干货|WHO《临床试验用药品 GMP 指南》中英文对照版!|质量|临床试验|药品|记录|生产|-健康界 (2023)

WHO发布的Working document QAS/20.863 《临床试验用药GMP指南》,该文件翻译如下,供大家参考:

Good manufacturing practices for investigational products 临床试验用药品 GMP 指南


1.1.In view of an old publication date,and the recent need for new guidelines arising from inspections carried out forCOVID-19 therapeutics, the World Health Organization (WHO) PrequalificationTeam-Inspection Services (PQT INS) raisedthe urgency for a revision of the WHO Good manufacturing practices forinvestigational pharmaceutical products for clinicaltrials in humans(1). The Fifty-fifth Expert Committee on Specifications forPharmaceutical Preparations (ECSPP) concurred with this proposal.


1.2.The objective of this update is tobring the guideline in line with current expectations and trends in goodmanufacturing practices and to harmonize the text with the principles fromother related international guidelines.



2.1.Investigational products are used fortesting purposes; as a reference in a clinical trial; for an unauthorizedindication; and to gain further information about the authorized form.


2.2.In some cases, marketed products whichhave been re-packaged or modified in some way, are used for investigationalpurposes.


2.3.The legal status of investigationalproducts for human and veterinary use varies from country to country.


2.4.These products are sometimes notcovered by legal and regulatory provisions in the areas of good practices (GxP)and inspection. These complexities, such as lack of high level goodmanufacturing practices (GMP) requirements, risk of contamination andcross-contamination, clinical trial designs, blinding and randomization,increase the risk. In addition, there are also instances where there isincomplete knowledge of the potency and toxicity of the investigationalproduct.


2.5.There are further risks associatedwith the production, validation, control, shipping, storage and use ofinvestigational products.


2.6.To minimize risks and to ensure thatthe results of clinical trials are unaffected by inadequate safety, quality orefficacy arising from unsatisfactory manufacture, investigational productsshould be manufactured and managed in accordance with an effective qualitymanagement system and the recommendations contained in this guideline.


2.7.Other guidelines and GxP should betaken into account, where relevant and as appropriate, as to the stages ofdevelopment, production and control of the product.


2.8. Proceduresshould be flexible to provide for changes whenever necessary, as knowledge ofthe process increases over time, and in accordance with the stages ofdevelopment of the product.


2.9.Investigational products should bemanufactured in a manner:


  • thatis compliant to GxP, as appropriate;

  • 符合GXP要求(适当时)

  • thatensures that subjects of clinical trials will be protected from poor qualityproducts due to unsatisfactory manufacturing;

  • 确保临床试验对象受到保护,不会使用因生产不足导致的劣质药品

  • toassure consistency between and within batches of the investigational product;and

  • 确保临床试验用药品批内和批间一致性,以及

  • toassure consistency between the investigational product and the futurecommercial product.

  • 确保临床试验药品和未来商业化药品之间的一致性

2.10. The selection of an appropriate dosageform for clinical trials is important. While it is accepted that the dosageform may be very different from the anticipated final formulation (e.g. acapsule instead of a tablet) in early trials, in the pivotal Phase III studies,it should be similar to the projected commercial presentation; otherwise thesetrials will not necessarily prove that the marketed product is both efficaciousand safe. If there are significant differences between the clinical andcommercial dosage forms, data should be submitted to the registrationauthorities to demonstrate that the final dosage form is equivalent, in termsof bioavailability and stability, to that used in the clinical trials.


2.11. Thequality of investigational products should be appropriate. For example, dosageforms in Phase III clinical studies should be characterized and assured at thesame level, as for routinely manufactured products.


2.12. Where production and/or quality controlis transferred from one site to another, the recommendations in the guidelinefor transfer of technology should be followed.


2.13.This document should be read inconjunction with other WHO GxP guidelines, including good clinical practice(GCP)(2).



3.1.The recommendations in this guidelineare applicable to investigational products for human and veterinary use.


3.2.Although the focus is on medicinal(pharmaceutical) products, some of the principles may be applied to otherinvestigational products.


4.Quality management质量管理

4.1.There should be a comprehensivelydesigned, clearly defined, documented and correctly implemented quality managementsystem in place. Senior management should assume responsibility for this aswell as the quality of the investigational product.


4.2.All parts of the quality system shouldbe adequately resourced and maintained.


4.3.The quality system should incorporateGxP which would be applied to all the lifecycle stages of the products,including the transfer of technology, and the interface between the manufactureand the trial site (e.g. shipment, storage, labelling).


4.4.The quality system should ensure that:


  • productsare designed and developed in accordance with the requirements of this documentand other associated guidelines such as good laboratory practice (GLP)(3), good clinical practice (GCP)(2)and good storage and distributionpractices (GSDP)(4), whereappropriate;

  • 产品根据本文件和其它相关指南如GLP、GCP和GSDP(适当时)的要求设计和起草

  • managerialresponsibilities are clearly specified in job descriptions;

  • 在岗位职责中清楚写明了管理职责;

  • operationsare clearly specified in a written form;

  • 以书面形式清楚规定了操作内容;

  • arrangementsare made for the manufacture, supply and use of the correct starting andpackaging materials;

  • 为生产、供应和使用正确的起始物料和包装材料做出安排

  • allnecessary controls on starting materials, intermediate products, bulk productsand other in-process controls should be in place;

  • 应对起始物料、中间体、散装产品和其它中间控制制订必要的控制

  • calibrationsand validations are carried out where necessary;

  • 进行校正和验证(必要时)

  • thefinished product is correctly processed and checked according to the definedprocedures;

  • 成品根据既定程序正确加工和检查

  • deviations and changes areinvestigated and recorded with an appropriate level of root cause analysis doneand appropriate corrective actions and/or preventive actions (CAPAs) identifiedand taken;

  • 偏差和变更有调查和记录,有恰当水平的根本原因分析,识别并采取恰当的CAPA

  • thereis a system for quality risk management (5); and

  • 订有质量风险管理体系,以及

  • satisfactoryarrangements exist to ensure, as far as possible, that the investigationalproducts are stored, distributed and subsequently handled so that their qualityis maintained.

  • 订有足够好的程序,可尽可能确保临床试验用药品在存贮、销售和后续处理过程中能维持其质量

5.Quality risk management质量风险管理

5.1.There should be a system for qualityrisk management.


5.2.The system for quality risk managementshould cover a systematic process for the assessment, control, communicationand review of risks to the quality of the product and, ultimately, to theprotection of the trial subject and patient.


5.3.The quality risk management systemshould ensure that:


theevaluation of the risk is based on scientific knowledge and experience with theprocess and product;


proceduresand records for quality risk management are retained; and the level of effort,formalityand documentation of the quality risk management process is commensurate withthe level of risk.


5.4.Quality risk management should beapplied both proactively and retrospectively, when appropriate.



6.1.There should be a sufficient number ofappropriately qualified personnel available to carry out all the tasks forwhich the manufacturer of investigational products is responsible.


6.2.Individual responsibilities should beclearly defined, recorded as written descriptions and understood by the personsconcerned.


6.3.A designated person, with a broadknowledge of product development and clinical trial

processes should ensure that there aresystems in place that meet the requirements of this guideline and other relevantGxP guidelines.


6.4. Personnelinvolved in the development, production and control of investigational productsshould be appropriately trained in relevant GxP and the requirements specificto investigational products.


6.5. Production and quality controloperations should be carried out under the control of clearly identifiedresponsible persons who are separately designated and independent, one from theother.



7.1.Good documentation is an essentialpart of a quality management system. Documents should be appropriatelydesigned, prepared, reviewed and distributed. They should also be appropriatefor their intended use.


7.2.Documents should be approved, signedand dated by the appropriate responsible persons. No authorized document shouldbe changed without the prior authorization and approval of another.



7.3.Specifications (for startingmaterials, primary packaging materials, intermediate, bulk and finishedproducts) should be available.


7.4.In developing specifications,attention should be paid to the characteristics which affect the efficacy andsafety of products, namely:


  • theaccuracy of the therapeutic or unitary dose: homogeneity, content uniformity;

  • 治疗或单位剂量的准确性:均匀性、含量均一性;

  • therelease of active ingredients from the dosage form: dissolution time, etc.;

  • 活性成分从制剂中释放情况:溶出时间等

  • thepackage size should be suitable for the requirements of the trial, whereapplicable;

  • 包装规格应适合于试验要求(适用时);

  • theestimated stability, if necessary, under accelerated conditions; and

  • 预估的加速稳定性(必要时)以及

  • thepreliminary storage conditions and the shelf life of the product.

  • 药品的初步存贮条件和货架期

7.5.As a result of new experience in thedevelopment of an investigational product, specifications may be changed byfollowing a documented procedure. Changes should be authorized by a responsibleperson. Each new version should take into account the latest data andinformation, current technology, regulatory and pharmacopoeia requirements.There should be traceability of the previous version(s). The reasons forchanges should be recorded. The impact of the change on any on-going clinicaltrials, on product quality, stability, bio-availability, and bio equivalence(where applicable) should be considered.



7.6.An order should be available for therequest of a certain number of units for processing, packaging, storage andtheir shipping.


7.7.The order should be given by thesponsor to the manufacturer of an investigational product.


7.8.The order should be in writing (e.g.by paper or electronic means), be authorized and contain sufficient detailincluding the approved product specification file (see below) and the relevantclinical trial protocol, as appropriate, to avoid any ambiguity.


7.9.Where commercially available productsare obtained to be used as reference products, such as for use inbio-equivalence studies, the relevant documentation, such as a purchase order,an invoice, storage and transport records, should be maintained and availablefor inspection.


Product specification file(s)产品标准文件

7.10. A product specification file (or files)should contain the information necessary to prepare detailed writteninstructions on processing, packaging, quality control testing, batch release,storage conditions and/or shipping.


7.11. The product specification file shouldindicate who has been designated or trained as the designated responsibleperson(s) for the release of batches.


7.12. The product specification file should becontinuously updated while, at the same time, ensuring appropriate traceabilityto the previous version(s).


7.13.The information should form the basis forassessment of the suitability for certification and release of a particularbatch by the designated responsible person. It should include or refer to thefollowing documents:


  • specificationsfor starting materials, packaging materials, intermediate, bulk and finishedproduct;

  • 起始物料、包装材料、中间体、散装和成品标准

  • analyticalmethods for starting materials, packaging materials, intermediate, bulk andfinished product;

  • 起始物料、包材、中间体、散装和成品分析方法

  • manufacturingmethods;

  • 生产方法

  • in-processtesting and methods;

  • 中控检测项目和方法

  • approvedlabel;

  • 经过批准的标签

  • relevantclinical trial protocols;

  • 相关临床试验方案

  • randomizationcodes, as appropriate;

  • 随机代码(适当时)

  • relevanttechnical agreements, as appropriate;

  • 相关技术协议(适当时)

  • stabilitydata; and

  • 稳定性数据,以及

  • storageand shipment conditions.

  • 存贮和运输条件

Note: The contents will vary depending on the product andstage of development.


Manufacturing formulae and processing instructions生产配方和加工指令

7.14. Normally, detailed manufacturingformulae, processing and packaging instructions and records should beavailable. Where this is not possible, other clear, written instructions andwritten records should be available for every manufacturing operation orsupply.


7.15. As a result of new experience in thedevelopment of an investigational product, manufacturing formulae andprocessing instructions may be changed by following a documented procedure.Each new version should take into account the latest data and information,current technology, regulatory and other requirements. There should be traceabilityto previous versions. The reasons for changes should be recorded. The impact ofthe change on any on-going clinical trial, product quality, stability,bio-availability and bio equivalence (where applicable) should be considered.Changes should b e authorized by a responsible person.


7.16. These records should be used whenpreparing the final version of the documents to be used in routine manufacture.


7.17.Batch processing and packaging recordsshould be retained for at least two years after the termination ordiscontinuance of the clinical trial, or after the approval of theinvestigational product.


7.18. Wherethe data are intended for inclusion in an application for product registration(marketing authorization) purposes, the records should be maintained until theend of the life cycle of the product.


Packaging instructions包装指导

7.19. The number of units to be packaged shouldbe specified before the start of the packaging operation. This should includethe number of units necessary for carrying out quality controls and the numberof samples from each batch used in the clinical trial to be kept as retentionsamples. Reconciliation should be carried out at defined intervals, whererequired, and at the end of the packaging and labelling process.


7.20. Investigational products may be packed inan individual way for each subject included in the clinical trial, or as bulkif required.


Labelling instructions贴标指令

7.21. Investigational products should belabelled in accordance with relevant legislation or best practices. The labelshould contain information such as:


  • thename, address and telephone number of the sponsor, contract researchorganization or investigator;

  • 申办人、合同研究机构或研究员的名称、地址和电话号码;

  • thestatement: "For clinical research use only";

  • 声明“仅供临床研究使用”;

  • areference number indicative of the trial, site, investigator and sponsor, ifnot given elsewhere;

  • 试验适用症索引号、试验场所、研究员和申办人,如果在其它地方未给出;

  • abatch or code number;

  • 批号或代码;

  • thetrial subject or patient identification number;

  • 试验对象或患者编号;

  • areference to the directions for use;

  • 对使用指导的索引;

  • informationon storage conditions;

  • 存贮条件的信息;

  • anexpiry date, use-by date or re-test date (month and year);

  • 有效期,最后使用日期或复验期(年月)

  • adosage form and route of administration;

  • 剂型和给药途径;

  • thequantity of dosage units and, in the case of open trials, the name/identifierand strength/potency; and

  • 给药单位的数量,如果是开放式试验,则为名称/标识和剂量/效价,以及

  • thestatement: “Keep out of reach of children”.

  • 声明“放在儿童接触不到的地方”

7.22. Additional information may be displayedin accordance with the order (e.g. treatment period, standard warnings).


7.23. When necessary for blinding purposes, thebatch number may be provided separately (see also "Blindingoperations").


7.24.A copy of each type of label should bekept in the batch packaging record.


7.25. The address and telephone number of themain contact for information on the product, clinical trial and for emergencyunblinding need not appear on the label where the subject has been given aleaflet or card which provides these details and who has been instructed tokeep this in their possession at all times.


7.26. Particulars should appear in the officiallanguage(s) of the country in which the investigational medicinal product is tobe used.


7.27. Where all the required information cannotbe displayed on primary packaging, secondary packaging should be providedbearing a label with those particulars. The primary packaging shouldnevertheless contain information such as the name of sponsor, contract researchorganization or investigator; route of administration; batch and/or codenumber; trial reference code and the trial subject identification number.


7.28.Symbols or pictograms may be included toclarify certain information. Warnings and/or handling instructions may bedisplayed.


7.29.If it becomes necessary to change theuse-by date, an additional label should be affixed to the investigationalmedicinal product. This additional label should state the new use-by date andrepeat the batch number. This labelling activity should be performed inaccordance with GMPprinciples, standard operatingprocedures and should be checked by a second person. This additional labellingshould be recorded in both the trial documentation and in the batch records.


Batch manufacturing records批生产记录

7.30. Processing, packaging and testing recordsshould be kept in sufficient detail for the sequence of operations to beaccurately traced. They should contain any relevant remarks which increase theexisting knowledge of the product, allow and reflect changes and improvementsin the manufacturing operations, and justify the procedures used.


Coding (or randomization) systems编号(或随机编号)系统

7.31. Procedures should be established for thegeneration, security, distribution, handling and retention of any randomizationcode used in packaging investigational products and code- break mechanisms. Theappropriate records should be maintained.


7.32.The coding system must permit thedetermination of the identity of the actual treatment product received byindividual subjects, without delay, in an emergency situation.



8.1.Premises, where investigationalproducts are manufactured, should be located, designed, constructed andmaintained to suit the operations to be carried out.


8.2.The layout and design of premisesshould aim to minimize the risk of errors and mix-ups and permit effectivecleaning and maintenance in order to avoid contamination, cross-contaminationand, in general, any adverse effect on the quality of the products.


8.3.Attention should be paid to lineclearance in order to avoid mix-ups.


8.4.Because the toxicity of some materialsmay not be fully known, cleaning is of particular importance. Validatedcleaning procedures should be followed in order to prevent cross-contamination. The visual inspection after cleaning, sampling and testprocedures should be appropriate and the acceptance limits used after cleaningshould be justifiable. Where cleaning agents are used, their selection shouldbe justifiable.


8.5.Where identified through riskassessment, campaign production should be considered. In other cases based onrisk, dedicated and self-contained facilities should be used.


9.Equipment and utilities设备和公用设施

9.1.Equipment and utilities should beselected, located, constructed and maintained to suit the operations to becarried out.


9.2.The layout, design, installation anduse of equipment and utilities should aim to minimize the risk of errors andpermit effective cleaning and maintenance in order to avoid cross-contamination, a build-up of dust or dirt and, in general, any adverse effecton the quality of products.



Starting materials起始物料

10.1.The consistency of the production ofinvestigational products may be influenced by the quality of the startingmaterials. Their physical, chemical and, when appropriate, microbiologicalproperties should therefore be defined, documented in their specifications, andcontrolled.


10.2.Existing compendial standards, whenavailable, should be taken into consideration.


10.3.Specifications for active ingredientsshould be as comprehensive as possible, given the current state of knowledge.


10.4.Specifications for both active ingredientsand excipients should be periodically reassessed and updated as required.


10.5.Detailed information on the quality ofactive ingredients and excipients (as well as of packaging materials) should beavailable so as to make it possible to recognize and, as necessary, allow forany variation in production.


Chemical and biological reference standards for analyticalpurposes分析用化学和生物对照品

10.6.Reference standards from reputablesources (WHO or national standards) should be used, if available; otherwise thereference substance(s) for the active ingredient(s) should be prepared, testedand released as reference material(s) by the producer of the investigationalpharmaceutical product, or by the producer of the active ingredient( s) used inthe manufacture of that product.


Principles applicable to reference products for clinicaltrials临床试验用药品参比制剂适用原则

10.7.In studies in which an investigationalproduct is compared with a marketed product, steps should be taken in order toensure the integrity and quality of the reference products (final dosage form,packaging materials, storage conditions, etc.).


10.8.If significant changes are to be made inthe product, data should be available (e.g. on stability, comparativedissolution) that demonstrate that these changes do not influence the originalquality characteristics of the product.



11.1.Products intended for use in clinicaltrials (late Phase II and Phase III studies) should, as far as possible, bemanufactured at a licensed facility. The batch size for investigationalproducts manufactured in a pilot plant or small-scale facility, as opposed tothe commercial batch size, may vary widely.


11.2.The guidelines in this document areapplicable to the following licensed facilities:


  • apilot plant, primarily designed and used for process development; and

  • 中试车间,原始设计并用于工艺开发,以及

  • asmall-scale facility (sometimes called a "pharmacy"), separate bothfrom the company's pilot plant and from routine production.

  • 小型设施(有时称为“药房”),与公司中试车间和常规生产分开

11.3.Facilities, as listed below, should besubject to all GMP requirements for pharmaceutical products;


  • alarge-scale production line assembled to manufacture materials in largerbatches (e.g. for late Phase III trials and first commercial batches); and

  • 大型生产线,装配用于生产较大批次产品(例如,三期临床晚期和首次商业化批次),以及

  • thenormal production line used for licensed commercial batches, and sometimes forthe production of investigational products if the number of, for example,ordered ampoules, tablets or other dosage forms, is large enough.

  • 用于已批准商业化批次的正常生产线,如果安瓿、片剂或其它剂型,订单数量足够大,有时用于临床试验药品的生产

11.4.Where activities are outsourced tocontract facilities, the contract must then clearly state, inter alia, theresponsibilities of each party, compliance with GMP or of this guideline, andthat the product(s) to be manufactured or controlled are intended for use inclinical trials. Close cooperation between the contracting parties isessential.


Manufacturing operations生产操作

11.5.As process validation may not always becomplete during the development phase ofproducts,provisional quality attributes, process parameters and in-process controlsshould beidentified, based on risk managementprinciples and experience with analogous products.


11.6.The necessary instructions should beidentified and may be adapted based on the experience gainedinproduction.


11.7.Where processes such as mixing have notbeen validated, additional quality control testing may benecessary.


11.8.For sterile investigational products, theassurance of sterility should be no less than for licensedproducts(see GMP for sterile products (6)).


Packaging and labelling包装和贴标

11.9.The packaging and labelling ofinvestigational products are likely to be more complex and more liable toerrors (which are also harder to detect) when "blinded" labels areused than for licensed products. Supervisory procedures such as labelreconciliation, line clearance, and so on, and the independent checks byquality unit personnel, should be intensified accordingly.


11.10. The packaging must ensure thatthe investigational product remains in good condition during transport andstorage. Any opening of, or tampering with, the outer packaging duringtransport should be readily discernible.


Blinding operations设盲操作

11.11. In the preparation of"blinded" products, the blind should be maintained until it isrequired to allow for the identification of the “blinded” product. In-processcontrol should include a check on the similarity in appearance and any otherrequired characteristics of the different products being compared.


11.12. A coding system should beintroduced to permit the proper identification of "blinded" products.The code, together with the randomization list, must permit the properidentification of the product, including any necessary traceability to thecodes and batch number of the product before the blinding operation.


12.Quality control质量控制

12.1. Quality control should cover, forexample, the sampling and testing of materials and products,ensuringthat these are not released for use, sale or supply until their quality hasbeen judged to be compliant with the specifications.


12.2.Each batch of product should be tested inaccordance with a Product Specification File and should meet its specification.Product release is often carried out in two stages; that is, before finalpackaging (bulk product testing) and after final packaging (finished producttesting).


12.3.Bulk product testing should cover allrelevant factors including production conditions, the results of in-processtesting, a review of manufacturing documentation and compliance with theProduct Specification File and the order. Finished product testing shouldcover, in addition to the bulk product assessment, all relevant factorsincluding packaging conditions, the results of in-process testing, a review ofpackaging documentation and compliance with the Product Specification File andthe order.


12.4.When necessary, quality control shouldalso be used to verify the similarity in appearance and other physicalcharacteristics such as the odour of "blinded" investigationalproducts.


12.5.End-product testing should be carried outin order to ensure that each batch meets its specification.


12.6.Reference and retention samples ofeach batch of product should be retained


12.7.Samples should be retained in the primarycontainer used for the study or in a suitable bulk container for at least twoyears after the termination or completion of the relevant clinical trial. Ifthe sample is not stored in the pack used for the study, stability data shouldbe available to justify the shelf life in the pack used.


12.8.Retention samples should be kept untilthe clinical report has been prepared in order to enable theconfirmationof product identity in the event of, and as part of an investigation into,inconsistent trial results.


12.9.The storage location of reference andretention samples should be defined in a technical agreement between thesponsor and manufacturer(s) and should allow for timely access by the competentauthorities.


12.10.The reference sample should be of sufficient size to permit the carryingout on, at least, two occasions of the full analytical controls on the batch inaccordance with the InvestigationalProduct dossier submitted forauthorization in order to conduct the clinical trial.


12.11. In the case ofretention samples, it is acceptable tostore information related to the final packaging as written or electronic recordsif such records provide sufficient information. In the case of referencesamples, the system should comply with the requirements of WHO guidelines forcomputerized systems (7).


12.12. The release of a batch of aninvestigational product should only occur after the designated responsibleperson has certified that the product meets the relevant requirements. Theserequirements include the assessment of, as appropriate:


  • batchrecords, including control reports, in-process test reports, changes,deviations and release reports demonstrating compliance with the productspecification file, the order, protocol and randomization code;

  • 批记录,包括检测报告、中控检测包括、变更、偏差和放行报告,证明符合药品标准文件、订单、方案和随机编码要求;

  • productionconditions;

  • 生产条件;

  • thevalidation status of facilities, processes and methods, as appropriate;

  • 设施、工艺和方法的验证状态(适当时);

  • theexamination of finished packs;

  • 成品的检查;

  • whererelevant, the results of any analyses or tests performed after importation;

  • (如有关)在进口之后进行的所有分析或检测的结果;

  • stabilityreports;

  • 稳定性报告;

  • thesource and verification of conditions of storage and shipment;

  • 来源和存贮与运输条件的核查;

  • auditreports concerning the quality system of the manufacturer, where applicable;

  • 对生产商质量体系的审计报告(如适用);

  • documentscertifying that the manufacturer is authorized to manufacture investigationalmedicinal products or comparators for export by the appropriate authorities inthe country of export; and

  • 认证生产商经过授权可生产临床试验用药品的文件,或经出口国适当机构认可出口的相应文件

  • whererelevant, regulatory requirements for marketing authorization, GMP standardsapplicable and any official verification of GMP compliance.

  • (如相关)上市许可的注册要求、适用的GMP标准和所有官方GMP符合性核查

Note: The relevance of the above elements is affected by thecountry of origin of the product, the manufacturer and the marketed status ofthe product


13.Qualification and validation确认与验证

13.1.The extent of qualification andvalidation may be different to that necessary for a routine productionoperation.


13.2.The scope of qualification and validationrequired should be determined based on risk assessment.


13.3.For sterile products, there should be noreduction in the degree of validation of sterilizing equipment required.Validation of aseptic processes presents special problems when the batch sizeis small since the number of units filled may be not adequate for a validationexercise. Filling and sealing, which is often done by hand, can compromise themaintenance of sterility. Greater attention should therefore be given toenvironmental monitoring



14.1.There should be a written proceduredescribing the managing of complaints.


14.2.Any complaint concerning a product defectshould be recorded with all the original details and thoroughly investigated.


14.3.Where necessary, appropriate follow-upaction, possibly including product recall, should be taken after investigationand evaluation of the complaint.


14.4.All decisions made and measures taken asa result of a complaint should be recorded and referenced to the correspondingbatch records.


14.5.The competent authorities should beinformed if a manufacturer is considering action following the identificationof serious quality problems with a product that may be impacting trial subjectsor patients.


14.6.The conclusions of the investigationscarried out in response to a complaint should be discussed between themanufacturer and the sponsor (if different) or between the persons responsiblefor manufacture and those responsible for the relevant clinical trial in orderto assess any potential impact on the trial and on the product development, inorder to determine the cause, and to take any necessary corrective action.



15.1.There should be a written proceduredescribing the managing of a recall of investigational products.


15.2.Recall procedures should be understood bythe sponsor, investigator and monitor, in addition to the person(s) responsiblefor recalls.


15.3.The recall of a product should bedocumented and inventory records should be kept.



16.1.Investigational products should bereturned under agreed conditions defined by the sponsor, specified in writtenprocedures and approved by authorized staff members.


16.2.Returned investigational products shouldbe clearly identified and stored in a dedicated area in a controlled manner.


16.3.Inventory records of returned productsshould be kept.



17.1.The shipping of investigational productsshould be carried out in accordance with written procedures laid down in theprotocol or shipping order given by the sponsor.


17.2.A shipment is sent to an investigatorafter following the defined release procedures, for example, quality controland authorization by the sponsor. Both releases should be recorded.


17.3.The sponsor should ensure that theshipment will be received and acknowledged by the correct addressee as statedin the protocol.


17.4.A detailed inventory of the shipmentsmade by the manufacturer should be maintained and should make particularmention of the addressee's identification.


17.5.The transfer of investigational productsfrom one trial site to another should be done in exceptional cases only. Suchtransfers should be justifiable, documented and carried out in accordance witha written procedure. Repackaging or relabelling should normally be done by themanufacturer. Records should be maintained and provide full traceability of theproduct and activities.



18.1. The sponsor is responsible for thedestruction of unused investigational products. Unused products should normallynot be destroyed by the manufacturer without prior authorization by thesponsor.


18.2.Destruction operations should be carriedout in accordance with written procedures and environmental safetyrequirements.


18.3.The delivered, used and recoveredquantities of a product should be recorded, reconciled and verified by or onbehalf of the sponsor for each trial site and each trial period. Thedestruction should be carried out only after any discrepancies have beeninvestigated, satisfactorily explained and the reconciliation has beenaccepted.


18.4.Destruction operations should be recordedin such a manner that all operations are accounted for. These records should bekept by the sponsor.


18.5. If the manufacturer is requested todestroy products, a Certificate of Destruction should be provided to thesponsor.



The definitions given below apply tothe terms used in this guideline. They may have different meanings in othercontexts.


clinical trial.Any systematic study on pharmaceutical products in humansubjects, whether in patients or other volunteers, in order to discover orverify the effects of, and/or identify any adverse reaction to, investigationalproducts, and/or to study the absorption, distribution, metabolism andexcretion of the products with the object of ascertaining their efficacy andsafety.


Clinical trials are generally dividedinto Phases I-IV. It is not possible to draw clear distinctions between thesephases, and different opinions about details and methodology do exist. However,the individual phases, based on their purposes as related to the clinicaldevelopment of pharmaceutical products, can be briefly defined as follows:


  • Phase I. These are the first trials ofa new active ingredient or new formulations in humans, often carried out inhealthy volunteers. Their purpose is to make a preliminary evaluation ofsafety, and an initial pharmacokinetic/pharmacodynamic profile of the activeingredient.

  • 一期临床:这是人用新活性成分或新制剂的首个临床试验阶段,通常在健康的志愿者中进行。其目的是对活性成分的安全性,以及药代/药效概况进行初步评估。

  • PhaseII. The purpose of these therapeutic pilot studies is to determine activity andto assess the short-term safety of the active ingredient in patients sufferingfrom a disease or condition for which it is intended. The trials are performedin a limited number of subjects and are often, at a later stage, of acomparative (e.g. placebo-controlled) design. This phase is also concerned withthe determination of appropriate dose ranges/regimens and (if possible) theclarification of dose-response relationships in order to provide an optimalbackground for the design of extensive therapeutic trials.

  • 二期临床:这些治疗试验研究的目的是确定活性,评估在准备使用该药品治疗的适用症患者中活性成分的短期安全性。试验对象数量有限,通常在后期会有比较设计(例如安慰组—控制组)。该阶段亦用于确定适当的剂量范围/给药方案和(如可能)明白剂量-效应关系,从而为大量治疗试验的设计提供优化背景。

  • PhaseIII:This phase involves trials inlarge (and possibly varied) patient groups for the purpose of determining theshort- and long-term safety-efficacy balance of formulation(s) of the activeingredient, and assessing its overall and relative therapeutic value. Thepattern and profile of any frequent adverse reactions must be investigated andspecial features of the product must be explored (e.g. clinically relevant druginteractions, factors leading to differences in effect, such as age). Thetrials should preferably be randomized double-blind but other designs may beacceptable for example,. long-term safety studies. In general, the conditionsunder which the trials are conducted should be as close as possible to thenormal conditions of use.

  • 三期临床:该阶段涉及较多患者群(规模可能会不同)的临床试验,其目的是确定活性成分配方的短中期的安全-有效性平衡关系,同时评估其总体相对治疗价值。所有频发不良反应的模式与概况均必须进行调查,还必须对药品的特殊性质进行探索(例如,临床相关药物相互作用,导致不同效果的因素如年龄)。试验最好是随机双盲,但其它设计也是可以的,例如,长期安全性研究。一般来说,试验实施条件应尽可能接近正常使用条件。

  • PhaseIV.In this phase, studies areperformed after the pharmaceutical product has been marketed. They are based onthe product characteristics on which the marketing authorization was grantedand normally take the form of post-marketing surveillance and assessment oftherapeutic value or treatment strategies. Although methods may differ, thesame scientific and ethical standards should apply to Phase IV studies as areapplied in premarketing studies. After a product has been placed on the market,clinical trials designed to explore new indications, new methods ofadministration or new combinations, and so on, are normally regarded as trialsof new pharmaceutical products.

  • 四期临床:本阶段是在药品已上市之后的实施的。此类研究是基于上市许可批准的药品特性,一般采用的上市后监管形式,评估治疗价值或治疗策略。虽然方法可能不同,但四期临床研究应使用上市前研究相民的科学和伦理标准。在药品上市销售之后,设计用于探索新适应症、新给药方法或新复方等的临床研究一般作为新药试验。

investigational product.Any pharmaceutical product (newproduct or reference product) or placebo being tested or used as a reference ina clinical trial.


investigator.The person responsible for the trialand for protecting the rights, health and welfare ofthe subjects in the trial.The investigator must be an appropriately qualified person, legally allowed topractice medicine/dentistry.


monitor.A person appointed by, and responsible to, the sponsor formonitoring and reporting the progress of the trial and for the verification ofdata.


order.An instruction to process, package and/or ship a certain numberof units of an investigational product.


pharmaceutical product.For the purpose of this document, thisterm is defined in the same way as in the WHO guidelines on GCP(3),i.e. as any substance orcombination of substances which has a therapeutic, prophylactic or diagnosticpurpose, or is intended to modify physiological functions, and is presented ina dosage form suitable for administration to humans.

药品:在本文中,该术语的定义与WHO GCP指南相同,即具备治疗、预防或诊断目的,或旨在改变生理功能,以一种适合人体抛入的剂型呈出的物质或多个物质的组合。

product specification file(s).Reference file(s) containing all theinformation necessary to draft the detailed written instructions on processing,packaging, labelling, quality control testing, batch release, storageconditions and shipping.


protocol.A document which gives the background, rationale and objectivesof the trial and describes· its design, methodology and organization, includingstatistical considerations and the conditions under which it is to be performedand managed. It should be dated and signed by the investigator/ institutioninvolved and the sponsor, and can, in addition, function as a contract.


reference sample. A sample of a batchof starting material, packaging material, product contained in itsprimarypackaging or finished product which is stored for the purpose of beinganalysed, should the need arise.


retention sample. A sample of apackaged unit from a batch of finished product for each packaging run/trialperiod. It is stored for identification purposes: for example, presentation,packaging, labelling, leaflet, batch number and expiry date, should the needarise.


shipping/dispatch.The assembly, packing for shipment and sending of orderedmedicinal products for clinical trials.


sponsor.An individual, company, institution or organization which takesresponsibility for the initiation, management and/or financing of a clinicaltrial. When an investigator independently initiates and takes full responsibilityfor a trial, the investigator also then assumes the role of the sponsor.




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