API开发生产和法规volume151质量控制和保证中英

1、.：.；7Quality Assurance and Control质量保证和质量控制MICHAEL C. VANDERZWANPharmaceutical Technical, Roche Pharmaceuticals, Basel, SwitzerlandI. Introduction引见 . . . . . . . . . . . . . . . . . . . . . . . . . . . 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 TOC o 1-3 h z u H

3、YPERLINK l _Toc426025944 I. INTRODUCTION引见 PAGEREF _Toc426025944 h 2 HYPERLINK l _Toc426025945 A. The Product产品 PAGEREF _Toc426025945 h 3 HYPERLINK l _Toc426025946 B. The Process工艺 PAGEREF _Toc426025946 h 4 HYPERLINK l _Toc426025947 C. The Facilities设备 PAGEREF _Toc426025947 h 5 HYPERLINK l _Toc42602

4、5948 D. The People人员 PAGEREF _Toc426025948 h 5 HYPERLINK l _Toc426025949 E. The Quality Management Department质量管理部门 PAGEREF _Toc426025949 h 6 HYPERLINK l _Toc426025950 F. The Regulatory Authorities 监管机构 PAGEREF _Toc426025950 h 7 HYPERLINK l _Toc426025951 G. The Regulations法规 PAGEREF _Toc426025951 h

5、7 HYPERLINK l _Toc426025952 II. DEFINING AND ASSURING THE QUALITY OF THE ACTIVE PHARMACEUTICAL INGREDIENT 原料药质量的定义和质量保证 PAGEREF _Toc426025952 h 9 HYPERLINK l _Toc426025953 A. Defining the API Quality 原料药质量的界定 PAGEREF _Toc426025953 h 10 HYPERLINK l _Toc426025954 B. Testing the API for Its Defined Att

6、ributes 原料药定义的属性测试 PAGEREF _Toc426025954 h 11 HYPERLINK l _Toc426025955 C. Designing Quality into the Process 工艺中的质量设计 PAGEREF _Toc426025955 h 12 HYPERLINK l _Toc426025956 D. Validation of the Process 工艺验证 PAGEREF _Toc426025956 h 14 HYPERLINK l _Toc426025957 E. Reality实践 PAGEREF _Toc426025957 h 16 H

7、YPERLINK l _Toc426025958 III. THE REGULATIONS FOR QUALITY质量法规 PAGEREF _Toc426025958 h 17 HYPERLINK l _Toc426025959 Introduction: The Emergence of Specific Regulations for APIs导言： API详细法规的出现 PAGEREF _Toc426025959 h 17 HYPERLINK l _Toc426025960 1. ICH Q7A Section I: Introduction第一部分：简介 PAGEREF _Toc426

8、025960 h 21 HYPERLINK l _Toc426025961 2. ICH Q7A Section 2: Quality Management第二部分 质量管理 PAGEREF _Toc426025961 h 22 HYPERLINK l _Toc426025962 3. ICH Q7A Section 3: Personnel第三部分 人员 PAGEREF _Toc426025962 h 24 HYPERLINK l _Toc426025963 4. ICH Q7A Section 4: Buildings and Facilities第四部分 厂房和设备 PAGEREF _T

9、oc426025963 h 26 HYPERLINK l _Toc426025964 5. ICH Q7A Section 5: Process Equipment第五部分 工艺设备 PAGEREF _Toc426025964 h 29 HYPERLINK l _Toc426025965 6. ICH Q7A Section 6: Documents and Records第六部分 文件和记录 PAGEREF _Toc426025965 h 31 HYPERLINK l _Toc426025966 7. ICH Q7A Section 7: Materials Management第7部分 物

10、料管理 PAGEREF _Toc426025966 h 36 HYPERLINK l _Toc426025967 8. ICH Q7A Section 8: Production and In-Process Controls第8部分 产品和过程控制 PAGEREF _Toc426025967 h 40 HYPERLINK l _Toc426025968 9. 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 PAGEREF _Toc42

11、6025968 h 44 HYPERLINK l _Toc426025969 10. ICH Q7A Section 10: Storage and Distribution储存和发运 PAGEREF _Toc426025969 h 45 HYPERLINK l _Toc426025970 11. ICH Q7A Section 11: Laboratory Controls 第11部分 实验室控制 PAGEREF _Toc426025970 h 46 HYPERLINK l _Toc426025971 12. ICH Q7A Section 12: Validation PAGEREF _T

12、oc426025971 h 46 HYPERLINK l _Toc426025972 13. ICH Q7A Section 13: Change Control第13部分 变卦控制 PAGEREF _Toc426025972 h 53 HYPERLINK l _Toc426025973 14. ICH Q7A Section 14: Rejection and Re-Use of Materials第14部分 物料的拒收和再用 PAGEREF _Toc426025973 h 55 HYPERLINK l _Toc426025974 15. ICH Q7A Section 15: Compla

13、ints and Recalls第15部分 赞扬与召回 PAGEREF _Toc426025974 h 59 HYPERLINK l _Toc426025975 16. ICH Q7A Section 16: Contract Manufacturers (Including Laboratories)第16部分 协议制造商包括实验室 PAGEREF _Toc426025975 h 60 HYPERLINK l _Toc426025976 IV. THE QUALITY CONTROL AND QUALITY ASSURANCE DEPARTMENT 质量控制和质量保证部 PAGEREF _T

14、oc426025976 h 61I. INTRODUCTION引见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 current good manufacturing practices (cGMPs) regulations. Most countri

15、es 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 operated to allow the manufacturer to assure the API consistently meets

16、 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) department.活性药物成分APIs的质量应被定义为符合相应的API规范，并且正在建立中的设备应符合ICH指南Q7A和FDA现行

17、的动态药品消费管理规范cGMP的规定。大多数国家对原料药的消费制造都有规定。这些法规要求有一个总的系统方法来保证API的质量在适当程度。这个系统中的一切组件必需经过正确的设计，验证，维护和操作，以保证制造商的API一直符合质量要求。该系统中普遍的组件包含工艺过程、设备和人员。本章内容包括这些组件，以及产质量量本身，法规条例和质量管理部QM。A. The Product产品The quality of an API is determined by two factors: its conformance to pre-established specifications and whether

18、 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 chemical attributes describe the appropriate purity and impurity limits. Imp

19、urity 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 characteristics for reliable pharmaceutical processing into final dosage forms. These

20、attributes are determined by empirical evidence from formulation trials to produce uniform and stable dosage forms of adequate bioavailability.API的质量是由两个要素决议：能否与预先建立的规范相一致，能否在符合cGMP要求的设备内并且根据成文的阅历证的工艺过程消费出来的。API必需具有适当的化学和物理属性，以确保它提供预期的药理学作用。化学属性描画了适当的纯度和杂质限制。杂质规范根据临床毒理学研讨建立，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

21、。物理属性描画了可靠药物加工成最终剂型的必要特征。这些属性由配方实验的阅历证据确定，以消费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 process through to end product.API的质量经过全面的制造工艺的开展被设计成分子，从实验室规模的合成过程通向最终产

22、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 impurities are not formed, eliminated, or certainly minimized. The specific co

23、ntrols 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 today, regulatory authorities require the API to be produced from a document

24、ed 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 APIs. The European Union, the Japanese Ministry of Health and the Unite

25、d States Food & Drug Administration adopted the guide.合成方法必需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，经过有效的工艺开发、产量最大化、废弃物最小化、不构成、消除或最小化杂质。所采用的开展化学家的详细控制来产生高收益、高质量的产品必需被记录;本文档构成了概念证明和验证报告的根底。在今天几乎一切的国家、监管部门要求API应在符合一切相应规范、有记录的工艺过程来消费。这方面由于国际会议的三方协调指南Q7A“良好消费实际指南的API的发行和经过得到了加强。 欧盟，日本监管部门和美国食品药品监视管理局经过了这个指南。C

26、. The Facilities设备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 governed by cGMP are therefore part of this chapter. The essence of cGMP for f

27、acilities or, for that matter, any aspect of API manufacture is that the facility performs as designed to assure the quality of the product.消费API的设备在本章节也进展讨论，由于API的质量的组成部分是经过cGMP的规范设备来消费的。因此，由cGMP管辖的设备的组成部分是本章节的一部分。对于这个问题，cGMP的设备或API制造的任何方面的的本质是设备执行的设计，以保证产品的质量。Further, the performance characteristi

28、c 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 components are all considered part of assuring quality of APIs.此外，性能特点必需

29、记录，管理必需证明该设备继续按设计执行。性能控制监控、预防性维护、精细控制和同意的设备部件的维修或变卦都被以为是保证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. To do their jobs effectively and to assure quality of the API, they must b

30、e 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. Finally, there must be an adequate number of people to allow sufficient ti

31、me to perform these responsibilities in a satisfactory manner.消费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任务，以确保API的质量，就必需进展适当的培训和配备。合格人员必需进展培训;设备必需有适当的设计和功能。人造API的监管人员也必需进展适当的培训来做好本职任务。最后，必需有适当的人数，以便有充足的时间、以令人称心的方式执行这些职责。E. The Quality Management Department质量管理部门As in most any other manufactur

32、ing enterprise, there is a quality control and or a quality assurance department. Today, these departments are usually combined into a QM department.由于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 department has also advanced from check-test-decide responsibility to being a

33、n 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、决议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 quality assurance arm, still has the responsibility vested in it by regula

34、tions 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 require that the QM department is responsible to review and approve productio

35、n 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，经过其质量保证的手臂，还有赋予的责任，经过法规来释放一切产品中运用，并最终推向市场。作为该系统的一个组成部分来消费原料药，活动和QM部门的职责是也产质量量的一个组成部分。大多数的cGMP要求质量管理部门担任审查和同意消费的程序，并且对它们的更改，大多数报告，程序和控制，以为

36、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，质量管理部门必需有足够的实验室设备和适当的培训，阅历丰富的人来有效地履行其职责。F. The Regulatory Authorities 监管机构Health authorities in every country regulate drug

37、 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 drug, or API, is not produced and controlled according to the established

38、 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 proof of control over any aspect that might affect product quality. The reg

39、ulators 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 the art, thereby always assuring the public that drug products are as safe

40、and effective as possible.每一个国家由卫生主管部门控制药品。在大多数国家，这些法规还包括原料药。这些的cGMP法规要求药品必需符合一切预定的质量规范，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，那么该药物被以为是掺假，因此不适宜运用或出卖。该法规涉及药品消费每一个环节，而且根本上要求消费者记录控制证明能够影响产质量量的任何方面。监管机构公布的法规即cGMP，不断要求制造商维持其设备和工艺的形状，从而保证一直如一的消费平安有效的药品。G. The Regulations法规The production of APIs is regulat

41、ed 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 adopted by the following agencies denoting its widespread acceptance:原料药的

42、消费在大多数国家是受监管的。良好消费实际指南API ICH-三方协调指点Q7A2000年11月10日被建议运用。以下机构表示普遍接受：_ 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, 2001 MSB notification NO. 1200日本MHLW采用2001年11月2日的MSB通知，第1200期_ United States

43、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 regulating government in which APIs will be used, and the facilities and syste

44、ms 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 regulated, approved process in a facility compliant with the appropriate

45、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 important to note that the approach toward quality described in this chapter

46、 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.消费过程中，一切的测试和控制必需由政府监管包括API，设备和系统，消费必需满足的制造规范。因此，原料药的质量是基于两部分组成：符合最终质量规范，按规定的已同意的工艺在适宜的设备中消费。留意，两个规范都必需满足。这两部分将在本章中另行论述。同样重要的是要留意，在本章中描画的API质量适用于原料药将在其中运用或出卖，不论这个国家能否受法规控

47、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 assurance of quality.This chapter will deal with the chemical synthesis o

48、f 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，基于合理的科学原那么，良好的质量管理原那么，适用于任何API。现实上，这些原那么适用于任何需求高质量的化学品的消费。本章将涉及原料药的化学合成。然而，一切的原那么规定也适用于其它的制备工艺，如发酵道路或者从天然提取。Finally, since it is ass

49、umed 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 principles on which the regulation is based should be seriously consid

50、ered.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, and_ validate the process to assure consistent production.As APIs are

51、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.本节处理了如何：_定义必要的质量属性_检验_将设计融入工艺_验证工艺，以确保消费的一致性。由于API是受控制物品，其质量不仅取决于令人称心的测试结果，也以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

52、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 process involved. These attributes are established to assure an API wi

53、ll 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 purity minimum is usually set at 98% to assure proper dosing in the dr

54、ug 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 opti

55、cally 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必需具有其最终的化学纯度和杂质，并规定其最终的物理属性;一些还需求微生物分析，这取决于最终的剂型和所涉及的制造工艺上。这些属性被建立以保证一个API将在药物制造过程中令人称心地执行，并导致最终剂型即药品将满足其最初版本的规格和最终稳定性的要求。化学纯度最低通常设定在98，以保证药品的适当剂量，并

56、且确保最小量的杂质。物理参数应建立与制药过程和最终剂型的知识根底上。其他属性通常包括固体方式的颜色和或溶液，熔点，比旋度假设有光学活性，晶体形状，等等。附录A提供了典型API的规范列表。When setting API physical attribute specifications, the most important aspect to consider is its use in the pharmaceutical process; namely, whether it will be wetted for granulation, dissolved for solution,

57、dry blended, and so on, and the type of drug product to be made: tablets, capsules, solutions, sterile or non sterile, or other. It is also important to know how the drug product will be used by the patient; for example, if it will be used as a powder blended with other excipients, careful considera

58、tion should be given to rate of dissolution and the eventual color of solution (for aesthetic reasons) when dissolved by the patient (or healthcare giver) prior to use. For this reason, final API specifications are always defined with the cooperation of the pharmaceutical development area. The quali

59、ty assurance function approves final API quality standards, taking into consideration all requirements: process related, governmental, and customer.当建立API的物理属性时，要思索的最重要的方面是其在制药过程中的运用;如被润湿造粒，溶解于溶液中，枯燥混合等，且可以制成的药品类型有：片剂，胶囊剂，溶液剂，无菌或非无菌的，或其他。同样重要的是要明白药品将用于患者;例如，赋形剂的粉末应思索到由患者或保健给予者溶解的速率和溶液在运用前的最终的颜色用于美观的

60、缘由。出于这个缘由，最终的API规范一直阐明需与药物开发领域的协作。质量保证职能应在最终同意的API质量规范中同时思索到一切要求：工艺相关的要求，政府和客户的要求。B. Testing the API for Its Defined Attributes 原料药质量属性的测试Each quality attribute required of the API must have a sound and proven test procedure. In regulatory compliance terms, this means the test must be validated; tha