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.
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.
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.
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.
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.
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.
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.
Q18：Is filtration required immediately before filling to produce the vaccine?
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.
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?
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.
Q20：Is egg-based vaccine classified as inactivated or activated?
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.
Q21：What steps need to be critically inspected from the lifecycle of vaccine manufacturing?
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.
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?
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.
Q23：What is the difference between Stage 3 and Stage 4 of vaccine development?
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.
Q24：Should the three phases of lot release be documented?
A24：Yes, the manufacturer should have a standard operating procedure (SOP) describing the lot release process.
Q25：Is a vector vaccine a special case of recombinant vaccine?
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.