(M1430-06-35) Compatibility of BiTE® (Bispecific T-cell Engager) Drug Product with Manufacturing Materials

Purpose: Novel BiTE® (bispecific T-cell engager) molecules are one of the promising modalities in biotech today. During production, drug product (DP) comes into contact with containers and surfaces of various materials used in the manufacturing process. Good manufacturing principles and regulatory guidelines dictate a thorough evaluation of the process conditions and product quality impact of DP exposed to these materials. In this study, we evaluated the compatibility of a model BiTE® molecule with various materials during processing to set manufacturing conditions for each of the unit operations.

Methods: Materials used in this study are classified into 2 categories: Category A materials are in which DP has transient contact (< 48 hours); Category B materials where DP (bulk) has an extended contact period (< 240 hours). Filtered DP was aliquoted into representative Category A and Category B materials, which were then stored at 2°C to 8°C and 25°C, for up to 48 and 240 hours respectively. The durations to which samples were held are in excess of normal manufacturing conditions but allow to understand the impact in cases of manufacturing deviations during operations. Samples were pulled at designated time points and either tested immediately (visual assessments, subvisible particles, protein concentration, pH) or frozen until further analysis (SEC, rCE-SDS, CEX-HPLC). High temperature was considered worst case for product quality impact and thereby samples stored at 25°C were subjected to analytical testing while samples stored 2°C to 8°C were kept as reserve.

Results: The model BITE® molecule was exposed to various materials used in DP manufacturing, held at 2°C to 8°C and 25°C, subsequently tested for product quality. Changes in appearance, color, clarity, pH, protein concentration and purity (high molecular weight species (HMW), low molecular weight species (LMW), charge variants) were evaluated for DP held within each contact material. No significant trends observed with respect to the material contact duration or temperature except for stainless steel contact for 240 hours at 25°C. Samples stored in stainless steel vessel for 240 hours at 25°C showed increased levels of acidic peaks (by CEX-HPLC) and LMW (by rCE-SDS). Further, no impact was observed at stainless steel samples stored at 5°C for 240 hours or at 25°C for 168 hours. Based on the data, stainless steel contact time was set < 168 hours at 25°C to avoid possible product quality impacts.

Conclusion: Materials used in drug product manufacturing can have tremendous impact on product quality if not compatible with the molecule. Hence, the material contact studies are an important undertaking to understand the compatibility relationship between material and product to ensure a safe and efficacious drug product can be manufactured. In this study, we observed that among all the contact materials tested, only stainless steel required active control of contact time to maintain the product quality attributes within acceptable range. The data generated here will be used to set manufacturing limits for temperature and time exposure for each of them. The recommended manufacturing limit was arrived based on the shortest duration in which none of the product quality attributes tested showed any significant changes compared to starting material. The recommended allowable exposure time for each material is summarized in Table 1.

Table 1. List of Materials Evaluated