors require the performance of 15-year long-term observational studies to evaluate the long-term safety and risk of secondary malignancies after treatment as part of the postmarketing requirements. Literally, the FDA writes:
"Although the overall benefits of these products for the approved uses continue to outweigh the potential risks, the FDA is investigating the identified risk of malignant development of T cells with serious consequences, including hospitalizations and deaths, and is considering the need for regulatory action."
It even speaks here of lifelong monitoring of such consequences.
This focus on the mentioned product groups and developments requires a response in the area of qualification, further education and training of the personnel employed. Concept Heidelberg (or the ECA Academy) also takes this into account with a constantly expanding range of courses and conferences on current topics in the fields of biotechnology, biopharmacy, cell and gene therapy and vaccines. In its working groups and task forces, e.g. with the ATMP Interest Group or the Pharmaceutical Microbiology Working Group and the EQPA interest groups, the ECA offers an opportunity to exchange views on current topics, comment on guidelines and develop supporting documents.
About the Authors:
Clemens Mundo has been with CONCEPT HEIDELBERG since 2023 as operational director and is in charge of the area of biotechnology
Dipl. Biol. Axel H. Schroeder has been working at CONCEPT HEIDELBERG since 2008 and is head of the microbiology department.
Literature:
US Food & Drug Administration, FDA Investigating Serious Risk of T-cell Malignancy Following BCMA-Directed or CD19-Directed Autologous Chimeric Antigen Receptor (CAR) T cell Immunotherapies, 11/28/2023, https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous
US Food & Drug Administration Breakthrough Therapy, 01704/2028, https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/breakthrough-therapy
European Medicines Agency (EMA), ICH Q5A(R2) Guideline on viral safety evaluation of biotechnology products derived from cell lines of human or animal origin - Scientific guideline, 03.01.2024, https://www.ema.europa.eu/en/ich-q5ar2-guideline-viral-safety-evaluation-biotechnology-products-derived-cell-lines-human-or-animal-origin-scientific-guideline
European Medicines Agency, PRIME: priority medicines, https://www.ema.europa.eu/en/human-regulatory-overview/research-and-development/prime-priority-medicines
