Toxicological risk assessment of leachables from a combination product

Client

A European manufacturer of viral-based gene therapy products.

Background

The client was developing a ready-to-use (RTU) process for the administration of a viral-based product in a clinical setting. Bibra was requested to assist with the assessment of extractables during the development phase, and leachables in the final RTU product.

Project goals

During the development phase, bibra was asked to assess extractables detected during the testing of single-use components of the viral vector manufacturing process and on components of the RTU process itself.

Subsequently, in order to demonstrate that neither the manufacturing process, nor the materials of construction of the final RTU process, were introducing substances of potential health concern into the viral-vector, bibra conducted toxicological risk assessments (TRAs) of leachables detected in stability studies.

Approach and outcome

Over a 4-year period bibra toxicologists worked closely with the client, providing toxicological screening assessments on extractables detected from the individual RTU process components. These screening assessments allowed decisions to be made on the final materials of construction. Key toxicological hazards (genotoxicity, carcinogenicity and sensitisation) of identified extractables were identified based on a combination of (Quantitative) Structure-Activity Relationship ((Q)SAR) analysis, human health classifications and expert judgement of each chemical structure. Following this initial hazard-based exercise, suitable health-precautionary benchmarks, including the Threshold of Toxicological Concern (TTC), were assigned to each extractable to allow comparison with estimated worst-case patient exposures. Those extractables presenting a potential health risk to patients, either through their inherent toxicity and/or estimated exposures, were prioritised for further monitoring in stability studies. At the request of the US FDA, bibra also assisted the client with a further screening assessment on a single-use component of the viral vector manufacturing process.

Stability studies were subsequently conducted over a 2-year period on the final RTU process - viral vector combination to identify any leachable compounds. At each timepoint, for each identified leachable, comprehensive literature searches were conducted to identify relevant and reliable toxicity data. Where substance-specific data were lacking, a read-across approach was considered and applied. Following this hazard characterisation phase, the critical toxicological endpoint of each substance was evaluated, and an appropriate Point of Departure (PoD) was identified from the key studies. Health-precautionary Uncertainty Factors (UFs) were applied to derive conservative Tolerable Intake (TI) values for each leachable. The TIs were then compared with the worst-case exposure estimates, and Margins of Safety generated. The outcome of all assessments was overwhelmingly favourable (Margin of Safety values >1), with no significant toxicological concerns identified for any of the prioritised extractables or any of the leachables detected in the stability studies. Having been involved in multiple stages of product development, and having produced six reports, bibra toxicologists were pleased to reassure our client that treatment with the RTU process - viral vector combination would not present a significant health risk to patients.