Q1：Are microbiology and virology laboratories required independently, or can the virology laboratory be operated as part of microbiology?
Q1：微生物实验室和病毒学实验室需要独立的吗？病毒学实验室能够作为微生物实验室的一部分运作吗?
A1：Organizationally, not necessary. However, function/responsibility of each laboratory should be well defined. Additionally, laboratory conditions and biosafety levels (BSLs) of the microbiology laboratory and the virology laboratory are different and should be appropriately managed.
A1：在组织形式上不需要独立。但是每个实验室的功能/职责都应该明确。此外，微生物实验室和病毒学实验室的实验室条件和生物安全等级(BSLs)不同，应适当管理。
Q2：Which department is in charge of assigning an authorized person? and who should be designated as an authorized person?
Q2：哪个部门负责指派授权人员？谁应该被指定为授权人？
A2：Top management should assign the authorized/qualified person responsible for batch release. The authorized/qualified person must have qualifications in line with good manufacturing practice (GMP) and the regulatory requirements of each country. In several countries, they must be a pharmacist who has work experience in the vaccine or sterile manufacturing industry. In other several countries, qualification requirements may be different and may require a certification of “qualified person”.
A2：最高管理者应指定授权/合格人员负责批次的放行。被授权/有资格的人员必须具有符合药品生产质量管理规范(GMP)和各国法规要求的资格。在一些国家，他们必须是在疫苗或无菌制造行业有工作经验的药剂师。在其他几个国家，资格要求可能不同，可能需要“合格人员”的资质证书。
Q3：What is the difference in quality control (QC) between sterile product and vaccine manufacturer premises?
Q3：在无菌产品和疫苗生产场所之间的质量控制(QC)有什么区别?
A3：QC premises depend on the tests to be done for the drug substance (DS) and drug product (DP). Most DS and DP vaccines require biological, immunological tests (identity, potency, impurities); some may require animal tests. Viral vaccine will require virological testing. Newer vaccines may require molecular biology laboratories. These tests are generally not required for chemical, sterile product.
A3：质量控制场所取决于对原料药(DS)和制剂(DP)进行的检测。大多数原料药和制剂疫苗需要生物、免疫检测(鉴别、效价、杂质)；有些可能需要动物试验。病毒疫苗需要进行病毒学检测。新疫苗可能需要分子生物学实验室。化学、无菌产品通常不需要做这些检测。
Q4：Is it acceptable, from a GMP point of view to contract QC services to another independent firm?
Q4：从药品生产质量管理规范的角度来看，是否可以将质量控制服务外包给另一家独立公司?
A4：It is acceptable. Please follow GMP for contract analysis. The contracting laboratory must be qualified, and a quality technical agreement should be available.
A4：是可以的。合同分析请按照药品生产质量规范进行。外包的实验室必须有资质，并应有一份质量技术协议。
Q5：What is the difference between safety and impurity specifications?
Q5：安全性和杂质规格有什么区别?
A5：Impurities could be process-related or product-related and may not be directly related to safety. Safety specifications are related to product safety, for example, endotoxins, sterility, etc., and may not be process-related or productrelated substances.
A5：杂质可能与工艺或产品有关，也可能与安全性没有直接关系。安全规范与产品安全性有关，例如内毒素、无菌性等，可能不是与工艺相关或产品相关的物质。
Q6：Many raw materials are not yet standardized in pharmacopeia, how can a company establish their specifications?
Q6：许多原料在药典中尚未标准化，企业如何建立其规格?
A6：The company can establish an in-house specification based on a supplier’s specification, their risk assessment, and prior knowledge of the material.
A6：公司可以根据供应商的规范、风险评估和材料的预先知识来建立相关内部规范。
Q7：Why is it the case that for some parameters, such as potency or quantification of active ingredients, manufacturers establish only lower limits but no upper limits.
Q7：为什么某些参数，如有效成分的效价或定量，生产商只设定下限，而没有上限呢?
A7：It depends on the vaccine platforms and safety profiles. Inactivated vaccines usually have only lower acceptance limits. Live attenuated vaccines generally have both upper and lower limits to ensure their safety, so they do not receive too much live antigen.
A7：这取决于疫苗平台和安全性。灭活疫苗通常只有接受下限。减毒活疫苗一般都有上限和下限，以确保其安全性，所以它们不会接收太多的活性抗原。
Q8：How can we set the limit for the microbial limits of utility (i.e. compressed air and nitrogen)?
Q8：我们如何设定微生物效用的限度(即压缩空气和氮气)?
A8：Microbial limits should be the same as the requirement for the room classification in which the compressed air/gas is used.
A8：微生物限度应与使用压缩空气/气体的空间分类要求相同。
Q9：Is it obligatory to control the inactivation agent in the final vaccine?
Q9：在成品疫苗中必须强制控制灭活剂吗?
A9：It is not an obligation. However, the specification of the final vaccine lot is established based on critical quality attributes (CQAs), the manufacturing process, nonclinical and clinical development data, and on risk assessment. Therefore, residue of inactivating agent is usually included in the final vaccine lot specification.
A9：不是强制性的。然而，成品疫苗批次的规范是根据关键质量属性(CQAs)、生产工艺、非临床和临床研发数据以及风险评估建立的。因此，灭活剂的残留通常包括在成品疫苗批次规范中。
Q10：Can the supplier of a material provide a separate container that can be considered as a sample for testing, obviating QC from performing supplementary sampling?
Q10：材料供应商是否可以提供一个单独的容器作为样品进行检测，从而避免质量控制进行补充抽样?
A10：It is an exceptional case as such sampling of the bulk antigen or ready-to-fill bulk (final bulk vaccine) could introduce a risk of contamination in the bulk or final bulk. In such a case, the supplier could take a sample for the vaccine manufacturer. However, the sampling procedure would have to be validated and the responsibility for sampling defined in the quality technical agreement.
A10：这是一个例外情况，因为这种原液抗原或准备灌装原液(半成品疫苗)的抽样可能会引发原液或半成品污染的风险。在这种情况下，供应商可以为疫苗制造商提取样本。然而，抽样程序必须经过验证，抽样的相关责任应在质量技术协议中规定。
Q11：How long is the retention period for the retention samples?
Q11：留样的留样期是多久?
A11：Reference and retention samples from each batch of finished product should be retained for at least one year after the expiry date.
A11：每批成品的参考样品和留样应在有效期过后至少保留一年。
Q12：Do vaccine sampling activities have to be performed by QC personnel?
Q12：疫苗抽样必须由质量控制人员进行吗?
A12：In principle, sampling is QC’s responsibility. In some cases, sampling may be done by production, but the sampler must be trained and qualified to follow the QC sampling procedure and the sampling should have quality unit oversight.
A12：原则上，抽样是质量控制的责任。在某些情况下，抽样可以由生产来完成，但抽样人员必须接受培训并获得资格，依照质量控制的抽样程序进行，并且抽样过程应由质量部门监督。
Q13：Should samples taken for QC be subject to an acceptable quality level (AQL) table? If so, how would we manage this huge number of samples for QC testing?
Q13：用于质量控制的样品是否符合可接受质量水平(AQL)表？如果是这样，如何管理这么多的样品进行质量控制检测?
A13：AQL sampling (special level sampling plans described in ANSI/ASQ Z1.4–2008 or ISO 2859) are appropriate for selection of sample size and acceptance criteria for testing visible particulates in injections according to USP <790>. But this sampling plan is not applied for QC of drug substances and intermediates and may not be applied for other QC tests of the drug products.
For sampling of vaccines, the sample size is usually based on the number and quantity required to complete all the tests stipulated in the specifications +2 times that quantity as a reference sample.
For drug substances and intermediates, only one or a few sample containers (to be aliquoted later for several laboratories) may be required and are taken based on risk assessment.
For drug products, other statistical sampling plans (random sampling or fixed-tray sampling) may be applied, but the principle that samples must be representative of the batch must be achieved. Sterility test and endotoxin test samples will have special requirements. The sampling plan used should be appropriately justified and based on a risk management approach (PIC/S GMP Part I, Chapter 6, par6.12).
A13：可接受质量水平抽样(ANSI/ASQ Z1.4-2008或ISO 2859中描述的特殊级别抽样计划)，适用于根据USP <790>抽取合适样本数量和可接受标准来检测注射剂中可见颗粒。但此抽样计划不适用于原料药和中间品的质量控制，也不适用于其他药品的质量控制检验。
对于疫苗的抽样，抽样数量通常是根据完成规格所规定的所有试验所需的数量2倍作为参考样本。
对于原料药和中间品，可能只需要一个或几个样品容器(稍后将在多个实验室中分配使用)，并基于风险评估进行采样。
对于药品，可以采用其他统计抽样方案(随机抽样或固定托盘抽样)，但必须遵循样品必须具有该批次代表性的原则。无菌试验和内毒素试验样品将有特殊要求。 采用的抽样方案应经过适当的论证，并基于风险管理方法(国际药品认证合作组织药品质量管理规范，第一部分，第6章，第6.12段)。
Q14：Should the company wait for the results of the in-process testing of samples before starting the next step of the process?
Q14：公司是否应该等待样品的过程中测试结果，然后再开始下一个步骤?
A14：Ideally, yes. However, in practice not waiting for the in-process testing results could put the next step at risk. Nevertheless, the finished product cannot be released until all in-process controls (IPCs) and release test results are available.
A14：理想情况下是的。在实践中不等待过程中测试结果可能会使下一步处于风险之中。然而，在过程质量控制(IPCs)和放行测试结果出来之前，成品不能放行。
Q15：How are variations in bioassay/in vivo testing results managed?
Q15：如何管理生物测定/体内检测结果的变化?
A15：They need to be evaluated on a case by case basis since it depends on the test. Animal challenge tests normally have higher variabilities than animal immunization before taking serum for enzyme-linked immunosorbent assay (ELISA) testing.
In general, you need to have all parameters under controlled and validated conditions, taking into considerations the Man (analysts) trained and qualified; Machine (equipment, instruments) qualified and calibrated; Materials (Reagents, Reference standards, Animals (age, sex, weight, strain, etc.); cells (passage number, seed lot system); Method validated; and Environment (clean room conditions, animal house air changes, etc.).
In some tests, more than one replication of the test (e.g., duplicate, triplicate) can be useful. In some animal tests, the increasing numbers of animals used in each test vaccine and reference vaccine dilution will be helpful.
Also, for some animal potency assays, two test determinations may be required, and the geometric/arithmetic mean calculated.
A15：他们需要根据实际情况进行评估，因为这取决于试验。在取血清进行酶联免疫吸附试验(ELISA)之前，动物挑战试验通常比动物免疫试验具有更强的变异性。
一般来说，要考虑经过培训和合格的分析师，需要将所有参数置于可控和有效的条件下；经检验合格和校准的机器(设备、仪器)；材料(试剂、标准品)；动物(年龄、性别、体重、品系等)；细胞(传代数、批种系统)；方法验证；环境(洁净室条件、动物舍换气等)。
在一些试验中，试验不止一次复制(例如，重复，三次复制)可能是有用的。在一些动物试验中，增加在每次试验疫苗和参考疫苗稀释液体使用的动物数量将有所帮助。
此外，对于某些动物效价测定，可能需要进行两项试验测定，并计算几何/算术平均值。
Q16：What would be the condition for resampling during out of specification (OOS) investigation?
Q16：在检验结果偏差 (OOS)调查期间重新采样的条件是什么?
A16：
1) If OOS investigation phase 1b shows that there is sample error.
2) If OOS investigation phase 2 (and/or phase 3) requires resampling/additional sampling according to the approved protocol.
A16：
1)检验结果偏差调查1b阶段显示存在样本误差。
2)检验结果偏差调查第2阶段(和/或第3阶段)需要根据批准的方案重新抽样/额外抽样。
Q17：Should we document an OOS investigation even when its invalidity may be an analytical error?
Q17：当对检验结果偏差调查的无效性出现分析错误时，我们也应该将其记录在案吗?
A17：Yes, it should be documented in the OOS investigation record form according to the approved standard operating procedure (SOP).
A17：是的，应根据批准的标准操作程序(SOP)将其记录在检验结果偏差调查记录表中。
Q18：How can a manufacturer identify out of trend (OOT) for test results with high result variation?
Q18：制造商如何识别具有高变异性的超常检验结果(OOT) ?
A18：The company needs to carry out a trend analysis before they can determine if the test result is OOT. Validity of the test should be verified to ensure that the result really is OOT.
A18：在确定测试结果是否为超常检验结果之前公司需要进行趋势分析。检验的有效性应得到验证，以确保结果确实是超常检验结果。
Q19：Regarding OOS and OOT results in microbiological tests, should the same procedures as those for analytical tests be used?
Q19：关于微生物检测中的检验结果偏差和超常检验结果，是否应采用与分析测试相同的程序?
A19：Yes, but the investigation checklist could be designed to ft microbiological tests.
There is a requirement that sterility tests cannot be retested except where there is supportive evidence that the tests are invalid.
A19：是的，但调查清单可以设计成微生物测试。有一项规定，除非有证据证明无菌检测无效，否则不能重新进行无菌检测。
Q20：In QC, what standard tools should we follow for trend analysis?
Q20：在质量控制中，我们应该遵循哪些标准工具来进行趋势分析?
A20：Standard deviation: +/- 2 and 3 SDs.
A20： +/- 2和3倍的标准偏差。
Q21：What is the difference between atypical results and OOT?
Q21：非典型结果和超常检验结果有什么区别?
A21：OOT is determined from trend analysis; atypical results are not
A21：超常检验结果由趋势分析确定；非典型结果不是。
Q22：Is analytical method validation required for both compendial methods and in-house methods?
Q22：药典方法和内部方法都需要进行分析方法验证吗?
A22：Non-compendial analytical procedure (such as in-house method) should be fully validated according to ICH Q2 (R1) Validation of analytical procedures: text and methodology. For compendial methods (such as those in pharmacopeial
monographs, WHO Technical Report Series, etc.), only analytical method verification is required.
A22：非药典分析方法(如内部方法)应根据ICH Q2 (R1)进行充分验证。分析方法验证：文本和方法学。对于药典方法(如药典专著、世卫组织技术报告系列等中的方法)，只需要对分析方法进行验证。
Q23：If minor changes have been made to a compendial method, can it then be considered as an in-house method, and does it require full validation?
Q23：如果对药典方法做了微小的修改，那么是否可以将其视为一种内部方法，还需要完全的验证吗?
A23：It depends on the change(s). Please proceed through the change control process and do risk assessment to determine if a method validation or method verification is needed.
A23：这取决于变化。请继续进行变更控制程序并进行风险评估，以确定是否需要方法验证。
Q24：What is the difference between method verifcation and method transfer?
Q24：方法验证和方法转移有什么区别？
A24：Method transfer is the transfer of an analytical procedure from a sending laboratory to a receiving laboratory. Comparability between the sending laboratory and the receiving laboratory should be demonstrated.
Method verification is an assessment that the compendial procedure can apply in the laboratory to yield acceptable results utilizing the personnel, equipment and reagents available. Only some of the validation characteristics can be evaluated to verify the suitability of the procedure. There is no comparison with other laboratories.
A24：方法转移是指分析过程从发送实验室转移到接收实验室。应证明发送实验室和接收实验室之间的可比性。
方法验证是指利用现有人员、设备和试剂，对药典程序可在实验室中应用并产生可接受结果的评估。只评估部分验证特性以验证程序的适配性。没有其他实验室可以与之相比。
Q25：Is checking the requirements of system suitability parameters on the monograph enough for method verification?
Q25：检查专著中对系统适宜性参数的要求是否足以进行方法验证?
A25：It is not enough. For more detail, please refer to the USP <1226>.
A25：这还不够。有关更多细节，请参阅USP <1226>。
Q26：Is method validation required for all in-process and drug product specification tests? For example, how do we to perform validation for the visible particle test?
Q26：是否所有中间品和药品规格的检测都需要方法验证？例如，如何对可见粒子检测执行验证?
A26：All analytical procedures applied to drug substances and products, and in-process tests should be validated/verified.
The Visible Particulates in Injections (USP<790>) test is the simplest instrumental
method. Method verification may not be necessary, but the equipment/instrument must be qualified, and analysts must be trained and qualified using the visual inspection defects kit.
A26：所有适用于原料药和制剂的分析方法，以及过程中的检测都应进行验证。
注射剂中可见颗粒(USP<790>)检测是最简单的仪器检测方法。方法验证可能不是必须的，但设备/仪器必须合格，分析人员必须经过培训并有资质使用目检缺陷工具。
Q27：Given the heat sensitivity of vaccines, what is the purpose of performing an accelerated stability study of them?
Q27：考虑到疫苗的热敏性，对其进行加速稳定性研究的目的是什么?
A27：An accelerated stability study provides useful support data in: establishing the expiration date; providing product stability information for future product development (e.g. preliminary assessment of proposed manufacturing changes such as change in formulation, scale-up); assisting in the validation of analytical methods for the stability programme; and generating information which may help elucidate the degradation profile of the drug substance or drug product. Studies under stress conditions may be useful in determining whether accidental exposure to conditions other than those proposed (e.g. during transportation) are deleterious to the product and also in evaluating which specific test parameters may be the best indicators of product stability (ICH Q5C Quality of biotechnological products: Stability testing of biotechnological/biological products). Accelerated stability studies may provide useful support data to establish the shelflife or release specifications but should not be used to forecast real-time, real-condition stability of a vaccine. They could also provide preliminary information on vaccine stability at early developmental stages and assist in assessing the stability profile of a vaccine after manufacturing changes (WHO Technical Report Series 962, 2011, Annex 3: “Guidelines on stability evaluation of vaccines”.)
A27：加速稳定性研究在以下方面提供了有用的支持数据：确定有效期；为未来产品开发提供产品稳定性信息(例如，对拟议的生产变更(如配方变更、扩大生产)进行初步评估)；协助稳定性项目分析方法的验证；并生成有助于阐明原料药或制剂的降解概况的信息。在压力条件下的研究可能是有用的，用于确定在一些情况(如运输)下的意外暴露是否对产品产生有害影响，也评估哪些特定检测的参数可能是最好的产品稳定性检测指标(IQ5C生物技术的产品质量：生物技术/生物制品的稳定性检测)。
加速稳定性研究可提供有效的支持数据，以规定疫苗的保质期或放行规格，但不应用于预测疫苗的实时、真实状态的稳定性。它们还可以提供早期开发阶段疫苗稳定性的初步信息，并协助评估生产变更后疫苗的稳定性概况(2011年世卫组织技术报告系列962，附录3:“疫苗稳定性评价指南”)。
Q28：Is it enough to include only one batch for evidence of the photostability of the product?
Q28：只提供一批疫苗的产品光稳定性证明足够吗?
A28：Yes. Please refer to ICH Topic Q1B: Photostability testing of new active substances and medicinal products.
However, please note that photostability is not mandatory for vaccine stability studies (WHO Technical Report Series 962, 2011, Annex 3).
A28：是的。请参阅ICH主题Q1B：新活性物质和药品的光稳定性测试。
但是，请注意，光稳定性对疫苗稳定性研究并不是强制性的(2011年世卫组织技术报告系列962，附录3)。
Q29：What is the purpose/use of real-time stability and ongoing stability?
Q29：实时稳定性和持续稳定性的目的/用途是什么?
A29：Real-time stability studies will be required for clinical trial approval, licensing, and shelf-life determination.
Ongoing stability study is required after marketing to monitor the product over its shelf life and to determine that the product remains, and can be expected to remain, within specifcations under the labelled storage conditions (see PIC/S GMP Part I, Chapter 6, paras. 6.26–6.36).
A29：临床试验的批准、上市许可和保质期的确定需要实时的稳定性研究。
在产品上市后，需要进行持续的稳定性研究，以监测产品的保质期，以及确定产品在说明书存储条件下，在规格范围内，可以保存和可预期保存的时间(见国际药品认证合作组织药品质量管理规范第一部分，第6章，6.26-6.36段)。
Q30：Is stability evaluation necessary for vaccines that have undergone extended controlled temperature conditions (ECTC)?
Q30：是否需要对经过长期控制温度条件(ECTC)的疫苗进行稳定性评估?
A30：Yes. It is important to have enough supportive stability data to ensure that a vaccine exhibits a stability profile suitable for the ECTC prior to administration, while remaining compliant with the approved vaccine specifications. Stability evaluation of a specific vaccine planned for use under ECTC must generate sufficient scientifically valid data to support regulatory approval of labelling for such use (see WHO Technical Report Series 999, 2016, Annex 5).
A30：是的。要有足够的支持性稳定性数据，以确保疫苗在给药前显示出适合长期控制温度条件的稳定性，同时符合已批准的疫苗规格。计划在长期控制温度条件使用的特定疫苗，其稳定性评估必须生成足够的科学有效数据，以支持监管部门批准此类使用的说明书(见2016年世卫组织技术报告系列999，附录5)。
Q31：What is the minimum stability that needs to be demonstrated before using internal reference standards or working standards?
Q31：在使用内部参考标准或工作标准之前需要证明的最少稳定性数据是什么?
A31：Stability data are not required before using the reference material. But a stability monitoring programme must be in place to monitor quality/stability of the material. It is important that the reference material must be qualified before use. For some in-house reference vaccines, qualification includes testing of that material (as specification) and testing some parameters (e.g. potency) in many replicates so as to have enough data for a statistical evaluation to assign the reference value with limits.
For working standards, calibration against international standards with an appropriate dataset for statistical evaluation would be required.
(See ISO GUIDE 35: Reference materials – general and statistical principles for certification.)
A31：在使用参考材料之前不需要稳定性数据。但是必须有一个稳定性监测程序来监测材料的质量/稳定性。参考材料在使用前必须经过鉴定，这一点很重要。对于一些内部参考疫苗，鉴定包括检测该材料(作为规范)和在许多重复中检测某些参数(例如效价)，以便有足够的数据进行统计评价，以确定可信限的参考值。
对于工作标准，需要根据国际标准和适当的数据集进行校准，以便进行统计评价。
(参见ISO 指南35：参考材料-认证的一般和统计原则。)
Q32：Should samples submitted to stability studies in the climate chamber include a secondary package or is the primary package sufficient?
Q32：提交给气候室稳定性研究的样品是否应包含二级包装还是初级包装就足够了?
A32：Samples in the primary package are used for stability studies for clinical approval and registration. For ongoing stability studies, products in the package in which they are sold should be used.
A32：初级包装中的样品用于临床批准和注册的稳定性研究。对于正在进行的稳定性研究，应使用其在销售的产品包装。
Q33：What is the Inspector’s position on the use of loose worksheets as opposed to bound notebooks for recording laboratory data?
Q33：检验员对使用松散的工作表而不是装订好的笔记本记录实验室数据有什么看法?
A33：The laboratory test record worksheets are compiled as “batch testing records” and combined into the batch record for batch release decision.
There must be evidence that data are not altered. Loose worksheets are not considered appropriate. Laboratory notebooks may be used to record other laboratory activities such as reagent preparation, standardization of reagents, equipment/instrument usage.
A33：实验室检测记录工作表编制为“批次检测记录”，并合并到批次记录中，以决定批次放行。
必须有证据表明数据没有被修改。松散的工作表是不合格的。实验室笔记可以用来记录其他的实验室活动，如试剂的准备，试剂的标准化，设备/仪器的使用。
Q34：In vaccine-importing countries, how does the regulator monitor the quality of incoming vaccines without duplicating retesting?
Q34：在疫苗进口国，监管者如何在不重复检测的情况下监测进口疫苗的质量?
A34：The National Regulatory Authority (NRA) may choose to review the summary protocol of an imported batch of vaccine or may take a sample to test some parameters to confirm the quality of the batch or may use a data logger to verify if there have been any deviations/ temperature excursions during transportation.
The recipient country will usually receive the lot release certificate from the NRA and may rely on the already performed release and testing. See also the WHO guidelines for independent lot release of vaccines by regulatory authorities and the WHO operational tool for efficient and effective lot release of SARS-CoV-2 (Covid-19) vaccines.
A34：国家监管机构(NRA)可以选择查看进口批次疫苗的摘要方案或可能需要一个样品来测试一些参数以确认批次的质量或可能使用一个数据记录器来验证运输期间是否有任何偏差/温度超出预期。
接收国通常会收到来自NRA的批签发证书，或依靠已经执行的放行和检测。另见世卫组织对监管部门独立疫苗批签发指南和世卫组织高效和有效批签发SARS-CoV-2 (Covid-19)疫苗的操作工具。
Q35：Should the NRA perform the same vaccine control validation as a manufacturer?
Q35：国家监管机构是否应该与制造商进行相同的疫苗控制验证?
A35：The NRA should follow the same rule:
• in-house/non-compendial method – full validation
• compendial method – verification
• analytical transfer – partial validation/ verification.
A35：国家监管机构也应该遵循同样的规则：
• 内部/非药典方法-完全验证
• 药典方法-验证
• 分析转移-部分验证。