【正文】 r APIs導言： API具體法規(guī)的出現(xiàn) 171. ICH Q7A Section I: ‘‘Introduction’’第一部分：簡介 212. ICH Q7A Section 2: ‘‘Quality Management’’第二部分 質(zhì)量管理 223. ICH Q7A Section 3: ‘‘Personnel’’第三部分 人員 244. ICH Q7A Section 4: ‘‘Buildings and Facilities’’第四部分 廠房和設施 265. ICH Q7A Section 5: ‘‘Process Equipment’’第五部分 工藝設備 296. ICH Q7A Section 6: ‘‘Documents and Records’’第六部分 文件和記錄 317. ICH Q7A Section 7: ‘‘Materials Management’’第7部分 物料管理 368. ICH Q7A Section 8: ‘‘Production and InProcess Controls’’第8部分 產(chǎn)品和過程控制 409. 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 4410. ICH Q7A Section 10: ‘‘Storage and Distribution’’儲存和發(fā)運 4511. ICH Q7A Section 11: ‘‘Laboratory Controls’’ 第11部分 實驗室控制 4612. ICH Q7A Section 12: ‘‘Validation’’ 4613. ICH Q7A Section 13: ‘‘Change Control’’第13部分 變更控制 5314. ICH Q7A Section 14: ‘‘Rejection and ReUse 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 投訴與召回 5916. ICH Q7A Section 16: ‘‘Contract Manufacturers (Including Laboratories)’’第16部分 協(xié)議制造商（包括實驗室） 60IV. THE QUALITY CONTROL AND QUALITY ASSURANCE DEPARTMENT 質(zhì)量控制和質(zhì)量保證部 61I. INTRODUCTION介紹The quality of active pharmaceutical ingredients (APIs) is defined as meeting the appropriate specifications for the API and being produced in a facility pliant with ICH guidelines ‘‘Q7A’’ and FDA’s current 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 ponents in this system must be properly designed, validated, maintained, and operated to allow the manufacturer to assure the API consistently meets quality requirements. The general ponents of the system are the process, facilities, and the people. This chapter concerns these ponents, 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)量應被定義為符合相應的API規(guī)范，并且正在建設中的設施應符合ICH指南39。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 controls used by the developmental chemist to produce the highyield, highquality product must be documented。為了有效地做好本職工作，以確保API的質(zhì)量，就必須進行適當?shù)呐嘤柡脱b備。在大多數(shù)國家，這些法規(guī)還包括原料藥。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 principles on which the regulation is based should be seriously considered.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 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)解決了如何：_定義必要的質(zhì)量屬性_檢驗_將設計融入工藝_驗證工藝，以確保生產(chǎn)的一致性。例如，賦形劑的粉末應考慮到由患者（或保健給予者）溶解的速率和溶液在使用前的最終的顏色（用于美觀的原因）。處于經(jīng)濟和環(huán)境的原因制造商希望有一個安全，可靠地工藝來達到產(chǎn)品的高產(chǎn)量和高質(zhì)量。有幾種不同的規(guī)定定義（cGMP），基本意味著或暗示39。每次合成的挑戰(zhàn)都代表原料藥制造業(yè)的現(xiàn)實，因此在某些時候，進一步的研究與商業(yè)化風險必須進行評估其可行性（失去寶貴的時間在市場上）去獲得（實現(xiàn)一個卓越的技術(shù)）。隨著歐盟，日本厚生省和美國FDA的ICH Q7A指南的制定和實施，原料藥的cGMP生產(chǎn)現(xiàn)在是可以實現(xiàn)的。當然回顧和參考是必要的。 there were few with specific regulations for the APIs used therein. With the development and subsequent adoption of the ICH Q7A Guide, by the EU, MHLW and US FDA, a consistent approach to cGMPs for the manufacture of APIs is now achievable.藥物的有效成分必須滿足兩個截然不同的兩套標準才可以用于生產(chǎn)合適的藥品銷售于世界上的大多數(shù)國家。為優(yōu)化每一步的純度和收率所進行的實驗，都作為工藝工程師用來描述必要的控制手段和反應條件。While the term ‘‘validation’’ has various definitions in several different regulations (cGMPs), all essentially mean or imply ‘‘proof of knowledge of control.’’ In essence, the validation of the process is the description of the process after all development work is pleted, with the elaboration of the proof of synthetic pathway, controls over process conditions, and finally, sound analytical proof of quality from samples obtained during actual manufacturing campaigns in the plant. Critical process parameters such as time, temperature, and mixing conditions should be defined, controlled, and monitored. The kinetics of the synthetic pathway is documented in a process manual. The establishment of a process manual for each API is the foundation of process validation. In this manual, one describes proof of the knowledge of the process and the controls necessary for consistent results. Hence, the scientific design process to build the perfect process requires full knowledge of the chemistry of the process. That knowledge is described in the chemical pathway from raw materials to the final API.術(shù)語39。這也許是化學工藝驗證最顯著的方面和大多數(shù)法規(guī)要求的質(zhì)量保證基石。 namely, whether it will be wetted for granulation, dissolved for solution, 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。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 of 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，基于合理的科學原則，良好的質(zhì)量管理原則，適用于任何API。作為該系統(tǒng)的一個組成部分來生產(chǎn)原料藥，活動和QM部門的職責是也產(chǎn)品質(zhì)量的一個組成部分。Further, the performance characteristic must be documen