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Evaluation of the Quality, Safety and Efficacy of Messenger RNA

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Evaluation of the Quality, Safety and Efficacy of Messenger RNA 1 2 3 WHO/BS/2021.2402 4 ENGLISH ONLY 5 6 7 8 9 Evaluation of the quality, safety and efficacy of messenger RNA vaccines for 10 the prevention of infectious diseases: regulatory considerations 11 12 13 14 15 16 NOTE: 17 18 This draft document has been prepared for the purpose of inviting comments and suggestions on 19 the proposals contained therein which will then be considered by the WHO Expert Committee on 20 Biological Standardization (ECBS). The distribution of this draft document is intended to 21 provide information on the proposed document: Evaluation of the quality, safety and efficacy of 22 messenger RNA vaccines for the prevention of infectious diseases: regulatory considerations to a 23 broad audience and to ensure the transparency of the consultation process. 24 25 The text in its present form does not necessarily represent the agreed formulation of the 26 ECBS. Written comments proposing modifications to this text MUST be received by 17 27 September 2021 using the Comment Form available separately and should be addressed to 28 the Department of Health Products Policy and Standards, World Health Organization, 20 Avenue 29 Appia, 1211 Geneva 27, Switzerland. Comments may also be submitted electronically to the 30 Responsible Officer: Dr Tiequn Zhou at: [email protected]. 31 32 The outcome of the deliberations of the Expert Committee will be published in the WHO 33 Technical Report Series. The final agreed formulation of the document will be edited to be in 34 conformity with the second edition of the WHO style guide (KMS/WHP/13.1). 35 WHO/BS/2021.2402 Page 2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 © World Health Organization 2021 23 24 All rights reserved. 25 26 The designations employed and the presentation of the material in this draft document do not imply the expression 27 of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, 28 territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines 29 on maps represent approximate border lines for which there may not yet be full agreement. 30 31 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 32 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. 33 Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 34 35 All reasonable precautions have been taken by the World Health Organization to verify the information contained in 36 this draft document. However, the printed material is being distributed without warranty of any kind, either 37 expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no 38 event shall the World Health Organization be liable for damages arising from its use. 39 40 This draft document does not necessarily represent the decisions or the stated policy of the World Health 41 Organization. The named authors [or editors as appropriate] alone are responsible for the views expressed herein. 42 43 WHO/BS/2021.2402 Page 3 1 Evaluation of the quality, safety and efficacy of messenger RNA vaccines for 2 the prevention of infectious diseases: regulatory considerations 3 4 5 6 1. Introduction x 7 8 2. Purpose and scope x 9 10 3. Terminology x 11 12 4. General considerations x 13 14 5. Special considerations x 15 16 6. Manufacture and control of mRNA vaccines x 17 6.1 General manufacturing overview x 18 6.2 General information and description of vaccine construct and composition x 19 6.3 Control of starting and raw materials and excipients x 20 6.4 Process development and in-process controls x 21 6.5 Product characterization x 22 6.6 Consistency of manufacture x 23 6.7 Manufacture and control of bulk purified mRNA (drug substance) x 24 6.8 Manufacture and control of final formulated vaccine (drug product) x 25 6.9 Records x 26 6.10 Retained samples x 27 6.11 Labelling x 28 6.12 Distribution and transport x 29 30 7. Nonclinical evaluation of mRNA vaccines x 31 7.1 Pharmacology/immunology/proof-of-concept x 32 7.2 Safety/toxicity in animal models x 33 7.3 Accelerating nonclinical evaluation in the context of rapid vaccine 34 development against a priority pathogen during a public health emergency x 35 36 8. Clinical evaluation of mRNA vaccines x 37 8.1 Safety and immunogenicity evaluation x 38 8.2 Efficacy evaluation x 39 8.3 Efficacy evaluation in the context of a public health emergency in which 40 immune-escape and other variants arise x 41 WHO/BS/2021.2402 Page 4 1 9. Authors and acknowledgements x 2 3 10. References x 4 5 6 7 8 9 10 Guidance documents published by the World Health Organization (WHO) are intended to be 11 scientific and advisory in nature. Each of the following sections constitutes regulatory 12 considerations for national regulatory authorities (NRAs) and for manufacturers of biological 13 products. 14 15 16 WHO/BS/2021.2402 Page 5 1 Abbreviations 2 3 AESI adverse events of special interest 4 COVID-19 coronavirus disease 2019 5 DNA deoxyribonucleic acid 6 dsRNA double-stranded RNA 7 ELISA enzyme-linked immunosorbent assay 8 GMP good manufacturing practice(s) 9 HPLC high-performance liquid chromatography 10 IU International Unit(s) 11 IVT in vitro transcription 12 LNP lipid nanoparticle 13 mRNA messenger RNA 14 NRA national regulatory authority 15 ORF open reading frame 16 PCR polymerase chain reaction 17 PEG polyethylene glycol 18 PEGylation polyethylene-glycol-ylation 19 PEGylated polyethylene-glycol-ylated 20 RNA ribonucleic acid 21 RT-PCR reverse transcription polymerase chain reaction 22 SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 23 tRNA transfer RNA 24 UTR untranslated region 25 WHO World Health Organization 26 27 WHO/BS/2021.2402 Page 6 1 1. Introduction 2 3 Although the immunostimulatory effects of RNA have been known since the early 1960s (1), the 4 possibility of using direct in vivo administration of in vitro transcribed messenger RNA (mRNA) 5 to temporarily introduce genes expressing proteins (including antigens) was demonstrated in 6 1990 following the direct injection of “naked” nucleic acids (2). Subsequent improvements in 7 stabilizing mRNA, increasing the feasibility of manufacturing RNA-based products and 8 decreasing RNA-associated inflammatory responses have led to significant advances in the 9 development of mRNA vaccines and therapeutics (3–6). There are several reasons why the 10 mRNA platform has emerged at the forefront of vaccine technology. Among these are the rapid 11 speed at which mRNA candidate vaccines can be constructed and manufactured, and the need to 12 rapidly develop vaccines against emerging pathogens, such as zoonotic influenza virus strains, 13 Zika virus and most recently severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 14 the causative agent of coronavirus disease 2019 (COVID-19). 15 16 A number of publications have now discussed some of the safety, production and regulatory 17 issues associated with this new technology (7–11). In addition, the rapidity with which clinical 18 trials have progressed for COVID-19 candidate vaccines, their emergency use approval or 19 authorization (or conditional marketing authorization) by NRAs, and subsequent widespread use 20 have created a pressing need for WHO guidance on evaluating the quality, safety and efficacy of 21 mRNA products used for the prevention of infectious diseases in humans. Such evaluations must 22 take into account; (a) the inherent immunological, physiochemical and structural properties of 23 mRNA; (b) the need for formulation to ensure stability and efficient delivery; and (c) the novel 24 manufacturing process. Because detailed information is not yet available on the methods used for 25 production, controls are not yet standardized for safe and efficacious mRNA vaccines, and (in 26 the case of candidate vaccines) certain details remain proprietary and thus not publicly available, 27 it is not feasible to develop specific international guidelines or recommendations at this time. 28 Consequently, regulatory flexibility is currently needed. The detailed production and control 29 procedures, as well as any significant changes in them that may affect the quality, safety and 30 efficacy of mRNA vaccines, should be discussed with and approved by the NRA on a case-by- 31 case basis. Nevertheless, the key principles described in this document are applicable to the class 32 of preventive mRNA vaccines for human use in general and are intended to provide guidance 33 until more detailed information becomes available. For mRNA vaccines that target diseases for 34 which there are existing vaccines and corresponding WHO guidance, it may be appropriate to 35 consider the relevant sections of this document for issues specific to mRNA vaccines in 36 conjunction with the corresponding Part B (nonclinical evaluation) and Part C (clinical 37 evaluation) of the respective WHO Recommendations and Guidelines for guidance on issues 38 specific to the evaluation of vaccines against that disease (12). 39 WHO/BS/2021.2402 Page 7 1 Any given manufacturer’s mRNA vaccines might potentially be viewed as a platform technology 2 in which the gene insert can readily be changed without necessarily having to change the 3 manufacture or control of the resulting new product (except for immunogen-specific tests for 4 identity, stability and potency). However, this will depend on the resulting characteristics of the 5 final vaccine. If significant changes are made to the final vaccine, resulting in changes to the 6 critical quality attributes as well as subsequent cellular interaction, then further consideration of 7 the manufacturing process, controls and testing of the product will be required.
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