Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Quality-related Challenges of Viral Vector-based Gene Therapy ***

Dr. Sarah Matheisl (Abschlußjahr: 2021)

Summary
Language: English
Development of gene therapy products has increased globally with 359 ongoing clinical trials worldwide (as of August 2020). This thesis focuses on the jurisdictions in the United States and the European Union, where the highest number of gene therapy products has been authorized so far. Here, viral vector-based gene therapies are legally defined as biologics, and regulatory expectations regarding product quality are in essence the same as for well characterized biologics: A defined, robust, reproducible and validated production process paired with the development of an adequate control strategy and a sufficiently characterized product. However, due to the variability inherent to their production process, their structural complexity and limited industry experience, GT products are not considered well characterized why a higher degree of flexibility and a unique, anticipatory risk-based approach are necessary. Therefore, specific guidance and legislation for gene therapies have been developed in both jurisdictions, yet the gene therapy field is progressing with exponential pace leaving multiple quality-related challenges.
Transfer of the genetic material to the cells is achieved by an engineered delivery vehicle. For this, mostly recombinant viral vectors are employed, why the focus of this thesis is set hereupon. Cells can be modified by viral vector administration inside (in vivo) or outside (ex vivo) the patient’s body. The latter also involves transfer of genetically modified cells to the patient requiring technical and regulatory aspects of cell therapy, which are not in scope of this thesis.
After a short introduction into the basics, the history, the regulatory and legal frameworks as well as into the manufacturing process (Section 2), this thesis focuses on the quality-related regulatory environment and challenges for viral vectors in gene therapies. Subsequently, corresponding recommendations are discussed.
Firstly, the requirements for the starting materials for vector production are oftentimes unclear where particularly vector systems are in focus. For raw/ancillary materials the right quality level is also uncertain and eventually the manufacturer has to demonstrate a reproducible production process (Section 3.1). Further, the purification process has not yet been fully optimized for viral vector production. The impurity profile consists of a complex mixture regarding viral capsid integrity, residual deoxyribonucleic acid, empty and partially filled viral particles. Paired with an increased risk for viral contamination, this impedes viral safety why a viral vector-specific strategy is required (Section 3.2). The complex mechanism of action of gene therapies oftentimes results in challenges to develop a potency assay, which measures multiple underlying biological activities and adequately reflects the in vivo situation. Thus, also potency assay development requires viral vector-specific adjustments (Section 3.3). Limited manufacturing experience and process knowledge can lead to unknown critical quality attributes and missed critical process parameters, making comparability exercises challenging. Therefore, avoidance of changes or in case this is not feasible, a stage-specific risk-based assessment to customize comparability studies are necessary (Section 3.4). Generally, viral vectors can only be purified in small quantities and low concentrations leading to impeded frequent testing at all stages and challenges for the comparability exercise and process validation. Moreover, many gene therapies received a Health Authority designation qualifying for expedited development, which results in accelerated chemistry, manufacturing and control timescales, associated with pressured process and control strategy design. Suitable strategies to overcome challenges for limited material and fast development need to be established (Section 3.5). Finally, the gene sequence of interest should ideally be expressed lifelong while not only being safe for the patient, but also for the environment. Adjustments to the genetically modified organism-related legislation will be crucial (Section 3.6) and a sophisticated long-term follow-up strategy to monitor both, long-term efficacy and adverse events specific to the long-term treatment with gene therapies is required (Section 3.7).
Taken together, the awareness of existing quality-related challenges and their corresponding recommendations can assist in successful development of high quality viral vectors for GTs to eventually improve and safe patients’ lives.
Pages: 93
Annexes: 1, Pages: 3