Q1：Should the phase 3 clinical trial batch size be pilot-scale or commercial-scale?

A1：It could be produced in either pilot scale or commercial scale.

However, for prequalification vaccines, WHO recommends that phase 3 clinical trial batches be similar to commercial batches. Expectations from the WHO prequalification programme are that during the manufacturing of phase 3 clinical material, consistency lots (i.e. process validation lots) should be produced as part of adequate validation studies.

Therefore, phase 3 batches should be produced on an industrial scale using the same manufacturing process/scale for commercialization to ensure the same quality for clinical phase 3 batches as for commercial batches. In addition, consistency between the batches for the clinical studies should be demonstrated.

Please refer to Validation of Production Processes for Vaccines for WHO prequalification Compliance Expectations: A note for guidance for the manufacture of prequalified vaccines for supply to United Nations agencies, July 2013.

A1：它可以在中试规模或商业规模两种情况下生产。

然而，对于预认证疫苗，世卫组织建议3期临床试验批次与商业批次相似。

世卫组织预认证的期望是，在3期临床材料的生产过程中，批次间一致性(即工艺验证批次)作为充分验证研究的一部分。因此，3批次应采用与商业化相同的生产工艺/规模进行工业化生产，以确保用于3期临床试验批次与商业批次的质量相同。此外，应证明用于临床研究批次之间的一致性。请参阅2013年7月《为满足世卫组织预认证遵守预期而验证疫苗生产流程:供应给联合国机构的经预认证疫苗生产指南说明》。

Q2：What are the principal differences between good manufacturing practice (GMP) for investigational medicinal products (IMP) and GMP for commercial production?

A2：In clinical trials, there may be added risk to participating subjects compared to patients treated with marketed products. The application of GMP to the manufacturing of IMP is intended to ensure that trial subjects are not placed at risk, and that the results of clinical trials are unaffected by inadequate safety, quality or efficacy arising from unsatisfactory manufacture.

Please refer to Pharmaceutical Inspection Co-operation Scheme (PIC/S) GMP Annex 13 which applies to IMP.

Q2：临床试验药品（IMP）与商业化生产GMP之间的主要区别是什么?

A2：在临床试验中，与使用上市产品治疗的患者相比，参与试验的受试者可能有额外的风险。GMP在IMP生产中的应用旨在确保试验对象不面临风险，且临床试验结果不受因不合格生产而导致安全性、质量或有效性不足的影响。请参阅适用于IMP的国际药品认证合作组织 (PIC/S) GMP附件13。

Q3：Where in the vaccine life cycle should the National Regulatory Authority (NRA) be involved?

A3：The NRA can be involved at all stages of a vaccine life cycle, from pharmaceutical development to product discontinuation. Normally, the NRA will grant approvals for clinical trials execution and then, for marketing authorization. It will approve GMP facilities, and will inspect IMP GMP compliance, good clinical practices (GCPs), and routine GMP compliance (commercial production).

Once marketing authorization has been granted, the NRA has the regulatory oversight of the vaccine for its entire life cycle. For changes to manufacturing processes/ specifications, the NRA should be noticed or approve the change to the marketing authorization.

Q3：国家监管机构(NRA)应参与疫苗生命周期的哪个阶段?

A3：NRA可以参与疫苗生命周期的所有阶段，从药物开发到产品停产。通常，NRA会批准执行临床试验，然后批准上市许可。NRA将批准GMP设施，并将检查IMP GMP合规性、良好临床实践（GCP）和常规GMP合规性(商业生产)。

一旦获得上市许可，NRA就对疫苗的整个生命周期进行监管。对于生产工艺/规格的变更，应通知NRA或批准上市许可的变更。

Q4：What makes protein subunit particularly desirable as a vaccine technology platform, given that it commands the largest percentage of Covid-19 vaccine in development?

A4：The advantages of protein subunit are safety, safe handling, and low biosafety concerns. Therefore, it does not require a high level of biosafety facilities and operations.

Q4：考虑到蛋白质亚单位疫苗在Covid-19疫苗开发中的占比最大，是什么让它成为受欢迎的疫苗技术平台?

A4：蛋白质亚单位疫苗的优点是安全性、安全处理和低生物安全的顾虑。因此，它不需要高水平的生物安全设施和操作。

Q5：Given the difference in doses, is there a significant difference in the immunogenic capacity between DNA and messenger RNA (mRNA) vaccines?

A5：Both DNA and mRNA vaccines will let our body express protein antigen to stimulate the immune responses to that antigen. The differences between immunogenicity induced by DNA and mRNA vaccines could come from the encoded gene optimization and efficiency of gene delivery system used which can impact the level of gene expression.

Q5：考虑到剂量的差异，DNA疫苗和信使RNA (mRNA)疫苗的免疫原性是否存在显著差异?

A5：DNA和mRNA疫苗都能让我们的身体表达蛋白抗原，从而刺激对该抗原的免疫反应。DNA疫苗和mRNA疫苗导致的免疫原性之间的差异可能来自编码的基因优化和使用的基因传递系统的效率，这会影响基因表达水平。

Q6：Why is sterility required for orally administered vaccines?

A6：Taking the example of oral poliomyelitis vaccine (OPV), the vaccine contains live attenuated virus in culture mediIf there is any contamination, other viruses, bacteria or fungi can grow, and the contaminated vaccine cannot be used.

Q6：为什么口服疫苗需要无菌?

A6：以口服脊髓灰质炎疫苗(OPV)为例，疫苗在培养基中含有减毒活病毒，如果有任何污染，其他病毒、细菌或真菌会生长，污染的疫苗不能使用。

Q7：How to manage the toxicity issues of the formaldehyde used in the process?

A7：The concentration of formaldehyde used as well as time and temperature conditions are critical process parameters which must be optimized, validated and controlled.

Q7：如何管理生产过程中使用的甲醛的毒性问题?

A7：甲醛的使用浓度、时间和温度条件是必须优化、验证和控制的关键工艺参数

Q18：Is filtration required immediately before filling to produce the vaccine?

Q18：生产疫苗灌装前是否需要立即过滤?

A18：Yes, if the product can be filter sterilized, the final sterile filtration step must be as close as possible to the  filling point. This is a requirement for sterile manufacturing products. However, some vaccines cannot be filter sterilized just before filling, such as those containing aluminium adjuvant. Therefore, aseptic processing must be applied from the formulation step.

A18：是的，如果产品可以过滤灭菌，最后的无菌过滤步骤必须尽可能靠近灌装点，这是无菌生产产品的要求。然而，有些疫苗在灌装前不能进行过滤灭菌，例如那些含有铝佐剂的疫苗。因此，从配方步骤开始必须进行无菌处理。

Q19：For a technology transfer of vaccine production from one plant to another plant, will this require clinical trials before a marketing authorization can be provided to the receiving plant?

Q19：对于从一家工厂到另一家工厂的疫苗生产技术转让，在接收工厂获得上市许可之前是否需要进行临床试验?

A19：This issue has to be discussed with the NRA or example, if there is a good technology transfer with supportive data such as process validation and comparability studies (process and analytical comparability), clinical trials may not be necessary. However, the regulators may ask for a clinical bridging study, if they deem it necessary.

A19：这一问题必须与国家监管机构讨论。例如，如果有一个良好的技术转让具有支持性数据，如工艺验证和可比性研究(工艺和分析可比性)，则可能没有必要进行临床试验。然而，如果监管机构认为有必要，他们可以要求临床桥接试验。

Q20：Is egg-based vaccine classified as inactivated or activated?

Q20：蛋基疫苗归类为灭活疫苗还是减毒活疫苗?

A20：It depends. Egg-based vaccine is not always necessarily regarded as an inactivated vaccine if there is no inactivation process.

There is an egg-based Newcastle disease virus vectored COVID-19 vaccine (under development) which is a live-attenuated vaccine for intranasal administration.

A20：视情况而定。如果没有灭活过程，蛋基疫苗并不一定被视为灭活疫苗。

有一种以蛋基的新城疫病毒载体的COVID-19疫苗(正在开发中)，这是一种用于鼻内给药的减毒活疫苗。

Q21：What steps need to be critically inspected from the lifecycle of vaccine manufacturing?

Q21：在疫苗生产的生命周期中，哪些步骤需要严格检查?

A21：This is mainly related to the manufacturing process and technology platform of each vaccine. However, the critical process parameters (CPPs) and critical quality attributes (CQAs) of each vaccine must be continuously monitored through its lifecycle.

A21：这主要与每种疫苗的生产工艺和技术平台有关。然而，每一种疫苗的关键工艺参数(CPPs)和关键质量属性(CQA)必须在其生命周期中持续监测。

Q22：What will be the most difficult task during inactivation of the vaccine manufacturing stage and how can one ensure that these steps are well done?

Q22：在灭活疫苗生产阶段，最困难的任务是什么?如何确保做好这些步骤?

A22：The most crucial and difficult task for the inactivation process is to control all critical material attributes (CMAs) and the CPPs of the inactivation process such as concentration of bulk antigen before inactivation, concentration of inactivating agent(s), buffer, excipients, temperature, time, agitation, etc., which must be validated and monitored for process performance and product quality. In-process control and in- process testing should be done. For some vaccines, the manufacturer will take samples during the inactivation process to determine the kinetic energy of inactivation. The inactivated product should be tested for live virus to verify if the inactivation process is complete or not.

A22：灭活过程中最关键和最困难的任务是控制灭活过程中的所有关键物质属性(CMAs)和关键工艺参数，如灭活前原液抗原浓度、灭活剂浓度、缓冲液、辅料浓度、温度、时间、搅拌等，必须验证和监控过程性能和产品质量。应进行过程控制和过程检测。对于某些疫苗，制造商会在灭活过程中取样，以确定灭活动态过程。灭活产品应进行活病毒检测，以验证灭活过程是否完整。

Q23：What is the difference between Stage 3 and Stage 4 of vaccine development?

Q23：疫苗开发的第三阶段和第四阶段有什么区别?

A23：Vaccine development Stage 3 is the clinical trials phase, and Stage 4 is post-marketing pharmacovigilance. The main difference is that Stage 3 is undertaken before obtaining marketing authorization and Stage 4 is undertaken after getting marketing authorization.

A23：第三阶段是临床试验阶段，第四阶段是上市后药物警戒阶段。主要区别在于，第三阶段是在获得上市许可之前进行的，第四阶段是在获得上市许可之后进行的。

Q24：Should the three phases of lot release be documented?

Q24：批签发的三个阶段是否应记录在案?

A24：Yes, the manufacturer should have a standard operating procedure (SOP) describing the lot release process.

A24：是的，制造商应该有一个标准操作程序(SOP)来描述批签发的过程。

Q25：Is a vector vaccine a special case of recombinant vaccine?

Q25：载体疫苗是一种特殊的重组疫苗吗?

A25：The recombinant DNA technology is often used in new generation vaccines, and a vectored vaccine is not a special case of recombinant vaccine. However, viral vectored vaccine is considered a genetically modified organism (GMO) while some other recombinant proteins, such as virus-like particle (VLP), DNA, mRNA vaccines are not GMO.

A25：重组DNA技术常用于新一代疫苗，载体疫苗并不是重组疫苗的特例。然而，病毒载体疫苗被认为是一种转基因生物产品(GMO)，而其他一些重组蛋白，如病毒样粒子(VLP)、DNA、mRNA等疫苗则不是转基因生物产品。