2025年9月22日，FDA 發(fā)布了 CohanceLimited Lifesciences的483缺陷報(bào)告，其中提及缺陷如下：
一批被決定銷毀的不合格片劑，在倉庫中部分失蹤。公司QA總經(jīng)理和運(yùn)營高級總經(jīng)理無法解釋數(shù)量差異，且沒有關(guān)于這些物料去向的處置和核對文件。從2023年8月被拒到2025年8月檢查當(dāng)日，近23個(gè)月未處理。
對一次OOS含量測定不合格的調(diào)查結(jié)論草率。被簡單歸咎于“操作員可能遺漏步驟”，但未評估和解決其背后“操作員假設(shè)主管不在場即可跳過步驟”這一嚴(yán)重的流程和操作漏洞，也未采取預(yù)防措施。
決定更換取樣小瓶類型以消除稱重誤差，但未評估原小瓶材料是否對檢測結(jié)果有影響，未進(jìn)行假設(shè)檢驗(yàn)。
對直接接觸藥品的包裝容器未進(jìn)行可提取物和浸出物研究。公司無法提供任何相關(guān)研究文件，無法保證包裝材料不會影響藥品的安全性和質(zhì)量。
對關(guān)于片劑在瓶內(nèi)碎裂、產(chǎn)生粉塵的投訴，調(diào)查結(jié)論為“不成立”，且未采取任何行動。未建立成品放行標(biāo)準(zhǔn)來界定片劑邊緣碎裂、崩解等物理特性的可接受限度。檢查中在留樣樣品上也觀察到同樣問題，但未進(jìn)行深入評估，如索取原始對照樣品比對。根據(jù)內(nèi)部SOP，此類情況應(yīng)上報(bào)FDA現(xiàn)場警報(bào)報(bào)告，但未執(zhí)行且無任何解釋。
針對產(chǎn)品中發(fā)現(xiàn)手套碎片的投訴，新制定的《手套處理SOP》未包含要求員工在發(fā)現(xiàn)手套破損時(shí)通知主管或記錄事件的條款，無法防止未來類似事件的發(fā)生。
瓶內(nèi)片劑規(guī)格混淆的投訴應(yīng)記錄到現(xiàn)場警報(bào)報(bào)告日志，但是未被記錄。QA部門以“對程序不了解”為由，未遵守SOP QA084-02的要求。
儀器使用日志缺失或不完整，原因再次歸咎于“操作員和QA對程序不了解”；關(guān)鍵質(zhì)量相關(guān)儀器沒有或未按要求填寫使用日志。分析天平#PD/AWB-06沒有使用日志；脆碎度測試儀PD/FBL-01的使用日志未按SOP要求填寫。
生產(chǎn)設(shè)備訪問權(quán)限控制不足，生產(chǎn)設(shè)備面板（HMI）共享高級別用戶名和密碼，且無風(fēng)險(xiǎn)評估。操作員被授予了本應(yīng)僅限主管知曉的密碼，該權(quán)限允許他們編輯循環(huán)時(shí)間、設(shè)定點(diǎn)等關(guān)鍵工藝參數(shù)。這違反了設(shè)備供應(yīng)商手冊的規(guī)定，且公司沒有對此安排進(jìn)行書面風(fēng)險(xiǎn)評估。
包裝主管可以且確實(shí)刪除了包裝線計(jì)算機(jī)系統(tǒng)中的審計(jì)追蹤和批次數(shù)據(jù)文件。該系統(tǒng)的登錄賬戶也在操作員和主管間共享，IT管理員承認(rèn)此為“疏忽”。
在設(shè)備PD ×× 01內(nèi)部觀察到可見污漬，擦拭取樣檢測出前序產(chǎn)品的殘留；膠囊填充機(jī)PD/CFM-03上觀察到可見的產(chǎn)品殘留，但清潔記錄顯示已完成清潔，檢查時(shí)的擦拭取樣結(jié)果證實(shí)清潔無效。
壓片機(jī)PD/TCM-03存在多項(xiàng)維護(hù)問題，設(shè)備上有污漬、凹痕、部件損壞/碎裂、金屬顆粒，存在污染產(chǎn)品和影響片劑質(zhì)量的風(fēng)險(xiǎn)。
關(guān)鍵設(shè)備出現(xiàn)裂紋，但未記錄事件、未進(jìn)行評估、也未進(jìn)行維護(hù)。
引入多個(gè)新產(chǎn)品未納入清潔驗(yàn)證評估；僅用一種片劑代表所有劑型進(jìn)行清潔驗(yàn)證；日常清潔中使用的清潔劑未包含在最初的清潔驗(yàn)證中。
設(shè)備部件出現(xiàn)在不應(yīng)出現(xiàn)的生產(chǎn)區(qū)域，且無記錄和解釋；關(guān)鍵部件在批間斷開連接，重新連接使用前無功能驗(yàn)證程序。
樣品制備程序和允許的樣品質(zhì)量差異范圍未進(jìn)行評估。歷史上多次OOS結(jié)果被歸因于“取樣誤差”，但根本性的方法問題未得到解決。
具體缺陷內(nèi)容如下：
OBSERVATION 1
觀察項(xiàng)1
There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed.未能對任何無法解釋的差異以及某一批次或其任何組件不符合任何規(guī)格要求的情況進(jìn)行徹底審查，無論該批次是否已分發(fā)。
A) There is no documentation on the disposition status and reconciliation of approximately ×× of rejected ×× tablets, ×× mg, Batch No. ×× that have gone missing after being rejected on August 23, 2023, as part of Deviation DEV/NCR/23/0033, Deviation Initiation Date: June 19, 2023. Specifically, ×× total containers, which consists of ×× of Batch No. ×× compressed tablets, had fallen on the floor from the ×× during transfer from the hold area to Bottle packing line ××. According to the final investigation report, the decision was made to destroy the entire batch due to the high number of rejects after tablet reinspection and probable impact on physical characteristics for all compressed tablets. According to the General Manager of Quality Assurance (QA), the rejected batch has not been disposed of as of the current inspection; this is approximately 23 months since the final investigation report was closed and approved by the QA and Production department in August 2023. However, only ×× out of the ×× total containers, which consists of ×× out of the ×× total rejected batch material, remained in the warehouse facility during my inspection walkthrough on August 08, 2025. The General Manager of QA and Senior General Manager of Operations stated that they were unable to explain the discrepancy and unable to account for the missing quantity of rejected compressed tablets for Batch No. ×× which was initially intended for distribution to the U.S market.
關(guān)于于 2023 年 8 月 23 日被拒收后失蹤的、屬于偏差 DEV/NCR/23/0033（偏差發(fā)起日期：2023 年 6 月 19 日）的一部分的、約 ×× 的 ×× 毫克、批號為 ×× 的拒收片劑的處置狀態(tài)和核對，沒有相關(guān)文件記錄。具體來說，在從暫存區(qū)轉(zhuǎn)移到瓶裝包裝線 ×× 的過程中，包含批號為 ×× 的 ×× 片壓片的 ×× 個(gè)總?cè)萜鲝?×× 掉到了地上。根據(jù)最終調(diào)查報(bào)告，由于片劑復(fù)檢后拒收數(shù)量眾多，且可能對所有壓片的物理特性產(chǎn)生影響，決定銷毀整批產(chǎn)品。根據(jù)質(zhì)量保證（QA）總經(jīng)理的說法，截至本次檢查，被拒收的批次尚未被處理；自 2023 年 8 月 QA 和生產(chǎn)部門關(guān)閉并批準(zhǔn)最終調(diào)查報(bào)告以來，已經(jīng)過去了大約 23 個(gè)月。然而，在我 2025 年 8 月 8 日的檢查巡視中，只有 ×× 個(gè)總?cè)萜鳎ò?×× 的總拒收批次物料）仍在倉庫設(shè)施中。QA 總經(jīng)理和運(yùn)營高級總經(jīng)理表示，他們無法解釋這一差異，也無法說明最初擬分銷到市場的批號為 ×× 的拒收壓片的缺失數(shù)量的去向。
B) OOS/IP/21/020 was initiated on March 30, 2021, due to ×× Tablets USP, Batch No. ×× Mfg. Date: 03/2021, Exp. Date: ×× HPLC assay test not meeting specification limits for the ×× stage. The batch was initially intended for the U.S market but ultimately rejected due to the following root cause: Operator potentially missing steps for ×× and subsequently leading to inadequate ××. According to the investigation report personnel interview section, it was understood that the ×× step was possibly missed by the Operator due to assumption that the Executive (BMR Reviewer) being absent for verification. The investigation further stated that since the executed procedure was performed during ×× the assumption/overlook tendency of the operator and unavailability of operator for missing the step is inferred to be inherent. However, there was no further assessment and preventive actions initiated to address the process and operational gaps that may continue to remain during critical manufacturing and packaging steps (especially during ××).
OOS/IP/21/020 于 2021 年 3 月 30 日發(fā)起，原因是 ×× USP片劑，批號 ××，生產(chǎn)日期：2021 年 3 月，有效期：××，高效液相色譜（HPLC）含量測定測試在 ×× 階段不符合規(guī)格限值。該批次最初擬用于美國市場，但最終因以下根本原因被拒收：操作員可能遺漏了 ×× 的步驟，進(jìn)而導(dǎo)致 ×× 不充分。根據(jù)調(diào)查報(bào)告的人員訪談部分，了解到操作員可能由于認(rèn)為主管（BMR 審核員）不在場無法進(jìn)行驗(yàn)證，而遺漏了 ×× 步驟。調(diào)查進(jìn)一步指出，由于在 ×× 期間執(zhí)行了該程序，操作員的假設(shè) / 疏忽傾向以及操作員因遺漏步驟而無法到場的情況被推斷為固有存在的。然而，沒有進(jìn)一步開展評估和啟動預(yù)防措施，以解決在關(guān)鍵生產(chǎn)和包裝步驟（尤其是在 ×× 期間）可能持續(xù)存在的工藝和操作差距。
C) OOS/QC/23/010 was initiated on April 28, 2023, due to ×× Tablets USP ×× mg, ×× mg, ×× mg, ×× mg and ×× mg /In-process, Batch No. ×× having out-of-specification (OOS) results for the mean of individual assay: ×× % (Specification: ×× %) for Sample Set ×× Sample Set ×× had passing results and no assignable root cause was identified for the Sample Set ×× OOS results. As a preventive action, it was proposed to collect the ×× content assay samples at ×× stage in ×× vials (instead of ×× vials) to eliminate error during ×× weighing of sample vials. However, no further hypothesis testing, or detailed assessment was performed to evaluate the effects that ×× material may have on altering sample results before switching to the usage of ×× vials.
OOS/QC/23/010 于 2023 年 4 月 28 日發(fā)起，原因是 ×× USP片劑，×× 毫克、×× 毫克、×× 毫克、×× 毫克和 ×× 毫克 / 過程中，批號 ×× 的單個(gè)含量測定平均值出現(xiàn)超出規(guī)格（OOS）的結(jié)果：××%（規(guī)格：××%）。樣本組 ××、樣本組 ×× 有合格結(jié)果，且未確定樣本組 ××OOS 結(jié)果的可指定根本原因。作為預(yù)防措施，提議在 ×× 階段用 ×× 小瓶（而非 ×× 小瓶）收集 ×× 含量測定樣本，以消除在 ×× 樣本小瓶稱重過程中的誤差。然而，在改用 ×× 小瓶之前，沒有進(jìn)行進(jìn)一步的假設(shè)檢驗(yàn)或詳細(xì)評估，以評估 ×× 材料可能對改變樣本結(jié)果產(chǎn)生的影響。
Compressed tablets and finished product capsules are then packaged into ×× bottles that are distributed to the U.S market. ×× Tablets ×× mg, final batch No. ×× Mfg. Date: April 2023 was ultimately released to the U.S market based on passing ×× of dosage unit results and Sample Set ×× testing results in June 2023 of ×× Tablets within ×× Bottles).
壓片和成品膠囊隨后被包裝到 ×× 瓶中，分銷到美國市場。×× 毫克的 ×× 片劑，最終批號 ××，生產(chǎn)日期：2023 年 4 月，最終基于 2023 年 6 月 ×× 瓶內(nèi) ×× 片劑的劑量單位結(jié)果合格以及樣本組 ×× 測試結(jié)果合格，被放行到美國市場。
According to the Assistant General Manager of Quality Assurance, there is no documentation or record onsite for extractable and leachable studies being performed for ×× bottle containers used for ×× packaging of all tablets and capsules distributed to the US and other markets. During the current inspection, your firm was unable to provide any documentation of extractable and leachable studies performed for the ×× containers ×× for finished product tablet compression or capsule filling operations.
根據(jù)質(zhì)量保證總經(jīng)理助理的說法，現(xiàn)場沒有關(guān)于對用于向美國和其他市場分銷的所有片劑和膠囊的 ×× 包裝的 ×× 瓶容器進(jìn)行可萃取和可浸出研究的文件或記錄。在本次檢查中，貴公司無法提供任何關(guān)于對用于成品片劑壓片或膠囊填充操作的 ×× 容器 ×× 進(jìn)行可萃取和可浸出研究的文件。
OBSERVATION 2
觀察項(xiàng)2
Written records of investigation of a drug complaint do not include the follow - up.
藥品投訴調(diào)查的書面記錄不包含后續(xù)跟進(jìn)內(nèi)容。
A) Complaint #PC/NCR/FDF/23 - 020, was filed on October 5th, 2023 for ×× tablets USP ×× mg, due to the firm's customer receiving a complaint from the pharmacy that the tablets were disintegrating and found the tablets in the bottle to be crumbly, disintegrating, pitted, had dust in the in the bottles that came from the pill itself and did not have crisp markings on the tablet. The investigation report root cause analysis stated that: based on the investigation, it can be drawn that the tablets photographs of the control/reference sample resemble the tablet photographs of the complaint sample. The probability of generation of powder could be due to ×× nature of the tablets. In addition, the subjected complaint was considered as 'Not Substantiated' and no corrective and/or preventive actions was initiated. However, there is no finished drug product release and stability specification established to determine the acceptability limit of ×× tablets with chipped edges and disintegrating like physical characteristics. These physical characteristics was also observed during review of retain samples during the current inspection. According to the General Manager of Quality Assurance (QA), there was also no attempt made to request the original comparator sample for comparison purposes and further evaluation.
投訴 #PC/NCR/FDF/23 - 020 于 2023 年 10 月 5 日提出，涉及 ×× 毫克的 ×× USP片劑。原因是該公司的客戶收到藥房投訴，稱片劑正在崩解，且發(fā)現(xiàn)瓶中的片劑易碎、崩解、有凹痕，瓶中有來自藥片本身的粉塵，并且片劑上沒有清晰的標(biāo)識。調(diào)查報(bào)告的根本原因分析表明：根據(jù)調(diào)查，對照 / 參考樣品的片劑照片與投訴樣品的片劑照片相似。產(chǎn)生粉末的可能性可能是由于片劑的 ×× 特性。此外，該投訴被認(rèn)定為 “不成立”，且未啟動任何糾正和 / 或預(yù)防措施。然而，沒有制定成品藥品的放行和穩(wěn)定性規(guī)格來確定具有邊緣碎裂和類似崩解等物理特性的 ×× 片劑的可接受限度。在本次檢查期間對留樣進(jìn)行審查時(shí)，也觀察到了這些物理特性。據(jù)質(zhì)量保證（QA）總經(jīng)理稱，也沒有嘗試要求提供原始對照樣品以作比較和進(jìn)一步評估。
Furthermore, SOP QA084 - 02, Field Alert Report, Effective Date: December 31, 2022, states that: the following are some examples which need to be reported as a Field Alert Report (FAR): Crumbled, broken, disintegrated tablets found inside bottles...However, there is no documented explanation as to why there was no communication with the customer in regards to potentially filing a U.S FDA field alert report for the complaint as described in the procedure.
此外，SOP QA084 - 02《現(xiàn)場警戒報(bào)告》，生效日期：2022 年 12 月 31 日，規(guī)定：以下是一些需要作為現(xiàn)場警戒報(bào)告（FAR）上報(bào)的例子：瓶內(nèi)發(fā)現(xiàn)碎裂、破損、崩解的片劑…… 然而，對于為何沒有按照程序所述，就該投訴與客戶溝通是否可能提交美國食品藥品監(jiān)督管理局（FDA）現(xiàn)場警戒報(bào)告，沒有書面說明。
B) Complaint # PC/NCR/FDF/24 - 024 was initiated on May 10, 2024, for ×× Tablets, ×× mg, Batch No. ×× due to customer finding medical grade piece of glove, which is/could be a finger part of the glove, upon opening the sealed bottle on April 23, 2024. It was determined that the glove might have torn during ×× activity prior to tablet inspection and then ×× the tablets and filled in the CAPA/030/24 was initiated on June 24, 2024, to propose a new procedure: SOP PD289 - 00 Handling of Gloves in Manufacturing and Packing Area, Effective Date: October 03, 2024. However, the SOP does not include provisions for notifying the supervisor or documenting any potential future incidences concerning ripped pieces of gloves.
投訴 #PC/NCR/FDF/24 - 024 于 2024 年 5 月 10 日發(fā)起，涉及 ×× 毫克的 ×× 片劑，批號 ××。原因是客戶在 2024 年 4 月 23 日打開密封瓶時(shí)，發(fā)現(xiàn)了醫(yī)用級別的手套碎片，該碎片可能是手套的手指部分。經(jīng)確定，手套可能在片劑檢驗(yàn)前的 ×× 活動中撕裂，然后 ×× 片劑并裝入（瓶中）。CAPA/030/24 于 2024 年 6 月 24 日啟動，旨在提出一項(xiàng)新程序：SOP PD289 - 00《生產(chǎn)和包裝區(qū)域手套的處理》，生效日期：2024 年 10 月 3 日。然而，該 SOP 沒有包含通知主管或記錄未來任何與手套撕裂碎片相關(guān)的潛在事件的條款。
OBSERVATION 3
觀察項(xiàng)3
The responsibilities and procedures applicable to the quality control unit are not in writing and fully followed.
適用于質(zhì)量控制部門的職責(zé)和程序未形成書面文件且未被完全遵守。
A) Complaint investigations that are involved with field alert reporting activities are not logged into the Field Alert Report Log (Annexure I) for further follow - up and reference as per SOP QA084 - 02, Field Alert Report, Effective Date: December 31, 2022, requirement. This include the lack of documentation in the Field Alert Report Log for Complaint MC 036/20, Complaint Received on: December 04, 2020 by the customer for ×× tablets ×× mg, Batch No. ×× Manufacturing, Date: 01/2020, Exp. Date: ×× Due to pharmacist stating that one completed seal bottle had ×× tablets under the strength of ×× mg and ×× tablet under the strength of ×× mg, Initial FAR Date: December 08, 2020, Final FAR Date: December 08, 2020. According to General Manager of Quality Assurance (QA), this event was not logged to procedural unawareness by the QA department.
涉及現(xiàn)場警戒報(bào)告活動的投訴調(diào)查未按照 SOP QA084 - 02《現(xiàn)場警戒報(bào)告》（生效日期：2022 年 12 月 31 日）的要求，記錄到《現(xiàn)場警戒報(bào)告日志》（附件 I）中，以作進(jìn)一步跟進(jìn)和參考。這包括《現(xiàn)場警戒報(bào)告日志》中缺少對投訴 MC 036/20 的記錄，該投訴于 2020 年 12 月 4 日由客戶針對 ×× 毫克的 ×× 片劑（批號 ××，生產(chǎn)日期：2020 年 1 月，有效期：××）提出，原因是藥劑師稱一個(gè)完整密封的瓶子里有 ×× 片含量低于 ×× 毫克的片劑和 ×× 片含量低于 ×× 毫克的片劑。初始 FAR 日期：2020 年 12 月 8 日，最終 FAR 日期：2020 年 12 月 8 日。據(jù)質(zhì)量保證（QA）總經(jīng)理稱，由于 QA 部門對程序不了解，該事件未被記錄。
B) There is no instrument usage log for Analytical Balance #PD/AWB - 06 used to routinely perform in - process analytical testing of compressed tablets of various drug products manufactured in Production Block ×× In addition, the instrument usage log for friability test apparatus PD/FBL - 01 has not been completed as per SOP PD240 - 02 Operation, Cleaning and Calibration of Friability Test Apparatus, Effective Date: October 28, 2023, section 6.2 Annexure II. Usage Log for Friability Test Apparatus (PD240 - F02 - 01) requirement. According to General Manager of Quality Assurance (QA), this was due to procedural unawareness by operators and QA.
用于對生產(chǎn)區(qū)域 ×× 生產(chǎn)的各類藥品壓片進(jìn)行常規(guī)過程分析測試的分析天平 #PD/AWB - 06 沒有儀器使用日志。此外，脆碎度測試儀 PD/FBL - 01 的儀器使用日志未按照 SOP PD240 - 02《脆碎度測試儀的操作、清潔和校準(zhǔn)》（生效日期：2023 年 10 月 28 日）第 6.2 節(jié)附件 II《脆碎度測試儀使用日志（PD240 - F02 - 01）》的要求完成。據(jù)質(zhì)量保證（QA）總經(jīng)理稱，這是由于操作人員和 QA 對程序不了解。
C) There is no documented rationale and quality risk assessment for assigning the same User ID and passwords shared amongst production block operators, supervisors, and managers for login into manufacturing equipment Human Machine Interface (HMI). For example, ×× operators are provided with the supervisor level password for ×× Equipment ID: PD ×× 01 and ×× Equipment ID: PD ×× 02 as per SOP PD052 - 08 Operation of ×× (Capacity) ×× Effective Date: November 24, 2023. This is despite the software vendor manual stating that supervisor level password prevents access to the program details, and it should be known only to the supervisor or in charge of the plant. The supervisor level user access allows for edits of the following data points:
對于為生產(chǎn)區(qū)域的操作員、主管和經(jīng)理分配相同的用戶 ID 和密碼以登錄生產(chǎn)設(shè)備的人機(jī)界面（HMI），沒有書面的基本原理和質(zhì)量風(fēng)險(xiǎn)評估。例如，根據(jù) SOP PD052 - 08《××（產(chǎn)能）×× 的操作》（生效日期：2023 年 11 月 24 日），×× 操作員被提供了用于 ×× 設(shè)備 ID：PD ×× 01 和 ×× 設(shè)備 ID：PD ×× 02 的主管級密碼。盡管軟件供應(yīng)商手冊中說明主管級密碼可防止訪問程序細(xì)節(jié)，且該密碼應(yīng)僅為主管或工廠負(fù)責(zé)人所知，但實(shí)際情況并非如此。主管級用戶權(quán)限允許編輯以下數(shù)據(jù)點(diǎn)：
Process Time (total cycle time)
過程時(shí)間（總循環(huán)時(shí)間）
×× Off time (time during which ×× is switched off or during the time of ×× is taking place).
×× 關(guān)閉時(shí)間（×× 關(guān)閉期間或 ×× 發(fā)生期間的時(shí)間）。
On and Off (time duration during which ××)
開啟和關(guān)閉（×× 期間的持續(xù)時(shí)間）
On and Off (time during which ××)
開啟和關(guān)閉（×× 期間的時(shí)間）
set point
設(shè)定點(diǎn)
low and high limit
上下限
setpoint.
設(shè)定點(diǎn)。
The following additional manufacturing equipment Human Machine Interface (HMI) screens also have shared user IDs and passwords for Production Block ×× in which operators are assigned supervisor level access:
以下額外的生產(chǎn)設(shè)備人機(jī)界面（HMI）屏幕對于生產(chǎn)區(qū)域 ×× 也存在共享的用戶 ID 和密碼，在這些屏幕中，操作員被分配了主管級訪問權(quán)限：
D) On August 06, 2025, I observed that the Packaging Supervisor was able to cut and delete logged software audit trail and packaging batch data files within the Countec Data System Windows application account used for the ×× Bottle Packing Line ×× operations. The account login is also shared between operators and packaging supervisors. According to the IT Administrator, this was an oversight.
2025 年 8 月 6 日，我觀察到包裝主管能夠在用于 ×× 瓶裝包裝線 ×× 操作的 Countec 數(shù)據(jù)系統(tǒng) Windows 應(yīng)用程序賬戶內(nèi)，剪切和刪除已記錄的軟件審計(jì)追蹤和包裝批次數(shù)據(jù)文件。該賬戶登錄信息也在操作員和包裝主管之間共享。據(jù) IT 管理員稱，這是一個(gè)疏忽。
OBSERVATION 4
觀察項(xiàng)4
Equipment and utensils are not cleaned, maintained and sanitized at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality or purity of the drug product.
設(shè)備和器具未在適當(dāng)?shù)臅r(shí)間間隔進(jìn)行清潔、維護(hù)和消毒，以防止污染，而這種污染可能會改變藥品的安全性、鑒別性、效價(jià)、質(zhì)量或純度。
A) During the inspectional walkthrough on August 4th, 2025, visible ×× stains were observed within the ×× which remains open during ×× operations for drug products intended for the U.S and other global markets. PD ×× 01 was last used to manufacture ×× tablets ×× mg, ×× mg, and ×× mg, Batch No. ×× prior to Product Changeover (Type-B) cleaning being completed on July 30, 2025. However, the following test results were reported after swab sampling performed as per the current inspection request for the same equipment on August 4th, 2025:
在 2025 年 8 月 4 日的檢查巡視中，在 ×× 內(nèi)觀察到可見的 ×× 污漬，該 ×× 在針對美國和其他全球市場的藥品的 ×× 操作期間一直處于開啟狀態(tài)。PD ×× 01 最后一次用于生產(chǎn) ×× 毫克、×× 毫克和 ×× 毫克的 ×× 片劑，批號 ××，之后在 2025 年 7 月 30 日完成了產(chǎn)品轉(zhuǎn)換（B 型）清潔。然而，根據(jù)本次檢查要求，于 2025 年 8 月 4 日對同一設(shè)備進(jìn)行擦拭取樣后，報(bào)告了以下測試結(jié)果：
An additional peak in the sample chromatograms for all ×× swab sample locations was identified to be traces of ×× which is a ×× used in the treatment of ×× The identified peak for ×× had a higher area response compared to previously last manufactured product: ×× For example:
在所有 ×× 擦拭取樣位置的樣品色譜圖中，發(fā)現(xiàn)了一個(gè)額外的峰，經(jīng)鑒定為 ×× 的痕跡，×× 是用于治療 ×× 的一種 ××。與之前最后生產(chǎn)的產(chǎn)品 ×× 相比，×× 的已鑒定峰具有更高的面積響應(yīng)。例如：
Swab Analysis results for ×× Duct
×× 管道的擦拭分析結(jié)果
×× Tablets ×× mg, was last manufactured on March 2025 using PD ×× 01. ×× additional drug product batches have been manufactured using the same equipment since then for the U.S and other global markets, including:
×× 毫克的 ×× 片劑最后一次是在 2025 年 3 月使用 PD ×× 01 生產(chǎn)的。從那以后，使用同一設(shè)備為美國和其他全球市場生產(chǎn)了 ×× 批額外的藥品，包括：
×× Tablets ×× mg and ×× mg (USA), Batch No.
×××× 毫克和 ×× 毫克的 ×× 片劑（美國），批號 ××
Mfg. Date: ×× Status: Dispatched
生產(chǎn)日期：×× 狀態(tài)：已發(fā)運(yùn)
×× Tablets ×× mg and ×× mg (USA), Batch No.
×××× 毫克和 ×× 毫克的 ×× 片劑（美國），批號 ××
Mfg. Date: ×× Status: Dispatched
生產(chǎn)日期：×× 狀態(tài)：已發(fā)運(yùn)
×× Tablets ×× mg and ×× mg (USA), Batch No.
×××× 毫克和 ×× 毫克的 ×× 片劑（美國），批號 ××
Mfg. Date: ×× Status: Dispatched
生產(chǎn)日期：×× 狀態(tài)：已發(fā)運(yùn)
×× Tablets ×× mg and ×× mg (USA), Batch No.
×××× 毫克和 ×× 毫克的 ×× 片劑（美國），批號 ××
Mfg. Date: ×× Status: Dispatched
生產(chǎn)日期：×× 狀態(tài)：已發(fā)運(yùn)
This is despite the following product changeover cleaning steps being sign - off as completed and verified after production of ×× Batch No.
××盡管在 ×× 批號 ×× 的產(chǎn)品生產(chǎn)后，以下產(chǎn)品轉(zhuǎn)換清潔步驟已被簽署為完成并經(jīng)過驗(yàn)證，但仍出現(xiàn)了上述情況。
B) During the inspectional walkthrough on August 4th, 2025, visible ×× product residue was observed on the ×× upper and outer surfaces, corner surface of the empty capsule reservoir, and outer surface of the empty capsules reservoir within Capsule filling machine (ID: PD/CFM - 03). PD/CFM - 03 was last used to manufacture ×× capsules USP ×× mg, Batch No. ×× on July 22, 2025, prior to Product Changeover (Type B) cleaning being completed on July 24, 2025. However, the following test results were reported after swab sampling performed as per the current inspection request for the same equipment on August 4th, 2025:
在 2025 年 8 月 4 日的檢查巡視中，在膠囊填充機(jī)（ID：PD/CFM - 03）內(nèi)的 ×× 上表面和外表面、空膠囊儲槽的角表面以及空膠囊儲槽的外表面觀察到可見的 ×× 產(chǎn)品殘留。PD/CFM - 03 最后一次用于生產(chǎn) ×× 毫克的USP膠囊，批號 ××，時(shí)間為 2025 年 7 月 22 日，之后在 2025 年 7 月 24 日完成了產(chǎn)品轉(zhuǎn)換（B 型）清潔。然而，根據(jù)本次檢查要求，于 2025 年 8 月 4 日對同一設(shè)備進(jìn)行擦拭取樣后，報(bào)告了以下測試結(jié)果：
This is despite the following product changeover cleaning steps being sign - off as completed and verified:
盡管以下產(chǎn)品轉(zhuǎn)換清潔步驟已被簽署為完成并經(jīng)過驗(yàn)證，但仍出現(xiàn)了上述情況：
C) On August 08, 2025, the following poor equipment conditions were observed for Compression Machine PD/TCM - 03 located in Production Block ×× and routinely used to compressed tablets for the U.S market:
2025 年 8 月 8 日，對于位于生產(chǎn)區(qū)域 ×× 且常規(guī)用于為美國市場生產(chǎn)壓片的壓片機(jī) PD/TCM - 03，觀察到以下不良設(shè)備狀況：
×× stains and spots observed on the ×× and
××在 ×× 和 ×× 上觀察到 ×× 污漬和斑點(diǎn)
Visible dents on the ×× of the
××在 ×× 的 ×× 上有可見的凹痕
Damaged/chipping parts for the ×× In addition, ×× was observed across the
×××× 的部件有損壞 / 碎裂情況。此外，在 ×× 上觀察到 ××
A shiny metal particle found on the ×× of the compression machine.
在壓片機(jī)的 ×× 上發(fā)現(xiàn)了一個(gè)有光澤的金屬顆粒。
The equipment was last to manufacture ×× Tablets USP ×× mg, Batch No. ×× intended for the U.S market.
該設(shè)備最后一次用于生產(chǎn) ×× 毫克的USP片劑，批號 ××，用于美國市場。
D) During my inspection walkthrough on August 04, 2025, I observed what appeared to be very visible inner stress cracks and scratches within the product - contact view glass of ×× PD ×× 01. PD ×× 01 is routinely used for ×× operations for drug products distributed to the U.S and other global markets, including: ×× Tablets ×× and ×× mg last manufactured on May 9th, 2025. There has been no incident report raised or maintenance check conducted for this matter until the current inspection.
在 2025 年 8 月 4 日的檢查巡視中，我觀察到 ×× PD ×× 01 與產(chǎn)品接觸的視鏡玻璃內(nèi)似乎有非常明顯的內(nèi)應(yīng)力裂紋和劃痕。PD ×× 01 常規(guī)用于向美國和其他全球市場分銷的藥品的 ×× 操作，包括：最后一次生產(chǎn)于 2025 年 5 月 9 日的 ×× 毫克和 ×× 毫克的 ×× 片劑。在本次檢查之前，沒有就此事提交過事故報(bào)告或進(jìn)行過維護(hù)檢查。
E) During my inspection walkthrough on August 06, 2025, two visible large cracks was observed within the ×× directly above the tablet and capsule ×× of Tablets/Capsule Counting Machine ID: PD/TCC - 03. According to the Packaging Supervisor, the cracks had recently occurred. However, there is no documentation of this incident, timeline of the occurrence, or maintenance check conducted for this matter until the current inspection.
在 2025 年 8 月 6 日的檢查巡視中，在片劑 / 膠囊計(jì)數(shù)機(jī)（ID：PD/TCC - 03）的片劑和膠囊 ×× 正上方的 ×× 內(nèi)觀察到兩條明顯的大裂縫。據(jù)包裝主管稱，這些裂縫是最近出現(xiàn)的。然而，在本次檢查之前，沒有關(guān)于該事件的文件記錄、發(fā)生時(shí)間線或就此事進(jìn)行的維護(hù)檢查。
OBSERVATION 5
觀察項(xiàng)5
Written procedures are not established for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product.對于用于藥品生產(chǎn)、加工、包裝或貯存的設(shè)備（包括器具）的清潔和維護(hù)，未制定書面程序。
A) Your firm's cleaning validation revised Protocol No. ECV/NP/008-05, MACO Establishment Protocol, Effective Date: January 25, 2019, established (Total Score: ××) as the worst-case product to conduct cleaning validation study for all non-dedicated equipment product contact surfaces used to product U.S and non-U.S marketed finished drug products. This was based on a total score and assessment done for toxicity, solubility and hardest to clean considerations. However, there is no documented scientific justification as to why ×× tablets (Total Score: ××) was instead selected to perform the cleaning validation study and 2023 recleaning validation study for all equipment product contact surfaces, given the following total scores reported in the protocol as per the table below:
貴公司的清潔驗(yàn)證修訂方案編號 ECV/NP/008-05《MACO 建立方案》，生效日期：2019 年 1 月 25 日，確定（總得分：××）為最差情況產(chǎn)品，用于對所有用于生產(chǎn)美國和非美國市場成品藥的非專用設(shè)備產(chǎn)品接觸表面開展清潔驗(yàn)證研究。這是基于對毒性、溶解性和最難清潔情況的總得分和評估。然而，鑒于方案中如下表報(bào)告的總得分，對于為何選擇 ×× 片劑（總得分：××）來對所有設(shè)備產(chǎn)品接觸表面開展清潔驗(yàn)證研究和 2023 年再清潔驗(yàn)證研究，沒有書面的科學(xué)依據(jù)：
Total score based on Toxicity, Solubility, and Hardest to clean considerations:
基于毒性、溶解性和最難清潔情況的總得分：
During the inspection, the Assistant General Manager of Quality Assurance (QA) stated that ×× tablets, Total Score: ×× was mistakenly chosen instead of the actual previously identified hardest-to-clean product ×× (Total Score: ××) to conduct the cleaning validation study due to ×× having the lowest maximum carry-over (MACO) limit.
在檢查過程中，質(zhì)量保證（QA）總經(jīng)理助理表示，×× 片劑（總得分：××）被錯(cuò)誤地選擇，而非之前確定的實(shí)際最難清潔產(chǎn)品 ××（總得分：××）來開展清潔驗(yàn)證研究，原因是 ×× 具有最低的最大殘留（MACO）限值。
B) Since the 2018 cleaning validation, there has been no further evaluation and cleaning validation study for more than ×× newly introduced finished drug products to assess overall toxicity, Solubility, and Hardest to clean considerations for shared non-dedicated equipment surfaces, including: ×× In addition, your firm has performed a single cleaning verification study for certain finished drug products dating back to 2015, without any written justification on the frequency, timeline, drug product selection, and selection of only some hardest-to-clean areas for swab analysis versus all hardest-to-clean areas reviewed during visual inspection.
自 2018 年清潔驗(yàn)證以來，對于超過 ×× 種新推出的成品藥，沒有進(jìn)一步的評估和清潔驗(yàn)證研究，以評估共享非專用設(shè)備表面的整體毒性、溶解性和最難清潔情況，包括：×× 此外，貴公司自 2015 年以來對某些成品藥僅開展了一次清潔驗(yàn)證研究，對于擦拭分析僅選擇部分最難清潔區(qū)域而非目視檢查中審查的所有最難清潔區(qū)域，以及頻率、時(shí)間線、藥品選擇，均沒有書面依據(jù)。
C) There is no documented scientific rationale and quality risk assessment for having one cleaning validation study representative for all finished drug product profiles. The 2018 cleaning validation study protocol and report did not assess the differences in physical properties and manufacturing processes for various types of drug products, including: capsules ×× and compressed tablets ×× Tablets was instead selected as the sole drug product to conduct the cleaning validation study.
對于用一項(xiàng)清潔驗(yàn)證研究代表所有成品藥情況，沒有書面的科學(xué)依據(jù)和質(zhì)量風(fēng)險(xiǎn)評估。2018 年清潔驗(yàn)證研究方案和報(bào)告未評估各類藥品在物理性質(zhì)和生產(chǎn)工藝上的差異，包括：膠囊 ×× 和壓片 ××。反而選擇 ×× 片劑作為開展清潔驗(yàn)證研究的唯一藥品。
D) SOP PD291-01, Operation and Cleaning of Tablet Compression Machine, Effective Date: March 13, 2025, instructs operators to solely use ×× and a ×× cloth for cleaning surfaces of the ×× and table compression machine surface. However, ×× was not assessed as part of the original cleaning validation study and sampling plan. Only ×× was evaluated for ×× residue for all surfaces. According to the Production Manager, the firm has decided to use ×× as part of their routine cleaning operations instead of ×× to prevent rusting of equipment surfaces. He stated the ×× was not evaluated as part of the cleaning validation program due to an oversight.
SOP PD291-01《壓片機(jī)的操作與清潔》，生效日期：2025 年 3 月 13 日，指導(dǎo)操作人員僅使用 ×× 和一塊 ×× 布來清潔 ×× 和壓片機(jī)表面。然而，×× 未作為原始清潔驗(yàn)證研究和取樣計(jì)劃的一部分進(jìn)行評估。僅對所有表面的 ×× 殘留進(jìn)行了 ×× 評估。據(jù)生產(chǎn)經(jīng)理稱，公司已決定將 ×× 作為日常清潔操作的一部分，而非 ××，以防止設(shè)備表面生銹。他表示，由于疏忽，×× 未作為清潔驗(yàn)證程序的一部分進(jìn)行評估。
E) During my inspection walkthrough on August 04, 2025, I observed an unidentified ×× bowl stored within Module ×× area, Production Block ×× last used to manufacture ×× tablets ×× mg, and ×× mg, Batch No. ×× According to the Production Manager, the ×× bowl is not used in the production of ×× and is instead used as part of the ×× Equipment ID: PD ×× -04. Equipment ID: PD ×× -04 was last documented as being used in the ×× area for manufacturing operations involving ×× Tablets, USP ×× mg, ×× mg, and ×× mg, Batch No. ×× on July 27, 2025. However, the Production Manager and Senior General Manager of Operations, was unable to explain and provided documentation for why, how, and when the ×× was placed in the different drug production area for a different product.
在 2025 年 8 月 4 日的檢查巡視中，我觀察到在生產(chǎn)區(qū)域 ×× 的模塊 ×× 區(qū)域內(nèi)存放著一個(gè)不明 ×× 碗，該區(qū)域最后一次用于生產(chǎn) ×× 毫克和 ×× 毫克的 ×× 片劑，批號 ××。據(jù)生產(chǎn)經(jīng)理稱，該 ×× 碗不用于 ×× 的生產(chǎn)，而是作為 ××（設(shè)備 ID：PD ×× -04）的一部分使用。設(shè)備 ID：PD ×× -04 最后一次有記錄的使用是在 2025 年 7 月 27 日，在 ×× 區(qū)域用于涉及 ×× 毫克、×× 毫克和 ×× 毫克的USP ×× 片劑（批號 ××）的生產(chǎn)操作。然而，生產(chǎn)經(jīng)理和運(yùn)營高級總經(jīng)理無法解釋并提供文件說明為何、如何以及何時(shí)將 ×× 放置在不同藥品生產(chǎn)區(qū)域用于不同產(chǎn)品。
F) On August 06, 2025, ×× (ID: PD ×× 1) was observed to be unplugged/disconnected and stationed on the production floor with other equipment parts. According to General Manager (GM) of QA, the ×× is disconnected after batch production involving ×× tablets USP ×× mg, ×× mg, and ×× mg. ID: PD ×× was last used on June 12, 2025, for Batch No. ×× It was also previously used on May 31, 2025, to produce Batch No. ×× The batch record instructions require the operator to maintain the ×× at a ×× between ×× However, there is no procedure to verify the functionality of the ×× after reconnection and before usage for batch production operations.
2025 年 8 月 6 日，觀察到 ××（ID：PD ×× 1）處于未插電 / 斷開連接狀態(tài)，并與其他設(shè)備部件一起放置在生產(chǎn)車間。據(jù) QA 總經(jīng)理稱，在涉及 ×× 毫克、×× 毫克和 ×× 毫克的USP ×× 片劑的批次生產(chǎn)后，×× 會被斷開連接。ID：PD ×× 最后一次使用是在 2025 年 6 月 12 日，用于批號 ×× 的生產(chǎn)。它之前還在 2025 年 5 月 31 日用于生產(chǎn)批號 ×× 的產(chǎn)品。批次記錄說明要求操作人員將 ×× 保持在 ×× 至 ×× 之間。然而，沒有程序來驗(yàn)證 ×× 在重新連接后以及用于批次生產(chǎn)操作之前的功能。
OBSERVATION 6
觀察項(xiàng)6
The accuracy, sensitivity, specificity and reproducibility of test methods have not been established.
檢測方法的準(zhǔn)確性、靈敏度、特異性和可重復(fù)性尚未得到確認(rèn)。
A) The ×× analytical method for ×× Tablets USP ×× mg, ×× mg, ×× mg, ×× mg, and ×× mg, which is routinely used in - process testing, has not been evaluated for accuracy, sensitivity, specificity and reproducibility according to the Assistant General Manager of QA. This includes that lack of evaluation for the ×× sample preparation procedure and suitability of sample mass differences. For example:
據(jù)質(zhì)量保證（QA）總經(jīng)理助理稱，用于 ×× 毫克、×× 毫克、×× 毫克、×× 毫克和 ×× 毫克的USP ×× 片劑的 ×× 分析方法，該方法常規(guī)用于過程中檢測，但尚未對其準(zhǔn)確性、靈敏度、特異性和可重復(fù)性進(jìn)行評估。這包括對 ×× 樣品制備程序以及樣品質(zhì)量差異的適用性缺乏評估。例如：
×× testing protocol for ×× Tablets USP ×× mg, ×× mg, ×× mg and ×× mg /In - process instructs Quality Assurance (QA) personnel to collected of the finished product individual dosage form. For ×× Tablets USP ×× mg, ×× Batch No. ×× this equates to a sample size quantity specification of: ×× mg to ×× mg according to the range of the sample size allowed to be taken by QA for establishing the lower and higher Assist QA Manager, there is no study available for ×× testing. In addition, the following out - of - specification (OOS) results were reported since June 2021 and were attributed to probable sampling errors:
用于 ×× 毫克、×× 毫克、×× 毫克和 ×× 毫克的USP ×× 片劑 / 過程中的 ×× 檢測方案，指導(dǎo)質(zhì)量保證（QA）人員收集成品的單個(gè)劑型。對于批號為 ×× 的 ×× 毫克的USP ×× 片劑，根據(jù) QA 為確定上下限可采集的樣品量范圍，這相當(dāng)于樣品量規(guī)格為：×× 毫克至 ×× 毫克。據(jù)助理 QA 經(jīng)理稱，沒有可用于 ×× 檢測的研究。此外，自 2021 年 6 月以來報(bào)告了以下超出規(guī)格（OOS）的結(jié)果，這些結(jié)果被歸因于可能的取樣誤差：
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