Author:
Danielle DiTirro, PhD
Milipore Sigma
USA
The roundtable session on "Demonstrating Comparability: Are Potency Assays Necessary?" was moderated by Scott R. Burger, MD and the panelists included:
- Lee Lee Ong, PhD, Regulatory Consultant, Health Sciences Authority (HSA) – Singapore
- Rhianna Thompson, MBBS, Medical Officer, Advanced and Biological Therapies Section, Therapeutic Goods Administration (TGA) – Australia
- Kathleen Francissen, PhD, Global Head PT Cell & Gene Therapy Regulatory, Genentech, A Member of the Roche Group – USA
- Pille Säälik, PhD, Member, Committee for Advanced Therapies, European Medicines Agency (CAT-EMA), State Agency of Medicines (SAM) – Estonia
The session was guided by a case study by Christopher Bravery disseminated to the panelists prior to the meeting, which included questions. Each panelist had the opportunity to respond based on the expectations from their relevant country regulatory agencies, experience, and the scientific soundness of approach.
The case study presented a hypothetical future gene therapy company that has developed an autologous blood stem cell platform, leveraging LV-mediated gene modification to target rare diseases. By 2030, they obtain approval for their third gene-modified stem cell therapy and have three others in the clinic, all using the same platform. Their approach demonstrated the ability to accelerate product development, reduce costs, and has led to higher-than-anticipated sales. However, they face challenges with the supplier of the proprietary culture media, resulting in shortages of two commercial products and regulatory scrutiny. The R&D department is considering a change in the culture media to address the supply issue and reduce costs. They seek regulatory guidance on a comparability study to support the media changes across their platform.
Question 1: The opening question proposed that three batches of the new process with the new media should be adequate to demonstrate comparability, based on the consistency of the LV-mediated modification process in the autologous blood stem cells. The panelists were asked if they agreed and whether these three batches should be: a. three donor batches from a single product or b. one donor-derived batch from each approved product split into three prior to gene modification?
The panelists unanimously agreed that neither approach was adequate to demonstrate comparability. They all agreed that patient variation needed to be addressed for each of the three approved products. Therefore, the panelists decided the best minimal approach would be to use three donor-derived batches, each batch split into three prior to gene modification for each approved product.
At this point, the panelists and moderator commented that this question really highlighted the need for a robust process development program that would have ideally qualified two different media suppliers to avoid this very issue.
Question 2: The subsequent question addressed whether supplemental data from a scaled down process of a single GMP batch could be used to demonstrate comparability, for example, for potency?
The panelists concurred that a scaled down model could be used to supplement comparability data. However, they cautioned that the scaled-down model would first need to be accepted as representative. Furthermore, they unanimously agreed that a single GMP batch from the scaled-down process would not be acceptable, considering the multiple products in question and the potential variability in patient-derived starting material which would be impacted by the patient disease conditions and treatment history.
Question 3: The following question asked whether the product reference standard would need to be changed.
This question generated extensive discussion among the participants, but ultimately the conclusion was that it depends. The panelists recognized that changing the product reference standard could be challenging but emphasized the need for the reference standard to describe a pivotal study showing efficacy. Several panelists pointed out that the reference standard would need to be changed if release tests were affected, as data drift might occur in the results without a new reference standard.
Question 4: The final question from the case study focused on system suitability for product release, given the change in the matrix. Can system suitability testing for bioburden/sterility, mycoplasma, and viral testing be performed using any three batches across the six products presented in the case study?
The panelists suggested that validating system suitability with a single product would be acceptable since same analytical methods are used across the six products; one panelist even suggested a single batch would be sufficient. However, the panelists advised using material from a healthy donor to conserve material from the six products.
To conclude the session, the moderator revisited the session title and asked, “Are potency assays necessary to show comparability?”. The panelists acknowledged that designing proper potency assays can be very challenging but emphasized the necessity for sponsors to develop an approach to describe potency for comparability purposes. They understood that some potency assays may rely on a surrogate marker of efficacy, but they unanimously agreed that potency assays were necessary to show comparability.
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