Quality by design modelling to support rapid RNA vaccine production against emerging infectious diseases

Damien Van De Berg,Karnyart Samnuan,Robin Shattock,Cleo Kontoravdi,Anna K Blakney,Nilay Shah,Zoltán Kis,Carl Fredrik Behmer

doi:10.1038/s41541-021-00322-7

Damien Van De Berg, Karnyart Samnuan + Show 6 more

Open Access

https://doi.org/10.1038/s41541-021-00322-7

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Abstract

Rapid-response vaccine production platform technologies, including RNA vaccines, are being developed to combat viral epidemics and pandemics. A key enabler of rapid response is having quality-oriented disease-agnostic manufacturing protocols ready ahead of outbreaks. We are the first to apply the Quality by Design (QbD) framework to enhance rapid-response RNA vaccine manufacturing against known and future viral pathogens. This QbD framework aims to support the development and consistent production of safe and efficacious RNA vaccines, integrating a novel qualitative methodology and a quantitative bioprocess model. The qualitative methodology identifies and assesses the direction, magnitude and shape of the impact of critical process parameters (CPPs) on critical quality attributes (CQAs). The mechanistic bioprocess model quantifies and maps the effect of four CPPs on the CQA of effective yield of RNA drug substance. Consequently, the first design space of an RNA vaccine synthesis bioreactor is obtained. The cost-yield optimization together with the probabilistic design space contribute towards automation of rapid-response, high-quality RNA vaccine production.

Highlights

The outbreak and spread of viral diseases, such as the COVID-19 pandemic caused by the SARS-CoV-2 virus, the 2015–2016 Zika virus epidemic in Brazil and American continents, the re-emerging Nipah outbreaks in South and Southeast Asia, and the 2013–2016 Ebola virus epidemic in West Africa, pose tremendous healthcare and economic challenges[1,2,3]
The messenger RNA (mRNA) and self-amplifying RNA (saRNA) vaccine production process involves cellfree DNA-templated RNA synthesis based on the in vitro transcription (IVT) reaction catalysed by the T7 RNA polymerase enzyme (T7RNAP)[5,6]
The Quality by Design (QbD) framework development cycle starts with patient need identification and quality target product profile definition. This is followed by critical quality attributes (CQAs) and critical process parameters (CPPs) definition, CQA–CPP relation, design space (DS) and normal operating range (NOR) definition and, production process automation and control using model predictive control

Summary

Introduction

The outbreak and spread of viral diseases, such as the COVID-19 pandemic caused by the SARS-CoV-2 virus, the 2015–2016 Zika virus epidemic in Brazil and American continents, the re-emerging Nipah outbreaks in South and Southeast Asia, and the 2013–2016 Ebola virus epidemic in West Africa, pose tremendous healthcare and economic challenges[1,2,3]. The development of vaccines using conventional production methods is becoming too slow to effectively respond to new viral outbreaks in the 21st century[4], the frequency of which is predicted to increase[3]. To address this pressing need, rapid-response vaccine production platform technologies are being deployed, such as the messenger RNA (mRNA) and self-amplifying RNA (saRNA) platforms, collectively referred to as RNA vaccine platforms. The RNA (both mRNA and saRNA) drug substance is purified using tangential flow filtration (TFF) and chromatography techniques, such as ion-exchange or multimodal chromatography[4,7]. A process diagram showing RNA vaccine drug substance and drug product manufacturing are shown in Supplementary Fig. 1

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