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近日，FDA發(fā)布了對中國藥企BBC Group Limited的警告信，為其恢復國外現場檢查以來首次基于現場檢查發(fā)布的對中國藥企的警告信，缺陷包括如下：

 

FDA要求審查氣相色譜儀(GC)的分析數據。然而，該公司表示，在檢查開始之前大約一個月，所有2018年至2020年的檢驗數據都已丟失。這些數據已不可恢復。

 

該公司僅保留實驗室記錄的靜態(tài)副本(即紙質記錄)進行審查，FDA認為這是不夠的，因為它們沒有保留完整色譜的動態(tài)記錄格式來支持測試結果，并且它們不包括完整原始記錄的一部分的系統(tǒng)適應性記錄。

 

FDA檢查人員發(fā)現GC相關的計算機系統(tǒng)和軟件缺乏訪問限制。例如，使用GC執(zhí)行藥品分析的實驗室員工都以“系統(tǒng)管理員”身份登錄，不需要密碼，并具有完全的系統(tǒng)管理權限。此外，沒有啟用GC上的審計追蹤。

 

FDA發(fā)現該公司的黏度計和紫外線-可見光度計是能夠在產品/物料測試過程中保存數據的。盡管有這種能力，但該公司分析人員未能保存完整的動態(tài)測試數據。

 

該公司還使用電子表格進行穩(wěn)定性試驗數據輸入。但是，這些電子表格不受控，也沒有保護措施來防止數據操縱、覆蓋或刪除。

 

分析測試方法沒有得到充分驗證。具體來說，沒有系統(tǒng)適應性性要求，也沒有確定對照標準。

 

FDA檢查人員在生產現場發(fā)現設備產品接觸表面上的銹跡，隨后要求查看設備維護日志。這些文件僅提供中文。FDA翻譯后發(fā)現所提供的文件與檢查期間要求的設備不同。

 

缺陷翻譯如下：

 

CGMP Violations

 

1. Your firm failed to exerciseappropriate controls over computer or related systems to assure that onlyauthorized personnel institute changes in master production and controlrecords, or other records (21 CFR 211.68(b)).

貴公司未能對計算機或相關系統(tǒng)實施適當的控制，以確保只有經授權的人員才能對主生產和控制記錄或其他記錄進行更改(21 CFR 211.68(b))。

 

Your firm manufactures over-the-counter (OTC) drug products,including alcohol-based hand sanitizers[1]. During the inspection of your facility, ourinvestigator attempted to review analytical data from your gas chromatograph(GC) supporting the release of drug products distributed to the United States.However, your firm stated that all testing data from 2018 to 2020 was lostapproximately one month prior to the initiation of our inspection. The GC isused to analyze the identity and strength of active ingredients and impuritiescontained in your OTC drug products, as well as other critical parameters.According to firm management, the data is unrecoverable. While your firmretained a static copy of laboratory records for review (i.e., paper record),they were inadequate as they did not preserve the dynamic record format of thefull chromatographs to support test results and they did not include systemsuitability documentation that are part of the complete, original record.

貴公司生產非處方(OTC)藥品，包括含酒精洗手液[1]。在對你們工廠的檢查期間，我們的檢查人員試圖審查你們氣相色譜儀(GC)的分析數據。然而，貴公司表示，在我們開始檢查之前大約一個月，所有2018年至2020年的檢驗數據都已丟失。氣相色譜用于分析你們OTC藥品中所含活性成分和雜質的鑒別和檢測，以及其他關鍵參數。根據公司的管理，這些數據已不可恢復。而貴公司保留實驗室記錄的靜態(tài)副本(即紙質記錄)進行審查，這是不夠的，因為它們沒有保留完整色譜的動態(tài)記錄格式來支持測試結果，并且它們不包括完整原始記錄的一部分的系統(tǒng)適應性記錄。

 

Additionally, our investigator observed that the computerizedsystem and software associated with your GC lacked restricted access. Forexample, your laboratory employees who used the GC to perform analyses of drugproducts all logged in as “System Administrator,” which does not require apassword, and had full system administration rights. In addition, audit trailson your GC were not enabled.

此外，我們的檢查人員發(fā)現與你們的GC相關的計算機系統(tǒng)和軟件缺乏訪問限制。例如，使用GC執(zhí)行藥品分析的實驗室員工都以“系統(tǒng)管理員”身份登錄，不需要密碼，并具有完全的系統(tǒng)管理權限。此外，沒有啟用GC上的審計追蹤。

 

Furthermore, you did not retain all original, dynamic records,obtained during the course of testing on other laboratory equipment. Yourviscometer and UV-Vis spectrophotometer had the capability to save data fromproduct/material testing. Despite having this capability, your analysts failedto save the complete, dynamic testing data, and therefore the data was notavailable for review by the FDA investigator. The viscometer is used to measurethe viscosity of finished drug products during release testing and the UV-Visspectrophotometer is used to measure ethanol content during raw materialtesting.

此外，你們亦沒有保留在其他實驗室設備測試過程中獲得的所有原始動態(tài)記錄。你們的黏度計和紫外線-可見光度計是能夠在產品/物料測試過程中保存數據的。盡管有這種能力，你們的分析人員未能保存完整的動態(tài)測試數據，因此數據無法供 FDA 檢查人員查看。黏度計用于檢測成品放行測試的黏度，紫外線-可見光度計用于檢測原料乙醇含量。

 

Your firm also utilizes electronic spreadsheets to input datafor your stability program. However, these spreadsheets are not controlled andthere is no protection to prevent data manipulation, overwriting, or erasure.

貴公司還使用電子表格進行穩(wěn)定性試驗數據輸入。但是，這些電子表格不受控，也沒有保護措施來防止數據操縱、覆蓋或刪除。

 

In your response, you indicated that you purchased and/orinstalled additional equipment to address this violation, including, but notlimited to, an uninterrupted power source, remote hard drive, electricalequipment, and new software. Your response also states that you have updatedand developed associated procedures, created individual accounts for allpersonnel that utilize laboratory equipment, and conducted accompanyingtrainings. However, your response is inadequate because it lacked supportingdocumentation, including evidence to support that the computer securitycontrols were effective at preventing data and document manipulation.Additionally, you did not perform a retrospective risk assessment into howsystem vulnerabilities may have impacted data integrity.

在回復中，你們表示你們購買和/或安裝了其他設備來解決此不合規(guī)問題，包括但不限于UPS電源、遠程硬盤、電氣設備和新軟件。你們的答復還指出，你們已更新并開發(fā)了相關程序，為所有使用實驗室設備的人員創(chuàng)建了個人帳戶，并進行了相應的培訓。但是，你們的回復是不充分的，因為它缺乏支持性文檔，包括支持計算機安全控制有效防止數據和記錄操縱的證據。此外，你們沒有對系統(tǒng)性缺陷如何影響數據完整性進行追溯性風險評估。

 

Your firm does not adequately ensure the accuracy and integrityof data to support the safety, effectiveness, and quality of the drugs youmanufacture. See FDA’s guidance document Data Integrity and Compliance WithDrug CGMP for guidance on establishing and following CGMP compliant dataintegrity practices at https://www.fda.gov/media/97005/download.

貴公司沒有充分確保數據的準確性和完整性，以支持你們生產的藥品的安全性、有效性和質量。有關建立和遵循符合CGMP的數據完整性規(guī)范的指導，請參見FDA指南《數據完整性與藥品CGMP符合性》：https://www.fda.gov/media/97005/download。

 

2. Your firm failed to establishlaboratory controls that include scientifically sound and appropriatespecifications, standards, sampling plans, and test procedures designed toassure that components, drug product containers, closures, in-processmaterials, labeling, and drug products conform to appropriate standards ofidentity, strength, quality, and purity (21 CFR 211.160(b)).

貴公司未能建立實驗室控制，包括科學合理和適當的規(guī)范、標準、取樣計劃和測試程序，以確保原輔料、藥品容器、密封部件、過程物料、標簽和成品符合適當的鑒別、強度、質量，和純度標準(21 CFR 211.160(b))。

 

Your analytical test methods were not adequately validated,including those for the active ingredient ethanol, which is used to manufactureyour alcohol-based hand sanitizers, and analysis for the impurity (b)(4).Specifically, no system suitability requirements were present and referencestandards were not identified. Data must be available to establish that theanalytical procedures used in testing meet proper standards of accuracy,sensitivity, specificity, and reproducibility and are suitable for theirintended purpose.

你們的分析測試方法沒有得到充分驗證，包括用于生產成品的活性物質乙醇的分析方法，以及雜質(xx)的分析方法。具體來說，沒有系統(tǒng)適應性性要求，也沒有確定對照標準。應有數據來確定用于檢測的分析方法在準確性、靈敏性、特異性和重現性方面符合適當的標準，并適合于其預期用途。

 

In your response, you indicated that you updated test methods, establishedmethod validation protocols, and completed test method evaluation. However,your response is inadequate for the following reasons.

在你們的回復中，你們指出你們更新了測試方法，建立了方法驗證方案，并完成了分析方法評估。然而，由于以下原因，你們的回復是不充分的。

 

The response lacked information on the analyte reference standards used forthe method validation.

缺乏用于方法驗證的分析物對照標準的信息。

 

The response lacked method validation details on identity of the testedanalytes, system suitability, method specificity data, preparations of theanalyte stock solutions, and accuracy and precision data from spike andrecovery experiments at different concentration levels.

缺乏方法驗證細節(jié)，包括被測試的分析物的鑒定、系統(tǒng)適應性、方法特異性數據、分析溶液的準備，以及不同濃度下的峰和回收率實驗的準確性和精密度數據。

 

The response lacked an assessment of drug products manufactured utilizing thedeficient methods.

缺乏對已使用有缺陷方法生產的藥品的評估。

 

3. Your firm failed to clean, maintain,and, as appropriate for the nature of the drug, sanitize and/or sterilizeequipment and utensils at appropriate intervals to prevent malfunctions orcontamination that would alter the safety, identity, strength, quality, orpurity of the drug product beyond the official or other establishedrequirements (21 CFR 211.67(a)).

貴公司沒有根據藥品的性質以適當的時間間隔對設備和用具進行清潔、維護和消毒，以防止故障或污染，從而改變安全性、特性、強度、質量，或藥品純度超過官方或其他既定要求(21 CFR 211.67(a))。

 

During our inspection, the investigator observed rust on (b)(4) andproduct contact surfaces of four of the (b)(4) used tomanufacture drug products, including the manufacture of your OTC handsanitizers. Upon request, you provided our investigator with manufacturingequipment maintenance logs for the aforementioned (b)(4).These documents were only available in Chinese. After the conclusion of theinspection, the FDA had the document translated and found that the documentprovided was for equipment identified as “liquid washing pan” with serialnumber WJB-001, which is located in Workshop (b)(4) onthe (b)(4) floor, and not the (b)(4) withequipment ID’s 12 through 15 located in Workshop (b)(4) onthe (b)(4) floor that were observed with rust. FDA isconcerned that you provided maintence records for different equipment thanthose requested during the inspection.

在我們的檢查中，檢查人員觀察到用于制造藥物產品的四種（b）（4）的銹跡（b）（4）和產品接觸表面，包括制造您的OTC洗手液。應要求，您向我們的調查人員提供了上述（b）（4）的制造設備維護日志。這些文件僅提供中文。檢查結束后，FDA翻譯了文件，發(fā)現所提供的文件用于編號為WJB-001的"液體洗滌鍋"的設備，該設備位于（b）（4）樓的車間（b）（4），而不是設備ID的12至15的設備，位于（b）（4）樓層的車間（b）（4）中，這些車間位于用鐵銹觀察到的車間（b）（4）樓。FDA擔心您提供的主記錄與檢查期間要求的設備不同。

 

In your response, you indicated that you replaced all the (b)(4) inyour (b)(4). However, your response failed to address the rustdocumented in other parts of the (b)(4). Additionally, your response isinadequate as you failed to revise your cleaning and maintenance procedures toprevent recurrence of this issue, you failed to perform a risk assessment ofdrug products manufactured in the four (b)(4) thatcontained rust, and you did not determine the root cause of why employees whoperform (b)(4) inspections of manufacturing equipment did notobserve the rust in the (b)(4).

在你們的回復中，你們表示你們更換了你們xx中的所有xx。然而，你們的回復沒有解決xx其他部分的生銹問題。此外，你們的回復是不充分的，因為你們未能修改你們的清潔和維護程序以防止該問題的再次發(fā)生，你們未能對生銹的4個xx所生產的藥品進行風險評估，你們沒有確定對生產設備進行xx檢查的員工沒有在xx中發(fā)現生銹的根本原因。