Introduction
In the past several decades, outbreaks of epidemics, such as SARS,
Ebola, MERS, Zika virus, and the still rampant COVID-19, have become
surprisingly more frequent, posing an egregious threat to public health
and safety. Despite the challenges in developing biologics in a shorter
time than usual, the high efficacy and accuracy in neutralizing and
containing pathogens have made these biologics more and more favored by
both academic research and the pharmaceutical industry (Baum et al.,
2020; Brouwer et al., 2020; Cao et al., 2020; Gao et al., 2020; Hansen
et al., 2020; Ju et al., 2020; Lan et al., 2020; Nyon et al., 2018;
Pinto et al. 2020; Rogers et al., 2020; Shi et al., 2020; Wang et al.,
2020; Zhang et al., 2020). This change of preference would be quite
unrealistic without vast experiences of developing countless biologics,
as witnessed by the global pharmaceutical industry (Li et al., 2010;
Kunert et al., 2016). However, even though there have been many
different types of CMC strategies in accommodating all kinds of
biologics development scenarios, the currently fastest CMC timeline from
DNA to IND of 10- or 12-months are yet insufficient against the
challenge of a global public health emergency. How to conduct the CMC
activities with greater time-efficiency without compromising product
quality while meeting regulatory requirements has put both the biologics
development projects and the business interests under test (Sempowski et
al., 2020).
Traditional CMC activities contain cell line development (CLD) and
process development, including upstream, downstream, formulation, and
analytical method development before toxicology and GMP production. To
find the most appropriate clone from hundreds or thousands of clone
candidates, usually, at least 4 months are required for exhaustive
screening efforts during cell line development. Meanwhile, process
development dedicated to the specific molecules, including cell culture
process, purification process, formulation, and assay development,
requires approximately 3 months before at least one round of process
qualification with the final clone. To save these 3 months from
painstaking developments and qualifications of process and assay,
pandemic neutralizing antibody projects usually favor the molecules with
less complexity, or the molecules with established platform
architecture, since it is beneficial to take advantage of the platform
process, which helps to avoid the complications of process or assay
incompatibility and the uncertain time cost for the traditional tedious
but indispensable developments and qualifications (Kelley, 2020;
Bolisetty et al., 2020). Another recent advance in time-efficient
strategy is by shifting the materials produced for pre-clinical
toxicological study from by the selected top clone to an appropriate
stable cell pool, which has been elaborated and exercised by several
leading pharmaceutical companies (Bolisetty et al., 2020; Fan et al.,
2017; Hu et al., 2017; Munro et al., 2017; Rajendra et al., 2017;
Scarcelli et al., 2017; Wright et al., 2017). Typically, performing one
round of limited-dilution cloning or FACS cloning with the subsequent
clone selection requires at least 7 weeks beyond the establishment of a
stable cell pool. Bringing the pre-clinical toxicology ahead of the
traditional schedule replaces the speed-limiting activities to how to
wisely unfold the CMC paths. With successful precedents of such
practice, it is feasible to leverage the acceleration strategies with
respect to the life-saving pre-clinical toxicological and Phase I
first-in-human study against the global public health emergency. Because
of the returning of the critical path to CMC, together with limited time
for the process, assay, and formulation optimization, the beginning of a
biologics CMC, cell line development, has a crucial significance for the
subsequent manufacturing planning and decisions, which is also the
perspective from which we prefer to rethink and reshape the CMC
strategies.
Here we described a series of key steps to accelerating the overall CMC
timeline per the CLD scope. First of all, transfections were
performed under cGMP conditions and recovered stable cell pools were
used directly for toxicology and cGMP production. Second,
high-throughput clone screening was implemented to obtain top clones,
then thorough clone culturing evaluation and preliminary cell line
stability study with these selected top clones were carried out in
parallel. Next, the clone with the closest product quality from the
culturing evaluation to the preceding cGMP pool material was selected as
the final clone for master cell bank (MCB) creation and the
manufacturing henceforward. Meanwhile, the platform process should be
tested whenever possible for qualification and optimization with no time
to squander.