Case Studies
The foregoing approach has been successfully incorporated into the CMC development of several molecules for pandemics at WuXi Biologics. Once the molecule sequence was received, a large-scale transient expression would be initiated either in parallel with or prior to the CLD (the beginning of Gen2 activities) and the seed train of toxicology batch and GMP production batch (Gen1 core activities). The materials from transient expressions were typically used for the evaluation and verification of the platform process and assay. Some alterations might be made to the process or assay accordingly to prepare for the upcoming Gen1 manufacturing campaigns. If any potential risky sequence of nucleotide or amino acid is identified in the complementarity-determining regions (CDRs), it will need to be altered, and the potency of the replacement sequences should be further evaluated by the live-virus assay with transient materials before unfolding the entire CMC landscape. The product quality attributes of two different COVID-19 molecules at different stages, on different scales (early transient batch, toxicology batch, GMP batch, and the Gen2 GMP batch) were shown in Fig. 6. By the platform process, the toxicology and GMP batches had quite consistent product quality attributes. Advanced CLD tools, such as FACS (Fluorescence Activated Cell Sorting) cloning, high throughput screening with 24-deep well plates, and single-cell qPCR for genetic stability were all used to obtain the most favorable clones for the MCBs. The top clone candidates displayed broad spectra of product quality profiles, especially for the charge variant and glycan profiles. The clone with the closest product quality attributes was selected for the MCB creation and future GMP productions. Judging from the product quality profiles in Fig. 6A-C, we managed to control the changes to a very narrow and acceptable range, especially between the GMP batches of Gen1 and Gen2, both the most strategically important materials. The consistent profiles of the product guaranteed smooth transition from the materials by SSI-pools to those by clones. In Fig. 6D-G, there are some other proven successful examples of CMC and manufacturing of different COVID-19 therapeutic molecules using such strategy, already en route to late-stage clinical studies.