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.