Advancing Gene Therapy: Updates from the European Pharmacopoeia
Gene therapy represents a transformative frontier in modern medicine, offering hope for treating previously untreatable medical conditions. As this field advances, regulatory frameworks and quality standards must evolve to ensure quality, safety, efficacy, and accessibility. The European Directorate for the Quality of Medicines & HealthCare (EDQM) has taken significant steps to refine these frameworks, which will become legally binding on April 1, 2025.
Key Updates in the Ph. Eur.
The EDQM has replaced General Chapter 5.14 (suppressed as of April 1st, 2025) with a comprehensive framework that includes General Chapter 5.34, General Chapter 5.2.12, and Monograph 3186 (implemented on April 1st 2025). These updates will become legally binding on August 1, 2025 (see also Supplement 11.7), reflect advancements in gene therapy and focus on:
- Expanded Scope: Covering recombinant vectors for human use (revised), genetically modified cells including autologous cells modified by viral vectors, oncolytic herpes simplex viruses, genetically modified bacterial cells, and genome editing tools.
- Standardized Quality Requirements: Emphasizing genetic integrity, phenotypic stability, and contamination control.
- Flexible Testing: Adopting a risk-based approach that allows for justified alternatives, balancing rigor with adaptability.
Notably, gene-editing tools, are now explicitly addressed, with requirements for describing editing tools and their impact on product safety and efficacy.
Gene Therapy Medicinal Products (GTMPs): Definitions and Standards
Monograph 3186 introduces detailed definitions and production standards for GTMPs, including:
- Recombinant Vectors: Requirements for viral and nucleic acid-based vectors, ensuring genetic stability and reducing risks like replication-competent viruses.
- Genetically Modified Cells: Standards for cells modified by integrating vectors or genome editing tools, including additional testing depending on the modification process.
- Plasmid vectors for human use: Requirements for plasmids as in nanoparticles to genetically modify cells (e.g. CAR-T) or as medicinal product itself.
- Production Quality: Emphasis on consistent quality, stability, and contamination control across all stages of manufacturing.
These measures align with broader goals of protecting public health and fostering innovation.
Risk-Based Flexibility in Testing
The updated framework introduces built-in flexibility (no numerical acceptance criteria), allowing manufacturers to:
- Justify alternative testing stages (suitable method) for recombinant vectors and genetically modified cells.
- Reduce redundant testing by focusing on critical quality attributes (CQAs).
- Perform risk analyses to determine acceptable levels of impurities.
Not all the tests in Monograph 3186 need to be performed, but rather a scientifically sound and generally data-driven justification is required. For example, replication-competent viruses (RCV) testing can be omitted in the final lot, if appropriate testing is performed at the level of the viral vector. Furthermore, process-related impurities such as residual DNA from plasmids or host cells need to be quantified (known titer) using a suitable method. Historically, this is done by quantitative PCR (General Chapter 2.6.21 Nucleic Acid Amplification Techniques) but now, alternative methods (e.g. droplet digital PCR) can be used, ensuring compliance without an unnecessary duplication. More importantly, the Ph. Eur. update does not state numerical acceptance criteria meaning that one needs to demonstrate an adequate clearance of impurities. Consider the detection limit of the analytical procedure or acceptable levels set by the competent authority.
Advances in Manufacturing Standards
The Ph. Eur. now integrates and references advanced methodologies, such as:
- Nucleated cell count & viability (recently revised, 2.7.29)
- Microbiological examination of cell-based preparations (recently revised, 2.6.27)
- Bacterial Endotoxin Testing (BET) using recombinant Factor C (rFC) (2.6.14 or 2.6.32)
- Flow Cytometry (recently revised, 2.7.24): Used for cell counting and viability tests, critical for ensuring the quality of hematopoietic and genetically modified cell-based products.
These technologies support the production of high-quality, consistent gene therapy products while meeting regulatory requirements.
Balancing Innovation and Compliance
One of the most notable aspects of the Ph. Eur. updates is their focus on flexibility and innovation. By adopting a risk-based approach, the EDQM allows manufacturers to:
- Develop tailor-made control strategies to specific products and processes.
- Leverage emerging technologies like AI and automation in quality control.
- Streamline compliance through data-driven design and validation studies.
This adaptability is critical as new therapeutic modalities, such as lipid nanoparticles (LNPs) and antisense oligonucleotides (AONs), enter the market.
Summary
The updates to the European Pharmacopoeia mark a significant milestone in the regulation of gene therapies. By embracing flexibility, risk-based approaches, and cutting-edge technologies, these updates ensure a balanced approach to innovation and regulation. As the landscape of gene therapy continues to evolve, these frameworks will play a crucial role in balancing innovation with public health needs.
Join the Conversation: What do you think of the new Ph. Eur. standards for gene therapy? Share your insights on LinkedIn or explore more at the upcoming Dutch ATMP Summit 2025. At the Summit, for example, Thijs Booiman will present on changes in automation in QC for ATMPs and implications of the changes in Ph. Eur. regulations.
