13. CHANGE CONTROL 13.變更的控制

　　13.10 A formal change control system should be established to evaluate all changes that could affect the production and control of the intermediate or API.

　　13.10 應(yīng)當(dāng)建立正式的變更控制系統(tǒng)，以評估可能影響中間體或原料藥生產(chǎn)和控制的所有變更。

　　13.11 Written procedures should provide for the identification, documentation, appropriate review, and approval of changes in raw materials, specifications, analytical methods, facilities, support systems, equipment (including computer hardware), processing steps, labeling and packaging materials, and computer software.

　　13.11 對原料、質(zhì)量標(biāo)準(zhǔn)、分析方法、設(shè)施、支持系統(tǒng)、設(shè)備(包括計算機(jī)硬件)、工藝步驟、標(biāo)簽和包裝材料、計算機(jī)軟件的變更進(jìn)行認(rèn)證、提供文件、適當(dāng)?shù)膶徍撕团鷾?zhǔn)，應(yīng)當(dāng)提供書面程序。

　　13.12 Any proposals for GMP relevant changes should be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality unit(s). 13.12 與GMP有關(guān)的任何變更提案都應(yīng)當(dāng)由相應(yīng)的部門進(jìn)行擬定、審核和批準(zhǔn)，并由質(zhì)量部門審核和批準(zhǔn)。

　　13.13 The potential impact of the proposed change on the quality of the intermediate or API should be evaluated. A classification procedure may help in determining the level of testing, validation, and documentation needed to justify changes to a validated process. Changes can be classified (e.g., as minor or major) depending on the nature and extent of the changes, and the effects these changes may impart on the process. Scientific judgment should determine what additional testing and validation studies are appropriate to justify a change in a validated process. 13.13 應(yīng)當(dāng)評估所提議的變更對中間體或原料藥質(zhì)量的潛在影響。一種分類方法可能有助于確定為了說明對一個已驗證的工藝作變更所需的測試、驗證和文件工作的程度。變更可以根據(jù)變更的性質(zhì)和程度及其可能對工藝產(chǎn)生的影響來分類(如，次要的或主要的)。應(yīng)當(dāng)用科學(xué)的判斷來決定，為證明對一個已驗證工藝的變更可行，什么樣的附加測試和驗證研究是適當(dāng)?shù)摹?/span>

　　13.14 When implementing approved changes, measures should be taken to ensure that all documents affected by the changes are revised.

　　13.14 實施已核準(zhǔn)的變更時，應(yīng)當(dāng)采取措施確保所有變更影響的文件都已修訂。

　　13.15 After the change has been implemented, there should be an evaluation of the first batches produced or tested under the change.

　　13.15 變更實施后，應(yīng)當(dāng)對變更之后生產(chǎn)或測試的的頭幾個批次進(jìn)行評估。

　　13.16 The potential for critical changes to affect established retest or expiry dates should be evaluated. If necessary, samples of the intermediate or API produced by the modified process can be placed on an accelerated stability program and/or can be added to the stability monitoring program.

　　13.16 關(guān)鍵的變更對規(guī)定的復(fù)驗期和有效期的影響可能性應(yīng)當(dāng)進(jìn)行評估。如有必要，可以將用修改了的工藝生產(chǎn)的中間體或原料藥的樣品放入一個加速穩(wěn)定性計劃，并/或穩(wěn)定性監(jiān)測計劃。

　　13.17 Current dosage form manufacturers should be notified of changes from established production and process control procedures that can affect the quality of the API.

　　13.17 應(yīng)當(dāng)將可能影響原料藥質(zhì)量的對已確定的生產(chǎn)及工藝控制步驟所作的變更通知目前制劑藥制造商。

　　14. REJECTION AND RE-USE OF MATERIALS 14.拒收和物料的再利用

　　14.1 Rejection 14.1 拒收

　　14.10 Intermediates and APIs failing to meet established specifications should be identified as such and quarantined. These intermediates or APIs can be reprocessed or reworked as described below. The final disposition of rejected materials should be recorded.

　　14.10 不合格中間體和原料藥應(yīng)當(dāng)做有標(biāo)志，并隔離。這些中間體和原料藥可以按下述方法進(jìn)行返工或重新加工。應(yīng)當(dāng)記錄不合格物料的最終處置情況。

　　14.2 Reprocessing 14.2 返工

　　14.20 Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and reprocessing by repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process is generally considered acceptable. However, if such reprocessing is used for a majority of batches, such reprocessing should be included as part of the standard manufacturing process.

　　14.20 將不符合標(biāo)準(zhǔn)或規(guī)格的一個中間體或原料藥返回工藝過程，重復(fù)規(guī)定的生產(chǎn)工藝中的某一結(jié)晶步驟或其它合適的化學(xué)或物理處理步驟(如，蒸餾、過濾、層析、磨粉)，這種做法通常是可以接受的。然而，如果這種返工用于大多數(shù)的批號，那么該返工就應(yīng)當(dāng)作為標(biāo)準(zhǔn)生產(chǎn)工藝的一部分。

　　14.21 Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process. This is not considered to be reprocessing.

　　14.21 在中間控制的測試表明一工藝步驟沒有完成，從而繼續(xù)該步驟，是正常工藝的一部分，不屬于返工。

　　14.22 Introducing unreacted material back into a process and repeating a chemical reaction is considered to be reprocessing unless it is part of the established process. Such reprocessing should be preceded by careful evaluation to ensure that the quality of the intermediate or API is not adversely affected due to the potential formation of by-products and over-reacted materials. 14.22 將未反應(yīng)的物料返回某一工序，并重復(fù)化學(xué)反應(yīng)，這是進(jìn)行返工，除非它已被列入規(guī)定的工藝中。在進(jìn)行這種返工前，要仔細(xì)評估，以確保不會由于可能形成的副產(chǎn)物和過度反應(yīng)物而對中間體或原料藥的質(zhì)量產(chǎn)生不良影響。

　　14.3 Reworking 14.3 重新加工

　　14.30 Before a decision is taken to rework batches that do not conform to established standards or specifications, an investigation into the reason for nonconformance should be performed.

　　14.30 在決定對不符合規(guī)定的標(biāo)準(zhǔn)或規(guī)格的批號進(jìn)行重新加工前，應(yīng)當(dāng)對不符合的原因進(jìn)行調(diào)查。

　　14.31 Batches that have been reworked should be subjected to appropriate evaluation, testing, stability testing if warranted, and documentation to show that the reworked product is of equivalent quality to that produced by the original process. Concurrent validation is often the appropriate validation approach for reworked procedures. This allows a protocol to define the rework procedure, how it will be carried out, and the expected results. If there is only one batch to be reworked, a report can be written and the batch released once it is found to be acceptable. 14.31 重新加工的批號應(yīng)當(dāng)接受適當(dāng)?shù)脑u估、測試，如有理由還要做穩(wěn)定性測試，并成文備查，以表明重新加工后的產(chǎn)品與原工藝生產(chǎn)的產(chǎn)品質(zhì)量相等。同步驗證常常是重新加工程序的合適的驗證方法。允許用一方案來規(guī)定重新加工程序、如何進(jìn)行和預(yù)期結(jié)果。如果只有一批產(chǎn)品重新加工，利用寫一份報告，一旦認(rèn)為該批可接受，即可放行。

　　14.32 Procedures should provide for comparing the impurity profile of each reworked batch against batches manufactured by the established process. Where routine analytical methods are inadequate to characterize the reworked batch, additional methods should be used.

　　14.32 應(yīng)當(dāng)有程序?qū)γ恳恢匦录庸み^的批號與用規(guī)定的工藝生產(chǎn)的批號進(jìn)行雜質(zhì)概況的比較。如果常規(guī)分析方法不足以描繪重新加工批號的特征，應(yīng)當(dāng)采用另外的方法。

　　14.4 Recovery of Materials and Solvents 14.4 物料與溶劑的回收

　　14.40 Recovery (e.g., from mother liquor or filtrates) of reactants, intermediates, or the API is considered acceptable, provided that approved procedures exist for the recovery and the recovered materials meet specifications suitable for their intended use.

　　14.40 只要有核準(zhǔn)的回收方法，并且回收的物料符合其使用標(biāo)準(zhǔn)，反應(yīng)物、中間體或原料藥的回收(例如，從母液或濾液中)是可以接受的。

　　14.41 Solvents can be recovered and reused in the same processes or in different processes, provided that the recovery procedures are controlled and monitored to ensure that solvents meet appropriate standards before reuse or commingling with other approved materials.

　　14.41 溶劑可以回收，并在同一工序或不同工序重新使用，只要回收過程得到了控制和監(jiān)測，確保在重新使用或與其它核準(zhǔn)的物料混合前，這種溶劑符合一定的標(biāo)準(zhǔn)。

　　14.42 Fresh and recovered solvents and reagents can be combined if adequate testing has shown their suitability for all manufacturing processes in which they may be used.

　　14.42 新鮮的和回收溶劑和試劑可以混合，如果有足夠的測試表明它們適用于所參與的生產(chǎn)工序。

　　14.43 The use of recovered solvents, mother liquors, and other recovered materials should be adequately documented.

　　14.43 回收溶劑、母液和其它回收的物料的使用應(yīng)當(dāng)有足夠的文件作證。

　　14.5 Returns 14.5 退貨

　　14.50 Returned intermediates or APIs should be identified as such and quarantined. 14.50 退回的原料藥和中間體應(yīng)當(dāng)作有標(biāo)志，并隔離。

　　14.51 If the conditions under which returned intermediates or APIs have been stored or shipped before or during their return or the condition of their containers casts doubt on their quality, the returned intermediates or APIs should be reprocessed, reworked, or destroyed, as appropriate.

　　14.51 如果在中間體或原料藥退貨之前或退貨期間的儲存或運(yùn)輸條件，或者其包裝容器的狀況可能對其質(zhì)量產(chǎn)生影響，退回的中間體或原料藥應(yīng)當(dāng)根據(jù)情況進(jìn)行返工、重新加工或銷毀。

　　14.52 Records of returned intermediates or APIs should be maintained. For each return, documentation should be include:

　　14.52 退回的中間體或原料藥應(yīng)當(dāng)存有記錄。每次退貨的記錄內(nèi)容應(yīng)當(dāng)包括：

　　15. COMPLAINTS AND RECALLS 15.投訴與召回

　　15.10 All quality-related complaints, whether received orally or in writing, should be recorded and investigated according to a written procedure.

　　15.10 所有與質(zhì)量有關(guān)的投訴，無論以口頭或書面方式收到，都應(yīng)當(dāng)根據(jù)書面程序進(jìn)行記錄和調(diào)查。

　　15.12 Records of complaints should be retained to evaluate trends, product-related frequencies, and severity with a view to taking additional, and if appropriate, immediate corrective action.15.12投訴記錄應(yīng)當(dāng)保存，旨在評估其變化趨勢、涉及產(chǎn)品的發(fā)生頻率及其嚴(yán)重性，以便采取額外的，有時是即時的糾正措施。

　　15.13 There should be a written procedure that defines the circumstances under which a recall of an intermediate or API should be considered.

　　15.13 應(yīng)當(dāng)有書面程序規(guī)定在何種情況下應(yīng)當(dāng)考慮召回中間體或原料藥。

　　15.14 The recall procedure should designate who should be involved in evaluating the information, how a recall should be initiated, who should be informed about the recall, and how the recalled material should be treated.

　　15.14 召回程序應(yīng)當(dāng)規(guī)定參與評估情況的人員、啟動召回的方法、召回應(yīng)當(dāng)通知到的對象、以及召回后物料的處理方法。

　　15.15 In the event of a serious or potentially life-threatening situation, local, national, and/or international authorities should be informed and their advice sought.

　　15.15 如果情況嚴(yán)重或可能威脅生命，則應(yīng)當(dāng)通知地方、國家或國際當(dāng)局，并征求其建議。

　　16. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES)

　　16.協(xié)議生產(chǎn)商(包括實驗室)

　　16.10 All contract manufacturers (including laboratories) should comply with the GMP defined in this guidance. Special consideration should be given to the prevention of cross-contamination and to maintaining traceability.

　　16.10 所有協(xié)議生產(chǎn)商(包括實驗室)應(yīng)當(dāng)遵循本指南所規(guī)定的GMP。特別應(yīng)當(dāng)注意防止交叉污染，并保持可追溯性。

　　16.11 Companies should evaluate any contractors (including laboratories) to ensure GMP compliance of the specific operations occurring at the contractor sites.

　　16.11 合同委托方應(yīng)當(dāng)對協(xié)議生產(chǎn)商(包括實驗室)進(jìn)行評估，以確保在合同地點(diǎn)發(fā)生的特定操作符合GMP。

　　16.12 There should be a written and approved contract or formal agreement between a company and its contractors that defines in detail the GMP responsibilities, including the quality measures, of each party.

　　16.12 合同委托方與合同接受方之間應(yīng)當(dāng)有經(jīng)過認(rèn)定的書面合同或正式協(xié)議書，詳細(xì)規(guī)定各方的GMP責(zé)任，包括質(zhì)量措施。

　　16.13 A contract should permit a company to audit its contractor’s facilities for compliance with GMP.

　　16.13 合同應(yīng)當(dāng)允許合同委托方對合同接受方的設(shè)施進(jìn)行GMP審計。

　　16.14 When subcontracting is allowed, a contractor should not pass to a third party any of the work entrusted to it under the contract without the company’s prior evaluation and approval of the arrangements.

　　16.14 在允許分包的情況下，未經(jīng)合同委托方事先的評估和核準(zhǔn)，合同接受方不應(yīng)當(dāng)將合同中委托給他的工作轉(zhuǎn)交給第三方。

　　16.15 Manufacturing and laboratory records should be kept at the site where the activity occurs and be readily available.

　　16.15 生產(chǎn)和分析記錄應(yīng)當(dāng)保存在操作現(xiàn)場，并隨時可得。

　　16.16 Changes in the process, equipment, test methods, specifications, or other contractual requirements should not be made unless the contract giver is informed and approves the changes. 16.16 應(yīng)當(dāng)在通知合同委托方，并得到批準(zhǔn)后，才可以對工藝、設(shè)備、測試方法、規(guī)格標(biāo)準(zhǔn)或其它合同要求進(jìn)行變更。

　　17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS 17.代理商、經(jīng)紀(jì)人、貿(mào)易商、經(jīng)銷商、重新包裝者和重新貼簽者

　　17.1 Applicability 17.1適用性

　　17.10 This section applied to any party other than the original manufacturer who may trade and/or take possession, repack, relabel, manipulate, distribute, or store an API or intermediate.

　　17.10 本章內(nèi)容適用于除原生產(chǎn)商以外，參與貿(mào)易和/或持有、處理、重新包裝、重新貼簽、運(yùn)作和儲存原料藥或中間體的任何一方。

　　17.11 All agents, brokers, traders, distributors, repackers, and relabelers should comply with GMP as defined in this guidance.

　　17.11 所有的代理、經(jīng)紀(jì)人、貿(mào)易商、經(jīng)銷商、重新包裝者和重新貼簽者都必須遵循本指南的GMP。

　　17.2 Traceability of Distributed APIs and Intermediates

　　17.2已分發(fā)的原料藥和中間體的可追溯性

　　17.20 Agents, brokers, traders, distributors, repackers, and relabelers should maintain complete traceability of APIs and intermediates that they distribute. Documents that should be retained and available include:

　　17.20 代理、經(jīng)紀(jì)人、貿(mào)易商、經(jīng)銷商、重新包裝者和重新貼簽者應(yīng)當(dāng)保留完整的已分發(fā)原料藥和中間體的可追溯性。應(yīng)當(dāng)保留和可得到的文件包括：

　　17.3 Quality Management 17.3質(zhì)量管理

　　17.30 Agents, brokers, traders, distributors, repackers, or relabelers should establish, document and implement an effective system of managing quality, as specified in Section 2.

　　17.30 代理、經(jīng)紀(jì)人、貿(mào)易商、經(jīng)銷商、重新包裝者或重新貼簽者應(yīng)當(dāng)按第2節(jié)的規(guī)定建立并執(zhí)行一個有效的質(zhì)量管理系統(tǒng)。

　　17.4 Repackaging, Relabeling, and Holding of APIs and Intermediates

　　17.4原料藥和中間體的重新包裝、重新貼簽和待檢

　　17.40 Repackaging, Relabeling, and holding APIs and intermediates should be performed under appropriate GMP controls, as stipulated in this guidance, to avoid mix-ups and loss of API or intermediate identity or purity.

　　17.40 原料藥和中間體的重新包裝、重新貼簽和待檢應(yīng)當(dāng)在本指南中所制定的適當(dāng)?shù)腉MP控制下進(jìn)行，以防原料藥或中間體的特性或純度的混淆和損失。

　　17.41 Repackaging should be conducted under appropriate environmental conditions to avoid contamination and cross-contamination.

　　17.41 重新包裝應(yīng)當(dāng)在合適的，能防止污染和交叉污染的環(huán)境條件下進(jìn)行。

　　17.5 Stability 17.5穩(wěn)定性

　　17.50 Stability studies to justify assigned expiration or retest dates should be conducted if the API or intermediate is repackaged in a different type of container than that used by the API or intermediate manufacturer.

　　17.50 如果原料藥或中間體的重新包裝所使用的容器與原料藥或中間體的生產(chǎn)商所使用的不同，就應(yīng)當(dāng)進(jìn)行穩(wěn)定性研究，以確認(rèn)規(guī)定的失效期或復(fù)驗期。

　　17.6 Transfer of Information 17.6 信息的傳達(dá)

　　17.60 Agents, brokers, distributors, repackers, or relabelers should transfer all quality or regulatory information received from an API or intermediate manufacturer to the customer, and from the customer to the API or intermediate manufacturer.

　　17.60 代理、經(jīng)紀(jì)人、貿(mào)易商、經(jīng)銷商、重新包裝者或重新貼簽者應(yīng)當(dāng)將從原料藥或中間體生產(chǎn)商和客戶之間傳遞所有質(zhì)量或藥政的信息。

　　17.61 The agent, broker, trader, distributor, repacker, or relabeler who supplies the API or intermediate to the customer should provide the name of the original API or intermediate manufacturer and the batch number(s) supplied.

　　17.61 將原料藥或中間體提供給客戶的代理、經(jīng)紀(jì)人、貿(mào)易商、經(jīng)銷商、重新包裝者或重新貼簽者應(yīng)當(dāng)提供所供原料藥或中間體的原生產(chǎn)商的名稱和原批號。

　　17.62 The agent should also provide the identity of the original API or intermediate manufacturer to regulatory authorities upon request. The original manufacturer can respond to the regulatory authority directly or through its authorized agents, depending on the legal relationship between the authorized agents and the original API or intermediate manufacturer. (In this context authorized refers to authorized by the manufacturer.)

　　17.62 需要時，代理還應(yīng)當(dāng)向藥政當(dāng)局提供原生產(chǎn)商的身份。按照原料藥或中間體的原生產(chǎn)商和授權(quán)代理人之間的法律關(guān)系，原生產(chǎn)商可直接地或通過其授權(quán)代理向藥政當(dāng)局作回復(fù)。(此處授權(quán)是指由原生產(chǎn)商所給的授權(quán))

　　17.63 The specific guidance for certificate of analysis included in Section 11.4 should be met. 17.63 應(yīng)當(dāng)遵循第11.4章所述有關(guān)報告單的指南。

　　17.7 Handling of Complaints and Recalls 17.7 投訴和召回的處理

　　17.70 Agents, brokers, traders, distributors, repackers, or relabelers should maintain records of complaints and recalls, as specified in Section 15, for all complaints and recalls that come to their attention.

　　17.70 參照第15章的要求，代理、經(jīng)紀(jì)人、貿(mào)易商、經(jīng)銷商、重新包裝者或重新貼簽者應(yīng)當(dāng)保留他們收到的所有投訴和召回的記錄。

　　17.71 If the situation warrants, the agents, brokers, traders, distributors, repackers, or relabelers should review the complaint with the original API or intermediate manufacturer to determine whether any further action, either with other customers who may have received this API or intermediate or with the regulatory authority, or both, should be initiated. The investigation into the cause for the complaint or recall should be conducted and documented by the appropriate party. 17.71 如果情況允許，代理、經(jīng)紀(jì)人、貿(mào)易商、經(jīng)銷商、重新包裝者或重新貼簽者應(yīng)當(dāng)與原料藥或中間體的生產(chǎn)商一起審閱投訴，以確定是否應(yīng)當(dāng)與其它收到該原料藥或中間體的客戶，或者藥政當(dāng)局一起采取進(jìn)一步的措施。對投訴和召回的原因應(yīng)當(dāng)由合適的一方進(jìn)行調(diào)查，并記錄備查。

　　17.72 Where a complaint is referred to the original API or intermediate manufacturer, the record maintained by the agents, brokers, traders, distributors, repackers, or relabelers should include any response received from the original API or intermediate manufacturer (including date and information provided).

　　17.72 如果投訴是針對原料藥或中間體的原生產(chǎn)商，由代理、經(jīng)紀(jì)人、貿(mào)易商、經(jīng)銷商、重新包裝者或重新貼簽者保存的記錄應(yīng)當(dāng)包括從原料藥或中間體原生產(chǎn)商處得到的任何反饋信息(包括提供的日期和內(nèi)容)。

　　17.8 Handling of Returns 17.8 退貨的處理

　　17.80 Returns should be handled as specified in Section 14.5. The agents, brokers, traders, distributors, repackers, or relabelers should maintain documentation of returned APIs and intermediates.

　　17.80 退貨應(yīng)當(dāng)按照14.5章進(jìn)行處理。代理、經(jīng)紀(jì)人、貿(mào)易商、經(jīng)銷商、重新包裝者或重新貼簽者應(yīng)當(dāng)保留原料藥或中間體退貨的文檔。

　　18. Specific Guidance for APIs Manufactured by Cell Culture/Fermentation 18. 用細(xì)胞繁殖/發(fā)酵生產(chǎn)的原料藥的特殊指南

　　18.1 General 18.1 總則

　　18.10 Section 18 is intended to address specific controls for APIs or intermediates manufactured by cell culture or fermentation using natural or recombinant organisms and that have not been covered adequately in the previous sections. It is not intended to be a stand-alone Section. In general, the GMP principles in the other sections of this document apply. Note that the principles of fermentation for classical processes for production of small molecules and for processes using recombinant and nonrecombinant organisms for production of proteins and/or polypeptides are the same, although the degree of control will differ. Where practical, this section will address these differences. In general, the degree of control for biotechnological processes used to produce proteins and polypeptides is greater than that for classical fermentation processes.

　　18.10第18節(jié)旨在描述對通過細(xì)胞繁殖或用天然或重組組織發(fā)酵生產(chǎn)的原料藥或中間體的一些在前面的章節(jié)中沒有充分闡明的特殊控制。它不是一個獨(dú)立的章節(jié)。通常，本文件中其他章節(jié)的GMP 原則也適用。值得注意的是盡管生產(chǎn)小分子的經(jīng)典工藝的發(fā)酵原理和用重組或非重組組織生產(chǎn)蛋白質(zhì)和/或多肽類的發(fā)酵原理是一樣的，但是，它們的控制程度不同。本章節(jié)將在適當(dāng)?shù)牡胤疥U述這些不同點(diǎn)?？偟膩碚f，用于生產(chǎn)蛋白質(zhì)和多肽的生物技術(shù)工藝的控制要嚴(yán)于經(jīng)典的發(fā)酵工藝。

　　18.11 The term biotechnological process (biotech) refers to the use of cells or organisms that have been generated or modified by recombinant DNA, hybridoma or other technology to produce APIs. The APIs produced by biotechnological processes normally consist of high molecular weight substances, such as proteins and polypeptides, for which specific guidance is given in this Section. Certain APIs of low molecular weight, such as antibiotics, amino acids, vitamins, and carbohydrates, can also be produced by recombinant DNA technology. The level of control for these types of APIs is similar to that employed for classical fermentation.

　　18.11 生物技術(shù)是指用重組DNA、雜交瘤或其它技術(shù)產(chǎn)生或修飾的細(xì)胞或組織來生產(chǎn)原料藥。用生物技術(shù)生產(chǎn)的原料藥通常由蛋白質(zhì)和多肽這類高分子量的物質(zhì)組成，本節(jié)介紹其特殊指南。有些低分子量的原料藥，如抗生素、氨基酸、維生素和糖類也可以用重組DNA來生產(chǎn)。這幾類原料藥的控制程度與經(jīng)典發(fā)酵的相似。

　　18.12 The term classical fermentation refers to processes that use microorganisms existing in nature and/or modified by conventional methods (e.g. irradiation or chemical mutagenesis) to produce APIs. APIs produced by classical fermentation are normally low molecular weight products such as antibiotics, amino acids, vitamins, and carbohydrates.

　　18.12 經(jīng)典發(fā)酵是指用天然的和/或以傳統(tǒng)方法(如，輻照或化學(xué)誘變)修改的微生物來生產(chǎn)原料藥的工藝。用經(jīng)典發(fā)酵生產(chǎn)的原料藥通常是低分子量的產(chǎn)品，如，抗生素、氨基酸、維生素和糖類。

　　18.13 Production of APIs or intermediates from cell culture or fermentation involves biological processes such as cultivation of cells or extraction and purification of material from living organisms. Note that there may be additional process steps, such as physicochemical modification, that are part of the manufacturing process. The raw materials used (media, buffer components) may provide the potential for growth of microbiological contaminants. Depending on the source, method of preparation, and the intended use of the API or intermediate, control of bioburden, viral contamination, and/or endotoxins during manufacturing and monitoring of the process at appropriate stages may be necessary.

　　18.13用細(xì)胞培養(yǎng)或發(fā)酵來生產(chǎn)原料藥或中間體涉及到諸如細(xì)胞培養(yǎng)，或從活體組織提取和純化物料等生物過程。值得注意的是，還有一些附加的隸屬于生產(chǎn)工藝一部分的物理化學(xué)修飾。使用的原材料(培養(yǎng)基、緩沖成分)可能為微生物污染提供了可能性。根據(jù)物料來源、制備方法和原料藥或中間體的預(yù)期用途，可能有必要在制造和工藝監(jiān)測的適當(dāng)階段控制微生物、病毒污染和/或內(nèi)毒素。

　　18.14 Appropriate controls should be established at all stages of manufacturing to assure intermediate and/or API quality. While this Guide starts at the cell culture/fermentation step, prior steps (e.g. cell banking) should be performed under appropriate process controls. This Guide covers cell culture/fermentation from the point at which a vial of the cell bank is retrieved for use in manufacturing.

　　18.14制造過程的所有階段都應(yīng)當(dāng)建立必要的控制，以保證中間體和/或原料藥的質(zhì)量。盡管本指南從細(xì)胞培養(yǎng)/發(fā)酵步驟開始，但是前期步驟(如細(xì)胞庫) 應(yīng)當(dāng)在必要的控制下進(jìn)行。本指南含蓋了從細(xì)胞庫取得用于生產(chǎn)的細(xì)胞開始的細(xì)胞培養(yǎng)/發(fā)酵過程。

　　18.15 Appropriate equipment and environmental controls should be used to minimize the risk of contamination. The acceptance criteria for quality of the environment and the frequency of monitoring should depend on the step in production and the production conditions (open, closed, or contained systems).

　　18.15應(yīng)當(dāng)采取適當(dāng)?shù)脑O(shè)備和環(huán)境控制來將污染的風(fēng)險降低到最低程度。環(huán)境質(zhì)量的認(rèn)可標(biāo)準(zhǔn)和監(jiān)控的頻率應(yīng)當(dāng)根據(jù)生產(chǎn)步驟和生產(chǎn)條件(開口，閉口，或封閉系統(tǒng))而定。

　　18.17 Where appropriate, the removal of media components, host cell proteins, other process-related impurities, product-related impurities and contaminants should be demonstrated. 18.17應(yīng)當(dāng)根據(jù)情況證明培養(yǎng)基、宿主細(xì)胞蛋白、其它與工藝有關(guān)的雜質(zhì)、與產(chǎn)品相關(guān)的雜質(zhì)和污染物的去除效果。

　　18.2 Cell Bank Maintenance and Record Keeping 18.2細(xì)胞庫的維護(hù)和記錄的保存

　　18.20 Access to cell banks should be limited to authorized personnel.

　　18.20應(yīng)當(dāng)只有授權(quán)的人員才能進(jìn)入細(xì)胞庫。

　　18.21 Cell banks should be maintained under storage conditions designed to maintain viability and prevent contamination.

　　18.21細(xì)胞庫應(yīng)當(dāng)維持在保持細(xì)胞活力、防止污染的儲存條件下。

　　18.22 Records of the use of the vials from the cell banks and storage conditions should be maintained.

　　18.22細(xì)胞庫中小瓶細(xì)胞的使用和儲存條件應(yīng)當(dāng)有記錄。

　　18.23 Where appropriate, cell banks should be periodically monitored to determine suitability for use.

　　18.23細(xì)胞庫應(yīng)當(dāng)根據(jù)情況進(jìn)行周期性的監(jiān)測，以確定其適用性。

　　18.24 See ICH Guideline Q5D Quality of Biotechnological Products: Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products for a more complete discussion of cell banking.

　　18.24有關(guān)細(xì)胞庫的詳細(xì)論述請參見ICH 指南Q5D生物制品的質(zhì)量：用于生物技術(shù)/生物制品生產(chǎn)的細(xì)胞質(zhì)的誘導(dǎo)和特性描述。

　　18.3 Cell Culture/Fermentation 18.3細(xì)胞繁殖/發(fā)酵

　　18.30 Where aseptic addition of cell substrates, media, buffers, and gases is needed, closed or contained systems should be used where possible. If the inoculation of the initial vessel or subsequent transfers or additions (media, buffers) are performed in open vessels, there should be controls and procedures in place to minimize the risk of contamination.

　　18.30在需要進(jìn)行來進(jìn)行細(xì)胞質(zhì)、培養(yǎng)基、緩沖液和氣體的無菌添加的場合，如果可能的話，應(yīng)當(dāng)采用閉口或密閉系統(tǒng)。如果接種或轉(zhuǎn)種或加料(培養(yǎng)基，緩沖液)是在敞口容器中操作的，就應(yīng)當(dāng)有控制措施和程序?qū)⑽廴镜娘L(fēng)險減少到最低限度。

　　18.31 Where the quality of the API can be affected by microbial contamination, manipulations using open vessels should be performed in a biosafety cabinet or similarly controlled environment.

　　18.31在原料藥的質(zhì)量會受微生物污染的影響的情況下，使用敞口容器的操作應(yīng)當(dāng)在生物安全櫥中，或相似的控制環(huán)境下進(jìn)行。

　　18.32 Personnel should be appropriately gowned and take special precautions handling the cultures.

　　18.32操作人員應(yīng)當(dāng)著裝適宜，并采取特殊的處理培養(yǎng)物的措施。

　　18.33 Critical operating parameters (for example temperature, pH, agitation rates, addition of gases, pressure) should be monitored to ensure consistency with the established process. Cell growth, viability (for most cell culture processes), and, where appropriate, productivity should also be monitored. Critical parameters will vary from one process to another, and for classical fermentation, certain parameters (cell viability, for example) may not need to be monitored.

　　18.33應(yīng)當(dāng)監(jiān)測關(guān)鍵的操作參數(shù)(如溫度，pH，攪拌速度，通氣，壓力)，確保與工藝規(guī)定一致。對細(xì)胞生長，活性(大多數(shù)生物技術(shù)工藝)， 必要時對生產(chǎn)能力也應(yīng)當(dāng)進(jìn)行監(jiān)測。不同工藝的關(guān)鍵操作參數(shù)是不同的，對經(jīng)典發(fā)酵的某些參數(shù)可以不必監(jiān)測。

　　18.34 Cell culture equipment should be cleaned and sterilized after use. As appropriate, fermentation equipment should be cleaned, and sanitized or sterilized.

　　18.34細(xì)胞培養(yǎng)物的設(shè)備，使用后應(yīng)當(dāng)清洗和滅菌。發(fā)酵設(shè)備必要時應(yīng)當(dāng)清洗和消毒或滅菌。

　　18.35 Culture media should be sterilized before use when appropriate to protect the quality of the API.

　　18.35為了保證原料藥的質(zhì)量，細(xì)胞培養(yǎng)基必要時在使用前應(yīng)當(dāng)滅菌。

　　18.36 There should be appropriate procedures in place to detect contamination and determine the course of action to be taken. This should include procedures to determine the impact of the contamination on the product and those to decontaminate the equipment and return it to a condition to be used in subsequent batches. Foreign organisms observed during fermentation processes should be identified as appropriate and the effect of their presence on product quality should be assessed, if necessary. The results of such assessments should be taken into consideration in the disposition of the material produced.

　　18.36應(yīng)當(dāng)有合適的程序來檢測是否染菌，并決定所采取的措施。該程序應(yīng)當(dāng)包括確定染菌對產(chǎn)品質(zhì)量的影響，設(shè)備去污染，和恢復(fù)到用于以后批號的程序。適當(dāng)情況下，發(fā)酵工藝中發(fā)現(xiàn)的外來有機(jī)物應(yīng)當(dāng)根據(jù)需要進(jìn)行鑒別，必要時應(yīng)當(dāng)就其存在對產(chǎn)品質(zhì)量的影響進(jìn)行評估。在處理生產(chǎn)出來的物料時應(yīng)當(dāng)考慮該評估的結(jié)果。

　　18.37 Records of contamination events should be maintained. 18.37應(yīng)當(dāng)保存染菌記錄。

　　18.38 Shared (multi-product) equipment may warrant additional testing after cleaning between product campaigns, as appropriate, to minimize the risk of cross-contamination.

　　18.38共用(多產(chǎn)品)設(shè)備在換產(chǎn)品的清潔后，根據(jù)情況可以進(jìn)行額外測試，以便將交叉污染的風(fēng)險減少到最低限度。

　　18.4 Harvesting, Isolation and Purification 18.4收取、分離和精制

　　18.40 Harvesting steps, either to remove cells or cellular components or to collect cellular components after disruption, should be performed in equipment and areas designed to minimize the risk of contamination.

　　18.40收取步驟，不管去除細(xì)胞或細(xì)胞組分，還是收集破壞后的細(xì)胞組分，都應(yīng)當(dāng)在按盡可能減少污染的要求而設(shè)計的設(shè)備和區(qū)域內(nèi)進(jìn)行。

　　18.41 Harvest and purification procedures that remove or inactivate the producing organism, cellular debris and media components (while minimizing degradation, contamination, and loss of quality) should be adequate to ensure that the intermediate or API is recovered with consistent quality.

　　18.41將生產(chǎn)有機(jī)物、細(xì)胞碎片或培養(yǎng)基組分去除或滅活(同時減少降解、污染、質(zhì)量損失)的收取和精制工藝，應(yīng)當(dāng)充分保證回收到的中間體或原料藥是均質(zhì)的。

　　18.42 All equipment should be properly cleaned and, as appropriate, sanitized after use. Multiple successive batching without cleaning can be used if intermediate or API quality is not compromised.

　　18.42所有的設(shè)備使用后應(yīng)當(dāng)適當(dāng)?shù)厍逑?，根?jù)情況還應(yīng)當(dāng)消毒。如果對中間體和原料藥的質(zhì)量沒有危害，可以連續(xù)生產(chǎn)幾批后清洗。

　　18.43 If open systems are used, purification should be performed under environmental conditions appropriate for the preservation of product quality.

　　18.43如果使用開口系統(tǒng)，應(yīng)當(dāng)在適合于保持產(chǎn)品質(zhì)量的環(huán)境下進(jìn)行精制。

　　18.44 Additional controls, such as the use of dedicated chromatography resins or additional testing, may be appropriate if equipment is to be used for multiple products.

　　18.44如果設(shè)備用于多個產(chǎn)品，可能有必要作諸如使用專用的層析樹脂的額外精制控制，或額外的測試。

　　18.5 Viral Removal/Inactivation steps 18.5 病毒的去除/滅活步驟

　　18.50 See the ICH Guideline Q5A Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin for more specific information.

　　18.50更具體的資料參見ICH 指南Q5A生物制品的質(zhì)量：從人體或動物組織細(xì)胞族得到的生物制品的病毒安全性評估。

　　18.51 Viral removal and viral inactivation steps are critical processing steps for some processes and should be performed within their validated parameters.

　　18.51對于某些工藝來說，病毒的去除和滅活是關(guān)鍵的工藝步驟，并按其驗證過的參數(shù)進(jìn)行。

　　18.52 Appropriate precautions should be taken to prevent potential viral contamination from pre-viral to post-viral removal/inactivation steps. Therefore, open processing should be performed in areas that are separate from other processing activities and have separate air handling units.

　　18.52應(yīng)當(dāng)采取合適的預(yù)防措施來防止病毒去除/滅活前的步驟對病毒去除/滅活后的步驟的潛在病毒污染。因此，開口工藝應(yīng)當(dāng)在與其它操作活動分開的，有獨(dú)立的空氣處理裝置的區(qū)域內(nèi)進(jìn)行。

　　18.53 The same equipment is not normally used for different purification steps. However, if the same equipment is to be used, the equipment should be appropriately cleaned and sanitized before reuse. Appropriate precautions should be taken to prevent potential virus carry-over (e.g. through equipment or environment) from previous steps.

　　18.53不同的精制步驟通常不使用同一臺設(shè)備。如果使用同一臺設(shè)備，在再使用之前應(yīng)當(dāng)進(jìn)行適當(dāng)?shù)那鍧嵑拖?。?yīng)當(dāng)采取合適的預(yù)防措施來防止病毒從前面的步驟帶入(例如，通過設(shè)備或環(huán)境)。

　　19. APIs for Use in Clinical Trials 19. 用于臨床研究的原料藥

　　19.1 General 19.1 總則

　　19.10 Not all the controls in the previous sections of this Guide are appropriate for the manufacture of a new API for investigational use during its development. Section 19 provides specific guidance unique to these circumstances.

　　19.10不是本指南前面章節(jié)中所有的控制都適合于開發(fā)階段用于研究的新原料藥的制造。第19章提供了針對此種情況的特殊指南。

　　19.11 The controls used in the manufacture of APIs for use in clinical trials should be consistent with the stage of development of the drug product incorporating the API. Process and test procedures should be flexible to provide for changes as knowledge of the process increases and clinical testing of a drug product progresses from pre-clinical stages through clinical stages. Once drug development reaches the stage where the API is produced for use in drug products intended for clinical trials, manufacturers should ensure that APIs are manufactured in suitable facilities using appropriate production and control procedures to ensure the quality of the API.

　　19.11用于生產(chǎn)臨床試驗用原料藥的生產(chǎn)控制應(yīng)當(dāng)與含有該原料藥的藥品的開發(fā)階段一致。工藝和檢驗程序應(yīng)當(dāng)隨著工藝知識的積累，從前期臨床階段到臨床階段的藥品臨床測試的發(fā)展，提供變更的可能性。一旦藥物的開發(fā)到了為用于臨床試驗的藥品生產(chǎn)原料藥的階段，生產(chǎn)者應(yīng)當(dāng)確原料藥是在適當(dāng)?shù)脑O(shè)施中，采用保證原料藥質(zhì)量的適當(dāng)生產(chǎn)和控制程序生產(chǎn)的。

　　19.2 Quality 19.2 質(zhì)量

　　19.20 Appropriate GMP concepts should be applied in the production of APIs for use in clinical trials with a suitable mechanism of approval of each batch.

　　19.20在對每批有合適的批準(zhǔn)機(jī)制的臨床試驗用原料藥的生產(chǎn)中應(yīng)當(dāng)采用適當(dāng)?shù)腉MP觀念。

　　19.21 A quality unit(s) independent from production should be established for the approval or rejection of each batch of API for use in clinical trials.

　　19.21應(yīng)當(dāng)建立獨(dú)立于生產(chǎn)部的質(zhì)量部門，來確定每批用于臨床試驗的原料藥合格或不合格。

　　19.22 Some of the testing functions commonly performed by the quality unit(s) can be performed within other organizational units.

　　19.22某些通常由質(zhì)量部門執(zhí)行的測試功能可以在其它部門進(jìn)行。

　　19.23 Quality measures should include a system for testing of raw materials, packaging materials, intermediates, and APIs.

　　19.23質(zhì)量措施應(yīng)當(dāng)包括一個測試原料、包裝材料、中間體和原料藥的系統(tǒng)。

　　19.24 Process and quality problems should be evaluated.

　　19.24對工藝和質(zhì)量問題應(yīng)當(dāng)進(jìn)行評估。

　　19.25 Labelling for APIs intended for use in clinical trials should be appropriately controlled and should identify the material as being for investigational use.

　　19.25臨床實驗用原料藥的貼簽應(yīng)當(dāng)有適當(dāng)?shù)目刂疲⑽锪蠘?biāo)明用于研究。

　　19.3 Equipment and Facilities 19.3 設(shè)備和設(shè)施

　　19.30 During all phases of clinical development, including the use of small-scale facilities or laboratories to manufacture batches of APIs for use in clinical trials, procedures should be in place to ensure that equipment is calibrated, clean and suitable for its intended use.

　　19.30在臨床開發(fā)的所有階段，包括使用小型設(shè)備或?qū)嶒炇疫M(jìn)行臨床試驗用原料藥的生產(chǎn)，應(yīng)當(dāng)提供確保設(shè)備經(jīng)過校驗、清潔并適于其預(yù)定用途的程序。

　　19.31 Procedures for the use of facilities should ensure that materials are handled in a manner that minimizes the risk of contamination and cross-contamination.

　　19.31設(shè)施的使用程序應(yīng)當(dāng)確保原料以將污染和交叉污染減少到最低限度的方式操作。

　　19.4 Control of Raw Materials 19.4 原料的控制

　　19.40 Raw materials used in production of APIs for use in clinical trials should be evaluated by testing, or received with a supplier’s analysis and subjected to identity testing. When a material is considered hazardous, a supplier's analysis should suffice.

　　19.40用于臨床試驗用原料藥生產(chǎn)的原料應(yīng)當(dāng)通過測試來評估，或者憑供應(yīng)商的分析報告單接收，并進(jìn)行鑒別測試。如果原材料有毒性，一份供應(yīng)商的分析報告單應(yīng)當(dāng)夠了。

　　19.41 In some instances, the suitability of a raw material can be determined before use based on acceptability in small-scale reactions (i.e., use testing) rather than on analytical testing alone. 19.41有時，原料的適用性可以在使用前根據(jù)其在小規(guī)模反應(yīng)(如使用測試)中的可接受程度而定，而不單憑分析測試。

　　19.5 Production 19.5 生產(chǎn)

　　19.50 The production of APIs for use in clinical trials should be documented in laboratory notebooks, batch records, or by other appropriate means. These documents should include information on the use of production materials, equipment, processing, and scientific observations.

　　19.50臨床試驗用原料藥的生產(chǎn)應(yīng)當(dāng)在實驗室記錄本、批記錄中，或以其它適合的方式成文備查。這些文件應(yīng)當(dāng)包括所用的生產(chǎn)原料、設(shè)備、工藝，和科學(xué)觀察。

　　19.51 Expected yields can be more variable and less defined than the expected yields used in commercial processes. Investigations into yield variations are not expected.

　　19.51預(yù)期產(chǎn)量同正式生產(chǎn)的預(yù)期產(chǎn)量相比可能更具變異性、更不確定。無需對產(chǎn)量變化進(jìn)行調(diào)查。

　　19.6 Validation 19.6 驗證

　　19.60 Process validation for the production of APIs for use in clinical trials is normally inappropriate, where a single API batch is produced or where process changes during API development make batch replication difficult or inexact. The combination of controls, calibration, and, where appropriate, equipment qualification assures API quality during this development phase.

　　19.60在臨床試驗用原料藥只生產(chǎn)一批，或者有由于原料藥開發(fā)中工藝的變更使批次的重現(xiàn)困難或不精確的場合，不適合作原料藥的工藝驗證?？刂?、校驗和必要的設(shè)備確認(rèn)的結(jié)合會保證開發(fā)階段的原料藥質(zhì)量。

　　19.61 Process validation should be conducted in accordance with Section 12 when batches are produced for commercial use, even when such batches are produced on a pilot or small scale.19.61在生產(chǎn)商業(yè)用批號，甚至是中試或小規(guī)模生產(chǎn)批號時，應(yīng)當(dāng)按照第12章進(jìn)行工藝驗證。

　　19.7 Changes 19.7 變更

　　19.70 Changes are expected during development, as knowledge is gained and the production is scaled up. Every change in the production, specifications, or test procedures should be adequately recorded

　　19.70隨著知識的積累和生產(chǎn)規(guī)模的擴(kuò)大，在開發(fā)階段會有變更。生產(chǎn)、規(guī)格或檢驗方法的每一個變更都應(yīng)當(dāng)適當(dāng)?shù)赜涗洝?/span>

　　19.8 Laboratory Controls 19.8 實驗室控制

　　19.80 While analytical methods performed to evaluate a batch of API for clinical trials may not yet be validated, they should be scientifically sound.

　　19.80雖然評估一批臨床試驗用原料藥的分析方法可能還沒有驗證，但是，它們應(yīng)當(dāng)是科學(xué)，合理的。

　　19.81 A system for retaining reserve samples of all batches should be in place. This system should ensure that a sufficient quantity of each reserve sample is retained for an appropriate length of time after approval, termination, or discontinuation of an application.

　　19.81應(yīng)當(dāng)有一套保存所有批號留樣的系統(tǒng)。該系統(tǒng)應(yīng)當(dāng)確保在申請批準(zhǔn)、終止或中斷后能將足夠量的每一個留樣保存一段適當(dāng)?shù)臅r間。

　　19.82 Expiry and retest dating as defined in Section 11.6 applies to existing APIs used in clinical trials. For new APIs, Section 11.6 does not normally apply in early stages of clinical trials.

　　19.82按第11.6節(jié)規(guī)定的設(shè)定有效期或復(fù)驗期適用于現(xiàn)有的臨床試驗用原料藥。對新的原料藥，第11.6節(jié)通常不適于臨床試驗的前期階段。

　　19.9 Documentation 19.9 文件

　　19.90 A system should be in place to ensure that information gained during the development and the manufacture of APIs for use in clinical trials is documented and available.

　　19.90應(yīng)當(dāng)有一個系統(tǒng)確保在臨床試驗用原料藥的開發(fā)和生產(chǎn)過程中得到的信息均成文備查，并可獲得。

　　19.91 The development and implementation of the analytical methods used to support the release of a batch of API for use in clinical trials should be appropriately documented.

　　19.91支持放行一批臨床試驗用原料藥的分析方法的開發(fā)和實施應(yīng)當(dāng)適當(dāng)?shù)爻晌膫洳椤?/span>

　　19.92 A system for retaining production and control records and documents should be used. This system should ensure that records and documents are retained for an appropriate length of time after the approval, termination, or discontinuation of an application.

　　19.92應(yīng)當(dāng)采用一套保存生產(chǎn)和控制的記錄和文件的系統(tǒng)。該系統(tǒng)應(yīng)當(dāng)保證記錄和文件在申請批準(zhǔn)、終止或中斷后能記錄和文件保存一段適當(dāng)?shù)臅r間。

　　20. Glossary 20. 術(shù)語

　　Acceptance Criteria認(rèn)可標(biāo)準(zhǔn)

　　Numerical limits, ranges, or other suitable measures for acceptance of test results.

　　接收測試結(jié)果的數(shù)字限度、范圍或其它合適的量度標(biāo)準(zhǔn)。

　　Active Pharmaceutical Ingredient (API) (or Drug Substance)

　　Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.

　　活性藥用成分(原料藥)旨在用于藥品制造中的任何一種物質(zhì)或物質(zhì)的混合物，而且在用于制藥時，成為藥品的一種活性成分。此種物質(zhì)在疾病的診斷，治療，癥狀緩解，處理或疾病的預(yù)防中有藥理活性或其它直接作用，或者能影響機(jī)體的功能和結(jié)構(gòu)。

　　API Starting Material原料藥的起始物料

　　A raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API Starting Materials are normally of defined chemical properties and structure.

　　用在原料藥生產(chǎn)中的，以主要結(jié)構(gòu)單元被并入該原料藥的原料、中間體或原料藥。原料藥的起始物料可能是在市場上有售，能夠根據(jù)合同或商業(yè)協(xié)議從一個或多個供應(yīng)商處購得，或者自己生產(chǎn)。原料藥的起始物料通常有特定的化學(xué)特性和結(jié)構(gòu)。

　　Batch (or Lot) 批

　　A specific quantity of material produced in a process or series of processes so that it is expected to be homogeneous within specified limits. In the case of continuous production, a batch may correspond to a defined fraction of the production. The batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval.

　　由一個或一系列工藝過程生產(chǎn)的一定數(shù)量的物料，因此在規(guī)定的限度內(nèi)是均一的。在連續(xù)生產(chǎn)中，一批可能對應(yīng)于與生產(chǎn)的某一特定部分。其批量可規(guī)定為一個固定數(shù)量，或在固定時間間隔內(nèi)生產(chǎn)的數(shù)量。

　　Batch Number (or Lot Number) 批號

　　A unique combination of numbers, letters, and/or symbols that identifies a batch (or lot) and from which the production and distribution history can be determined.

　　用于標(biāo)識一批的一個數(shù)字、字母和/或符號的唯一組合，從中可確定生產(chǎn)和銷售的歷史。

　　Bioburden生物負(fù)載

　　The level and type (e.g. objectionable or not) of micro-organisms that can be present in raw materials, API starting materials, intermediates or APIs. Bioburden should not be considered contamination unless the levels have been exceeded or defined objectionable organisms have been detected.

　　可能存在于原料、原料藥的起始物料、中間體或原料藥中的微生物的水平和種類(例如，致病的或不致病的)。生物負(fù)載不應(yīng)當(dāng)當(dāng)作污染，除非含量超標(biāo)，或者測得致病生物。

　　Calibration校驗

　　The demonstration that a particular instrument or device produces results within specified limits by comparison with those produced by a reference or traceable standard over an appropriate range of measurements. 證明某個儀器或裝置在一適當(dāng)?shù)牧砍谭秶鷥?nèi)所測得的結(jié)果與一參照物，或可追溯的標(biāo)準(zhǔn)相比在規(guī)定限度內(nèi)。

　　Computer System計算機(jī)系統(tǒng)

　　A group of hardware components and associated software, designed and assembled to perform a specific function or group of functions.

　　設(shè)計安裝用于執(zhí)行某一項或一組功能的一組硬件元件和關(guān)聯(lián)的軟件。

　　Computerized System計算機(jī)化系統(tǒng)

　　A process or operation integrated with a computer system.

　　與計算機(jī)系統(tǒng)整合的一個工藝或操作。

　　Contamination污染

　　The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or onto a raw material, intermediate, or API during production, sampling, packaging or repackaging, storage or transport.

　　在生產(chǎn)、取樣、包裝或重新包裝、貯存或運(yùn)輸過程中，具化學(xué)或微生物性質(zhì)的雜質(zhì)或外來物質(zhì)進(jìn)入或沾染原料、中間體或原料藥。

　　Contract Manufacturer協(xié)議制造商

　　A manufacturer performing some aspect of manufacturing on behalf of the original manufacturer. 代表原制造商進(jìn)行部分制造的制造商。

　　Critical關(guān)鍵的

　　Describes a process step, process condition, test requirement, or other relevant parameter or item that must be controlled within predetermined criteria to ensure that the API meets its specification.用來描述為了確保原料藥符合規(guī)格標(biāo)準(zhǔn)，必須控制在預(yù)定范圍內(nèi)的工藝步驟、工藝條件、測試要求或其它有關(guān)參數(shù)或項目。

　　Cross-Contamination交叉污染

　　Contamination of a material or product with another material or product.

　　一種物料或產(chǎn)品對另一種物料或產(chǎn)品的污染。

　　Deviation偏差

　　Departure from an approved instruction or established standard.

　　對批準(zhǔn)的指令或規(guī)定的標(biāo)準(zhǔn)的偏離。

　　Drug (Medicinal) Product藥品

　　The dosage form in the final immediate packaging intended for marketing. (Reference Q1A) 經(jīng)最后包裝準(zhǔn)備銷售的制劑(參見Q1A)。

　　Drug Substance原料藥

　　See Active Pharmaceutical Ingredient 見活性藥物成分

　　Expiry Date (or Expiration Date) 有效期

　　The date placed on the container/labels of an API designating the time during which the API is expected to remain within established shelf life specifications if stored under defined conditions, and after which it should not be used.

　　原料藥容器/標(biāo)簽上注明的日期，在此規(guī)定時間內(nèi)，該原料藥在規(guī)定條件下貯存時，仍符合規(guī)格標(biāo)準(zhǔn)，超過這一期限則不應(yīng)當(dāng)使用。

　　In-Process Control (or Process Control) 過程控制

　　Checks performed during production in order to monitor and, if appropriate, to adjust the process and/or to ensure that the intermediate or API conforms to its specifications.

　　生產(chǎn)過程中為監(jiān)測，在必要時調(diào)節(jié)工藝和/或保證中間體或原料藥符合其規(guī)格而進(jìn)行的檢查。

　　Intermediate中間體

　　A material produced during steps of the processing of an API that undergoes further molecular change or purification before it becomes an API. Intermediates may or may not be isolated. (Note: this Guide only addresses those intermediates produced after the point that the company has defined as the point at which the production of the API begins.)

　　原料藥工藝步驟中產(chǎn)生的、必須經(jīng)過進(jìn)一步分子變化或精制才能成為原料藥的一種物料。中間體可以分離或不分離。(注：本指南只涉及該公司定義為原料藥生產(chǎn)起始點(diǎn)以后生產(chǎn)的中間體。)

　　Qualification確認(rèn)

　　Action of proving and documenting that equipment or ancillary systems are properly installed, work correctly, and actually lead to the expected results. Qualification is part of validation, but the individual qualification steps alone do not constitute process validation.

　　證明設(shè)備或輔助系統(tǒng)，安裝正確、工作正常、確實產(chǎn)生預(yù)期的結(jié)果，并以文件佐證的行為。確認(rèn)是驗證的一部分，但單獨(dú)的確認(rèn)步驟不構(gòu)成工藝驗證。

　　Quality Assurance (QA) 質(zhì)量保證

　　The sum total of the organised arrangements made with the object of ensuring that all APIs are of the quality required for their intended use and that quality systems are maintained.

　　以確保所有原料藥達(dá)到其應(yīng)用所要求的質(zhì)量，并維持質(zhì)量體系為目的的全部組織安排的總和。

　　Quality Unit(s) 質(zhì)量部門

　　An organizational unit independent of production which fulfills both Quality Assurance and Quality Control responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization. 獨(dú)立于生產(chǎn)部門的履行質(zhì)量保證和質(zhì)量控制職責(zé)的組織機(jī)構(gòu)。按照組織機(jī)構(gòu)的大小和結(jié)構(gòu)，可以是單獨(dú)的QA 和QC部門，或個人，或小組。

　　Quarantine待驗

　　The status of materials isolated physically or by other effective means pending a decision on their subsequent approval or rejection.

　　在實物上或以其它有效方式將物料隔離，等待對其隨后的批準(zhǔn)或拒收做出決定的狀態(tài)。

　　Raw Material原料

　　A general term used to denote starting materials, reagents, and solvents intended for use in the production of intermediates or APIs.

　　用來表示中間體或原料藥的生產(chǎn)中要用的起始物料、試劑和溶劑的通用專業(yè)名詞。

　　Reference Standard, Primary基準(zhǔn)參考標(biāo)準(zhǔn)品

　　A substance that has been shown by an extensive set of analytical tests to be authentic material that should be of high purity. This standard can be: (1) obtained from an officially recognised source, or (2) prepared by independent synthesis, or (3) obtained from existing production material of high purity, or (4) prepared by further purification of existing production material. 經(jīng)廣泛分析測試表明具有可信的高純度的物質(zhì)。這類標(biāo)準(zhǔn)品可以：1)來源于法定的機(jī)構(gòu)，2)獨(dú)立合成，3)來自于高純度的現(xiàn)有生產(chǎn)物料，或4)用進(jìn)一步精制現(xiàn)有生產(chǎn)物料的方法來制備。

　　Reference Standard, Secondary二級參考標(biāo)準(zhǔn)品

　　A substance of established quality and purity, as shown by comparison to a primary reference standard, used as a reference standard for routine laboratory analysis.

　　與基準(zhǔn)參考標(biāo)準(zhǔn)品比較顯示具有規(guī)定的質(zhì)量和純度，并用作日常實驗室分析的參考標(biāo)準(zhǔn)品。

　　Reprocessing返工

　　Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process. Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process, and not reprocessing.

　　將不符合標(biāo)準(zhǔn)或規(guī)格的一個中間體或原料藥返回工藝過程，重復(fù)規(guī)定的生產(chǎn)工藝中的某一結(jié)晶步驟或其它合適的化學(xué)或物理處理步驟(如蒸餾，過濾，層析，磨粉)，這種做法通常是可以接受的。在中間控制的測試表明一工藝步驟沒有完成，從而繼續(xù)該步驟，是正常工藝的一部分，而不是返工。

　　Reworking重新加工

　　Subjecting an intermediate or API that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain acceptable quality intermediate or API (e.g., recrystallizing with a different solvent).

　　將不符合規(guī)格標(biāo)準(zhǔn)的中間體或原料藥用不同于規(guī)定生產(chǎn)工藝的一個或幾個步驟進(jìn)行處理，以得到質(zhì)量可接受的中間體或原料藥(如：用不同溶劑的再結(jié)晶)。

　　Specification質(zhì)量標(biāo)準(zhǔn)

　　A list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the test described. It establishes the set of criteria to which a material should conform to be considered acceptable for its intended use. Conformance to specification means that the material, when tested according to the listed analytical procedures, will meet the listed acceptance criteria.

　　一系列的測試項目、有關(guān)的分析程序和適當(dāng)?shù)恼J(rèn)可標(biāo)準(zhǔn)，此標(biāo)準(zhǔn)可以是數(shù)值限度、范圍或所述測試項目的其它標(biāo)準(zhǔn)。它規(guī)定一套標(biāo)準(zhǔn)，物料應(yīng)當(dāng)符合該標(biāo)準(zhǔn)，才被認(rèn)為可以用作其預(yù)期的用途。符合規(guī)格表示物料按所列的分析程序測試時，會符合所列的接受標(biāo)準(zhǔn)。

　　Validation驗證

　　A documented program that provides a high degree of assurance that a specific process, method, or system will consistently produce a result meeting pre-determined acceptance criteria.

　　為某一特定的工藝、方法或系統(tǒng)能夠持續(xù)地產(chǎn)生符合既定接受標(biāo)準(zhǔn)的結(jié)果提供充分保證的文件程序。

　　Validation Protocol驗證方案

　　A written plan stating how validation will be conducted and defining acceptance criteria. For example, the protocol for a manufacturing process identifies processing equipment, critical process parameters/operating ranges, product characteristics, sampling, test data to be collected, number of validation runs, and acceptable test results.

　　說明如何進(jìn)行驗證和規(guī)定接受標(biāo)準(zhǔn)的書面計劃。例如，生產(chǎn)工藝驗證方案確定工藝設(shè)備、關(guān)鍵性工藝參數(shù)/操作范圍、產(chǎn)品特性、取樣、收集的測試數(shù)據(jù)、驗證的次數(shù)，以及可接受的測試結(jié)果。

　　Yield, Expected預(yù)期產(chǎn)量

　　The quantity of material or the percentage of theoretical yield anticipated at any appropriate phase of production based on previous laboratory, pilot scale, or manufacturing data.

　　在以前實驗室、中試規(guī)?；蛏a(chǎn)數(shù)據(jù)的基礎(chǔ)上，預(yù)計任何適當(dāng)?shù)纳a(chǎn)階段的物料的量或理論產(chǎn)量的百分比。