【正文】 reference should that be necessary.The reason for selecting the ICH guide is due to its widespread adoption, its prehensive approach and its high quality as a reference document.本章的這一部分遵循的ICH指南的格式為2000年11月定稿的ICH（ “質(zhì)量”章節(jié)，“Q7A”；）。相反，本文從實(shí)用的觀點(diǎn)提供了法規(guī)要求的某些方面的含義和原因。最后在開(kāi)始ICH指南介紹前還有個(gè)定義：當(dāng)描述cGMP時(shí)，總是由形容詞“現(xiàn)行的”做前綴。III. THE REGULATIONS FOR QUALITY質(zhì)量法規(guī)Introduction: The Emergence of Specific Regulations for APIs導(dǎo)言： API具體法規(guī)的出現(xiàn)The active ingredient of a pharmaceutical product must meet two distinct sets of criteria before it can be used for producing a drug product suitable for sale in most countries around the world. One set of criteria is the product specifications, addressed in Part II. The other set is the assurance that the product is produced according to cGMP, that is, the cGMPs prevalent in the regulated market in which the drug product will be sold. Most countries have approved and enforced regulations for drug products。它們還用來(lái)告知操作時(shí)反應(yīng)完??全和可能發(fā)生的下一個(gè)步驟。最后，工藝開(kāi)發(fā)過(guò)程中應(yīng)充分了解，獲得關(guān)于那些影響動(dòng)力學(xué)，產(chǎn)率和純度的每個(gè)步驟的參數(shù)和條件的知識(shí)。在本質(zhì)上，該方法的驗(yàn)證是開(kāi)發(fā)工作完成后的過(guò)程的證明，用擬定合成途徑，在控制的工藝條件，實(shí)際生產(chǎn)出可獲得的樣品。法規(guī)要求化學(xué)品制造過(guò)程必須進(jìn)行驗(yàn)證，作者個(gè)人定義為控制知識(shí)的證明。如果想象一個(gè)完美的工藝，沒(méi)有有毒物排放，沒(méi)有安全問(wèn)題或需要特殊的安全控制，每一步獲得的中間體，立體異構(gòu)體和最終產(chǎn)品的收率都是100%。為達(dá)到預(yù)定義的屬性，合成化學(xué)家和化學(xué)工程師有將質(zhì)量設(shè)計(jì)于工藝的任務(wù)，從而確保每一批將符合其標(biāo)準(zhǔn)。B. Testing the API for Its Defined Attributes 原料藥質(zhì)量屬性的測(cè)試Each quality attribute required of the API must have a sound and proven test procedure. In regulatory pliance terms, this means the test must be validated。When setting API physical attribute specifications, the most important aspect to consider is its use in the pharmaceutical process。 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 will perform satisfactorily in the pharmaceutical manufacturing process and will result in a final dosage form。同樣重要的是要注意，在本章中描述的API質(zhì)量適用于原料藥將在其中使用或出售，不管這個(gè)國(guó)家是否受法規(guī)管制。該法規(guī)涉及藥品生產(chǎn)每一個(gè)環(huán)節(jié)，而且基本上要求生產(chǎn)者記錄控制證明可能影響產(chǎn)品質(zhì)量的任何方面。For APIs and drug products, the QM department, through its quality assurance arm, still has the responsibility vested in it by regulations to release all products for use and eventually to the market. As a ponent of the system to produce APIs, the activities and responsibilities of the QM department are also a ponent of product quality. Most cGMPs require 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.對(duì)于原料藥和藥物產(chǎn)品，質(zhì)量管理部門(mén)，通過(guò)其質(zhì)量保證的手臂，還有賦予的責(zé)任，通過(guò)法規(guī)來(lái)釋放所有產(chǎn)品中使用，并最終推向市場(chǎng)。人造API的監(jiān)管人員也必須進(jìn)行適當(dāng)?shù)呐嘤?xùn)來(lái)做好本職工作。對(duì)于這個(gè)問(wèn)題，cGMP的設(shè)施或API制造的任何方面的的本質(zhì)是設(shè)施執(zhí)行的設(shè)計(jì)，以保證產(chǎn)品的質(zhì)量。因此，通過(guò)有效的工藝開(kāi)發(fā)、產(chǎn)量最大化、廢棄物最小化、不形成、消除或最小化雜質(zhì)?；瘜W(xué)屬性描述了適當(dāng)?shù)募兌群碗s質(zhì)限度。和FDA現(xiàn)行的動(dòng)態(tài)藥品生產(chǎn)管理規(guī)范（cGMP）的規(guī)定。這個(gè)系統(tǒng)中的所有組件必須經(jīng)過(guò)正確的設(shè)計(jì)，驗(yàn)證，維護(hù)和操作，以保證制造商的API始終符合質(zhì)量要求。這些屬性由配方試驗(yàn)的經(jīng)驗(yàn)證據(jù)確定，以生產(chǎn)具有足夠生物利用度、均勻且穩(wěn)定的劑型。在今天幾乎所有的國(guó)家、監(jiān)管部門(mén)要求API應(yīng)在符合所有相應(yīng)規(guī)范、有記錄的工藝過(guò)程來(lái)生產(chǎn)。D. The People人員The people who produce the API are considered a critical part of the system and, as such, bee part of the requirements for quality of APIs. To do their jobs effectively and to assure quality of the API, they must be properly trained and equipped. Qualified personnel must conduct the training。如今，這些部門(mén)通常被合并成一個(gè)質(zhì)量管理部門(mén)。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(mén)必須有足夠的實(shí)驗(yàn)室設(shè)施和適當(dāng)?shù)呐嘤?xùn)，經(jīng)驗(yàn)豐富的人來(lái)有效地履行其職責(zé)。良好生產(chǎn)實(shí)踐指南API ICH三方協(xié)調(diào)指導(dǎo)Q7A（2000年11月10日）被建議使用。本章將涉及原料藥的化學(xué)合成。這些屬性被建立以保證一個(gè)API將在藥物制造過(guò)程中令人滿(mǎn)意地執(zhí)行，并導(dǎo)致最終劑型即藥品將滿(mǎn)足其最初版本的規(guī)格和最終穩(wěn)定性的要求。如被潤(rùn)濕造粒，溶解于溶液中，干燥混合等，且可以制成的藥品類(lèi)型有：片劑，膠囊劑，溶液劑，無(wú)菌或非無(wú)菌的，或其他。一個(gè)驗(yàn)證過(guò)程包括8個(gè)特定的部分，讀者可參考現(xiàn)行USP或ICH分析方法驗(yàn)證的指導(dǎo)。When the manufacturing team takes on the mercial implementation of the process, and goes through the formal manufacturing validation process, they should rely heavily on this technical document to prove the quality of the final API. As stated in the introduction, quality is designed into the process not for regulatory purposes, but because it makes good manufacturing and business sense to do so. Manufacturers want a process that safely and reliably delivers high yield and quality for economic and environmental reasons.當(dāng)制造團(tuán)隊(duì)需要對(duì)工藝進(jìn)行商業(yè)化生產(chǎn)，并進(jìn)行正規(guī)的生產(chǎn)驗(yàn)證過(guò)程，在很大程度上依賴(lài)于該技術(shù)文件以證明最終API的質(zhì)量。然后，一個(gè)巧妙的設(shè)計(jì)可以開(kāi)發(fā)用以消除任何不良副反應(yīng)。驗(yàn)證39。對(duì)于每個(gè)API的工藝建立是工藝驗(yàn)證的基礎(chǔ)。E. Reality實(shí)際We realize that the perfect synthetic process will, in all likelihood, be too elusive. Eventually, we must make the decision to focus our resources on the best process available after thorough development work yields a sound and reliable process. Each synthetic challenge represents reality of the business of API manufacturing, and so at some point, the feasibility of further studies vs. mercializing what has been achieved to date must be evaluated on a risk (loosing precious time in the market) to reward (achieving a superior process) basis. It is sufficient to say here that to ensure quality of the final API, the development of the process provides the necessary information to design inprocess controls needed to monitor the progress of each step. These controls are the chemical and physical monitors that inform the operator that the synthesis is proceeding according to the original design. They are used also to inform the operator when the reaction is plete and when the next step may occur. In many cases, especially when the process is well defined and designed, including the quality of starting materials and reagents, a good control is simply the use of time, based on a knowledge of the kinetics of the reaction.我們意識(shí)到在所有的可能性中完美的合成過(guò)程是很難的。在某些情況下，可能有必要采取樣品，但應(yīng)避免。另一套是保證該產(chǎn)品符合cGMP生產(chǎn)，也就是所述的cGMP管制的市場(chǎng)，其中的藥品將被銷(xiāo)售。此外，由于“現(xiàn)行的”要求是指南的一部分，制造商需要了解這些技術(shù)前沿，并做出必要的改變以使他們的系統(tǒng)和設(shè)施保持兼容。The ICH guidance is laid out in the following format to demonstrate the scope and extent of their influence on the entire manufacturing process (note we are following the ICH numbering format), each of these ICH sections are discussed below:ICH指導(dǎo)原則按下列形式來(lái)證明其對(duì)整個(gè)制造過(guò)程影響的范圍和程度（注意我們下面ICH的編號(hào)格式），這些ICH章節(jié)討論如下