Followers of FDA warning letters and Form 483s will have noticed that over the last 12 – 18 months, there have been increasing mention of data integrity issues around manufacturing data, often as a result of outdated equipment and practices, such as:

　　FDA 警告信和 483 表發現，在過去 12 到 18 個月中，生產數據相關的數據完整性問題越來越多，這通常是由于老舊的設備和做法引起的，例如：

　　No backup of data from the SCADA system

　　SCADA系統數據沒有備份

　　No logs of alarm messages for in-process excursions for critical manufacturing operations

　　對于關鍵生產操作，沒有用于記錄生產過程漂移報警消息的日志

　　No tracking or trending of process alarms

　　過程報警沒有跟蹤或趨勢分析

　　Personnel were able to, and did, change process limits to values outside those specified in the batch recipe

　　操作人員具備將工藝限度更改超出批處理配方范圍的權限，且確實這樣做了。

　　Process parameters in?batch records jar with?the values recorded by the programmable logic controller （PLC）？of?manufacturing?machine.

　　批記錄中記錄的工藝參數與設備PLC上的數據相矛盾。

　　Standalone manufacturing equipment?not equipped with HMI/PLC/SCADA system. There is no time stamped audit trail, data management, alarm management, archival and retrieval of records on these standalone manufacturing equipment.”

　　單機版生產設備未配備 HMI/PLC/SCADA 系統。這些單機版生產設備上沒有帶時間戳的審計最終、數據管理、報警管理、記錄存檔和檢索。

　　典型的警告信如下：

　　印度Indoco Remedies Limited （PlantI）

　　While multiple batch records of （b）（4） mg tablet included handwritten values routinely within process parameters, the values recorded by the programmable logic controller （PLC） of your compression machine were frequently outside your established process parameters. For example, （b）（4） mg batch （b）（4） had compression force valuesh and written （b）（4） in the batch record ranging from （b）（4） （your limit was （b）（4））。

　　雖然多批XX片劑生產記錄中有手寫值均在工藝參數范圍內，但你們壓片機PLC所記錄的值頻繁超出你們設定的工藝參數。例如，批記錄中手寫的XX片劑的壓力值為XX（你們的限度為XX）。

　　However, the PLC data recorded individual values ranging from （b）（4） for the same time period. In addition to compression force values, handwritten values for filling depth and automatic weight control （AWC） did not accurately reflect the values within the PLC data.

　　同一時間段內PLC數據所記錄單值從XX至XX。除了壓力值外，自動重量控制（AWC）和充填高度的手寫值亦不能準確反映PLC數據中的值。

　　An inspection conducted by the （b）（4） in March 2018 found similar discrepancies between the compression force values in batch records and PLC data.

　　2018年3月由XX執行的檢查中發現類似缺陷，看到批記錄中和PLC中的壓力值有差異。

　　Your response acknowledged discrepancies including missing data, “mis-matched data,” non-contemporaneous entries, and other inconsistencies in your batch records. It also acknowledged inadequate procedures for compression machine setup and adjustments during operations intended to maintain process control, and a lack of documentation of these critical activities.

　　你們的回復提及這些情況，包括數據缺失、“不匹配的數據”、未同步錄入和其它批記錄中的不一致情況，還承認用于的壓片機設置和運行過程中為維持工藝控制而進行調整的程序不夠充分，并缺乏對這些關鍵動作的文件記錄。

　　Your response is insufficient. The integrity of all data within your manufacturing records is called into question by the actions of your staff involved in compression operations. You did not commit to perform a comprehensive retrospective evaluation of the integrity of data throughout your manufacturing operation. You also did not adequately address how you will ensure that AWC is consistently maintained and documented throughout compression by providing detailed procedures for setup and changing of parameters during a batch, and address how all associated parameters will be controlled.

　　你們的回復是不充分的。你們生產記錄中所有數據的完整性因為你們壓片操作員工的行為而引起質疑。你們未承諾對整個生產操作中的數據完整性進行全面回顧性評估，亦未充分說明你們將如何通過提供詳細的參數設置和參數修改程序以確保自動重量控制（AWC）在整個壓片過程中得到一致的保持和記錄，亦未說明如何對所有相關參數進行控制。

　　It is essential that you use appropriate continuous process controls to promptly respond to variation in your process, and prevent sporadic loss of control during processing. Additionally, you did not sufficiently detail your batch record changes for each strength of （b）（4） tablets.

　　使用適當的連續工藝控制以對你們工藝波動進行快速響應，防止生產過程中偶發性失控是非常有必要的。另外你們亦未足夠詳細地說明你們對每個規格的XX片劑的批記錄修改情況。

　　In response to this letter, provide:?

　　回復此函，請提交：

　　Procedures that establish use of appropriate AWC and other control procedures in your compression operation. This includes but is not limited to detailed procedures for batch setup and subsequent adjustments for AWC; identification of all parameters that can impact consistency of compression; and complete documentation of all batch production activities.

　　建立適當AWC和其它壓片操作控制程序，其中包括但不僅限于AWC的批設置和后續調整詳細程序、識別出所有可能影響壓片一致性的參數，以及所有批生產活動的完整記錄。

　　Your updated master production and control batch records for drug products that fully document each manufacturing operation. Also submit your most recent executed batch production and control record with full machine printouts for each strength of your （b）（4） ? ? tablet drug product.

　　修訂后可以完整記錄每個生產操作的藥品主生產和控制記錄以。亦請提交你們最近執行的批生產和控制記錄，包括你們XX片劑每個規格的完整設備打印件。

　　An independent review of all your process parameters for the manufacture of your （b）（4） dosage form drug products to ensure adequacy of ranges, setup parameters, and in-process monitoring for detecting variation in your process.

　　一份對你們XX劑型藥品生產的所有工藝參數的獨立審核，以確保范圍、設置參數和過程監測足以發現生產過程的波動。

　　A data-driven and scientifically sound program that identifies and controls variability, to ensure production and packaging processes consistently meet appropriate manufacturing standards and parameters. This includes, but is not limited to, evaluating suitability of equipment for its intended use, ensuring quality of input materials, and determining the capability and reliability of each manufacturing process step and control.

　　由數據支持的發現和控制波動的科學合理程序，以確保生產和包裝過程能一直符合適當的生產標準和參數。其中包括但不僅限于評估設備是否適合其既定用途、確保輸入物料的質量，以及確定每個生產工藝步驟和控制的能力與可靠性。

　　Your corrective action and preventive action （CAPA） plan as requested in the Data Integrity Remediation section of this letter below. As one facet of the comprehensive CAPA plan, an independent reviewer（s） should provide a thorough retrospective assessment of ?manufacturing data validity since February 1, 2016, and perform thorough interviews of production staff （both operators and supervisors）。 This assessment should augment the internal investigation that you have performed and include but not be limited to an independent review of the integrity of （b）（4） in-process checks （b）（4） and disintegration testing, and evaluate any missing compression operation data. The retrospective assessment should fully determine the degree to which this in-process testing data has information gaps （whether due to omissions or lost data）， personnel sign-offs occurred at times where staff were not present, and to what extent current data can be relied upon for ? ? this product and other products.

　　本函以下數據完整性補救措施部分中要求的CAPA計劃。作為CAPA計劃的一部分，應由一位獨立審核人員提交一份對2016年2月以來的生產數據有效性的徹底回顧性評估，并對生產員工進行深入面談（操作員和主管）。此項評估應在你們之前已執行調查的基礎上進行擴展，包括但不僅限于對中控檢查XX和崩解試驗完整性的獨立審核，以及對所有缺失壓片操作數據的評估。回顧性評估應全面確定該中控測試數據資料缺失的程度（是否由于疏忽或數據丟失）、員工不在場時的簽名情況，以及該產品和其它產品當前數據可依賴的程度。

　　印度Sun Pharmaceutical Industries Ltd.

　　You lacked audit trails or other sufficient controls to facilitate traceability of the individuals who access each of the programmable logic controller （PLC） levels or Man-Machine Interface （MMI） equipment. You had no way to verify that individuals have not changed, adjusted, or modified equipment operation parameters.

　　你們缺乏審計追蹤或其他充分的控制，以方便跟蹤每個訪問可編程邏輯控制器 （PLC） 或人機接口 （MMI） 設備的個人。你們無從確認個人是否未更改、調整或修改設備操作參數。

　　Access to production equipment used in parenteral manufacturing and solid （b）（4） dosage forms used a password shared by four or five individuals to gain access to each individual piece of equipment and access level. During our inspection, your Executive Production and QA manager confirmed that the password was shared. Neither your operators nor your supervisors had individual passwords.

　　使用四五個人共享的密碼，訪問無菌和固體制劑產品生產設備，獲取每一個設備和接入級別。在我們檢查期間，你們的生產經理和 QA 經理承認密碼是共享的。你們的操作人員和主管都沒有單獨的密碼。？

　　During our inspection, firm officials also confirmed that you had not established or documented a control program to describe the roles and responsibilities of production equipment system administrators. There was also no record documenting the individuals who have access to the production equipment or the manner in which individual personnel access production equipment.

　　在我們的檢查中，公司官員還確認你們沒有建立或制訂控制程序來描述生產設備系統管理員的角色和職責。也沒有記錄寫明有權限訪問生產設備的人員或人員訪問生產設備的方式。？

　　In your response, you indicated that you have performed a comprehensive review of the PLCs and manufacturing equipment associated with the production of parenteral and solid （b）（4） dosage forms to assess your access controls and traceability to individual operators. You suggested that traceability to the individual operator could be determined through a hybrid system using the batch manufacturing record and equipment logbook. However, because you used shared login credentials that did not permit identification of a specific person using the shared login, you have not shown how your hybrid system could link specific actions to a specific operator.

　　在你們的回復中，你們表示對與無菌和固體劑型相關的 PLC 和生產設備進行了全面審查，以評估權限控制和人員的可追溯性。你們表示，對于操作人員的追溯性可以通過使用批生產記錄和設備日志的混合系統來確定。但是，由于你們使用共享的登錄憑據，無法識別使用共享登錄的具體人員，因此你們沒有辦法證明你們的混合系統如何將特定操作鏈接到集體的操作人員。？

　　In your response, you also stated that you will conduct a retrospective risk assessment to evaluate the effects of your deficient computerized system controls on the quality of the products manufactured using this automated equipment. However, you did not indicated the timeframe for your review, your criteria for evaluating the effects of these deficiencies on your products, or any actions needed for products within expiry.

　　在答復中，你們還表示，你們將進行回顧性風險評估，以評估你們計算機系統控制不足對使用此自動化設備生產的產品質量的影響。但是，你們沒有說明審核的時間范圍、評估這些缺陷對產品影響的標準，以及對效期內產品需要采取的任何措施。

　　Finally, in your response, you indicated that you planned to （b）（4）。 Your response is inadequate because you did not indicate what controls you will implement in the interim to assure that only authorized personnel change your production or other records.

　　最后，在答復中，你們表示計劃 （b）（4）。你們的回復是不充分的，因為你們沒有說明在此過渡期間將實施哪些控制措施，以確保只有經過授權的人員才可更改生產或其他記錄。

　　In response to the letter, provide your retrospective review and risk assessment of lots manufactured using equipment with shared passwords. Explain how you will identify which operators or personnel performed and recorded specific activities, your criteria for evaluating how manufacturing and quality of your products has been affected by your deficient controls, and any actions needed to assure the quality, safety, and efficacy of products within expiry.

　　回復此函，請對使用帶有共享密碼的設備所生產的批次進行回顧性審核和風險評估。說明你們將如何確定哪些操作人員或個人執行并記錄了哪些活動，用于評估產品的生產和質量如何受到的控制不足的影響的標準，以及為確保效期內產品的質量、安全性和有效性需要采取的措施。

　　END

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