Q1：Can protocols replace batch production records (BPRs) during product registration application?
Q1：在产品注册申请过程中，方案是否可以取代批生产记录?
A1：This should be discussed with the National Regulatory Authority (NRA). Both documents serve different purposes and can be considered supplementary to each other during product registration. For example, process validation batches need a protocol to perform the process validation and also need BPRs for operators to record parameters/ operations carried out as defined in the protocol.
A1：这应与国家监管机构讨论。这两份文件有不同的用途，在产品注册过程中可以相互补充。例如，工艺验证批次需要一个执行工艺验证的方案，也需要批生产记录，以便操作人员记录方案中定义的参数/操作。
Q2：How long should a manufacturer retain relevant documentation after product discontinuation?
Q2：产品停产后，制造商应保留相关文件多久?
A2：The WHO good manufacturing practice (GMP) requirements state that related documents such as batch records and material records should be retained for at least one year after the expiry date. However, it is beneficial to keep them longer as it can be useful for the purpose of adverse event following immunization (AEFI) and investigation. In some vaccine companies, they never destroy any important product related records. With the increasing use of electronic systems for document retention, the problem of physical space is significantly reduced.
A2：WHO药品生产质量管理规范(GMP)要求，批记录、物料记录等相关文件应在有效期后至少保留一年。然而，延长它们的保存时间是有益的，因为它可以用于免疫接种后不良事件(AEFI)的目的和调查。在一些疫苗公司，他们从不销毁任何重要产品的相关记录。随着越来越多的电子系统用于文档保存，物理空间的问题大大减少。
Q3：How long should a manufacturer retain critical documents such as validation, clinical data, stability data, etc.?
Q3：制造商应保留如验证、临床数据、稳定性数据等关键文件多长时间?
A3：These critical documents should be kept until the end of the product’s life cycle, or one year after the expiry date, whichever is longer. Please see the previous answer for additional detail.
A3：这些关键文件应保存到产品生命周期结束或有效期后一年，以较长时间为准。详情请参阅先前的答案。
Q4：Is it possible to start drug substance (DS) production if the facilities have not yet received GMP?
Q4：如果工厂尚未获得GMP，是否可以开始原料药（DS）生产?
A4：The manufacturing may need to be done before receiving GMP because the manufacturer would need the information to prove that the process is robust and validated. For example, process validation lots.
A4：生产可能需要在获得GMP之前完成，因为制造商需要信息证明工艺是稳健和有效的。例如，工艺验证批。
Q5：What is the procedure to follow to correct an approved standard operating procedure (SOP) or batch record during the execution of a task?
Q5：在执行任务的过程中，纠正已批准的标准操作程序(SOP)或批生产记录应遵循什么程序?
A5：The best way is to revise such a document. However, in case it cannot be done immediately, the revision of a portion of the document should follow the document approval route. For example, signed and dated by the same people who approved the document plus the reason for alteration. However, if such correction is a change that requires a change control, it should not be corrected until a change control is approved.
A5：最好的方法是修改该文件。但是，如果不能立即进行，则应按照既定文件批准的方式修改文件的相关部分。例如，由批准文件的同一人签字并注明日期，并注明修改原因。但是，如果这种更正是需要进行变更控制，则在变更控制得到批准之前不应进行更正。
Q6：Why are third parties common in vaccine production?
Q6：为什么在疫苗生产中普遍存在第三方?
A6：Third parties are common for vaccine production and quality control (QC), mainly due to the complex technological requirement of vaccines. For large-scale production, it is common to see companies subcontract some parts of production and/or QC to specific plants/laboratories.
A6：疫苗生产和质量控制（QC）中普遍存在第三方，这主要是由于疫苗工艺要求复杂。对于大规模生产，通常会看到公司将部分生产和/或QC分包给特定的工厂/实验室。
Q7：What are the procedures to do requalification of QC personnel? and what is the right frequency to do the personnel requalification?
Q7：QC人员的再审查程序是什么？进行人员再审查的正确频率是多少？
A7：The requalification requirements of QC personnel should be considered based on the test activities. However, it is more common to see an analyst’s qualifications review done every 6–12 months depending on the test.
A7：质量控制人员的再审查要求应根据检测活动进行考虑。然而，更常见的情况是根据测试情况，每6-12个月对分析人员进行一次资格审查。
Q8：In order to maintain QC personnel’s qualifications, is it feasible to check an
analyst’s QC qualifications on the basis of test results that they have carried out to confirm that they are still qualified to carry out the test?
Q8：为了确保质量控制人员的资质，是否可以根据相关分析人员已经完成的检测结果来检查他们的质量控制资质，以确认他们仍有资格进行检测?
A8：It depends on the test and the requirement for qualification of such a test. However, in general, there should be some indicators that can be used to review an analyst’s performance before extending the qualification. For example, training, frequency of testing, invalidity rate, out of specification(OOS), out of trend (OOT) from analyst’s error, etc. These indicators and staff responsibilities should be justified and documented.
A8：这取决于相关测试和这种测试的资格要求。然而，一般来说，在延长资格之前，应该有一些指标可以用来审查分析人员的表现。例如，培训、测试频率、无效率、检验结果偏差、分析师的超常检验结果等。这些指标和员工职责应有所证明并记录在案。
Q9：When to a perform quality audit? Should it be done before the batch is released?
Q9：什么时候进行质量审核?是在这批产品放行之前进行吗?
A9：Quality audit of third parties, when required, should be done before starting a commercial business with a third party, which means before the batch that is involved with the third party is released. Additional audits may be required after starting a commercial business, depending on the activity of such a third party.
A9：如果需要第三方的质量审核，应该在与第三方开展商业业务之前，即涉及第三方的产品批次放行之前进行。在开始商业业务后，可能需要额外的审查，这取决于第三方的活动。
Q10：How much can we trust the data obtained through questionnaires from the
supplier?
Q10：供应商的问卷数据的可信度是多少?
A10：The quality questionnaire sent to the supplier should be used as a basic information to increase the knowledge about the supplier. However, it cannot totally replace the on-site audit.
A10：发给供应商的质量问卷应该作为一个基本信息来增加对供应商的了解，但不能完全替代现场审核。
Q11：Do we need supplier qualification of non-critical chemicals used in a QC laboratory?
Q11：我们是否需要质控实验室中使用非关键化学品的供应商资质?
A11：What is in scope and out of scope should be defined in the SOP on management of supplier. The definition of “non-critical” is also important in justifying in scope and out of scope. However, whenever a supplier of material is out of scope of the SOP on management of supplier, there should be another procedure to control these materials (e.g., chemical grade, supplier, manufacturer, etc.).
A11：在供应商管理的标准操作程序（SOP）中规定了哪些是范围内的，哪些是范围外的。“非关键性”的定义对判定在其范围内还是外也很重要。然而，当物料供应商超出了供应商管理的SOP范围时，应该有另一个程序来管控这些材料(例如，化学等级，供应商，制造商等)。
Q12：If auditing of the supplier is not possible, for example, if the supplier is in a remote country and resources are limited, is it acceptable to rely on history and in-house testing of incoming materials only?
Q12：如果不能对供应商进行审核，例如，如果供应商在一个偏远国家且资源有限，是否可以只依靠来料的历史和其内部测试来判定?
A12：Relying on in-house testing history means we rely on QC, but such information cannot replace the requirement to ensure quality management of the supplier. The adequate resources to ensure quality management of third parties should be considered.
A12：依靠内部检测历史意味着我们依赖于质量控制，但这些信息不能取代确保供应商质量管理的要求。应考虑准备充足的资源以确保对第三方的质量管理。
Q13：Is it a requirement to audit the suppliers of raw materials for bulk production or suppliers of packaging materials?
Q13：是否需要对批量生产的原材料供应商或包装材料供应商进行审核?
A13：Initially, all starting material/packaging material suppliers should be approved/qualified based on criteria documented in the SOP and from a risk-based approach before use. An audit may form part of such approval/qualification, as needed.
A13：最初，所有原材料/包装材料供应商在产品采用前应根据标准操作程序中记录的标准和基于风险的审核方法进行批准/审查。如有需要，审核可构成批准/资格的一部分。
Q14：Is it a requirement to audit the suppliers of bulk vaccine?
Q14：是否需要对生产疫苗原液的供应商进行审核?
A14：According to GMP, a bulk vaccine is one of the critical materials and so initially the supplier should be approved/qualified following the procedure. If the on-site audit is evaluated to be necessary, it should be carried out accordingly.
A14：根据药品生产质量管理规范的规定，疫苗原液是关键材料之一，因此最初供应商应遵循审核程序获得批准/认证。如果现场审核是必要的，则应按规定进行。
Q15：Do we need a change control to change a certified supplier?
Q15：我们是否需要通过变更控制来变更获得认证的供应商?
A15：Yes, a change control is needed to change an approved/certified supplier.
A15：是的，需要通过变更控制来变更经批准/认证的供应商。
Q16：What is the situation that virtual audit of the subcontractor cannot be acceptable?
Q16：在什么情况下不能接受对分包商进行虚拟审核?
A16：Virtual audit has its limitations and so cannot be used to fully replace the on-site audit.
One of the examples that the virtual audit may not be enough is the initial qualification audit of a production subcontractor. However, this should be documented in the company’s document.
A16：虚拟审核有其局限性，不能完全替代现场审核。
虚拟审核可能不充分的一个例子是对生产分包商的初始资格审核。但是，这应该记录在公司的文档中。
Q17：What is the difference between the desk GMP review and the virtual audit?
Q17： GMP书面材料审核和虚拟审核有什么区别?
A17： The processes involved should be similar to on-site audit with the exception that the auditor is not on site. Thus, the virtual audit includes opening the meeting, a virtual site tour, an interview with an auditee, as well as closing the meeting via an online meeting platform.
A17：所涉及的过程应类似于现场审核，但审核员不在现场。因此，虚拟审核包括会议的开始，一个虚拟的现场参观，与一个被审核方的面试，以及通过一个在线会议平台完成会议。
Q18：A planned deviation is usually a temporary thing and not permanent.
How can I issue a change control for a temporary planned deviation, especially when there is not enough time to update the document? Are planned deviations non-GMP compliant?
Q18：计划性偏差通常是临时的，而非永久的。
如何发布临时计划性偏差的变更控制，特别是在没有足够时间更新文件的情况下?计划性偏差是否不符合药品生产质量管理规范要求?
A18：The change control system should be designed to process temporary changes and emergency changes.
Change control procedures and action plans should be responsive to these temporary and emergency changes.
Treating a planned deviation as a deviation is not GMP compliant since deviation is an unexpected event.
A18：变更控制系统应设计为处理临时变更和紧急变更。
变更控制程序和行动计划应对这些临时和紧急变更作出迅速反应。
将计划性偏差视为偏差是不符合药品生产质量管理规范的，因为偏差是一个意外事件。
Q19：In some countries, the documents are prepared in local languages, which is very difficult for foreign auditors and even translators. Is it mandatory for companies to have English or other widely spoken languages in addition to their local language?
Q19：在一些国家，文件是用当地语言编写的，这对外国审核员甚至翻译员来说都很困难。除了本地语言，公司是否必须使用英语或其他广泛使用的语言?
A19：Having a document in the local language is better for their own workforce. For quality audit purposes, the language of audit and major documentation should be detailed in the quality agreement.
A19：有一份当地语言的文档对公司自己的员工更好。为了质量审核的目的，审核的语言和主要文件应在质量协议中详细说明。
Q20：What is a quality unit?
Q20：什么是质量部门?
A20：According to WHO GMP, quality unit(s) is an organizational unit independent
of production which fulfils both quality assurance (QA) and QC responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization.
A20：根据WHO药品生产质量管理规范，质量部门是独立于生产的组织单元，同时履行质量保证(QA)和质量控制(QC)职责。这可以是单独的质量保证和质量控制部门，也可以是单独的个人或小组，这取决于组织的规模和结构。
Q21：What are the administrative changes to GMP documents that do not need a change control?
Q21：哪些药品生产质量管理规范文件的管理变更不需要变更控制?
A21：The administrative changes to GMP documents are changes that do not
have an impact on GMP. For example, corrections to typographical errors, document formatting, etc.
A21：药品生产质量管理规范文件的管理变更是对药品生产质量管理规范没有影响的变更。例如，对排印错误的更正、文档格式等。
Q22：Are changes affecting key production and quality personnel required to follow change-management procedures?
Q22：变更是否会要求关键的生产和质量人员遵循变更管理程序?
A22：Yes, a change control should be used to handle changes affecting key personnel, including key production and quality personnel.
A22：是的，变更控制用于处理影响关键人员的变更，包括关键的生产和质量人员。
Q23：What are major and minor changes in change control?
Q23：变更控制中的主要变更和次要变更是什么?
A23：Major and minor changes are part of a change category that is evaluated
based on the risk of each change control request.
A23：主要变更和次要变更是变更种类的一部分，基于对每个变更控制请求进行的风险评估。
Q24：What happens if change controls are not completed or closed within the timeframe?
Q24：如果变更控制没有在规定的时间内完成或关闭会怎么样?
A24：The change proposed cannot be implemented for routine implementation. This includes the related batches that cannot be released for sale.
A24：所提议的变更不能用于日常实施。这包括不能出售的相关批次。
Q25：If we manufacture more than one finished product batch using the same batch of bulk vaccine, do all the finished product batches need to be released from the NRA/National Control Laboratory (NCL)?
Q25：如果我们使用同一批疫苗原液生产多批次的成品，是否所有的成品批次都需要从国家监管部门/国家药品检定机构(NCL)放行?
A25：Lot release of vaccines by regulatory authorities depends on the specific requirements in each country. However, in general, a lot release certificate provided by NRA/NCL will be for a lot of vaccine in the final container. For additional information, please refer to WHO Technical Report Series 978, Annex 2, “Guidelines for independent lot release of vaccines by regulatory authorities”.
A25：监管部门放行疫苗的批次取决于每个国家的具体要求。但是，一般情况下，国家监管部门/国家药品检定机构提供的批签发许可证书将用于最终原液中的大量疫苗。有关其他信息，请参阅世卫组织技术报告系列978，附录2，“监管部门独立批签发疫苗的指南”。
Q26：Is it mandatory for the product quality review (PQR) to be initialled on every page or can it be approved on either the first or last page?
Q26：产品质量审核是否必须在每一页上草签，或者可以在第一页或最后一页上批准?
A26：A PQR is a quality document, and it should be approved by the quality unit. The review and approval route of a PQR should be written in the SOP. The WHO GMP does not specify how the PQR is approved.
A26：产品质量审核（PQR）是一种质量文件，应由质量部门批准。PQR的评审和批准路径应写在标准操作程序中。WHO药品生产质量管理规范没有规定PQR是如何批准的。
Q27：Should a blank (unfilled) BPR have an effective date and a review due date?
Q27：空白的批生产记录是否有生效日期和审核截止日期?
A27：There must be a system detailing how a blank (unfilled) BPR is prepared, reviewed, approved, trained, effected, revised, and archived. Therefore, an effective date is compulsory.
The blank (unfilled) BPR is a living document and a periodic review of such a document is beneficial for identifying any potential improvement.
A27：必须有一个系统详细说明空白(未归档)的批生产记录是如何准备、审查、批准、培训、实施、修订和归档的。因此，生效日期是强制性的。
空白的批生产记录是一个动态文档，定期检查这样的文档有助于识别任何潜在的改进。
Q28：Which is a good trend analysis for a PQR?
Q28：对于产品质量审核，哪一种趋势分析比较好?
A28：Choosing a trend analysis tool depends on the type of data available. It is also possible to have different tools for different sets of datExamples of trend analysis tools are control charts, and process capability index.
A28：选择趋势分析工具取决于可用数据的类型。对于不同的数据集，也可以使用不同的工具。趋势分析工具的例子有控制图和过程能力指数。
Q29：Is it possible to perform root cause analysis (RCA) using 5 whys techniques in a fishbone diagram?
Q29：是否可能在“鱼骨图”中使用“5个为什么”技术来执行根本原因分析(RCA) ?
A29：It is possible to use a mixture of investigation tools depending on the nature and extent of a deviation.
A29：根据偏差的性质和程度，可以使用混合的调查工具。
Q30：Is it mandatory for a NCL to analyse all the lots of vaccine?
Q30：国家药品检定机构是否必须分析所有批次的疫苗?
A30：Not unless it is a specific requirement for the country. For WHO’s requirement, please refer to WHO technical Report Series 978, Annex 2: “Guidelines for independent lot release of vaccines by regulatory authorities”.
A30：除非是一些国家的特殊要求。关于世卫组织的要求，请参阅世卫组织技术报告系列978附件2:“监管部门独立批签发疫苗的指南”。
Q31：How many product batches are recommended for a PQR to be conducted?
Q31：建议对多少批次的产品进行产品质量评审？
A31：GMP guideline expects PQR to be done on an annual basis.
A31：药品生产质量管理规范指南要求产品质量评审按年度进行
Q32：In preventive maintenance, if some parts of the equipment were found not to be functioning, should they be changed through change procedure? Similarly, if there were a change to machine parts as a corrective action for a deviation, is a change control required?
Q32：在预防性检修中，如果发现设备的某些部分不工作，是否应通过更换程序进行更换?同样，如果为了纠正偏差而更换机器零件，是否需要变更控制?
A32：For both cases, if it is a like-for-like replacement, there is no need to do a change control. However, the like-for-like spare parts should be written clearly in the SOP. The replacement should be documented and traceable.
A32：对于这两种情况，如果它是一个同类的替换，就不需要进行变更控制。但是，同类的备件应在标准操作程序中清楚地写出来。更换过程应记录在案并可追溯。
Q33：For inactive vendors, how many years should they be kept on the approved list before being disqualified?
Q33：不活跃的供应商，应在核准名单上保留多少年，才会被取消资格?
A33：Inactive vendor management should be evaluated regularly, possibly during the third- party performance review. There should be a documented process for keeping inactive vendors on the approved vendor list.
A33：不活跃的供应商管理应定期评估，可能在第三方绩效评估期间进行。应该有一个记录在案的流程，将不活跃的供应商保留在批准的供应商名单上。
Q34：For the PQR of a vaccine product where the final bulk for filling and packaging is sent to several contract manufacturing organizations (CMOs), which also have filling and packaging activities, is it necessary to include their activities in the PQR of the product?
Q34：对于疫苗产品的质量评审，如果灌装和包装的最终原液被发送给几个代工生产机构（CMO），这些组织也有灌装和包装行为，是否有必要将其包括在产品的质量评审中？
A34：It would depend on the quality agreement. Each CMO may perform their own PQR on their activities and pass it to the contract giver; or provide information to the contract giver to perform PQR. Ultimately, as marketing authorization holder (MAH), the PQR of the whole manufacturing process should be available and be compliant with GMP.
Please refer to WHO Technical Report Series 986, 2014, Annex 2, for additional requirements on PQR.
A34：这要看质量协议。每个代工生产机构可以在其活动中执行自己的产品质量评审，并将其传递给合同的授予者;或向合同给予方提供信息以完成产品质量评审。最终，作为上市许可持有人(MAH)，应提供整个生产过程的产品质量评审，并符合药品生产质量管理规范要求。
有关产品质量评审的其他要求，请参阅2014年世卫组织技术报告系列986,附件2。
Q35：What is the minimum frequency for self-inspection of a vaccine production facility?
What is the minimum frequency for third- party quality audit?
Q35：对疫苗生产设施进行自查的最低频率是多少?
第三方质量审核的最低频率是多少?
A35：According to WHO GMP, self-inspection should be done at least annually. Third-party audit is not considered as self-inspection. The interval for a quality audit of third parties should be determined based on quality risk management (QRM).
A35：根据WHO药品生产质量管理规范要求，至少每年进行一次自检。第三方审核不被视为自检。第三方质量审核的时间间隔应基于质量风险管理(QRM)来确定。
Q36：What is the content that should be included in the sterility assurance report (SAR)?
Q36：无菌保证报告(SAR)应包括哪些内容?
A36：A SAR contains all sterility assurance information related to the batch. For example, environmental monitoring results, latest media fill status, related water monitoring results, etc.
A36：无菌保证报告包含与批次相关的所有无菌保证信息。如环境监测结果、最新介质充填状况、相关水质监测结果等。
Q37：Considering the effectiveness of virtual inspection, can we assume that virtual inspection is not generally encouraged for GMP assessment of facilities?
Q37：考虑到虚拟检查的有效性，我们是否可以假设虚拟检查一般不被鼓励用于设施的药品生产质量管理规范评估?
A37：Implementing virtual inspection depends on each country’s regulation and NR. However, in general, virtual inspection has its limitations and so may not be used to fully replace the on-site inspection. One example of when virtual inspection may not be enough is the initial assessment of GMP.
A37：虚拟检查的实施取决于各国的法规，但一般来说，虚拟检查有其局限性，不能完全替代现场检查。虚拟检查可能不充分的一个例子是对药品生产质量管理规范的初次评估。