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操作人員使用的洗手間污漬嚴(yán)重，且未提供洗手皂。

更衣室的儲物柜、工作服和操作人員的鞋子都很臟。

在主管人員的抽屜里還發(fā)現(xiàn)了明顯臟污的布手套，這些手套在生產(chǎn)過程中會與產(chǎn)品直接接觸。

清潔驗(yàn)證缺乏清潔過程的詳細(xì)信息（如溶劑或清潔劑的使用、關(guān)鍵清潔步驟的描述）。微生物殘留的取樣位置僅標(biāo)注為設(shè)備 “不同部位”，缺乏具體采樣位置及選擇的科學(xué)依據(jù)。

檢查人員發(fā)現(xiàn)了不可接受的記錄管理問題，包括但不限于：批記錄破損、在生產(chǎn)區(qū)域發(fā)現(xiàn)破損的分析色譜圖、包裝區(qū)域標(biāo)簽和放行記錄管理失控，以及在未上鎖的抽屜中發(fā)現(xiàn)未完成的標(biāo)簽和放行記錄。

關(guān)于生產(chǎn)批記錄，操作人員的做法是回填此前記錄在非受控表格上的數(shù)據(jù)，這些非受控表格未留存。生產(chǎn)記錄的非實(shí)時記錄引發(fā)了FDA對該公司記錄管理實(shí)踐和記錄的有效性及完整性的擔(dān)憂。

計算機(jī)數(shù)據(jù)備份程序稱數(shù)據(jù)數(shù)據(jù)歸檔至云服務(wù)器，但安捷倫 OpenLab 色譜數(shù)據(jù)系統(tǒng)（CDS）的數(shù)據(jù)卻（b)(4）歸檔至同一計算機(jī)的第二個硬盤。檢查期間，檢查人員發(fā)現(xiàn)第二個硬盤已損壞。

方法驗(yàn)證不足，含量測定的分析方法驗(yàn)證方案未包含精密度驗(yàn)證（相對標(biāo)準(zhǔn)偏差百分比）的可接受限度，且每項測試僅進(jìn)行了一次測定。

未進(jìn)行強(qiáng)制降解研究以證明穩(wěn)定性方法具有穩(wěn)定性指示作用。

工藝驗(yàn)證中未包含所生產(chǎn)的最小批量，缺乏每個工藝階段的取樣計劃，及所用原材料的測試要求。此外，報告中未對驗(yàn)證批次的關(guān)鍵工藝參數(shù)結(jié)果進(jìn)行評估。

金屬檢測器的驗(yàn)證缺乏對不同金屬類型的反應(yīng)測試、對不同尺寸和類型（b)(4）顆粒的敏感性評估、剔除機(jī)制的功能測試，以及不同流動速度或產(chǎn)品流量下的操作條件評估。

 

缺陷翻譯如下

 

During our inspection, our investigators observed specific deviations including, but not limited to, the following.
檢查期間，我們的檢查人員發(fā)現(xiàn)了以下具體違規(guī)情況（包括但不限于）：

 

1. Failure to properly maintain buildings and facilities used in the manufacture of API.
未能妥善維護(hù)用于生產(chǎn)原料藥的廠房和設(shè)施。

 

Facility Conditions
設(shè)施條件

You failed to maintain your drug manufacturing facility in a good state of repair. The washroom used by operators was observed to be heavily soiled, and soap for handwashing was not available. In addition, the gowning room was observed to have dirty lockers, garments, and operator shoes. Visibly soiled cloth gloves, which come into direct product contact with the (b)(4) USP (b)(4) API, were also observed in a supervisor’s desk drawer to be used by operators during manufacturing. You reported that these gloves are cleaned after use; however, you lacked documentation to support their cleaning.
貴公司未能將藥品生產(chǎn)設(shè)施保持在良好的維護(hù)狀態(tài)。操作人員使用的洗手間污漬嚴(yán)重，且未提供洗手皂。此外，更衣室的儲物柜、工作服和操作人員的鞋子都很臟。在主管人員的抽屜里還發(fā)現(xiàn)了明顯臟污的布手套，這些手套在生產(chǎn)過程中會與（b)(4) USP（b)(4）原料藥直接接觸。貴公司稱這些手套使用后會進(jìn)行清潔，但缺乏清潔記錄支持。

 

Equipment Cleaning and Maintenance
設(shè)備清潔與維護(hù)

You failed to have adequate procedures for cleaning and maintenance of manufacturing equipment. For example, our investigators observed manufacturing equipment labeled as “cleaned” but found with the following deficiencies.
貴公司缺乏足夠的生產(chǎn)設(shè)備清潔和維護(hù)程序。例如，我們的檢查人員發(fā)現(xiàn)標(biāo)有 “已清潔” 的生產(chǎn)設(shè)備存在以下缺陷：

A (b)(4) was labeled as clean and ready to be used; however, it was observed with residual product and a fraying rope inside the (b)(4).
一臺（b)(4）標(biāo)有清潔完畢可使用，但內(nèi)部發(fā)現(xiàn)有產(chǎn)品殘留和一根磨損的繩子。

A (b)(4) and (b)(4) were identified as cleaned; however, a significant amount of (b)(4) was observed on both pieces of equipment.
一臺（b)(4）和（b)(4）標(biāo)識為已清潔，但兩臺設(shè)備上均發(fā)現(xiàn)大量（b)(4）殘留物。

Equipment and utensils (e.g., (b)(4) and (b)(4)), used to (b)(4) the (b)(4) USP (b)(4) API, were found to be stored on a dirty (b)(4) during the manufacturing of lot (b)(4).
在生產(chǎn)批號為（b)(4）的API時，用于（b)(4）（b)(4) USP（b)(4）API的設(shè)備和器具（如（b)(4）和（b)(4））被發(fā)現(xiàn)存放在一個臟污的（b)(4）上。

(b)(4) were observed to be unclean, and these units lacked documentation of cleaning activities.
（b)(4）被發(fā)現(xiàn)未清潔，且這些設(shè)備缺乏清潔活動記錄。

You also failed to adequately document and validate cleaning procedures. For example, your cleaning validation lacked details of the cleaning process (e.g., use of solvent or detergent, and description of critical cleaning steps). Sampling performed for microbial residues was identified to be from “different places” on the equipment and lacked specific sample locations and scientific rationale for their selection. In addition, you did not adequately document your equipment cleaning as part of the batch record or a cleaning record.
貴公司還未能充分記錄和驗(yàn)證清潔程序。例如，清潔驗(yàn)證缺乏清潔過程的詳細(xì)信息（如溶劑或清潔劑的使用、關(guān)鍵清潔步驟的描述）。微生物殘留的取樣位置僅標(biāo)注為設(shè)備 “不同部位”，缺乏具體采樣位置及選擇的科學(xué)依據(jù)。此外，設(shè)備清潔未作為批記錄或清潔記錄的一部分進(jìn)行充分記錄。

 

It is essential that your facility is in a good state of repair and sanitary conditions are maintained to avoid product contamination. Inadequately cleaned and maintained manufacturing equipment can lead to potential cross-contamination that could compromise your API’s quality and safety.
保持設(shè)施良好維修狀態(tài)和衛(wèi)生條件以避免產(chǎn)品污染至關(guān)重要。清潔和維護(hù)不足的生產(chǎn)設(shè)備可能導(dǎo)致潛在的交叉污染，進(jìn)而影響原料藥的質(zhì)量和安全性。

 

2. Failure of your quality unit to exercise its responsibility to ensure the API manufactured at your facility are in compliance with CGMP.

質(zhì)量部門未能履行確保貴公司生產(chǎn)的API符合 CGMP 的職責(zé)。

 

Poor Documentation Practices
記錄管理缺陷

Your firm manufactures (b)(4) USP (b)(4) API. Your quality unit (QU) failed to implement adequate controls to ensure the integrity of data generated at your facility. Our investigators observed unacceptable documentation practices, including, but not limited to, the following: torn batch records, a torn testing chromatogram found in the manufacturing area uncontrolled labeling and clearance forms in the packaging area, and a partially completed labeling and clearance form in an unlocked desk drawer.
貴公司生產(chǎn)（b)(4) USP（b)(4）原料藥。質(zhì)量部門（QU）未能實(shí)施足夠控制以確保貴公司生成數(shù)據(jù)的完整性。我們的檢查人員發(fā)現(xiàn)了不可接受的記錄管理問題，包括但不限于：批記錄破損、在生產(chǎn)區(qū)域發(fā)現(xiàn)破損的分析色譜圖、包裝區(qū)域標(biāo)簽和放行記錄管理失控，以及在未上鎖的抽屜中發(fā)現(xiàn)未完成的標(biāo)簽和放行記錄。

In addition, manufacturing batch records were initiated after the (b)(4) stage of the crude (b)(4) was completed. Your operators’ practice was to backfill data that had previously been recorded on uncontrolled sheets for this initial API processing stage. These uncontrolled sheets were not maintained.
此外，生產(chǎn)批記錄在（b)(4）的（b)(4）階段完成后才開始填寫。操作人員的做法是回填此前在API初始加工階段記錄在非受控表格上的數(shù)據(jù)，這些非受控表格未留存。

CGMP activities must be documented at the time of performance. Non-contemporaneous documentation on manufacturing records raises concerns about the validity and integrity of your firm’s documentation practices and records.
CGMP 活動必須在執(zhí)行時記錄。生產(chǎn)記錄的非實(shí)時記錄引發(fā)了對貴公司記錄管理實(shí)踐和記錄的有效性及完整性的擔(dān)憂。

 

Inadequate Electronic Data Controls
電子數(shù)據(jù)控制不足

You failed to follow adequate controls for your computerized systems. For example, your computerized data backup procedure states that data is (b)(4) archived to a cloud server; however, data from the Agilent OpenLab Chromatographic Data System (CDS) was instead being archived (b)(4) to a second hard drive on the same computer. During the inspection, our investigators documented that the second hard drive was corrupted, and chromatographic data, obtained from February to September 2024, may have been affected.
貴公司未能對計算機(jī)系統(tǒng)實(shí)施足夠控制。例如，計算機(jī)數(shù)據(jù)備份程序稱數(shù)據(jù)（b)(4）歸檔至云服務(wù)器，但安捷倫 OpenLab 色譜數(shù)據(jù)系統(tǒng)（CDS）的數(shù)據(jù)卻（b)(4）歸檔至同一計算機(jī)的第二個硬盤。檢查期間，我們的檢查人員發(fā)現(xiàn)第二個硬盤已損壞，2024 年 2 月至 9 月的色譜數(shù)據(jù)可能已受影響。

You provided a document stating that the hard drive was sent to an external contractor for data recovery; however, you did not conduct a thorough investigation into this incident. Additionally, you failed to identify the specific data that may have been affected, including an evaluation of the potential impact on product quality.
貴公司提供文件稱硬盤已送外部承包商進(jìn)行數(shù)據(jù)恢復(fù)，但未對此事件進(jìn)行徹底調(diào)查。此外，貴公司未能確定可能受影響的具體數(shù)據(jù)，包括對產(chǎn)品質(zhì)量潛在影響的評估。

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download.
貴公司的質(zhì)量體系未能充分確保數(shù)據(jù)的準(zhǔn)確性和完整性，以支持所生產(chǎn)藥品的安全性、有效性和質(zhì)量。有關(guān)建立和遵循符合 CGMP 的數(shù)據(jù)完整性實(shí)踐的指南，請參見 FDA 指導(dǎo)文件《數(shù)據(jù)完整性與藥品 CGMP 合規(guī)性》，網(wǎng)址：https://www.fda.gov/media/119267/download。

 

3. Failure to test the identity of each batch of incoming production material and to appropriately qualify suppliers to rely upon their certificate of analysis.
未能對每批進(jìn)廠物料進(jìn)行鑒定，也未能適當(dāng)確認(rèn)供應(yīng)商以依賴其COA。

 

You failed to conduct an identity test on each lot of raw material used in the manufacture of your API. You instead relied on the certificates of analysis (COAs) from your suppliers without adequately qualifying them. You tested (b)(4), received as your primary raw material, for some quality attributes; however, an identity test was not performed before use in manufacturing.
貴公司未能對用于生產(chǎn)原料藥的每批原材料進(jìn)行鑒定，在未充分確認(rèn)供應(yīng)商的情況下依賴其分析證書（COA）。貴公司對作為主要原材料的（b)(4）進(jìn)行了某些質(zhì)量屬性測試，但未能在用于生產(chǎn)前進(jìn)行鑒定測試。

In addition, your procedure for vendor qualification states that critical vendors, such as suppliers of active raw materials, are required to be qualified. You did not qualify your suppliers of primary raw material and failed to establish the reliability of each of your suppliers’ COA for raw material specifications and characteristics.
此外，供應(yīng)商確認(rèn)程序規(guī)定，關(guān)鍵供應(yīng)商（如活性原材料供應(yīng)商）需通過確認(rèn)。貴公司未對主要原材料供應(yīng)商進(jìn)行確認(rèn)，也未能確認(rèn)每個供應(yīng)商關(guān)于原材料規(guī)格和特性的 COA 的可靠性。

Without adequate testing, there is no scientific evidence to assure that your raw materials conform to appropriate specifications before release.
缺乏足夠的測試，就沒有科學(xué)證據(jù)確保原材料在放行前符合適當(dāng)?shù)囊?guī)格。

 

4. Failure to ensure that all specifications and test procedures are scientifically sound and appropriate to ensure that your API conform to established standards of quality.
未能確保所有規(guī)程和測試程序科學(xué)合理且適當(dāng)，以確保API符合既定質(zhì)量標(biāo)準(zhǔn)。

 

Inadequate Testing of (b)(4) API
API測試不足

You failed to adequately test your (b)(4) USP (b)(4) API per the current USP monograph. For example, you did not conduct testing for “(b)(4)” and “(b)(4).” These tests are not required in your API specification. As a result, you distributed lots of (b)(4) API to the U.S. market without assurance that they meet the current USP standards. This may also render your (b)(4) USP adulterated under section 501(b) of the FD&C Act.
貴公司未能根據(jù)現(xiàn)行 USP 專論對（b)(4) USP（b)(4）API進(jìn)行充分測試。例如，未進(jìn)行 “（b)(4）” 和 “（b)(4）” 測試，這些測試在原料藥標(biāo)準(zhǔn)中未作要求。因此，貴公司將多批（b)(4）原料藥銷往市場時，無法確保其符合現(xiàn)行 USP 標(biāo)準(zhǔn)。這也可能導(dǎo)致（b)(4) USP 原料藥根據(jù) FD&C 法案第 501 (b) 條被認(rèn)定為摻假。

Inadequate Method Verification
方法驗(yàn)證不足

You failed to perform an adequate analytical method verification for (b)(4) assay. Your protocol did not include an acceptance limit for the verification of the precision (percent relative standard deviation). The verification exercise included a single determination of each test.
貴公司未能對（b)(4）含量測定進(jìn)行充分的分析方法驗(yàn)證。驗(yàn)證方案未包含精密度驗(yàn)證（相對標(biāo)準(zhǔn)偏差百分比）的可接受限度，且每項測試僅進(jìn)行了一次測定。

Inadequate Stability Method Validation
穩(wěn)定性方法驗(yàn)證不足

You failed to ensure that the analytical method used for stability testing of (b)(4) USP (b)(4) API is suitable for its intended use. For example, you did not perform forced degradation studies to demonstrate that the method is stability-indicating.
貴公司未能確保用于（b)(4) USP（b)(4）原料藥穩(wěn)定性測試的分析方法適合其預(yù)期用途。例如，未進(jìn)行強(qiáng)制降解研究以證明該方法具有穩(wěn)定性指示作用。

 

5. Failure to demonstrate that your manufacturing process can reproducibly manufacture an API meeting its predetermined quality attributes.
未能證明生產(chǎn)工藝可 reproducibly 生產(chǎn)出符合預(yù)定質(zhì)量屬性的原料藥。

 

Inadequate Process Validation
工藝驗(yàn)證不足

You failed to adequately validate your (b)(4) API manufacturing process. For example, your process validation lacked a scientific rationale for not including the smallest batch size your firm manufactures, a defined sampling plan for each stage, and testing requirements for raw materials used. In addition, your report lacked an evaluation of critical processing parameters results for the validation batches.
貴公司未能對（b)(4）API的生產(chǎn)工藝進(jìn)行充分驗(yàn)證。例如，工藝驗(yàn)證中未包含貴公司所生產(chǎn)的最小批量，未提供科學(xué)理由，缺乏每個工藝階段的取樣計劃，及所用原材料的測試要求。此外，報告中未對驗(yàn)證批次的關(guān)鍵工藝參數(shù)結(jié)果進(jìn)行評估。

 

Equipment Qualification
設(shè)備確認(rèn)

You lacked qualification for major equipment, such as the (b)(4) tank, (b)(4) machine, and (b)(4). In addition, the qualification of the (b)(4) lacked testing of the (b)(4) response to different types of metal, evaluation of its sensitivity to different sizes and types of (b)(4) particles, functionality of rejection mechanisms, and evaluation of operating conditions for different flow rates or product throughput. Furthermore, the qualification of the (b)(4) lacked a comprehensive range of operating parameters.
貴公司缺乏對主要設(shè)備的確認(rèn)，如（b)(4）儲罐、（b)(4）設(shè)備和（b)(4）。此外，（b)(4）的確認(rèn)缺乏對不同金屬類型的反應(yīng)測試、對不同尺寸和類型（b)(4）顆粒的敏感性評估、剔除機(jī)制的功能測試，以及不同流動速度或產(chǎn)品流量下的操作條件評估。此外，（b)(4）的確認(rèn)缺乏全面的操作參數(shù)范圍。