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18 months, there have been increasing mention of data integrity issues around manufacturing data, often as a result of outdated equipment and practices, such as: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(fā)現(xiàn)，在過(guò)去 12 到 18 個(gè)月中，生產(chǎn)數(shù)據(jù)相關(guān)的數(shù)據(jù)完整性問(wèn)題越來(lái)越多，這通常是由于老舊的設(shè)備和做法引起的，例如：

　　No backup of data from the SCADA system

　　SCADA系統(tǒng)數(shù)據(jù)沒(méi)有備份

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

　　對(duì)于關(guān)鍵生產(chǎn)操作，沒(méi)有用于記錄生產(chǎn)過(guò)程漂移報(bào)警消息的日志

　　No tracking or trending of process alarms

　　過(guò)程報(bào)警沒(méi)有跟蹤或趨勢(shì)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(quán)限，且確實(shí)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(shù)與設(shè)備PLC上的數(shù)據(jù)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(jī)版生產(chǎn)設(shè)備未配備 HMI/PLC/SCADA 系統(tǒng)。這些單機(jī)版生產(chǎn)設(shè)備上沒(méi)有帶時(shí)間戳的審計(jì)最終、數(shù)據(jù)管理、報(bào)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(chǎn)記錄中有手寫(xiě)值均在工藝參數(shù)范圍內(nèi)，但你們壓片機(jī)PLC所記錄的值頻繁超出你們?cè)O(shè)定的工藝參數(shù)。例如，批記錄中手寫(xiě)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(shí)間段內(nèi)PLC數(shù)據(jù)所記錄單值從XX至XX。除了壓力值外，自動(dòng)重量控制（AWC）和充填高度的手寫(xiě)值亦不能準(zhǔn)確反映PLC數(shù)據(jù)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(zhí)行的檢查中發(fā)現(xiàn)類(lèi)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(fù)提及這些情況，包括數(shù)據(jù)缺失、“不匹配的數(shù)據(jù)”、未同步錄入和其它批記錄中的不一致情況，還承認(rèn)用于的壓片機(jī)設(shè)置和運(yùn)行過(guò)程中為維持工藝控制而進(jìn)行調(diào)整的程序不夠充分，并缺乏對(duì)這些關(guān)鍵動(dòng)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(fù)是不充分的。你們生產(chǎn)記錄中所有數(shù)據(jù)的完整性因?yàn)槟銈儔浩僮鲉T工的行為而引起質(zhì)疑。你們未承諾對(duì)整個(gè)生產(chǎn)操作中的數(shù)據(jù)完整性進(jìn)行全面回顧性評(píng)估，亦未充分說(shuō)明你們將如何通過(guò)提供詳細(xì)的參數(shù)設(shè)置和參數(shù)修改程序以確保自動(dòng)重量控制（AWC）在整個(gè)壓片過(guò)程中得到一致的保持和記錄，亦未說(shuō)明如何對(duì)所有相關(guān)參數(shù)進(jìn)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(dāng)?shù)倪B續(xù)工藝控制以對(duì)你們工藝波動(dòng)進(jìn)行快速響應(yīng)，防止生產(chǎn)過(guò)程中偶發(fā)性失控是非常有必要的。另外你們亦未足夠詳細(xì)地說(shuō)明你們對(duì)每個(gè)規(guī)格的XX片劑的批記錄修改情況。

　　In response to this letter, provide:?

　　回復(fù)此函，請(qǐng)?zhí)峤唬?/span>

　　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(dāng)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(shè)置和后續(xù)調(diào)整詳細(xì)程序、識(shí)別出所有可能影響壓片一致性的參數(shù)，以及所有批生產(chǎn)活動(dòng)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(gè)生產(chǎn)操作的藥品主生產(chǎn)和控制記錄以。亦請(qǐng)?zhí)峤荒銈冏罱鼒?zhí)行的批生產(chǎn)和控制記錄，包括你們XX片劑每個(gè)規(guī)格的完整設(shè)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(duì)你們XX劑型藥品生產(chǎn)的所有工藝參數(shù)的獨(dú)立審核，以確保范圍、設(shè)置參數(shù)和過(guò)程監(jiān)測(cè)足以發(fā)現(xiàn)生產(chǎn)過(guò)程的波動(dòng)。

　　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(shù)據(jù)支持的發(fā)現(xiàn)和控制波動(dòng)的科學(xué)合理程序，以確保生產(chǎn)和包裝過(guò)程能一直符合適當(dāng)?shù)纳a(chǎn)標(biāo)準(zhǔn)和參數(shù)。其中包括但不僅限于評(píng)估設(shè)備是否適合其既定用途、確保輸入物料的質(zhì)量，以及確定每個(gè)生產(chǎn)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(shù)據(jù)完整性補(bǔ)救措施部分中要求的CAPA計(jì)劃。作為CAPA計(jì)劃的一部分，應(yīng)由一位獨(dú)立審核人員提交一份對(duì)2016年2月以來(lái)的生產(chǎn)數(shù)據(jù)有效性的徹底回顧性評(píng)估，并對(duì)生產(chǎn)員工進(jìn)行深入面談（操作員和主管）。此項(xiàng)評(píng)估應(yīng)在你們之前已執(zhí)行調(diào)查的基礎(chǔ)上進(jìn)行擴(kuò)展，包括但不僅限于對(duì)中控檢查XX和崩解試驗(yàn)完整性的獨(dú)立審核，以及對(duì)所有缺失壓片操作數(shù)據(jù)的評(píng)估。回顧性評(píng)估應(yīng)全面確定該中控測(cè)試數(shù)據(jù)資料缺失的程度（是否由于疏忽或數(shù)據(jù)丟失）、員工不在場(chǎng)時(shí)的簽名情況，以及該產(chǎn)品和其它產(chǎn)品當(dāng)前數(shù)據(jù)可依賴(lài)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?nèi)狈徲?jì)追蹤或其他充分的控制，以方便跟蹤每個(gè)訪問(wèn)可編程邏輯控制器 （PLC） 或人機(jī)接口 （MMI） 設(shè)備的個(gè)人。你們無(wú)從確認(rèn)個(gè)人是否未更改、調(diào)整或修改設(shè)備操作參數(shù)。

　　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(gè)人共享的密碼，訪問(wèn)無(wú)菌和固體制劑產(chǎn)品生產(chǎn)設(shè)備，獲取每一個(gè)設(shè)備和接入級(jí)別。在我們檢查期間，你們的生產(chǎn)經(jīng)理和 QA 經(jīng)理承認(rèn)密碼是共享的。你們的操作人員和主管都沒(méi)有單獨(dú)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(rèn)你們沒(méi)有建立或制訂控制程序來(lái)描述生產(chǎn)設(shè)備系統(tǒng)管理員的角色和職責(zé)。也沒(méi)有記錄寫(xiě)明有權(quán)限訪問(wèn)生產(chǎn)設(shè)備的人員或人員訪問(wèn)生產(chǎn)設(shè)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(fù)中，你們表示對(duì)與無(wú)菌和固體劑型相關(guān)的 PLC 和生產(chǎn)設(shè)備進(jìn)行了全面審查，以評(píng)估權(quán)限控制和人員的可追溯性。你們表示，對(duì)于操作人員的追溯性可以通過(guò)使用批生產(chǎn)記錄和設(shè)備日志的混合系統(tǒng)來(lái)確定。但是，由于你們使用共享的登錄憑據(jù)，無(wú)法識(shí)別使用共享登錄的具體人員，因此你們沒(méi)有辦法證明你們的混合系統(tǒng)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(fù)中，你們還表示，你們將進(jìn)行回顧性風(fēng)險(xiǎn)評(píng)估，以評(píng)估你們計(jì)算機(jī)系統(tǒng)控制不足對(duì)使用此自動(dòng)化設(shè)備生產(chǎn)的產(chǎn)品質(zhì)量的影響。但是，你們沒(méi)有說(shuō)明審核的時(shí)間范圍、評(píng)估這些缺陷對(duì)產(chǎn)品影響的標(biāo)準(zhǔn)，以及對(duì)效期內(nèi)產(chǎn)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(fù)中，你們表示計(jì)劃 （b）（4）。你們的回復(fù)是不充分的，因?yàn)槟銈儧](méi)有說(shuō)明在此過(guò)渡期間將實(shí)施哪些控制措施，以確保只有經(jīng)過(guò)授權(quán)的人員才可更改生產(chǎn)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(fù)此函，請(qǐng)對(duì)使用帶有共享密碼的設(shè)備所生產(chǎn)的批次進(jìn)行回顧性審核和風(fēng)險(xiǎn)評(píng)估。說(shuō)明你們將如何確定哪些操作人員或個(gè)人執(zhí)行并記錄了哪些活動(dòng)，用于評(píng)估產(chǎn)品的生產(chǎn)和質(zhì)量如何受到的控制不足的影響的標(biāo)準(zhǔn)，以及為確保效期內(nèi)產(chǎn)品的質(zhì)量、安全性和有效性需要采取的措施。

　　END

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