【正文】 IV. RECOMMENDATIONS四. 建議In the following sections, we describe general considerations for process validation, the remendedstages of process validation, and specific activities for each stage in the product lifecycle.在下述部分中，我們對(duì)工藝驗(yàn)證的總體考慮、建議的工藝驗(yàn)證和產(chǎn)品生命周期內(nèi)每一階段的特殊活動(dòng)進(jìn)行說明。)。 )。)。 ). Automated,mechanical, and electronic equipment must be calibrated, inspected, or checked according to a writtenprogram designed to assure proper performance (167。（ 可從以下網(wǎng)址獲得：）包含不具約束力的建議中文譯稿：北京大學(xué)藥物信息與工程研究中心 info9construction, and location to facilitate proper operations (167。對(duì)產(chǎn)品質(zhì)量與工藝性能不間斷的反饋是工藝維護(hù)的基本特征。10The CGMP regulations also describe and define activities connected with process design, development, andmaintenance. Section (e) requires that information and data about product quality and manufacturingexperience be periodically reviewed to determine whether any changes to the established process arewarranted. Ongoing feedback about product quality and process performance is an essential feature ofprocess maintenance.CGMP 法規(guī)還說明和定義了與工藝設(shè)計(jì)、開發(fā)和維護(hù)有關(guān)的活動(dòng)。這份法規(guī)的第二個(gè)原則最中間工藝規(guī)范做了進(jìn)一步要求“……應(yīng)當(dāng)源于之前認(rèn)可的工藝均值和工藝變異性估計(jì)值。第一個(gè)原則是，“……對(duì)這些（在加工材料和藥品）特性的中間工藝規(guī)格，應(yīng)當(dāng)與藥品成品規(guī)格一致。In addition to sampling requirements, the CGMP regulations also provide norms for establishing inprocessspecifications as an aspect of process validation. Section (b) establishes two principles to followwhen establishing inprocess specifications. The first principle is that “. . . inprocess specifications for suchcharacteristics [of inprocess material and the drug product] shall be consistent with drug product finalspecifications . . .” Accordingly, inprocess material should be controlled to assure that the final drug productwill meet its quality requirements. The second principle in this regulation further requires that inprocessspecifications “. . . shall be derived from previous acceptable process average and process variabilityestimates where possible and determined by the application of suitable statistical procedures whereappropriate.” This requirement, in part, establishes the need for manufacturers to analyze processperformance and control batchtobatch 除抽樣要求之外，作為工藝驗(yàn)證的一個(gè)方面，CGMP 法規(guī)也規(guī)定了建立中間工藝規(guī)范。 (c)和(d))。 (b)(3))。根據(jù)這一法規(guī)，即便設(shè)計(jì)周到的工藝也必須包括中間工藝控制程序以保證成品質(zhì)量。 (a)在加工材料和藥品的抽樣和檢測(cè)，要求控制程序“……應(yīng)被建立以監(jiān)測(cè)產(chǎn)量和驗(yàn)證可能是引起在加工材料和藥品特性變異原因的那些生產(chǎn)工藝進(jìn)行驗(yàn)證。 (a)).其它的CGMP 法規(guī)對(duì)驗(yàn)證的不同方面進(jìn)行了定義。 (c) and (d))。 (b)(3))。Other CGMP regulations define the various aspects of validation. For example, 167。 (a)中，規(guī)定了工藝驗(yàn)證的基礎(chǔ)，其中規(guī)定“應(yīng)當(dāng)有用于保證藥品具有其宣稱或據(jù)稱所有的鑒別、含量、質(zhì)量、純度的生產(chǎn)和工藝控制的書面程序……”（強(qiáng)調(diào)）。按照CGMP 第210 和211 節(jié)，在一般條款和具體條款中，工藝驗(yàn)證是必需的。The CGMP regulations require that manufacturing processes be designed and controlled to assure thatinprocess materials and the finished product meet predetermined quality requirements and do soconsistently and reliably. Process validation is required, in both general and specific terms, by the CGMPregulations in parts 210 and 211. The foundation for process validation is provided in 167。III. STATUTORY AND REGULATORY REQUIREMENTS FOR PROCESSVALIDATION三. 對(duì)工藝驗(yàn)證的法規(guī)和監(jiān)管要求Process validation for drugs (finished pharmaceuticals and ponents) is a legally enforceable requirementunder section 501(a)(2)(B) of the Act (21 . 351(a)(2)(B)), which states the following:根據(jù)法令（《美國聯(lián)邦法典 . 351(a)(2)(B), 21 編》）501(a)(2)(B)節(jié)，藥物（藥物成品與組分）工藝驗(yàn)證依法強(qiáng)制執(zhí)行，其規(guī)定如下：A drug . . . shall be deemed to be adulterated . . . if . . . the methods used in, or the facilities orcontrols used for, its manufacture, processing, packing, or holding do not conform to or are notoperated or administered in conformity with current good manufacturing practice to assure thatsuch drug meets the requirements of this Act as to safety and has the identity and strength, andmeets the quality and purity characteristics, which it purports or is represented to possess.一種藥品……應(yīng)當(dāng)被視為摻假藥品……如果……使用于制造、加工、包裝或置放的方法或設(shè)施、控制裝置不符合或沒有遵照在安全性上保證藥品符合本法令的規(guī)定，并保證符合其聲稱或據(jù)稱的鑒別和含量、質(zhì)量和純度特征的現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范操作和管理。包含不具約束力的建議中文譯稿：北京大學(xué)藥物信息與工程研究中心 info7processes. Implementation of the remendations in this guidance for legacy products and processeswould likely begin with the activities described in Stage 3.傳統(tǒng)產(chǎn)品生產(chǎn)商可利用從原先的工藝開發(fā)和確認(rèn)工作、以及生產(chǎn)經(jīng)驗(yàn)中獲得的知識(shí)，不斷改進(jìn)工藝。這些方案可以確定工藝或產(chǎn)品問題，或找出工藝改善的適當(dāng)時(shí)機(jī)，這些時(shí)機(jī)可以通過在第一階段和第二階段中描述的一些活動(dòng)進(jìn)行評(píng)估和實(shí)施。在建立和確認(rèn)工藝之后，生產(chǎn)商必須保持工藝在工藝生命期內(nèi)處于受控狀態(tài)，即便是材料、設(shè)備、生產(chǎn)環(huán)境、人員和生產(chǎn)工序發(fā)生變更的情況下。Each manufacturer should judge whether it has gained sufficient understanding to provide a high degree ofassurance in its manufacturing process to justify mercial distribution of the manufacturing process andassociated variations may not lead to adequate assurance of quality. After establishing and confirming theprocess, manufacturers must maintain the process in a state of control over the life of the process, even asmaterials, equipment, production environment, personnel, and manufacturing procedures 所有生產(chǎn)商均應(yīng)判斷是否已經(jīng)對(duì)生產(chǎn)工藝提供高度保證獲得足夠理解，為產(chǎn)品商業(yè)流通提供保證。這種知識(shí)和理解是建立能夠生產(chǎn)出具備期望得到的質(zhì)量屬性產(chǎn)品生產(chǎn)工藝控制方法的基礎(chǔ)。信息和數(shù)據(jù)應(yīng)該顯示，商品化制造工藝應(yīng)能在商品化制造條件下始終如包含不具約束力的建議中文譯稿：北京大學(xué)藥物信息與工程研究中心 info6一地生產(chǎn)出合格的優(yōu)質(zhì)產(chǎn)品。Before any batch from the process is mercially distributed for use by consumers, a manufacturer shouldhave gained a high degree of assurance in the performance of the manufacturing process such that it willconsistently produce APIs and drug products meeting those attributes relating to identity, strength, quality,purity, and potency. The assurance should be obtained from objective information and data from laboratory,pilot, and/or mercialscale studies. Information and data should demonstrate that the mercialmanufacturing process is capable of consistently producing acceptable quality products within mercialmanufacturing conditions.經(jīng)工藝生產(chǎn)出任何批次產(chǎn)品經(jīng)過商業(yè)流通給消費(fèi)者使用之前，生產(chǎn)商應(yīng)在生產(chǎn)工藝性能方面取得高度保證，以始終如一地生產(chǎn)出滿足與鑒別、含量、質(zhì)量、純度和效價(jià)相關(guān)的那些屬性的原料藥和藥品。? Stage 3 – Continued Process Verification: Ongoing assurance is gained during routineproduction that the process remains in a state of control.? 第三階段持續(xù)工藝核實(shí):在日常生產(chǎn)中獲得工藝保持處于受控狀態(tài)的持續(xù)和不斷