【CODEX翻译】新型冠状病毒预防用mRNA疫苗药学研究

技术指导原则（试行）-英文版

新型冠状病毒预防用mRNA疫苗药学研究技术指导原则（试行）

Technical Guidelines for Pharmaceutical Research on Preventive mRNA Vaccine against 2019 Novel Coronavirus (Trial)

一、前言

二、模板设计、转录模板质粒构建和菌种库研究资料

（一）目标抗原选择和DNA模板设计

（二）转录模板质粒的构建和制备

（三）种子库的建立和检定

三、生产工艺

（一）一般要求

（二）mRNA原液生产

（三）制剂处方及生产工艺

四、质量特性研究

（一）mRNA的结构分析和理化性质分析

（二）纳米颗粒的结构分析和理化性质分析

（三）杂质分析

（四）生物学活性研究

五、质量标准

（一）DNA转录模板

（二）mRNA原液

（三）制剂中间产物

（四）成品

（五）方法学研究和方法学验证

（六）标准品

六、稳定性研究

七、直接接触制品的包装材料和容器的来源、选择依据及质量标准等研究

八、应急状态下药学研发的阶段性考虑与研发期间的变更

（一）种子库

（二）生产工艺

（三）质量特性研究

（四）质量标准

（五）临床申报阶段应提供能够支持临床试验开展的稳定性研究数据

（六）研发期间的工艺变更

九、名词解释

十、参考文献

I. Introduction

II. Template Design, Transcription Template Plasmid Construction and Strain Bank Research Data

(I) Target antigen selection and DNA template design

(II) Construction and preparation of transcription template plasmid

(III) Establishment and verification of seed bank

III Production Process

(I) General requirements

(II) Production of mRNA drug substance

(III) Drug substance prescription and production process

IV. Research on quality characteristics

(I) Analysis of the structure and physicochemical properties of mRNA

(II) Analysis of the structure and physicochemical properties of nanoparticles

(III) Impurity analysis

(IV) Research on biological activity

V. Quality standard

(I) DNA transcription template

(II) mRNA drug substance

(III) Drug product intermediates

(IV) Finished Product

(V) Methodological research and methodological verification

(VI) Standard products

VI. Stability Research

VII. Research on the source, selection basis and quality standards of packaging materials and containers that directly contact products

VIII. Phased Considerations of Pharmaceutical Research and Development under Emergency Conditions and Changes during Research and Development

(I) Seed bank

(II) Production process

(III) Research on quality characteristics

(IV) Quality standard

(V) Stability research data that can support the development of clinical trials shall be provided in the clinical application stage

(VI) Process changes during research and development

IX. Terminology

X. References

一、前言

I. Introduction

      mRNA疫苗是将外源目的基因序列通过转录、合成等工艺制备的mRNA通过特定的递送系统导入机体细胞并表达目的蛋白、刺激机体产生特异性免疫学反应，从而使机体获得免疫保护的一种核酸制剂。

mRNA疫苗具有以下特点：（1）能导入细胞，在体内表达相应的抗原蛋白，避免了体外蛋白表达、纯化过程；（2）能够刺激免疫系统产生体液免疫和/或细胞免疫应答，发挥相应的免疫预防和/或免疫治疗作用；（3）其递送系统具有类似佐剂的部分特性，能够通过刺激机体免疫系统产生多种细胞因子等方式增强机体免疫反应能力或改变免疫应答类型；（4）由于mRNA的降解是通过细胞正常代谢完成，降低了因感染或整合诱发基因突变的潜在风险。

mRNA vaccine is a kind of nucleic acid preparation, which introduces mRNA prepared from the foreign target gene sequence through transcription, synthesis and other processes into the body's cells through a specific delivery system, expresses the target protein, and stimulates the body to produce a specific immunological response, thereby enabling the body to obtain immune protection.

      尽管mRNA疫苗在巨细胞病毒(CMV)、流感病毒、埃博拉病毒和寨卡病毒等多种传染病临床研究中取得了一定的研究进展，但尚存在待确证的诸多问题，如，mRNA本身具有的潜在免疫原性；递送系统（如，脂质纳米颗粒）的稳定性、纳米剂型安全性及所使用阳离子聚合物/脂质体安全性、递送靶向性及递送效力等诸多问题，影响疫苗的有效性、安全性和质量可控性。

The mRNA vaccine has the following characteristics: (1) It can be introduced into cells to express the corresponding antigen protein in vivo, avoiding the process of protein expression and purification in vitro; (2) It can stimulate the immune system to produce humoral and/or cellular immune response, and play the corresponding role of immune prevention and/or immunotherapy; (3) Its delivery system has some characteristics similar to adjuvants, which can enhance the immune response ability or change the type of immune response by stimulating the immune system of the body to produce a variety of cytokines; (4) Since the degradation of mRNA is accomplished through normal cell metabolism, the potential risk of gene mutation induced by infection or integration is reduced.

      mRNA疫苗通常需采用较为复杂的制剂系统，其药学研发和生产控制涉及诸多特殊考虑，包括：（1）mRNA序列的分子设计对mRNA稳定性、目的抗原的表达效率、免疫原性均可能产生影响，如加帽结构的选择、非翻译区序列的选择及序列的改构、目的序列的优化、核苷酸的化学修饰等方面；（2）制剂组成、结构和工艺具有特殊性，主要特点是涉及阳离子聚合物或脂质材料、递送系统的结构多样性及纳米级粒径特性、工艺复杂性等，需要通过研究确认主要的考察指标来进行制剂处方组成和工艺的优化以及控制策略的建立；（3）同时可能涉及新免疫调节组分表达及新辅料的使用，必要时，需要单独的安全性研究支持。

Although mRNA vaccine has made some progress in clinical research of many infectious diseases, such as cytomegalovirus (CMV), influenza virus, Ebola virus and Zika virus, there are still many problems to be confirmed, such as the potential immunogenicity of mRNA itself; many issues such as the stability of the delivery system (e.g., lipid nanoparticles), the safety of the nano dosage form, the safety of the cationic polymer/liposome used, the delivery targeting and the delivery effectiveness, etc., affect the effectiveness, safety and quality controllability of the vaccine.

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