API開發(fā)生產(chǎn)和法規(guī)volume151質(zhì)量控制和保證中英

1、.：.；7Quality Assurance and Control質(zhì)量保證和質(zhì)量控制MICHAEL C. VANDERZWANPharmaceutical Technical, Roche Pharmaceuticals, Basel, SwitzerlandI. Introduction引見 . . . . . . . . . . . . . . . . . . . . . . . . . . . 235II. Defining and Assuring the Quality of the Active Pharmaceutical Ingredient原料藥質(zhì)量的定義和保證 . . .

2、 . . . . . . . . . . . . . . . 240III. The Regulations for Quality 質(zhì)量監(jiān)管. . . . . . . . . . . . . . . . . 245IV. The Quality Control and Quality Assurance Department質(zhì)量控制和質(zhì)量保證 . . . . . . . . . . . . . . . . .273Appendix A附錄 . . . . . . . . . . . . . . . . . . . . . . . . . . . 280目錄 TOC o 1-3 h z u H

3、YPERLINK l _Toc426025944 I. INTRODUCTION引見 PAGEREF _Toc426025944 h 2 HYPERLINK l _Toc426025945 A. The Product產(chǎn)品 PAGEREF _Toc426025945 h 3 HYPERLINK l _Toc426025946 B. The Process工藝 PAGEREF _Toc426025946 h 4 HYPERLINK l _Toc426025947 C. The Facilities設(shè)備 PAGEREF _Toc426025947 h 5 HYPERLINK l _Toc42602

4、5948 D. The People人員 PAGEREF _Toc426025948 h 5 HYPERLINK l _Toc426025949 E. The Quality Management Department質(zhì)量管理部門 PAGEREF _Toc426025949 h 6 HYPERLINK l _Toc426025950 F. The Regulatory Authorities 監(jiān)管機構(gòu) PAGEREF _Toc426025950 h 7 HYPERLINK l _Toc426025951 G. The Regulations法規(guī) PAGEREF _Toc426025951 h

5、7 HYPERLINK l _Toc426025952 II. DEFINING AND ASSURING THE QUALITY OF THE ACTIVE PHARMACEUTICAL INGREDIENT 原料藥質(zhì)量的定義和質(zhì)量保證 PAGEREF _Toc426025952 h 9 HYPERLINK l _Toc426025953 A. Defining the API Quality 原料藥質(zhì)量的界定 PAGEREF _Toc426025953 h 10 HYPERLINK l _Toc426025954 B. Testing the API for Its Defined Att

6、ributes 原料藥定義的屬性測試 PAGEREF _Toc426025954 h 11 HYPERLINK l _Toc426025955 C. Designing Quality into the Process 工藝中的質(zhì)量設(shè)計 PAGEREF _Toc426025955 h 12 HYPERLINK l _Toc426025956 D. Validation of the Process 工藝驗證 PAGEREF _Toc426025956 h 14 HYPERLINK l _Toc426025957 E. Reality實踐 PAGEREF _Toc426025957 h 16 H

7、YPERLINK l _Toc426025958 III. THE REGULATIONS FOR QUALITY質(zhì)量法規(guī) PAGEREF _Toc426025958 h 17 HYPERLINK l _Toc426025959 Introduction: The Emergence of Specific Regulations for APIs導言： API詳細法規(guī)的出現(xiàn) PAGEREF _Toc426025959 h 17 HYPERLINK l _Toc426025960 1. ICH Q7A Section I: Introduction第一部分：簡介 PAGEREF _Toc426

8、025960 h 21 HYPERLINK l _Toc426025961 2. ICH Q7A Section 2: Quality Management第二部分 質(zhì)量管理 PAGEREF _Toc426025961 h 22 HYPERLINK l _Toc426025962 3. ICH Q7A Section 3: Personnel第三部分 人員 PAGEREF _Toc426025962 h 24 HYPERLINK l _Toc426025963 4. ICH Q7A Section 4: Buildings and Facilities第四部分 廠房和設(shè)備 PAGEREF _T

9、oc426025963 h 26 HYPERLINK l _Toc426025964 5. ICH Q7A Section 5: Process Equipment第五部分 工藝設(shè)備 PAGEREF _Toc426025964 h 29 HYPERLINK l _Toc426025965 6. ICH Q7A Section 6: Documents and Records第六部分 文件和記錄 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 產(chǎn)品和過程控制 PAGEREF _Toc426025967 h 40 HYPERLINK l _Toc426025968 9. ICH Q7A Section 9: Packaging and Identification Labeling of APIs and Intermediates 第9部分 原料藥和中間體的包裝和標識標簽 PAGEREF _Toc42

11、6025968 h 44 HYPERLINK l _Toc426025969 10. ICH Q7A Section 10: Storage and Distribution儲存和發(fā)運 PAGEREF _Toc426025969 h 45 HYPERLINK l _Toc426025970 11. ICH Q7A Section 11: Laboratory Controls 第11部分 實驗室控制 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 變卦控制 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 贊揚與召回 PAGEREF _Toc426025974 h 59 HYPERLINK l _Toc426025975 16. ICH Q7A Section 16: Contract Manufacturers (Including Laboratories)第16部分 協(xié)議制造商包括實驗室 PAGEREF _Toc426025975 h 60 HYPERLINK l _Toc426025976 IV. THE QUALITY CONTROL AND QUALITY ASSURANCE DEPARTMENT 質(zhì)量控制和質(zhì)量保證部 PAGEREF _T

14、oc426025976 h 61I. INTRODUCTION引見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.活性藥物成分APIs的質(zhì)量應(yīng)被定義為符合相應(yīng)的API規(guī)范，并且正在建立中的設(shè)備應(yīng)符合ICH指南Q7A和FDA現(xiàn)行

17、的動態(tài)藥品消費管理規(guī)范cGMP的規(guī)定。大多數(shù)國家對原料藥的消費制造都有規(guī)定。這些法規(guī)要求有一個總的系統(tǒng)方法來保證API的質(zhì)量在適當程度。這個系統(tǒng)中的一切組件必需經(jīng)過正確的設(shè)計，驗證，維護和操作，以保證制造商的API一直符合質(zhì)量要求。該系統(tǒng)中普遍的組件包含工藝過程、設(shè)備和人員。本章內(nèi)容包括這些組件，以及產(chǎn)質(zhì)量量本身，法規(guī)條例和質(zhì)量管理部QM。A. The Product產(chǎn)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的質(zhì)量是由兩個要素決議：能否與預先建立的規(guī)范相一致，能否在符合cGMP要求的設(shè)備內(nèi)并且根據(jù)成文的閱歷證的工藝過程消費出來的。API必需具有適當?shù)幕瘜W和物理屬性，以確保它提供預期的藥理學作用?；瘜W屬性描畫了適當?shù)募兌群碗s質(zhì)限制。雜質(zhì)規(guī)范根據(jù)臨床毒理學研討建立，同時基于從監(jiān)管部門和消費者那里得到預期的合理最低值

21、。物理屬性描畫了可靠藥物加工成最終劑型的必要特征。這些屬性由配方實驗的閱歷證據(jù)確定，以消費具有足夠生物利用度、均勻且穩(wěn)定的劑型。B. The Process工藝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的質(zhì)量經(jīng)過全面的制造工藝的開展被設(shè)計成分子，從實驗室規(guī)模的合成過程通向最終產(chǎn)

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.合成方法必需被設(shè)計成最小化的雜質(zhì)，尤其是那些證明在最后一個步驟難以除去的。因此，經(jīng)過有效的工藝開發(fā)、產(chǎn)量最大化、廢棄物最小化、不構(gòu)成、消除或最小化雜質(zhì)。所采用的開展化學家的詳細控制來產(chǎn)生高收益、高質(zhì)量的產(chǎn)品必需被記錄;本文檔構(gòu)成了概念證明和驗證報告的根底。在今天幾乎一切的國家、監(jiān)管部門要求API應(yīng)在符合一切相應(yīng)規(guī)范、有記錄的工藝過程來消費。這方面由于國際會議的三方協(xié)調(diào)指南Q7A“良好消費實際指南的API的發(fā)行和經(jīng)過得到了加強。 歐盟，日本監(jiān)管部門和美國食品藥品監(jiān)視管理局經(jīng)過了這個指南。C

26、. The Facilities設(shè)備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.消費API的設(shè)備在本章節(jié)也進展討論，由于API的質(zhì)量的組成部分是經(jīng)過cGMP的規(guī)范設(shè)備來消費的。因此，由cGMP管轄的設(shè)備的組成部分是本章節(jié)的一部分。對于這個問題，cGMP的設(shè)備或API制造的任何方面的的本質(zhì)是設(shè)備執(zhí)行的設(shè)計，以保證產(chǎn)品的質(zhì)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，性能特點必需

29、記錄，管理必需證明該設(shè)備繼續(xù)按設(shè)計執(zhí)行。性能控制監(jiān)控、預防性維護、精細控制和同意的設(shè)備部件的維修或變卦都被以為是保證API質(zhì)量的一部分。D. The People人員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.消費API的人員是該系統(tǒng)的一個重要組成部分，因此，成為API的質(zhì)量要求的一部分。為了有效地做好本職任務(wù)，以確保API的質(zhì)量，就必需進展適當?shù)呐嘤柡团鋫?。合格人員必需進展培訓;設(shè)備必需有適當?shù)脑O(shè)計和功能。人造API的監(jiān)管人員也必需進展適當?shù)呐嘤杹碜龊帽韭毴蝿?wù)。最后，必需有適當?shù)娜藬?shù)，以便有充足的時間、以令人稱心的方式執(zhí)行這些職責。E. The Quality Management Department質(zhì)量管理部門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.由于在大多數(shù)的任何其他制造企業(yè)，有一個質(zhì)量控制部和/或質(zhì)量保證部。如今，這些部門通常被合并成一個質(zhì)量管理部門。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.質(zhì)量管理部門的角色也從檢查、測試、決議的職責變?yōu)榕c制造和工程平等的參與者來提高全過程和系統(tǒng)的質(zhì)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.對于原料藥和藥物產(chǎn)品，質(zhì)量管理部門，經(jīng)過其質(zhì)量保證的手臂，還有賦予的責任，經(jīng)過法規(guī)來釋放一切產(chǎn)品中運用，并最終推向市場。作為該系統(tǒng)的一個組成部分來消費原料藥，活動和QM部門的職責是也產(chǎn)質(zhì)量量的一個組成部分。大多數(shù)的cGMP要求質(zhì)量管理部門擔任審查和同意消費的程序，并且對它們的更改，大多數(shù)報告，程序和控制，以為

36、有必要確保過程和產(chǎn)品的質(zhì)量。Finally, the QM department must have adequate laboratory facilities and properly trained and experienced people to effectively carry out their responsibilities.最后，質(zhì)量管理部門必需有足夠的實驗室設(shè)備和適當?shù)呐嘤枺啔v豐富的人來有效地履行其職責。F. The Regulatory Authorities 監(jiān)管機構(gòu)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.每一個國家由衛(wèi)生主管部門控制藥品。在大多數(shù)國家，這些法規(guī)還包括原料藥。這些的cGMP法規(guī)要求藥品必需符合一切預定的質(zhì)量規(guī)范，并從記錄驗證過程中產(chǎn)生的。此外，沒有按已建立的方法制備并控制的藥物或API，那么該藥物被以為是摻假，因此不適宜運用或出賣。該法規(guī)涉及藥品消費每一個環(huán)節(jié)，而且根本上要求消費者記錄控制證明能夠影響產(chǎn)質(zhì)量量的任何方面。監(jiān)管機構(gòu)公布的法規(guī)即cGMP，不斷要求制造商維持其設(shè)備和工藝的形狀，從而保證一直如一的消費平安有效的藥品。G. The Regulations法規(guī)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:原料藥的

42、消費在大多數(shù)國家是受監(jiān)管的。良好消費實際指南API ICH-三方協(xié)調(diào)指點Q7A2000年11月10日被建議運用。以下機構(gòu)表示普遍接受：_ European Union (EU) adopted by CPMP, November 2000, issued as CPMP/ICH/1935/00 歐盟采用CPMP，2000年11月，以CPMP/ICH/1935/00發(fā)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.美國FDA發(fā)表在聯(lián)邦注冊，第66卷第186期，2001年9月25日，2001年，第49028-49029頁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.消費過程中，一切的測試和控制必需由政府監(jiān)管包括API，設(shè)備和系統(tǒng)，消費必需滿足的制造規(guī)范。因此，原料藥的質(zhì)量是基于兩部分組成：符合最終質(zhì)量規(guī)范，按規(guī)定的已同意的工藝在適宜的設(shè)備中消費。留意，兩個規(guī)范都必需滿足。這兩部分將在本章中另行論述。同樣重要的是要留意，在本章中描畫的API質(zhì)量適用于原料藥將在其中運用或出賣，不論這個國家能否受法規(guī)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.質(zhì)量方針，以本章所述，基于合理的科學原那么，良好的質(zhì)量管理原那么，適用于任何API?，F(xiàn)實上，這些原那么適用于任何需求高質(zhì)量的化學品的消費。本章將涉及原料藥的化學合成。然而，一切的原那么規(guī)定也適用于其它的制備工藝，如發(fā)酵道路或者從天然提取。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 原料藥質(zhì)量的定義和質(zhì)量保證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.本節(jié)處理了如何：_定義必要的質(zhì)量屬性_檢驗_將設(shè)計融入工藝_驗證工藝，以確保消費的一致性。由于API是受控制物品，其質(zhì)量不僅取決于令人稱心的測試結(jié)果，也以為工藝是由驗證過程來保證的。A. Defining the API Quality 原料藥質(zhì)量的定

52、義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必需具有其最終的化學純度和雜質(zhì)，并規(guī)定其最終的物理屬性;一些還需求微生物分析，這取決于最終的劑型和所涉及的制造工藝上。這些屬性被建立以保證一個API將在藥物制造過程中令人稱心地執(zhí)行，并導致最終劑型即藥品將滿足其最初版本的規(guī)格和最終穩(wěn)定性的要求?；瘜W純度最低通常設(shè)定在98，以保證藥品的適當劑量，并

56、且確保最小量的雜質(zhì)。物理參數(shù)應(yīng)建立與制藥過程和最終劑型的知識根底上。其他屬性通常包括固體方式的顏色和或溶液，熔點，比旋度假設(shè)有光學活性，晶體形狀，等等。附錄A提供了典型API的規(guī)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.當建立API的物理屬性時，要思索的最重要的方面是其在制藥過程中的運用;如被潤濕造粒，溶解于溶液中，枯燥混合等，且可以制成的藥品類型有：片劑，膠囊劑，溶液劑，無菌或非無菌的，或其他。同樣重要的是要明白藥品將用于患者;例如，賦形劑的粉末應(yīng)思索到由患者或保健給予者溶解的速率和溶液在運用前的最終的顏色用于美觀的

60、緣由。出于這個緣由，最終的API規(guī)范一直闡明需與藥物開發(fā)領(lǐng)域的協(xié)作。質(zhì)量保證職能應(yīng)在最終同意的API質(zhì)量規(guī)范中同時思索到一切要求：工藝相關(guān)的要求，政府和客戶的要求。B. Testing the API for Its Defined Attributes 原料藥質(zhì)量屬性的測試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