10. STORAGE AND DISTRIBUTION 10.儲存和分發(fā)

　　10.1 Warehousing Procedures 10.1 入庫程序

　　10.10 Facilities should be available for the storage of all materials under appropriate conditions (e.g., controlled temperature and humidity when necessary). Records should be maintained of these conditions if they are critical for the maintenance of material characteristics.

　　10.10 應當提供在適當條件下(需要時控制溫度和濕度)貯存所有物料的設施。應當記錄對保持物料特性至關重要的貯存條件。

　　10.11 Unless there is an alternative system to prevent the unintentional or unauthorized use of quarantined, rejected, returned, or recalled materials, separate storage areas should be assigned for their temporary storage until the decision as to their future use has been made.

　　10.11 除非另有其它系統(tǒng)可以防止待驗的、不合格的退回或召回的物料的誤用或未經許可擅自使用，應當為其臨時存放指定單獨的存放區(qū)域，直至其今后用途確定為止。

　　10.2 Distribution Procedures 10.2 分發(fā)程序

　　10.20 APIs and intermediates should only be released for distribution to third parties after they have been released by the quality unit(s). APIs and intermediates can be transferred under quarantine to another unit under the company’s control when authorized by the quality unit(s) and if appropriate controls and documentation are in place.

　　10.20 原料藥和中間體經質量部門放行后才能分發(fā)給第三方。經質量部門授權，而且如果有合適的控制并有文件證明，可允許待驗的原料藥和中間體在公司的控制范圍下，轉移到另一部門。

　　10.21 APIs and intermediates should be transported in a manner that does not adversely affect their quality.

　　10.21 原料藥和中間體應當以對其質量不產生負面影響的方式運輸。

　　10.22 Special transport or storage conditions for an API or intermediate should be stated on the label.

　　10.22 原料藥或中間體的特殊運輸或貯存條件應當在標簽上注明。

　　10.23 The manufacturer should ensure that the contract acceptor (contractor) for transportation of the API or intermediate knows and follows the appropriate transport and storage conditions.

　　10.23 生產商應當確保運輸原料藥或中間體的合同接受方(訂約人)了解并遵從相關的運輸和貯存條件。

　　10.24 A system should be in place by which the distribution of each batch of intermediate and/or API can be readily determined to permit its recall.

　　10.24 應當建立一個系統(tǒng)，可用它來對每批中間體和/或原料藥的分發(fā)隨時決定召回。

　　11. LABORATORY CONTROLS 11.實驗室控制

　　11.1 General Controls 11.1 控制通則

　　11.10 The independent quality unit(s) should have at its disposal adequate laboratory facilities.

　　11.10 獨立的質量部門應當有受其支配的、足夠的實驗室設施。

　　11.11 There should be documented procedures describing sampling, testing, approval, or rejection of materials and recording and storage of laboratory data. Laboratory records should be maintained in accordance with Section 6.6.

　　11.11 應當備有闡述物料取樣、測試、物料批準或拒收，和實驗室的記錄及保存的書面程序。實驗室記錄應當按照6.6節(jié)中所述要求保存。

　　11.12 All specifications, sampling plans, and test procedures should be scientifically sound and appropriate to ensure that raw materials, intermediates, APIs, and labels and packaging materials conform to established standards of quality and/or purity. Specifications and test procedures should be consistent with those included in the registration/filing. There can be specifications in addition to those in the registration/filing. Specifications, sampling plans, and test procedures, including changes to them, should be drafted by the appropriate organizational unit and reviewed and approved by the quality unit(s).

　　11.12 所有的質量標準，取樣方案和測試程序都應當科學合理并適當，以確保原料、中間體、原料藥，標簽和包裝材料能達到規(guī)定的質量和/或純度標準。質量標準和測試方法應當與注冊/申報中的一致?？梢杂凶?申報以外的附加的質量標準。質量標準、取樣方案和測試程序，包括相應的變更，應當由相關的組織機構起草，并由質量部門審核、批準。

　　11.13 Appropriate specifications should be established for APIs in accordance with accepted standards and consistent with the manufacturing process. The specifications should include control of impurities (e.g., organic impurities, inorganic impurities, and residual solvents). If the API has a specification for microbiological purity, appropriate action limits for total microbial counts and objectionable organisms should be established and met. If the API has a specification for endotoxins, appropriate action limits should be established and met.

　　11.13 應當根據(jù)已接受的標準和與生產工藝的一致性來制訂合適的原料藥質量標準。質量標準應當包括對雜質的控制(如有機雜質、無機雜質，和殘留溶劑)。如果原料藥有微生物純度的質量規(guī)格，應當制訂并達到合適的總菌落數(shù)和致病菌的處置限度。如果原料藥有內毒素的質量規(guī)格，應當制訂并達到合適的內毒素的處置限度。

　　11.14 Laboratory controls should be followed and documented at the time of performance. Any departures from the above-described procedures should be documented and explained.

　　11.14 應當遵守實驗室控制，并邊操作邊記錄。對上述程序的任何偏離都應當有記錄并作解釋。

　　11.15 Any out-of-specification result obtained should be investigated and documented according to a procedure. This procedure should include analysis of the data, assessment of whether a significant problem exists, allocation of the tasks for corrective actions, and conclusions. Any resampling and/or retesting after OOS results should be performed according to a documented procedure.

　　11.15 得到的任何不符合質量標準的結果都應當按照程序進行調查，并備案。該程序應當要求對數(shù)據(jù)進行分析，評價是否有值得注意的問題存在，分配整改措施的任務和結論。發(fā)現(xiàn)不符合質量標準的結果后，任何重新取樣和/或重新測試都應當按照成文的程序進行。

　　11.16 Reagents and standard solutions should be prepared and labeled following written procedures. Use by dates should be applied, as appropriate, for analytical reagents or standard solutions.

　　11.16 應當按照書面程序來配制試劑和標準溶液以及貼標簽。分析試劑或標準溶液應當酌情采用用至日期。

　　11.17 Primary reference standards should be obtained, as appropriate, for the manufacture of APIs. The source of each primary reference standard should be documented. Records should be maintained of each primary reference standard’s storage and use in accordance with the supplier’s recommendations. Primary reference standards obtained from an officially recognized source are normally used without testing if stored under conditions consistent with the supplier’s recommendations.

　　11.17 原料藥生產時應當酌情獲得合適的基本參考標準品。每一個基本參考標準品的來源要備案。應根據(jù)標準品供應商的要求進行標準品的儲存和使用，并進行相應記錄同時保存記錄。對于從官方認可的渠道獲得的基本參考標準品，在按照供應商的建議的保存條件進行保存的情況下，通常無需檢驗就可以使用。

　　11.18 Where a primary reference standard is not available from an officially recognized source, an in-house primary standard should be established. Appropriate testing should be performed to establish fully the identity and purity of the primary reference standard. Appropriate documentation of this testing should be maintained.

　　11.18 從官方認可的貨源處無法得到基本參考標準品時，應該制備一個內部基本標準品。應當做合適的測試來全面制訂該基本參考標準品的鑒別和純度。該測試的相關證明文件應當保留。

　　11.19 Secondary reference standards should be appropriately prepared, identified, tested, approved, and stored. The suitability of each batch of secondary reference standard should be determined prior to first use by comparing against a primary reference standard. Each batch of secondary reference standard should be periodically requalified in accordance with a written protocol.

　　11.19 二級參考標準品應當用合適的方法來制備，鑒別，測試，批準和儲存。每一批二級參考標準品在第一次使用前，應當與基本參考標準品進行比較，來確定其適用性。每一批二級參考標準品應當根據(jù)書面方案，定期進行重新確認。

　　11.2 Testing of Intermediates and APIs 11.2 中間體和原料藥的測試

　　11.20 For each batch of intermediate and API, appropriate laboratory tests should be conducted to determine conformance to specifications.

　　11.20 每一批中間體和原料藥都應當進行適當?shù)膶嶒炇覝y試，以確定是否符合質量標準。

　　11.21 An impurity profile describing the identified and unidentified impurities present in a typical batch produced by a specific controlled production process should normally be established for each API. The impurity profile should include the identity or some qualitative analytical designation (e.g., retention time), the range of each impurity observed, and classification of each identified impurity (e.g., inorganic, organic, solvent). The impurity profile is normally dependent upon the production process and origin of the API. Impurity profiles are normally not necessary for APIs from herbal or animal tissue origin. Biotechnology considerations are covered in ICH guidance Q6B.

　　11.21 每一種原料藥都應當有雜質概況，描述用一特別控制的生產工藝生產出的典型批號中存在的已確定和未確定的雜質。雜質概況應當包括觀測到的每一個雜質的鑒別或某個定量分析的標志(如保留時間)、范圍，以及已確定雜質的類別(如有機的、無機的、溶劑)。雜質概況一般與原料藥的生產工藝和起源有關。從植物或動物組織中得到的原料藥通常不一定要有雜質概況。ICH指南Q6B講述了對生物技術的考慮。

　　11.22 The impurity profile should be compared at appropriate intervals against the impurity profile in the regulatory submission or compared against historical data to detect changes to the API resulting from modifications in raw materials, equipment operating parameters, or the production process.

　　11.22 每隔一端時間應當將雜質概況與藥政申報中的雜質概況，或與以往的數(shù)據(jù)比較，以查明原材料、設備操作參數(shù)和生產工藝的修改所造成的原料藥的變化。

　　11.23 Appropriate microbiological tests should be conducted on each batch of intermediate and API where microbial quality is specified.

　　11.23 在規(guī)定微生物質量時，應當對每一批中間體和原料藥作適當?shù)奈⑸餃y試。

　　11.3 Validation of Analytical Procedures 11.3 分析方法的驗證

　　See Section 12. 見第12章

　　11.4 Certificates of Analysis 11.4 分析報告單

　　11.40 Authentic certificates of analysis should be issued for each batch of intermediate or API on request.

　　11.40 有要求時應當為每一批中間體或原料藥出具可信的分析報告單。

　　11.41 Information on the name of the intermediate or API including, where appropriate, its grade, the batch number, and the date of release should be provided on the certificate of analysis. For intermediates or APIs with an expiry date, the expiry date should be provided on the label and certificate of analysis. For intermediates or APIs with a retest date, the retest date should be indicated on the label and/or certificate of analysis.

　　11.41 分析報告單應當提供中間體或原料藥的名稱，必要時包括其等級、批號和放行日期。有有效期的中間體或原料藥，應當在標簽和分析報告單上提供失效期。有復驗期的中間體或原料藥，應當在標簽和/或分析報告單上提供復驗期。

　　11.42 The certificate should list each test performed in accordance with compendial or customer requirements, including the acceptance limits, and the numerical results obtained (if test results are numerical).

　　11.42 報告單應當列明按藥典或客戶要求所做的各項測試，包括可接受的限度，和得到的數(shù)值結果(如果測試結果是數(shù)值)。

　　11.43 Certificates should be dated and signed by authorized personnel of the quality unit(s) and should show the name, address, and telephone number of the original manufacturer. Where the analysis has been carried out by a repacker or reprocessor, the certificate of analysis should show the name, address, and telephone number of the repacker/reprocessor and reference the name of the original manufacturer.

　　11.43 報告單應當由指定的質量部門人員寫明日期并簽名，而且應當注明原生產商的名稱、地址和電話。如果測試是由重新包裝者或重新加工者做的，則分析報告單應當注明重新包裝者/重新加工者的名稱、地址和電話，并附注原生產商的名稱。

　　11.44 If new certificates are issued by or on behalf of repackers/reprocessors, agents or brokers, these certificates should show the name, address, and telephone number of the laboratory that performed the analysis. They should also contain a reference to the name and address of the original manufacturer and to the original batch certificate, a copy of which should be attached.

　　11.44 如果由重新包裝者/重新加工者、代理人，中間人或由其代表出具新的報告單，這些報告單上應當注明做分析的實驗室的名稱、地址和電話。還應當附注原生產商的名稱和地址，并附上原始檢驗報告單復印件。

　　11.5 Stability Monitoring of APIs 11.5 原料藥的穩(wěn)定性監(jiān)測

　　11.50 A documented, on-going testing program should be established to monitor the stability characteristics of APIs, and the results should be used to confirm appropriate storage conditions and retest or expiry dates.

　　11.50 應當建立一個文件化的、持續(xù)監(jiān)測的規(guī)程，以監(jiān)測原料藥的穩(wěn)定性特征，而其結果應當用于確定適當?shù)馁A存條件和復驗日期或有效期。

　　11.51 The test procedures used in stability testing should be validated and be stability indicating.

　　11.51 用于穩(wěn)定性測試的測試規(guī)程應當經過驗證，并能顯示穩(wěn)定性。

　　11.52 Stability samples should be stored in containers that simulate the market container. For example, if the API is marketed in bags within fiber drums, stability samples can be packaged in bags of the same material and in small-scale drums of similar or identical material composition to the market drums.

　　11.52 穩(wěn)定性樣品應當存放在與銷售容器相仿的容器中。例如，如果原料藥是裝在纖維桶內的袋子里銷售的，穩(wěn)定性樣品可以包裝在同樣材料的袋中，放入相似或相同與銷售容器的材料的材料較小的桶中。

　　11.53 Normally, the first three commercial production batches should be placed on the stability monitoring program to confirm the retest or expiry date. However, where data from previous studies show that the API is expected to remain stable for at least 2 years, fewer than three batches can be used.

　　11.53 通常頭三個銷售批號應當放入穩(wěn)定性監(jiān)測計劃，以證實復驗期或有效期。然而，如果以前的研究數(shù)據(jù)表明原料藥至少在兩年內可望保持穩(wěn)定，則所用的批號可少于三批。

　　11.54 Thereafter, at least one batch per year of API manufactured (unless none is produced that year) should be added to the stability monitoring program and tested at least annually to confirm the stability.

　　11.54 以后每年至少應當加一批生產的原料藥到穩(wěn)定性監(jiān)測計劃(除非當年不生產)，并且至少每年測試，以證實其穩(wěn)定性。

　　11.55 For APIs with short shelf-lives, testing should be done more frequently. For example, for those biotechnological/biologic and other APIs with shelf-lives of one year or less, stability samples should be obtained and should be tested monthly for the first three months, and at 3-month intervals after that. When data exist that confirm that the stability of the API is not compromised, elimination of specific test intervals (e.g., 9-month testing) can be considered.

　　11.55 對于儲存期較短的原料藥，應當更頻繁的測試。例如，儲存期不超過一年的生物工程/生物制品或其它原料藥，應當有穩(wěn)定性樣品，頭三個月內應當每月測試，隨后每三個月測試一次。如果有數(shù)據(jù)表明原料藥的穩(wěn)定性不會受影響，可以考取消特定的測試間隔(如9個月的測試)。

　　11.56 Where appropriate, the stability storage conditions should be consistent with the ICH guidances on stability.

　　11.56 根據(jù)情況，穩(wěn)定性儲存條件應當與ICH的穩(wěn)定性指南一致。

　　11.6 Expiry and Retest Dating 11.6 有效期和復驗期

　　11.60 When an intermediate is intended to be transferred outside the control of the manufacturer’s material management system and an expiry or retest date is assigned, supporting stability information should be available (e.g., published data, test results).

　　11.60 當一個中間體要運送到生產商物料管理系統(tǒng)控制范圍以外，并已制定了有效期或復驗期時，那就應當有支持的穩(wěn)定性信息(如發(fā)表的數(shù)據(jù)、測試結果)。

　　11.61 An API expiry or retest date should be based on an evaluation of data derived from stability studies. Common practice is to use a retest date, not an expiration date.

　　11.61 一種原料藥的有效期或復驗期應當基于穩(wěn)定性研究所得數(shù)據(jù)的評估。通常會用復驗期，而不用有效期。

　　11.62 Preliminary API expiry or retest dates can be based on pilot scale batches if (1) the pilot batches employ a method of manufacture and procedure that simulates the final process to be used on a commercial manufacturing scale and (2) the quality of the API represents the material to be made on a commercial scale.

　　11.62 如果(1)中試批號采用的生產方法和規(guī)程是模擬用于商業(yè)生產規(guī)模的最終工藝，而且(2)原料藥的質量代表了商業(yè)生產規(guī)模的物料，則原料藥的初步有效期或復驗期可基于中試規(guī)模的批號。

　　11.63 A representative sample should be taken for the purpose of performing a retest.

　　11.63 應當取一個具有代表性的樣品進行復驗。

　　11.7 Reserve/Retention Samples 11.7 留樣

　　11.70 The packaging and holding of reserve samples is for the purpose of potential future evaluation of the quality of batches of API and not for future stability testing purposes.

　　11.70 留樣的包裝和儲存是為了今后可能會對原料藥批號的質量進行評價，而不是以將來的穩(wěn)定性測試為目的的。

　　11.71 Appropriately identified reserve samples of each API batch should be retained for 1 year after the expiry date of the batch assigned by the manufacturer, or for 3 years after distribution of the batch, whichever is longer. For APIs with retest dates, similar reserve samples should be retained for 3 years after the batch is completely distributed by the manufacturer.

　　11.71 適當標識的每一批原料藥的留樣應當保留到由生產商規(guī)定的該批號的有效期滿后一年，或該批產品銷售后三年，以較長時間為準。對于有復驗期的原料藥，相似的留樣應當保留到生產商全部銷售完該批號后三年。

　　11.72 The reserve sample should be stored in the same packaging system in which the API is stored or in one that is equivalent to or more protective than the marketed packaging system. Sufficient quantities should be retained to conduct at least two full compendial analyses or, when there is no pharmacopoeial monograph, two full specification analyses.

　　11.72 留樣應當儲存在原料藥儲存的同樣的包裝系統(tǒng)中，或者與銷售包裝相同，或更具保護性。應當留足夠的量來至少做兩次法定的全檢，或者沒有藥典專論時，兩次質量標準的全檢。

　　12. VALIDATION 12.驗證

　　12.1 Validation Policy 12.1 驗證方針

　　12.10 The company’s overall policy, intentions, and approach to validation, including the validation of production processes, cleaning procedures, analytical methods, in-process control test procedures, computerized systems, and persons responsible for design, review, approval, and documentation of each validation phase, should be documented.

　　12.10 公司的總體驗證原則、目的和方法，包括生產工藝、清潔規(guī)程、分析方法、過程控制測試規(guī)程以及計算機系統(tǒng)的驗證和負責設計、審核、批準和為各個驗證階段提供證明文件的人員都應當明文規(guī)定。

　　12.11 The critical parameters/attributes should normally be identified during the development stage or from historical data, and the necessary ranges for the reproducible operation should be defined. This should include:

　　Defining the API in terms of its critical product attributes

　　Identifying process parameters that could affect the critical quality attributes of the API

　　Determining the range for each critical process parameter expected to be used during routine manufacturing and process control

　　12.11 關鍵的工藝參數(shù)/屬性通常應當在開發(fā)階段或從以往的數(shù)據(jù)中加以確定，并應當規(guī)定工藝可重復性操作所必需的范圍。包括：

　　定義原料藥生產的關鍵產品屬性;

　　確認可能對原料藥關鍵質量屬性有影響的工藝參數(shù);

　　確定在日常生產和工藝控制中會用到的每個關鍵工藝參數(shù)的范圍。

　　12.12 Validation should extend to those operations determined to be critical to the quality and purity of the API.

　　12.12 驗證還應當涉及到那些對原料藥質量和純度至關重要的操作。

　　12.2 Validation Documentation 12.2 驗證文件

　　12.20 A written validation protocol should be established that specifies how validation of a particular process will be conducted. The protocol should be reviewed and approved by the quality unit(s) and other designated units.

　　12.20 應當有書面的驗證方案，闡明如何進行某個工藝的驗證。驗證方案應當由質量部門和其他指定的部門審核并批準。

　　12.21 The validation protocol should specify critical process steps and acceptance criteria as well as the type of validation to be conducted (e.g., retrospective, prospective, concurrent) and the number of process runs.

　　12.21 驗證方案應當明確規(guī)定驗證的關鍵工序和認可標準，所要進行的驗證類型(回顧性驗證、預驗證、同步驗證)和工序運轉的次數(shù)。

　　12.22 A validation report that cross-references the validation protocol should be prepared, summarizing the results obtained, commenting on any deviations observed, and drawing the appropriate conclusions, including recommending changes to correct deficiencies.

　　12.22 應當擬定一份能交叉引用驗證方案的驗證報告，概括得到的結果，說明發(fā)現(xiàn)的任何偏差，并作出必要的結論，包括為整改而必須做的變更。

　　12.23 Any variations from the validation protocol should be documented with appropriate justification.

　　12.23 任何對驗證方案的偏離都應當歸檔備案，并作適當說明。

　　12.3 Qualification 12.3 確認

　　12.30 Before initiating process validation activities, appropriate qualification of critical equipment and ancillary systems should be completed. Qualification is usually carried out by conducting the following activities, individually or combined:

　　Design Qualification (DQ): documented verification that the proposed design of the facilities, equipment, or systems is suitable for the intended purpose

　　Installation Qualification (IQ): documented verification that the equipment or systems, as installed or modified, comply with the approved design, the manufacturer’s recommendations and/or user requirements

　　Operational Qualification (OQ): documented verification that the equipment or systems, as installed or modified, perform as intended throughout the anticipated operating ranges

　　Performance Qualification (PQ): documented verification that the equipment and ancillary systems, as connected together, can perform effectively and reproducibly based on the approved process method and specifications

　　12.30 在開始工藝驗證活動前，應當完成適當?shù)年P鍵設備和輔助系統(tǒng)的確認。確認一般是通過單獨或聯(lián)合進行以下活動來實行的：

　　設計確認(DQ)：是對提議的設施、設備或系統(tǒng)適用于預期的目的的一種成文的確認;

　　安裝確認(IQ)：對安裝好的和調整過的設備或系統(tǒng)符合已批準的設計、制造商建議的和/或用戶的要求的成文的確認;

　　運行確認(OQ)：對安裝好的和調整過的設備或系統(tǒng)能在整個預期的操作范圍內按要求運行的成文的確認;

　　性能確認(PQ)：是對設備或其輔助系統(tǒng)在相互連接后，能根據(jù)已獲準工藝方法和質量標準有效的、重現(xiàn)的進行運轉的成文的確認。

　　12.4 Approaches to Process Validation 12.4 工藝驗證的方法

　　12.40 Process Validation (PV) is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes.

　　12.40 工藝驗證(PV)是證明在預定的工藝參數(shù)范圍內運行的工藝能持續(xù)有效地生產出符合預定的質量標準和質量屬性的中間體或原料藥的證明文件。

　　12.41 There are three approaches to validation. Prospective validation is the preferred approach, but there are situations where the other approaches can be used. These approaches and their applicability are discussed here.

　　12.41 驗證方法有三種，預驗證是首選的方法，但在其它方法可采用的情況下也有例外。這些方法及其適用性見下文。

　　12.42 Prospective validation should normally be performed for all API processes as defined in 12.1. Prospective validation for an API process should be completed before the commercial distribution of the final drug product manufactured from that API.

　　12.42 12.1中所述的所有原料藥生產工藝一般來說都應當進行預驗證。對原料藥工藝所作的預驗證的結果，必須在用該原料藥制成的制劑產品銷售前完成。

　　12.43 Concurrent validation can be conducted when data from replicate production runs are unavailable because only a limited number of API batches have been produced, API batches are produced infrequently, or API batches are produced by a validated process that has been modified. Prior to the completion of concurrent validation, batches can be released and used in final drug product for commercial distribution based on thorough monitoring and testing of the API batches. 12.43 有時由于原料藥生產批號有限，原料藥批號不是經常生產，或原料藥是用驗證過的，但已變更的工藝生產的，無法從連續(xù)生產中得到數(shù)據(jù)，可進行同步驗證。同步驗證完成之前，只要對原料藥批號進行了充分的監(jiān)控和測試，這些批號可以放行并用于最終制劑藥的商業(yè)銷售。

　　12.44 An exception can be made for retrospective validation well-established processes that have been used without significant changes to API quality due to changes in raw materials, equipment, systems, facilities, or the production process. This validation approach may be used where:

　　1. Critical quality attributes and critical process parameters have been identified

　　2. Appropriate in-process acceptance criteria and controls have been established

　　3. There have not been significant process/product failures attributable to causes other than operator error or equipment failures unrelated to equipment suitability

　　4. Impurity profiles have been established for the existing API

　　12.44 某些工藝已確立了很久，而且原料、設備、系統(tǒng)、設施或生產工藝的變化對原料藥的質量沒有明顯的影響，此時就可以例外地進行回顧性驗證。這一驗證方法適合于下列情況：

　　1. 關鍵質量屬性和關鍵工藝參數(shù)均已確定;

　　2. 已確立了合適的過程控制和認可標準;

　　3. 從來沒有因為除了操作人員失誤或設備故障這些與設備適應性無關的因素之外的原因而造成值得注意的工藝/產品的不合格;

　　4. 現(xiàn)有原料藥的雜質概況已確定。

　　12.45 Batches selected for retrospective validation should be representative of all batches produced during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency. Retained samples can be tested to obtain data to retrospectively validate the process.

　　12.45 回顧性驗證選用的批號應當能夠代表審核時段中的所有批號，包括任何不合格的批號，而且應當有足夠的批數(shù)來證明工藝的穩(wěn)定?？捎脺y試留樣來獲取回顧性工藝驗證數(shù)據(jù)。

　　12.5 Process Validation Program 12.5 工藝驗證的程序

　　12.50 The number of process runs for validation should depend on the complexity of the process or the magnitude of the process change being considered. For prospective and concurrent validation, three consecutive successful production batches should be used as a guide, but there may be situations where additional process runs are warranted to prove consistency of the process (e.g., complex API processes or API processes with prolonged completion times). For retrospective validation, generally data from 10 to 30 consecutive batches should be examined to assess process consistency, but fewer batches can be examined if justified.

　　12.50 驗證時生產工藝的運行次數(shù)，應當由工藝的復雜性或要考慮的工藝變更的大小來決定。作為一個指南，預驗證和同步驗證應當采用三個連續(xù)的、成功的批號，但可能在某些情況下需要更多的批號來保證工藝的一致性(例如，復雜的原料藥生產工藝，或原料藥工藝耗時很長)?；仡櫺则炞C一般應當審查從10到30個連續(xù)批號得到的數(shù)據(jù)來評估工藝的一致性，但是，如果有理由，審查的批數(shù)可以少些。

　　12.51 Critical process parameters should be controlled and monitored during process validation studies. Process parameters unrelated to quality, such as variables controlled to minimize energy consumption or equipment use, need not be included in the process validation.

　　12.51 在工藝驗證研究時應當控制并監(jiān)測關鍵的工藝參數(shù)。與質量無關的參數(shù)，例如為了將能量消耗或所用設備減到最低而控制的變量，無需包括在工藝驗證中。

　　12.52 Process validation should confirm that the impurity profile for each API is within the limits specified. The impurity profile should be comparable to, or better than, historical data and, where applicable, the profile determined during process development or for batches used for pivotal clinical and toxicological studies.

　　12.52 工藝驗證應當確認每一個原料藥的雜質概況都在規(guī)定的限度內。雜質概況應當與以往的數(shù)據(jù)相似或更好，如果可能，應當與工藝開發(fā)階段確定的雜質概況，或用于關鍵的臨床和毒理研究的批號的數(shù)據(jù)相似或更好。

　　12.6 Periodic Review of Validated Systems 12.6驗證系統(tǒng)的定期審核

　　12.60 Systems and processes should be periodically evaluated to verify that they are still operating in a valid manner. Where no significant changes have been made to the system or process, and a quality review confirms that the system or process is consistently producing material meeting its specifications, there is normally no need for revalidation.

　　12.60 應當對系統(tǒng)和工藝進行周期性的評價，以確認它們仍然能有效地運作。如果系統(tǒng)或工藝并沒有大的變動，而質量回顧證實系統(tǒng)和工藝在穩(wěn)定地生產著符合其質量標準的物料，通常就不必驗證了。

　　12.7 Cleaning Validation 12.7 清洗驗證

　　12.70 Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality. For example, in early production it may be unnecessary to validate equipment cleaning procedures where residues are removed by subsequent purification steps. 12.70 通常應當驗證清洗程序。一般來說，清洗驗證應當針對那些如果受到污染或偶然帶入異物就會對原料藥的質量帶來極大危險的情況或工序。例如，在生產的前期階段，可能就無需驗證設備的清洗程序，那里的殘留物會被后面的純化步驟除去。

　　12.71 Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a representative intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability.

　　12.71 清洗程序的驗證應當反映實際的設備使用情況。如果多個原料藥或中間體都在同一設備內生產，而該設備用同一個程序清洗，那么就要選擇代表性的中間體或原料藥來作清洗驗證。應當根據(jù)溶解性，清洗難度，以及依據(jù)效價、毒性和穩(wěn)定性計算出來的殘留物的限量來作選擇。

　　12.72 The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods. The protocol should also indicate the type of samples to be obtained and how they are collected and labeled.

　　12.72 清洗驗證方案應當描述要清洗的設備、程序、物料、可接受的清洗程度、要監(jiān)測和控制的參數(shù)、以及分析方法。方案還應當指出要得到的樣品的種類，和如何取樣及標記。

　　12.73 Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers).

　　12.73 取樣應當包括擦拭法、沖洗法或可供選擇的方法(如直接萃取)，如果合適的話，同時檢測不溶性和可溶性的殘留物。所用的取樣方法應當能定量地檢測出清洗之后留在設備表面的殘留物質。當與產品接觸的表面，由于設備的設計和/或工藝限制(如，軟管的內表面，運輸管道，反應釜的開口很小或裝卸有毒物質，以及一些小的復雜的設備，如微粉粉碎機，流化床式微粉機)，很難觸及時，擦拭取樣就無法實施。

　　12.74 Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method’s attainable recovery level should be established. Residue limits should be practical, achievable, verifiable, and based on the most deleterious residue. Limits can be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious component.

　　12.74 應當采用驗證過的、具有檢測殘留物或污染物的靈敏度的分析方法。每一個分析方法的檢測限度必須足夠靈敏，來檢測到殘留物或污染物的規(guī)定的可接受水平。應當規(guī)定方法的可達到的回收率。殘留物的限度切實可行的，可檢測的，并由最有害的殘留物來確定。可以根據(jù)原料藥或其最有害的組分的已知最小藥理、毒理或生理活性濃度來制定限度。

　　12.75 Equipment cleaning/sanitation studies should address microbiological and endotoxin contamination for those processes where there is a need to reduce total microbiological count or endotoxins in the API, or other processes where such contamination could be of concern (e.g., non-sterile APIs used to manufacture sterile products).

　　12.75 對于需要降低原料藥中的總微生物數(shù)或內毒素的工藝，或擔心此類污染的其它工藝(如，用于生產無菌產品的非無菌原料藥)，設備清洗/消毒的研究應當對付微生物和內毒素污染。

　　12.76 Cleaning procedures should be monitored at appropriate intervals after validation to ensure that these procedures are effective when used during routine production. Equipment cleanliness can be monitored by analytical testing and visual examination, where feasible. Visual inspection can allow detection of gross contamination concentrated in small areas that could otherwise go undetected by sampling and/or analysis.

　　12.76 驗證后，清洗程序應當在適當?shù)臅r間間隔進行監(jiān)測，以確保這些程序用在日常生產中是有效的。設備的清潔程度可以根據(jù)可行性通過測試或目測來監(jiān)測。目測能檢測到用取樣和/或分析方法測不到的集中在小面積上的嚴重的污染。

　　12.8 Validation of Analytical Methods 12.8 分析方法的驗證

　　12.80 Analytical methods should be validated unless the method employed is included in the relevant pharmacopoeia or other recognized standard reference. The suitability of all testing methods used should nonetheless be verified under actual conditions of use and documented. 12.80 分析方法應當進行驗證，除非采用的方法列在相關的藥典或其它公認的參照標準中。然而，所有測試方法的適應性應當在實際使用條件下加以證實，并歸檔備查。

　　12.81 Methods should be validated to include consideration of characteristics included within the ICH guidances on validation of analytical methods. The degree of analytical validation performed should reflect the purpose of the analysis and the stage of the API production process.

　　12.81 方法驗證應當包括ICH分析方法驗證指南中的特征的考慮。方法驗證進行的程度應當反映分析的目的和原料藥生產工藝的步驟。

　　12.82 Appropriate qualification of analytical equipment should be considered before initiating validation of analytical methods.

　　12.82 在開始分析方法驗證前，應當考慮對分析設備的適當?shù)拇_認。

　　12.83 Complete records should be maintained of any modification of a validated analytical method. Such records should include the reason for the modification and appropriate data to verify that the modification produces results that are as accurate and reliable as the established method. 12.83已驗證過的分析方法的任何修改都應當保存完整的記錄。這類記錄應當包括修改的理由和合適的數(shù)據(jù)，以證實該修改所產生的結果和規(guī)定的方法同樣準確、可靠。