操作人員使用的洗手間污漬嚴重，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現了明顯臟污的布手套，這些手套在生產過程中會與產品直接接觸。

清潔驗證缺乏清潔過程的詳細信息（如溶劑或清潔劑的使用、關鍵清潔步驟的描述）。微生物殘留的取樣位置僅標注為設備 “不同部位”，缺乏具體采樣位置及選擇的科學依據。

檢查人員發現了不可接受的記錄管理問題，包括但不限于：批記錄破損、在生產區域發現破損的分析色譜圖、包裝區域標簽和放行記錄管理失控，以及在未上鎖的抽屜中發現未完成的標簽和放行記錄。

關于生產批記錄，操作人員的做法是回填此前記錄在非受控表格上的數據，這些非受控表格未留存。生產記錄的非實時記錄引發了FDA對該公司記錄管理實踐和記錄的有效性及完整性的擔憂。

計算機數據備份程序稱數據數據歸檔至云服務器，但安捷倫 OpenLab 色譜數據系統（CDS）的數據卻（b)(4）歸檔至同一計算機的第二個硬盤。檢查期間，檢查人員發現第二個硬盤已損壞。

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

未進行強制降解研究以證明穩定性方法具有穩定性指示作用。

工藝驗證中未包含所生產的最小批量，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，報告中未對驗證批次的關鍵工藝參數結果進行評估。

金屬檢測器的驗證缺乏對不同金屬類型的反應測試、對不同尺寸和類型（b)(4）顆粒的敏感性評估、剔除機制的功能測試，以及不同流動速度或產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，我們的檢查人員發現了以下具體違規情況（包括但不限于）：

 

1. Failure to properly maintain buildings and facilities used in the manufacture of API.
未能妥善維護用于生產原料藥的廠房和設施。

 

Facility Conditions
設施條件

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設施保持在良好的維護狀態。操作人員使用的洗手間污漬嚴重，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現了明顯臟污的布手套，這些手套在生產過程中會與（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行清潔，但缺乏清潔記錄支持。

 

Equipment Cleaning and Maintenance
設備清潔與維護

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設備清潔和維護程序。例如，我們的檢查人員發現標有 “已清潔” 的生產設備存在以下缺陷：

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）標有清潔完畢可使用，但內部發現有產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）標識為已清潔，但兩臺設備上均發現大量（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).
在生產批號為（b)(4）的API時，用于（b)(4）（b)(4) USP（b)(4）API的設備和器具（如（b)(4）和（b)(4））被發現存放在一個臟污的（b)(4）上。

(b)(4) were observed to be unclean, and these units lacked documentation of cleaning activities.
（b)(4）被發現未清潔，且這些設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證清潔程序。例如，清潔驗證缺乏清潔過程的詳細信息（如溶劑或清潔劑的使用、關鍵清潔步驟的描述）。微生物殘留的取樣位置僅標注為設備 “不同部位”，缺乏具體采樣位置及選擇的科學依據。此外，設備清潔未作為批記錄或清潔記錄的一部分進行充分記錄。

 

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.
保持設施良好維修狀態和衛生條件以避免產品污染至關重要。清潔和維護不足的生產設備可能導致潛在的交叉污染，進而影響原料藥的質量和安全性。

 

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

質量部門未能履行確保貴公司生產的API符合 CGMP 的職責。

 

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（b)(4) USP（b)(4）原料藥。質量部門（QU）未能實施足夠控制以確保貴公司生成數據的完整性。我們的檢查人員發現了不可接受的記錄管理問題，包括但不限于：批記錄破損、在生產區域發現破損的分析色譜圖、包裝區域標簽和放行記錄管理失控，以及在未上鎖的抽屜中發現未完成的標簽和放行記錄。

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據，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 活動必須在執行時記錄。生產記錄的非實時記錄引發了對貴公司記錄管理實踐和記錄的有效性及完整性的擔憂。

 

Inadequate Electronic Data Controls
電子數據控制不足

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系統實施足夠控制。例如，計算機數據備份程序稱數據（b)(4）歸檔至云服務器，但安捷倫 OpenLab 色譜數據系統（CDS）的數據卻（b)(4）歸檔至同一計算機的第二個硬盤。檢查期間，我們的檢查人員發現第二個硬盤已損壞，2024 年 2 月至 9 月的色譜數據可能已受影響。

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行數據恢復，但未對此事件進行徹底調查。此外，貴公司未能確定可能受影響的具體數據，包括對產品質量潛在影響的評估。

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.
貴公司的質量體系未能充分確保數據的準確性和完整性，以支持所生產藥品的安全性、有效性和質量。有關建立和遵循符合 CGMP 的數據完整性實踐的指南，請參見 FDA 指導文件《數據完整性與藥品 CGMP 合規性》，網址：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.
未能對每批進廠物料進行鑒定，也未能適當確認供應商以依賴其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原料藥的每批原材料進行鑒定，在未充分確認供應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）進行了某些質量屬性測試，但未能在用于生產前進行鑒定測試。

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，供應商確認程序規定，關鍵供應商（如活性原材料供應商）需通過確認。貴公司未對主要原材料供應商進行確認，也未能確認每個供應商關于原材料規格和特性的 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，就沒有科學證據確保原材料在放行前符合適當的規格。

 

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.
未能確保所有規程和測試程序科學合理且適當，以確保API符合既定質量標準。

 

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.
貴公司未能根據現行 USP 專論對（b)(4) USP（b)(4）API進行充分測試。例如，未進行 “（b)(4）” 和 “（b)(4）” 測試，這些測試在原料藥標準中未作要求。因此，貴公司將多批（b)(4）原料藥銷往市場時，無法確保其符合現行 USP 標準。這也可能導致（b)(4) USP 原料藥根據 FD&C 法案第 501 (b) 條被認定為摻假。

Inadequate Method Verification
方法驗證不足

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）含量測定進行充分的分析方法驗證。驗證方案未包含精密度驗證（相對標準偏差百分比）的可接受限度，且每項測試僅進行了一次測定。

Inadequate Stability Method Validation
穩定性方法驗證不足

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）原料藥穩定性測試的分析方法適合其預期用途。例如，未進行強制降解研究以證明該方法具有穩定性指示作用。

 

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

 

Inadequate Process Validation
工藝驗證不足

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的生產工藝進行充分驗證。例如，工藝驗證中未包含貴公司所生產的最小批量，未提供科學理由，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，報告中未對驗證批次的關鍵工藝參數結果進行評估。

 

Equipment Qualification
設備確認

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備的確認，如（b)(4）儲罐、（b)(4）設備和（b)(4）。此外，（b)(4）的確認缺乏對不同金屬類型的反應測試、對不同尺寸和類型（b)(4）顆粒的敏感性評估、剔除機制的功能測試，以及不同流動速度或產品流量下的操作條件評估。此外，（b)(4）的確認缺乏全面的操作參數范圍。