Effects of the COVID-19 pandemic: new approaches for accelerated delivery of gene to first-in-human CMC data for recombinant proteins

Figures & data

Figure 1. Example of standard workflow from gene to final clone.

A flow chart describing the successive operations and timelines from transfection to selection of the final clone. The operations include transfection, cell pool generation, establishment of pre-research cell banks, cloning, establishment of research cell banks and evaluation of stability of expression.

Figure 2. Traditional and accelerated development timelines.

Two Gantt charts describing the sequence and critical path of CMC activities in accordance with the traditional or accelerated approach.

Table 1. Acceleration options to CMC development (from gene to First-in-Human) (text in bold relates to acceleration options for traditional programs whereas text in italic reflects additional pathways potentially applicable to accelerated programs only).

Stage	Lever
Parental cell line	Select an appropriate parental cell line depending on the development strategy: high or low demand product
Cell line generation	Prioritize a gene integration approach that maximizes the homogeneity of the post-insertion cells and the stability of expression Select the final clone candidate based on abbreviated stability data but supported by a genetic stability test (e.g., single-cell qPCR) Establish non-clonal RCBs in accordance with GMPs
Product and process development	Use in silico predictive tools for ensuring an adequate product design and manufacturability Prioritize the use of upstream, downstream, and analytical platforms Check that product design fits with the manufacturing and testing platforms Use transient expression for early process/analytical development activities
Preclinical manufacturing	Produce preclinical material from a non-clonal RCB
Phase 1 manufacturing	Minimize (no) process changes between preclinical and Phase 1 manufacturing Produce Phase 1 material from a non-clonal RCB and commit with authorities (1) to establish a clonal MCB immediately afterward with a clone selection process aiming at ensuring high level of comparability, (2) to assess the comparability of materials issued from the RCB and the MCB, and (3) to manufacture for Phase 2/3 using a clonal cell bank system Mitigate risk of genetic instability through an augmented control strategy (e.g., peptide mapping – mass spectrometry) Implement wide-ranges specifications and commit with regulatory authorities to revise the control strategy based on accumulated experience Support stability claim with available clinical stability data, preclinical stability data, forced degradation studies and stability modeling and commit with authorities on continuous delivery of real-time, real-conditions stability data, and information in case of out-of-specification Implement conditional release of drug substance
Prevention of viral risks	Implement broad molecular methods in lieu of in vitro and in vivo testing for adventitious agents Reduce product-specific viral clearance data based on modular claims Replace product-specific viral clearance data with accumulated platform data and prior knowledge

Table 2. Approved COVID-19 monoclonal antibodies.

INN (tradename)	Code	Company	Regulatory status	Clinical Trial ID	Sales (2021/2022)	References
Casirivimab + imdevimab (REGEN-COV)	REGN10933 + REGN10987	Regeneron + Genentech	EUA granted but no longer authorized due to lack of efficacy against new subvariants, approved in Japan	NCT04452318	M$ 6190/1832	^Citation7,Citation14,Citation139
Bamlanivimab + etesevimab	LYCoV555 (LY3819253) + LYCoV016 (LY3832479)	AbCellera/Eli Lilly	EUA for bamlanivimab/etesevimab combination therapy granted but no longer authorized due to lack of efficacy against new subvariants	NCT04501978	M$ 2240/2024	^Citation140
Sotrovimab (Xevudy)	VIR-7831/GSK4182136	Vir Biotechnology & GlaxoSmithKline	EUA granted but no longer authorized due to lack of efficacy against new subvariants, approved in Australia, UK, EU	NCT04545060	M$ 1317/2846	^Citation13,Citation16,Citation141,Citation142
Tixagevimab + cilgavimab (Evusheld)	AZD7442 (AZD8895 + AZD1061)	AstraZeneca	EUA granted, approved in Korea and EU	NCT04625972	M$ 855/2184	^Citation143
Bebtelovimab	LYCoV1404	Eli Lilly	EUA granted but no longer authorized (Dec. 1^st, 2022) due to lack of efficacy against new subvariants	NCT04634409	M$ 720/0	^Citation144
Regdanvimab (Regkirona)	CT-P59	Celltrion	Approved in Korea and EU	NCT04602000	M$ 0/10	^Citation145
Amubarvimab + romlusevimab	-	Brii Biosciences, Tsinghua University and the Third People’s Hospital of Shenzhen	Approved in China	-	-	^Citation146
-	JS016	Shanghai Junshi Biosciences, China National Institutes for Food and Drug Control	Approved in China	NCT04479644	-	^Citation101,Citation147

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