Discussion
Nowadays, the pre-clinical toxicological study has been benefiting from
the change of strategy to acquire materials directly from the
SSI-transfectant cell pools. Against the backdrop of global pandemic
outbreaks of COVID-19, this development further intrigues us with the
possibility to generate materials for the Phase I clinical study from
SSI-transfectant cell pools. To meet the safety requirements for the
materials for the first-in-human clinical study, the entire Gen1 CMC
campaign, including the transfection, seed train, cell banking, and
manufacturing campaign should undoubtedly comply with the cGMP
regulations. This strategy will rely heavily on the nature and origin of
the neutralizing antibody; presumably, an antibody isolated from a
convalescent patient with strong RBD (Receptor-Binding Domain)
neutralizing activity should be more appropriate for such idea of Gen1
for clinical materials, which saves time from the complications
introduced by other artificial biologics formats. Therefore, having a
lineage directly diverging from the cell pool that was a transfectant
from the cGMP-compliant facilities could suffice to both the needs of
the rapid generation of consecutive batches of clinical materials (Gen1
production) and the critical classical clone screening and the
monoclonal MCB generation (Gen2 activities). With the Gen1 production
and the Gen2 development carried out in parallel, the Gen2 GMP batch
materials from the monoclonal MCB will be available as soon as just one
month after the second batch of the Gen1 GMP materials. The proximity of
the critical quality attributes (CQA) between the Gen1 and the Gen2 is
critically important, even though the well-established downstream
process platform should be capable of removing common impurities, which
should already be probed by the pilot transient expression study. This
necessitates the CLD segment to screen the derivative clones extensively
in search of the top clone candidates with both good proximity of CQA
and excellent productivity. It is also advantageous if the upstream
process segment could evaluate several chosen candidates on bioreactors,
which could provide a more accurate performance evaluation for both the
culturing and the purifying process. The rather painstaking clone
selection would greatly help to minimize the need for process
development, which could be very costly for time-sensitive pandemic
projects. So far, the incorporation of advanced automation and
high-throughput technology into our WuXiaTM cell line
development platform has made the cell screening effort much less
labor-intensive than ever, which helps us to find a desirable clone from
thousands of clone candidates in a highly tensed CMC context.
In the pharmaceutical industry, safety shall never be compromised
regardless. After the decision of the MCB clone, there will be a set of
biosafety tests for the RCBs or pre-MCBs before they are permitted to
enter the cGMP facilities. The full set of biosafety testing typically
takes at least 6-8 weeks to conclude, which is very difficult to
maneuver in an aggressive CMC context. However, unwarranted clearance
into the cGMP facilities of an RCB or pre-MCB, usually generated under
non-cGMP condition, is going to stake the ongoing or forthcoming
business activity of cGMP facilities, which could be egregiously costly
for both the pandemic project and the core business interests. To solve
this problem, we adopt the pre-warning NGS-based screening to provide a
precautionary biosafety check for the RCBs, which should suffice with
very scarce risks of contamination from the current industrial practice
and experience. Comparing with the typical biological assays, the
turnaround time for the NGS-based detection is just as short as one
week, saving 5-7 weeks to continue the subsequent CMC activities.
To conclude, we have devised and successfully implemented a biologics
development strategy spanning as short as 2.5 months from the top
molecule decision to IND for several COVID-19 biologics. While the
industry has been progressing from 18 months to 12 months or even less
to IND, the outbreak of global pandemics, such as COVID-19, can still
impose very threatening and tense situations to global public health.
This needs our industry to come up with meaningful solutions to combat
such an outbreak and protect public health. The successful execution of
this unprecedentedly expedited CMC and manufacturing strategy relies
very closely on the experiences accumulated from hundreds of antibody
molecules, the well-furnished platforms of development protocols, as
well as the efficient communications between different functionalities
within the CMC team. Even with the carefully intended preceding material
generation steps, the whole team should still make careful and
economical use of the raw materials, to blaze the trail for the incoming
strategic planning and manufacturing. With hundreds of valuable
successful precedents of CMC for biologics, the team has already
developed an accurate sense of material planning and accumulated enough
experience to avoid premature attempts on unnecessary and time-costly
trial and error, which are very valuable for the industry against the
global pandemic emergency.