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.