2022-04-21 来源 :注射剂工业网站

Q1Are microbiology and virology laboratories required independently, or can the virology laboratory be operated as part of microbiology?


A1Organizationally, 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.



Q2Which department is in charge of assigning an authorized person? and who should be designated as an authorized person?


A2Top 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”.



Q3What is the difference in quality control (QC) between sterile product and vaccine manufacturer premises?


A3QC 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.



Q4Is it acceptable, from a GMP point of view to contract QC services to another independent firm?


A4It is acceptable. Please follow GMP for contract analysis. The contracting laboratory must be qualified, and a quality technical agreement should be available.



Q5What is the difference between safety and impurity specifications?


A5Impurities 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.



Q6Many raw materials are not yet standardized in pharmacopeia, how can a company establish their specifications?


A6The company can establish an in-house specification based on a supplier’s specification, their risk assessment, and prior knowledge of the material.



Q7Why 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.


A7It 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.



Q8How can we set the limit for the microbial limits of utility (i.e. compressed air and nitrogen)?


A8Microbial limits should be the same as the requirement for the room classification in which the compressed air/gas is used.



Q9Is it obligatory to control the inactivation agent in the final vaccine?


A9It 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.



Q10Can the supplier of a material provide a separate container that can be considered as a sample for testing, obviating QC from performing supplementary sampling?


A10It 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.



Q11How long is the retention period for the retention samples?


A11Reference and retention samples from each batch of finished product should be retained for at least one year after the expiry date.



Q12Do vaccine sampling activities have to be performed by QC personnel?


A12In 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.



Q13Should 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?


A13AQL 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 Z1.4-2008ISO 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) 


Q14Should the company wait for the results of the in-process testing of samples before starting the next step of the process?


A14Ideally, 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.



Q15How are variations in bioassay/in vivo testing results managed?


A15They 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.






Q16What 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?


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.





Q17Should we document an OOS investigation even when its invalidity may be an analytical error?


A17Yes, it should be documented in the OOS investigation record form according to the approved standard operating procedure (SOP).



Q18How 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超常检验结果(OOT) ?

A18The 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.



Q19Regarding OOS and OOT results in microbiological tests, should the same procedures as those for analytical tests be used?


A19Yes, 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.



Q20In QC, what standard tools should we follow for trend analysis?


A20Standard deviation: +/- 2 and 3 SDs.

A20+/- 23倍的标准偏差。


Q21What is the difference between atypical results and OOT?


A21OOT is determined from trend analysis; atypical results are not



Q22Is analytical method validation required for both compendial methods and in-house methods?


A22Non-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。


Q23If 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?


A23It 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.



Q24What is the difference between method verifcation and method transfer?


A24Method 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.




Q25Is checking the requirements of system suitability parameters on the monograph enough for method verification?


A25It 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>


Q26Is 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?


A26All 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.




Q27Given the heat sensitivity of vaccines, what is the purpose of performing an accelerated stability study of them?


A27An 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”.)




Q28Is it enough to include only one batch for evidence of the photostability of the product?


A28Yes. 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).




Q29What is the purpose/use of real-time stability and ongoing stability?


A29Real-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).




Q30Is stability evaluation necessary for vaccines that have undergone extended controlled temperature conditions (ECTC)?


A30Yes. 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).



Q31What is the minimum stability that needs to be demonstrated before using internal reference standards or working standards?


A31Stability 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.)



(参见ISO 指南35参考材料-认证的一般和统计原则。)


Q32Should samples submitted to stability studies in the climate chamber include a secondary package or is the primary package sufficient?


A32Samples 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.



Q33What is the Inspector’s position on the use of loose worksheets as opposed to bound notebooks for recording laboratory data?


A33The 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.




Q34In vaccine-importing countries, how does the regulator monitor the quality of incoming vaccines without duplicating retesting?


A34The 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.


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。


Q35Should the NRA perform the same vaccine control validation as a manufacturer?


A35The NRA should follow the same rule:

in-house/non-compendial method – full validation

compendial method – verification

analytical transfer – partial validation/ verification.