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1、7Quality Assurance and Control质量保证和质量控制MICHAEL C. VANDERZWANPharmaceutical Technical, Roche Pharmaceuticals, Basel, SwitzerlandI. Introduction介绍 . . . . . . . . . . . . . . . . . . . . . . . . . . . 235II. Defining and Assuring the Quality of the Active Pharmaceutical Ingredient原料药质量的定义和保证 . . . . .

2、 . . . . . . . . . . . . . 240III. The Regulations for Quality 质量监管. . . . . . . . . . . . . . . . . 245IV. The Quality Control and Quality Assurance Department质量控制和质量保证 . . . . . . . . . . . . . . . . .273Appendix A附录 . . . . . . . . . . . . . . . . . . . . . . . . . . . 280目录I. INTRODUCTION介绍2A. T

3、he Product产品3B. The Process工艺4C. The Facilities设备5D. The People人员5E. The Quality Management Department质量管理部门6F. The Regulatory Authorities 监管机构7G. The Regulations法规7II. DEFINING AND ASSURING THE QUALITY OF THE ACTIVE PHARMACEUTICAL INGREDIENT 原料药质量的定义和质量保证9A. Defining the API Quality 原料药质量的界定10B. Te

4、sting the API for Its Defined Attributes 原料药定义的属性测试11C. Designing Quality into the Process 工艺中的质量设计12D. Validation of the Process 工艺验证14E. Reality实际16III. THE REGULATIONS FOR QUALITY质量法规17Introduction: The Emergence of Specific Regulations for APIs导言： API具体法规的出现171. ICH Q7A Section I: Introduction第一

5、部分：简介212. ICH Q7A Section 2: Quality Management第二部分 质量管理223. ICH Q7A Section 3: Personnel第三部分 人员244. ICH Q7A Section 4: Buildings and Facilities第四部分 厂房和设施265. ICH Q7A Section 5: Process Equipment第五部分 工艺设备296. ICH Q7A Section 6: Documents and Records第六部分 文件和记录317. ICH Q7A Section 7: Materials Managem

6、ent第7部分 物料管理368. ICH Q7A Section 8: Production and In-Process Controls第8部分 产品和过程控制409. ICH Q7A Section 9: Packaging and Identification Labeling of APIs and Intermediates 第9部分 原料药和中间体的包装和标识标签4410. ICH Q7A Section 10: Storage and Distribution储存和发运4511. ICH Q7A Section 11: Laboratory Controls 第11部分 实验室

7、控制4612. ICH Q7A Section 12: Validation4613. ICH Q7A Section 13: Change Control第13部分 变更控制5314. ICH Q7A Section 14: Rejection and Re-Use of Materials第14部分 物料的拒收和再用5515. ICH Q7A Section 15: Complaints and Recalls第15部分 投诉与召回5916. ICH Q7A Section 16: Contract Manufacturers (Including Laboratories)第16部分 协

8、议制造商（包括实验室）60IV. THE QUALITY CONTROL AND QUALITY ASSURANCE DEPARTMENT 质量控制和质量保证部61I. INTRODUCTION介绍The quality of active pharmaceutical ingredients (APIs) is defined as meeting the appropriate specifications for the API and being produced in a facility compliant with ICH guidelines Q7A and FDAs curr

9、ent good manufacturing practices (cGMPs) regulations. Most countries regulate the manufacture of APIs. These regulations require a total systems approach to assuring an API has the appropriate level of quality. All components in this system must be properly designed, validated, maintained, and opera

10、ted to allow the manufacturer to assure the API consistently meets quality requirements. The general components of the system are the process, facilities, and the people. This chapter concerns these components, as well as the product quality itself, the regulations, and the quality management (QM) d

11、epartment.活性药物成分（APIs）的质量应被定义为符合相应的API规范，并且正在建设中的设施应符合ICH指南Q7A和FDA现行的动态药品生产管理规范（cGMP）的规定。大多数国家对原料药的生产制造都有规定。这些法规要求有一个总的系统方法来保证API的质量在适当水平。这个系统中的所有组件必须经过正确的设计，验证，维护和操作，以保证制造商的API始终符合质量要求。该系统中普遍的组件包含工艺过程、设施和人员。本章内容包括这些组件，以及产品质量本身，法规条例和质量管理部（QM）。A. The Product产品The quality of an API is determined by tw

12、o factors: its conformance to pre-established specifications and whether it is produced according to a documented validated process in a cGMP compliant facility. The API must possess appropriate chemical and physical attributes to assure that it delivers the intended pharmacological effect. The chem

13、ical attributes describe the appropriate purity and impurity limits. Impurity specifications are established from clinical toxicological studies and are also based on reasonable minimums expected from regulatory authorities and consumers. The physical attributes describe the necessary characteristic

14、s for reliable pharmaceutical processing into final dosage forms. These attributes are determined by empirical evidence from formulation trials to produce uniform and stable dosage forms of adequate bioavailability.API的质量是由两个因素决定：是否与预先建立的标准相一致，是否在符合cGMP要求的设施内并且根据成文的经验证的工艺过程生产出来的。API必须具有适当的化学和物理属性，以确

15、保它提供预期的药理学作用。化学属性描述了适当的纯度和杂质限度。杂质规范根据临床毒理学研究建立，同时基于从监管部门和消费者那里得到预期的合理最低值。物理属性描述了可靠药物加工成最终剂型的必要特征。这些属性由配方试验的经验证据确定，以生产具有足够生物利用度、均匀且稳定的剂型。B. The Process工艺The quality of the API is designed into the molecule through the development of the full manufacturing process, from the laboratory scale synthetic

16、process through to end product.API的质量通过全面的制造工艺的发展被设计成分子，从实验室规模的合成过程通向最终产品。The synthetic process must be designed to minimize impurities, especially those that prove difficult to remove in the last step. Thus, through effective process development, yields are maximized, waste is minimized, and impuri

17、ties are not formed, eliminated, or certainly minimized. The specific controls used by the developmental chemist to produce the high-yield, high-quality product must be documented; this documentation forms the basis for the proof of concept and for the validation report. In nearly all countries toda

18、y, regulatory authorities require the API to be produced from a documented process that reliably meets all appropriate specifications. This was strengthened by the issuance and adoption of the International Conference on Harmonization Tripartite Guideline of Q7A Good Manufacturing Practice Guide for

19、 APIs. The European Union, the Japanese Ministry of Health and the United States Food & Drug Administration adopted the guide.合成方法必须被设计成最小化的杂质，尤其是那些证明在最后一个步骤难以除去的。因此，通过有效的工艺开发、产量最大化、废弃物最小化、不形成、消除或最小化杂质。所采用的发展化学家的具体控制来产生高收益、高品质的产品必须被记录;本文档构成了概念证明和验证报告的基础。在今天几乎所有的国家、监管部门要求API应在符合所有相应规范、有记录的工艺过程来生产。这方面

20、因为国际会议的三方协调指南Q7A“良好生产实践指南的API”的发行和通过得到了加强。 欧盟，日本监管部门和美国食品药品监督管理局通过了这个指南。C. The Facilities设施The facilities in which APIs are produced are also addressed in this chapter because a component of quality of an API is that it be produced in cGMP-compliant facilities. Those components of the facility gover

21、ned by cGMP are therefore part of this chapter. The essence of cGMP for facilities or, for that matter, any aspect of API manufacture is that the facility performs as designed to assure the quality of the product.生产API的设施在本章节也进行讨论，因为API的质量的组成部分是通过cGMP的标准设施来生产的。因此，由cGMP管辖的设施的组成部分是本章节的一部分。对于这个问题，cGMP的

22、设施或API制造的任何方面的的本质是设施执行的设计，以保证产品的质量。Further, the performance characteristic must be documented, and management must demonstrate the facility continually performs as designed. Performance control monitoring, preventative maintenance, and carefully controlled and approved repairs or changes to facility

23、 components are all considered part of assuring quality of APIs.此外，性能特点必须记录，管理必须证明该设施持续按设计执行。性能控制监控、预防性维护、精密控制和批准的设备部件的维修或变更都被认为是保证API质量的一部分。D. The People人员The people who produce the API are considered a critical part of the system and, as such, become part of the requirements for quality of APIs. T

24、o do their jobs effectively and to assure quality of the API, they must be properly trained and equipped. Qualified personnel must conduct the training; the equipment must be of proper design and function. The supervisors of people manufacturing APIs must also be properly trained to do their jobs. F

25、inally, there must be an adequate number of people to allow sufficient time to perform these responsibilities in a satisfactory manner.生产API的人员是该系统的一个重要组成部分，因此，成为API的质量要求的一部分。为了有效地做好本职工作，以确保API的质量，就必须进行适当的培训和装备。合格人员必须进行培训;设备必须有适当的设计和功能。人造API的监管人员也必须进行适当的培训来做好本职工作。最后，必须有适当的人数，以便有充足的时间、以令人满意的方式执行这些职责。

26、E. The Quality Management Department质量管理部门As in most any other manufacturing enterprise, there is a quality control and or a quality assurance department. Today, these departments are usually combined into a QM department.因为在大多数的任何其他制造企业，有一个质量控制部和/或质量保证部。如今，这些部门通常被合并成一个质量管理部门。The role of the QM depa

27、rtment has also advanced from check-test-decide responsibility to being an equal partner with manufacturing and engineering to manage and improve the quality of the entire process and system.质量管理部门的角色也从检查、测试、决定的职责变为与制造和工程平等的参与者来提高全过程和系统的质量。For APIs and drug products, the QM department, through its q

28、uality assurance arm, still has the responsibility vested in it by regulations to release all products for use and eventually to the market. As a component of the system to produce APIs, the activities and responsibilities of the QM department are also a component of product quality. Most cGMPs requ

29、ire that the QM department is responsible to review and approve production procedures, and any changes to them, most reports, procedures, and controls, deemed necessary to assure the quality of the process and product.对于原料药和药物产品，质量管理部门，通过其质量保证的手臂，还有赋予的责任，通过法规来释放所有产品中使用，并最终推向市场。作为该系统的一个组成部分来生产原料药，活动和

30、QM部门的职责是也产品质量的一个组成部分。大多数的cGMP要求质量管理部门负责审查和批准生产的程序，并且对它们的更改，大多数报告，程序和控制，认为有必要确保过程和产品的质量。Finally, the QM department must have adequate laboratory facilities and properly trained and experienced people to effectively carry out their responsibilities.最后，质量管理部门必须有足够的实验室设施和适当的培训，经验丰富的人来有效地履行其职责。F. The Reg

31、ulatory Authorities 监管机构Health authorities in every country regulate drug products. In most countries, these regulations also include APIs. These cGMP regulations require that a drug must meet all predefined quality specifications and be produced from a documented validated process. Further, if the

32、drug, or API, is not produced and controlled according to the established process, then the drug is considered adulterated, and therefore not fit for use or sale. The regulations address every aspect of drug product manufacture, and essentially require that the producer has documented evidence of pr

33、oof of control over any aspect that might affect product quality. The regulators were deliberate in their use of the word current when the cGMPs were promulgated. This qualifier enables the agencies to continuously require that manufacturers maintain their facilities and processes at the state of th

34、e art, thereby always assuring the public that drug products are as safe and effective as possible.每一个国家由卫生主管部门管制药品。在大多数国家，这些法规还包括原料药。这些的cGMP法规要求药品必须符合所有预定的质量标准，并从记录验证过程中产生的。此外，没有按已建立的方法制备并控制的药物或API，则该药物被认为是掺假，因此不适合使用或出售。该法规涉及药品生产每一个环节，而且基本上要求生产者记录控制证明可能影响产品质量的任何方面。监管机构颁布的法规即cGMP，不断要求制造商维持其设备和工艺的状态，

35、从而保证始终如一的生产安全有效的药品。G. The Regulations法规The production of APIs is regulated in most countries. The ICH-harmonized tripartite guideline Q7A entitled as Good Manufacturing Practice Guide for APIs was recommended for adoption at Step 4 of the ICH process on the 10th of November 2000. This document was a

36、dopted by the following agencies denoting its widespread acceptance:原料药的生产在大多数国家是受监管的。良好生产实践指南API ICH-三方协调指导Q7A（2000年11月10日）被建议使用。下列机构表示普遍接受：_ European Union (EU) adopted by CPMP, November 2000, issued as CPMP/ICH/1935/00 欧盟采用CPMP，2000年11月，以CPMP/ICH/1935/00发行_ Japanese MHLW adopted November 2nd, 200

37、1 MSB notification NO. 1200日本MHLW采用2001年11月2日的MSB通知，第1200期_ United States FDA published in the Federal Register, Vol. 66, No 186, September 25th, 2001, pages 4902849029.美国FDA发表在联邦注册，第66卷第186期，2001年9月25日，2001年，第49028-49029页The production process and all tests and controls must be approved by the regu

38、lating government in which APIs will be used, and the facilities and systems in which they are produced must meet the manufacturing standards set down by the governing body. Thus, the quality of APIs is based on two components: meeting final quality specifications and being produced according to the

39、 regulated, approved process in a facility compliant with the appropriate manufacturing standards. It is important to note that both criteria must be met: final specifications and compliance to manufacturing standards. These two components will be dealt with separately in this chapter. It is also im

40、portant to note that the approach toward quality described in this chapter should apply to any API regardless of the country in which it will be used or sold, or whether or not it will be a regulated item.生产过程中，所有的测试和控制必须由政府监管包括API，设施和系统，生产必须满足的制造标准。因此，原料药的质量是基于两部分组成：符合最终质量规范，按规定的已批准的工艺在适合的设施中生产。注意，

41、两个标准都必须满足。这两部分将在本章中另行阐述。同样重要的是要注意，在本章中描述的API质量适用于原料药将在其中使用或出售，不管这个国家是否受法规管制。The approach to quality, described in this chapter, is based on sound scientific principles, good QM principles, and applies to any API. In fact, these principles apply to the manufacture of any chemical that requires a high

42、 assurance of quality.This chapter will deal with the chemical synthesis of APIs. However, all the principles and regulations also apply to other means of preparation, such as fermentation routes or extraction from natural sources.质量方针，以本章所述，基于合理的科学原则，良好的质量管理原则，适用于任何API。事实上，这些原则适用于任何需要高质量的化学品的生产。本章将

43、涉及原料药的化学合成。然而，所有的原则规定也适用于其它的制备工艺，如发酵路线或者从天然提取。Finally, since it is assumed throughout this chapter that the API will be subject to regulatory requirements, reference will be made to the regulations. If the reader is dealing with an unregulated item, such reference may be ignored, but the scientific

44、principles on which the regulation is based should be seriously considered.II. DEFINING AND ASSURING THE QUALITY OF THE ACTIVE PHARMACEUTICAL INGREDIENT 原料药质量的定义和质量保证This section of the chapter addresses how to:_ define the necessary quality attributes_ test for them,_ design them into the process,

45、and_ validate the process to assure consistent production.As APIs are regulated articles, their quality is determined not only by satisfactory test results, but also the assurance that the process was conducted according to a validated process.本节解决了如何：_定义必要的质量属性_检验_将设计融入工艺_验证工艺，以确保生产的一致性。由于API是受管制物品

46、，其质量不仅取决于令人满意的测试结果，也认为工艺是由验证过程来保证的。A. Defining the API Quality 原料药质量的定义The API must have its final chemical purity and impurity and its final physical attributes specified; some articles also require microbiological analyses to be determined, depending on the final dosage form and the manufacturing

47、process involved. These attributes are established to assure an API will perform satisfactorily in the pharmaceutical manufacturing process and will result in a final dosage form; i.e., the drug product that will meet its initial release specifications and final stability requirements. The chemical

48、purity minimum is usually set at 98% to assure proper dosing in the drug product and to assure a minimal amount of impurities. The physical parameters should be established with knowledge of the pharmaceutical process and the ultimate final dosage form. Other attributes usually include color of the solid form and or a solution, melting point, specific rotation if optically active, crystal morphology, and so forth. A list of typical API specifications is provided in Appendix A along with the rationale for each one.API必须具有其最终