OBSERVATION 1

觀察項1

QUALITY SYSTEM
質量體系

The responsibilities and procedures applicable to the quality control unit are not in writing or fully followed.

適用于質量控制部門的職責和程序未形成書面文件，或未得到充分遵循。

Specifically,
具體而言：

a. Your drug product stability sample testing and control program is deficient. Drug product stability samples, including those that are pending testing or have completed testing, were placed on xx located in QC Analytical LAB - xx Room # xx which were accessible to all QC and R&D personnel. According to your QC analyst, no procedural system was implemented to ensure that only the right sample and the right amount of sample can be used to conduct the requisite stability testing. According to your OOS investigations, “error in sample selection is the likely cause of the initial out - of - specification (OOS) results” (OOS - AL2 - 24 - 0033, ) and “the root cause for the failure is due to selection of wrong samples” (OOS - AL2 - 25 - 0001) were concluded as the root causes of the respective OOS events. However, the proposed CAPA (CAP - AL2 - 25 - 0001) was to include a control measure (verification of samples) by revising the SOP (SOP - AL2 - QC - 0007 - 005). Both OOS investigations were for closed without verifying the effectiveness of the proposed CAPA.

a. 貴公司的藥品穩定性樣品測試和控制程序存在缺陷。藥品穩定性樣品，包括待測試或已完成測試的樣品，被放置在質量控制分析實驗室 - xx 房間內的 xx 處，所有質量控制和研發人員均可進入。據貴公司質量控制分析人員稱，沒有實施程序化的系統來確保只有正確的樣品和正確數量的樣品被用于必要的穩定性測試。根據貴公司的OOS調查，“樣品選擇錯誤可能是初始OOS結果的原因”（OOS - AL2 - 24 - 0033）以及 “失敗的根本原因是選擇了錯誤的樣品”（OOS - AL2 - 25 - 0001）被判定為相應 OOS 事件的根本原因。然而，提議的糾正和預防措施（CAPA，CAP - AL2 - 25 - 0001）是通過修訂標準操作規程（SOP，SOP - AL2 - QC - 0007 - 005）來納入一項控制措施（樣品核查）。兩項 OOS 調查均在未確認 CAPA 有效性的情況下關閉。

b. Your firm failed to follow the Stability Program for Finished Products SOP - AL21204.05 Studies Procedure and established Stability Studies Protocols for xx and xx Ointment xx % and xx %. The Stability Program for Finished Products procedure establishes that stability samples should be completed within xx of sample receiving. However, it was documented in Deviation DEV - AL2 - 24 - 0058, that the stability samples were not tested within the requisite timeframe. In addition, in your documents provided in the submission for xx Ointment xx and xx % the dates of analysis provided are not accurate as to the dates testing was completed. In occasions, the testing was completed six (6) months after the specify timepoint. Similarly, for xx Ointment, stability samples were not completed within the established procedure and protocol. In addition, in your documents provided in the submission for xx Ointment xx and xx % the dates of analysis provided are not accurate as to the dates testing was completed. In occasions, the testing was completed six (6) months or over a year after the specify timepoint.
b. 貴公司未遵循成品穩定性程序 SOP - AL21204.05 試驗程序以及已制定的穩定性試驗方案。成品穩定性程序規定，穩定性樣品應在接收樣品后的 xx 內完成檢測。然而，在偏差報告 DEV - AL2 - 24 - 0058 中記錄，穩定性樣品未在規定時間內進行檢測。此外，在提交的關于 xx 軟膏（xx 和 xx%）的文件中，所提供的分析日期與實際完成測試的日期不符。有時，測試在規定時間點之后的六個月才完成。同樣，對于 xx 軟膏，穩定性樣品也未在既定程序和方案規定的時間內完成檢測。另外，在提交的關于 xx 軟膏（xx 和 xx%）的文件中，所提供的分析日期與實際完成測試的日期不符。有時，測試在規定時間點之后的六個月甚至一年多才完成。

c. Your QC analysts have access to R&D projects in the Empower 3.0 chromatography data system (CDS).
c. 貴公司的質量控制分析人員可訪問 Empower 3.0 色譜數據系統（CDS）中的研發項目。

d. The standard operating procedure (SOP) Change Control Procedure Document No. SOP - ABN - QA - 0002 Version No. 009, establishes changes would be classify as minor, major and critical, depending on its impact to the identity, safety, strength, quality, purity and efficacy of the product or validation status of process, equipment, utility, facility or GMP compliance/procedures and systems or regulatory filings. However, the firm does not follow the established procedure for example, changes that should be classify as major or critical are classified as minor. Change Control CC - AL2 - 23 - 0197 was initiated on 22 - Dec - 2023 for introduction of a xx to be installed in Room xx even when this change required introduction of xx to the room and may impact validated utilities, the change was classified as Minor. In another example, CC - AL2 - 21 - 0248 was initiated on 30 - Nov - 2021 for introduction of xx in the facility, however, the change which may impact the validation status of process, and impact other drug products was classified as minor.
d. 標準操作規程（SOP）變更控制程序文件（文件編號 SOP - ABN - QA - 0002，版本號 009）規定，根據變更對產品的屬性、安全性、效力、質量、純度和功效，或對工藝、設備、公用設施、設施或 GMP 合規性 / 程序和系統或法規申報的驗證狀態的影響，將變更分為微小、主要和關鍵變更。然而，貴公司未遵循既定程序，例如，應歸類為主要或關鍵的變更被歸類為微小變更。變更控制 CC - AL2 - 23 - 0197 于 2023 年 12 月 22 日發起，是為了在 xx 房間安裝 xx，即便該變更需要向房間引入 xx 且可能影響已驗證的公用設施，該變更仍被歸類為微小變更。再如，CC - AL2 - 21 - 0248 于 2021 年 11 月 30 日發起，是為了在工廠引入 xx，然而，這種可能影響工藝驗證狀態并對其他藥品產生影響的變更被歸類為微小變更。

e. There are not procedures established for introduction of new drug products at the facility. The quality unit lacks a procedure to establish a process for introducing new products to the existing manufacturing lines which will need a risk assessment of the impact to existing validated processes and equipment.
e. 工廠未制定引入新藥品的程序。質量部門缺乏為將新產品引入現有生產線制定流程的程序，而這需要對現有已驗證工藝和設備所受影響進行風險評估。

f. Comprehensive reviews of raw manufacturing and analytical data including audit trails are not performed by the Quality Assurance (QA) unit for standalone and network equipment records/systems for all production records and QC testing results (prior to the final approval of manufacturing batch records (MBR)). According to your QA reviewers, comprehensive batch record review by QA – prior to final approval of such record – is limited to paper review of the manufacturing record and verification of QC study reports including ELN. You do not review and verify critical raw data including equipment process parameters and/or audit trails to ensure completeness and accuracy of the critical process parameters and test results. In addition, you do not conduct periodic QA review of the quality system including QC analytical data to ensure ongoing compliance and product quality.
f. 質量保證（QA）部門未對所有生產記錄和質量控制測試結果的單機版設備和網絡版設備記錄 / 系統的原始生產和分析數據，包括審計追蹤，進行全面審查（在生產批記錄（MBR）最終批準之前）。據貴公司 QA 審核人員稱，QA 在最終批準此類記錄之前的全面批記錄審查僅限于對生產記錄的紙質審查以及對包括電子實驗室筆記本（ELN）在內的質量控制試驗報告的確認。貴公司未審查和確認關鍵原始數據，包括設備工藝參數和 / 或審計追蹤，以確保關鍵工藝參數和測試結果的完整性和準確性。此外，貴公司未對質量體系（包括質量控制分析數據）進行定期 QA 審查，以確保持續合規和產品質量。

g. Temperature, humidity, and pressure differential in drug product manufacturing areas (Grade D) are not continuously monitored. According to your manufacturing manager and QA personnel, the above environmental controls are monitored and recorded only xx. The current monitoring system does not provide assurance that any excursions from the normal operating ranges during manufacturing operations would be monitored, corrected, and documented.
g. 藥品生產區域（D 級）的溫度、濕度和壓差未得到持續監測。據貴公司生產經理和 QA 人員稱，上述環境控制僅在 xx 進行監測和記錄。當前的監測系統無法確保在生產操作過程中，對超出正常操作范圍的情況進行監測、糾正和記錄。

OBSERVATION 2
觀察項 2

There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed. Specifically, the following deviations were reviewed and found deficient:
對于任何無法解釋的差異，無論批次是否已分發，均未進行徹底審查。具體而言，經審查發現以下偏差存在缺陷：

a. Investigation Report for Device Malfunction for xx Solution USP, xx Complaint Number A - PC2024 - 001 opened on 01/11/2024 is deficient. The investigation was initiated after complaint was received due to xx malfunction. During your investigation report, you didn't identify a root cause associated to manufacturing process. However, your investigation failed to mention that previously, investigations INV - NC - 018 - 015, INV - NCAL - 018 - 001, INV - NCAL - 019 - 004 and DEV - 19 - 013, were initiated for malfunction of the xx during the submission batches manufactured in 2018. It was identified a potential root cause as xx to the bottles prior to filling may disrupt the xx and inability of the xx to function, however, after changes to the process were implemented, your firm received over a hundred (100) of complaints for xx malfunction. Your investigation was deficient and corrective and preventive actions were not adequate to prevent recurrence of this issue.
a. 2024 年 1 月 11 日發起的關于 xx 溶液的設備故障調查報告（投訴編號 A - PC2024 - 001）存在缺陷。在收到因 xx 故障的投訴后展開調查。在貴公司的調查報告中，未確定與生產工藝相關的根本原因。然而，貴公司的調查未提及此前在 2018 年生產的提交批次中，曾針對 xx 故障發起過 INV - NC - 018 - 015、INV - NCAL - 018 - 001、INV - NCAL - 019 - 004 和 DEV - 19 - 013 等調查。已確定一個潛在根本原因，即在灌裝前對瓶子進行 xx 操作可能會干擾 xx，且 xx 無法正常運行，然而，在對工藝進行變更后，貴公司仍收到了一百多起關于 xx 故障的投訴。貴公司的調查存在缺陷，糾正和預防措施不足以防止該問題再次發生。

b. During the review of Out of Specification (OOS) Investigation OOS - AL2 - 23 - 0008, we noted the following deficiencies: in - process test for xx Solution USP, xx (Lot xx) testing for assay of in - process sample was out of specification. The % Assay of xx in xx was found to be xx ng xx (%). The result for the xx of xx Solution USP, xx was xx mg xx (%). The reportable limit for the xx of xx (s) xx ng xx (%) to xx ng xx (%). The in - process acceptance criteria is each should contain not less than xx ng and not more than xx ng xx (%) to xx (%) of labeled amount. Re - testing the original sample confirmed the out of specification. Your firm identified the root cause as a sampling issue; however, the same sampling approach was used for the validation batches manufactured in April 2023 and not out of specifications were reported. In addition, your firm did not propose a corrective and preventive action nor efficacy checks to prevent future recurrences. This batch of xx Solution USP, xx was released and distributed to the market.
b. 在審查OOS 調查 OOS - AL2 - 23 - 0008 時，我們注意到以下缺陷：xx 溶液 xx（批次 xx）的中間產品含量測試超標。在 xx 中 xx 的含量百分比被發現為 xx ng xx（%）。xx 美國藥典溶液 xx 的 xx 結果為 xx mg xx（%）。xx（s）xx ng xx（%）至 xx ng xx（%）的報告限。中間產品接受標準是每個應包含不低于 xx ng 且不高于 xx ng xx（%）至 xx（%）的標示量。對原始樣品重新測試證實了超標情況。貴公司將根本原因確定為取樣問題；然而，2023 年 4 月生產的驗證批次使用了相同的取樣方法，卻未報告超標情況。此外，貴公司未提出糾正和預防措施，也未進行有效性檢查以防止未來再次發生。這批 xx 美國藥典溶液 xx 被放行并投放市場。

c. During the review of Out of Specification (OOS) Investigation OOS - AL2 - 22 - 0005, we noted the following deficiencies: testing for content of xx mg xx (Lot: xx) and xx mg xx (Lot: xx) release reported an out of specification. On December 21, 2022, the content of xx observed in the samples was xx % (specification xx %). Your firm could not identify a laboratory error and therefore decided to repeat the test in a new sample over xx after the OOS. As the results for the new sample were acceptable, the investigation was closed. Your firm did not initiate a Phase 2 investigation as required by the Handling and Investigation of Out of Specification Results in Quality control Laboratory Document No. SOP - AL21203.10 effective on 14Nov2022. Similarly, during the review of OOS Investigation Report INV - NCAL - 22 - 020, initiated in 03Nov2022, the OOS for xx mg (Lot: xx) was reported. The most probable root cause for this investigation was an analyst error during standard preparation, however, there was no indication that the standards prepared were not complying with your testing method acceptance criteria for percentage (9%) of recovery. Your firm invalidated the initial OOS results and continue repeating the test with new samples on 29DEC2022 with acceptable results. Your investigation approach and these out of the specifications cannot be considered thorough, as other root causes were not evaluated. In addition, your investigations do not extend to other batches, even when the same lot of xx is used for different xx strengths.
c. 在審查超標OOS 調查 OOS - AL2 - 22 - 0005 時，我們注意到以下缺陷：xx mg xx（批次：xx）和 xx mg xx（批次：xx）放行時的含量測試報告超標。2022 年 12 月 21 日，在樣品中觀察到的 xx 含量為 xx%（標準為 xx%）。貴公司未能確定實驗室誤差，因此決定在超標后 xx 時間對新樣品重復測試。由于新樣品的結果可接受，調查關閉。貴公司未按照 2022 年 11 月 14 日生效的《質量控制實驗室超標結果的處理和調查》（文件編號 SOP - AL21203.10）的要求啟動第二階段調查。同樣，在審查 2022 年 11 月 3 日發起的 OOS 調查報告 INV - NCAL - 22 - 020 時，報告了 xx mg（批次：xx）的 OOS 情況。此次調查最可能的根本原因是標準制備過程中的分析人員失誤，然而，沒有跡象表明所制備的標準品不符合貴公司回收率（9%）的測試方法驗收標準。貴公司判定初始 OOS 結果無效，并于 2022 年 12 月 29 日使用新樣品繼續重復測試，結果可接受。貴公司的調查方法以及這些超標情況不能被認為是徹底的，因為未評估其他根本原因。此外，貴公司的調查未延伸到其他批次，即使同一批次的 xx 用于不同 xx 規格。

d. Investigation Reports for deviation investigation for Staphylococcus epidermidis found in microbial limit test of xx JSP (DEV - AL2 - 23 - 0009) and the associated CAPA (CAP - AL2 - 23 - 0009) are deficient. The deviation was opened on 03/24/2023 due to observation of microbial colony growth during microbial limit testing of the drug product。A CAPA was performed to investigate and pinpoint the potential source of contamination. Bacillus spp. and Paenibacillus amylolyticus were recovered from swabs of the area floor in the manufacturing area. No follow - up actions were taken and there was no data confirming that the xx did not support microbial growth. Subject CAPA was completed and approved by QA on 12/06/2023. These examples are not all inclusive but demonstrate that your investigations not always are conducted in a thoroughly manner and not all the potential root causes are evaluated.

d. 關于在 xx 日本藥局方（JSP）微生物限度測試中發現表皮葡萄球菌的偏差調查（DEV - AL2 - 23 - 0009）報告及相關糾正和預防措施（CAPA，CAP - AL2 - 23 - 0009）存在缺陷。該偏差于 2023 年 3 月 24 日因在藥品微生物限度測試中觀察到微生物菌落生長而開啟。已進行 CAPA 以調查并確定潛在污染源。從生產區域地面的拭子中回收到了芽孢桿菌屬和淀粉水解類芽孢桿菌。未采取后續行動，也沒有數據證實 xx 不支持微生物生長。相關 CAPA 于 2023 年 12 月 6 日由 QA 完成并批準。這些例子并非全部，但表明貴公司的調查并非總是徹底進行，且并非所有潛在根本原因都得到評估。

OBSERVATION 3
觀察項 3

A xx field Alert Report was not submitted within three working days of receipt of information concerning a failure of one or more distributed batches of a drug to meet the specifications established for it in the application.

在收到有關一種或多種已分發藥品批次不符合申請中既定規格的信息后，未在三個工作日內提交 xx 現場警報報告。

Specifically,
具體而言，

Your firm failed to submit a Field Alert Report (FAR) to the agency within three (3) working days. Your firm failed to follow standard operating procedure (SOP) APL - GP - GEN - 0039 Field Alert Reporting Version 1.0.0.0, which establishes that an event investigation that indicates potential/confirmed failure of one or more batches of the drug product that is distributed in market is a condition for filing FAR from manufacturing site. Your firm received a complaint for the distributed drug product xx Solution USP xx Lot Number xx on 01/11/2024 due to xx malfunction where the patient could not extract drug product from the bottle due to xx malfunction, however, not FAR was submitted. In addition, your firm received similar complaints for distributed drug product xx Solution USP xx Lot Number xx between February 7, 2024, and March 27, 2024. Your firm had received six (6) complaints due to xx malfunction, xx malfunction and initial FAR was submitted to the agency on March 28, 2024. Your firm submitted a FAR after seventy - seven (77) days has passed since your firm became aware of the product quality defect.

貴公司未能在三個工作日內向本機構提交現場警報報告（FAR）。貴公司未遵循標準操作規程（SOP）APL - GP - GEN - 0039《現場警報報告》（版本 1.0.0.0），該規程規定，對表明一種或多種在市場上分發的藥品批次存在潛在 / 已確認不合格情況的事件調查，是生產場地提交 FAR 的條件。貴公司于 2024 年 1 月 11 日收到關于已分發藥品 xx 美國藥典溶液（批次編號 xx）的投訴，原因是 xx 故障，患者因 xx 故障無法從瓶中取出藥品，但未提交 FAR。此外，貴公司在 2024 年 2 月 7 日至 3 月 27 日期間收到了關于已分發藥品 xx 美國藥典溶液（批次編號 xx）的類似投訴。貴公司共收到六起因 xx 故障、xx 故障的投訴，最初的 FAR 于 2024 年 3 月 28 日提交給本機構。貴公司在意識到產品質量缺陷 77 天后才提交 FAR。

FACILITIES AND EQUIPMENT SYSTEM

OBSERVATION 4
觀察項 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.

設備和器具未按適當間隔進行清潔、維護和消毒，以防止污染改變藥品的安全性、屬性、效力、質量或純度。

Specifically,
具體而言：

a. Compounding Room xx of the xx manufacturing area, where compounding unit operation for commercial production of xx is performed, houses xx pieces of equipment – xx. Until December 2024, this xx equipment collectively shared the same equipment ID number MF - EOP - 18 as evidenced by xx.
a. 在 xx 生產區域的配料室 xx，進行 xx 商業化生產的配料單元操作，此處有 xx 件設備 - xx 。截至 2024 年 12 月，如 xx 所示，這些 xx 設備共用設備編號 MF - EOP - 18 。

Concurrently with the commercial production of xx drug products were performed in the Compounding Room xx. This was evidenced by logbook entries in Log Book #: xx.
在配料室 xx 同時進行 xx 藥品的商業化生產。這在日志編號 xx 的日志條目中有體現。

Multiple manufacturing equipment were shared during the manufacturing production of the above products including xx.
在上述產品的生產過程中，共用了多種生產設備，包括 xx 。

According to Equipment Cleaning Verification Protocol for Manufacturing Equipment (SOP - AL2 - PR - 0007, which governs xx manufacturing equipment cleaning) and Cleaning Validation Protocol for xx, the effectiveness of the equipment cleaning is demonstrated by 1) visual inspection of the equipment, and 2) analytical testing with an acceptance limit of not more than xx ppm of the residual drug substance content. There were no scientific justification or data to demonstrate that potential safety risks of carryover contamination of the previous drug products are adequately mitigated. The protocols did not consider or justify, with data, the hardest to clean areas. Equipment specific cleaning programs were not evaluated or validated as part of the validation or verification protocols. No dirty and clean hold time limits were defined and validated. There was also no evidence that the analytical method for xx residue detection was validated under the actual condition of use.
根據《生產設備清潔驗證方案》（SOP - AL2 - PR - 0007，用于管理 xx 生產設備的清潔）和 xx 的《清潔驗證方案》，設備清潔的有效性通過以下方式證明：1）對設備進行目視檢查；2）分析測試，殘留藥物物質含量的可接受限度不超過 xx ppm 。沒有科學依據或數據證明先前藥品的殘留污染所帶來的潛在安全風險已得到充分緩解。這些方案沒有用數據考慮或證明最難清潔的區域。作為驗證或核查方案的一部分，未對設備特定的清潔程序進行評估或驗證。未定義和驗證臟污和清潔的保留時間限制。也沒有證據表明用于 xx 殘留檢測的分析方法在實際使用條件下經過了驗證。

b. According to AuroLife xx Preventive Maintenance (PM) Checklist (Form FE - 1201 - F02.00), xx Equipment ID #: MF - EQP - 18 preventive maintenance was performed on the equipment on July 31, 2024. The same information was not recorded in the Cleaning and Usage Log Book (Log Book #: xx from 02Jan2024 to 31Dec2024). No cleaning action was recorded in the Log Book following the preventive maintenance. During this period, xx was manufactured using the same equipment: xx.

b. 根據 AuroLife xx 預防性維護（PM）檢查表（表格 FE - 1201 - F02.00），2024 年 7 月 31 日對設備 ID 為 MF - EQP - 18 的 xx 設備進行了預防性維護。同樣的信息未記錄在 2024 年 1 月 2 日至 12 月 31 日的《清潔和使用日志》（日志編號 xx）中。預防性維護后，日志中未記錄清潔操作。在此期間，使用同一設備生產了 xx：xx 。

OBSERVATION 5
觀察項 5

Buildings used in the manufacture, processing, packing or holding of drug products are not maintained in a clean and sanitary condition and are free of infestation by insects and other vermin.

用于藥品生產、加工、包裝或儲存的建筑物未保持清潔衛生，且未杜絕昆蟲和其他害蟲侵擾。

Specifically,
具體而言：

a. Filth, spider web, and insects are found on xx pallets used to stack and store boxes containing packaging/xx such as xx in the warehouse.
a. 在倉庫中，用于堆放和儲存包含包裝 /xx（如 xx）的箱子的 xx 托盤上發現了污垢、蜘蛛網和昆蟲。

SOP for Pest and Rodent Control (SOP - HS 1203.00) describes that the Pest and Rodent Control are outsourced to outside contractors. The SOP did not describe how your firm would evaluate the effectiveness of the pest control services to ensure that the manufacturing process, testing, and storage areas are free from infestation of vermin. Upon request, your firm provided xx pest and rodent finding reports generated by the outside contractor. However, there is no documented evidence that such reports were reviewed by your quality unit and that the effectiveness of the pest control was evaluated, maintained, and trended on a regularly basis.
《蟲害和鼠害控制標準操作規程》（SOP - HS 1203.00）規定蟲害和鼠害控制工作外包給外部承包商。該 SOP 未說明貴公司將如何評估蟲害控制服務的有效性，以確保生產、測試和儲存區域無蟲害侵擾。經要求，貴公司提供了外部承包商生成的 xx 蟲害和鼠害檢查報告。然而，沒有書面證據表明質量部門審查了這些報告，也沒有證據表明定期對蟲害控制的有效性進行了評估、維護和趨勢分析。

b. According to the SOP for Cleaning of All Manufacturing Rooms and Clearance (SOP - MF 1202.02), xx water xx is used to clean the floor of the manufacturing rooms including those in Grade D area. Effectiveness of the cleaning/sanitization using such cleaning agents was not established.
b. 根據《所有生產車間清潔和清理標準操作規程》（SOP - MF 1202.02），使用 xx 水 xx 清潔包括 D 級區域在內的生產車間地面。未確定使用此類清潔劑進行清潔 / 消毒的有效性。

OBSERVATION 6
觀察項 6

Routine calibration of automatic equipment is not performed according to a written program designed to assure proper performance.

自動設備的定期校準未按照旨在確保正常運行的書面程序進行。

Specifically,
具體而言，

The balance with Equipment Id. MF - BS - 11 (Serial No. xx) used for in - process controls in the xx manufacturing area Room: xx is not calibrated within the range of use. For example, the weight balance is use for the in - process controls of xx all strengths. The xx calibration of balance is conducted using standard weights between the range of xx, however, the in - process controls for xx to determine xx weight ranges from xx. Inaccurate weight of in process samples can lead to acceptance of xx with a variance greater than the established for the xx weight and discrepancies in drug content.

設備編號為 MF - BS - 11（序列號 xx）的天平，用于 xx 生產區域 xx 房間的中間控制，其校準范圍不符合使用要求。例如，該天平用于所有規格 xx 的中間控制。天平的 xx 校準使用的標準砝碼范圍為 xx，但用于確定 xx 重量的中間控制范圍為 xx 。中間樣品的重量不準確可能導致接受 xx 時的偏差大于既定的 xx 重量偏差，并造成藥物含量差異。

LABORATORY CONTROL SYSTEM

OBSERVATION 7
觀察項 7

Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the final specifications prior to release. Specifically,
藥品分發的測試和放行，在放行前未通過適當的實驗室檢測來確定其是否符合最終規格。具體而言：

a. During the review of Out of Specification (OOS) Investigation OOS - AL2 - 24 - 0003, we noted the following deficiencies: testing for xx in xx Solution (Lot xx) an out of specification was reported with results of xx % (Acceptance criteria xx % to xx %). Your investigation could not identify a root cause in the laboratory, and therefore, continue to repeat the test with other bottles as the original sample could not be located. The new tested samples complied with the acceptance criteria and therefore the lot was released for distribution.
a. 在審查超標（OOS）調查 OOS - AL2 - 24 - 0003 時，我們注意到以下缺陷：xx 溶液（批次 xx）中 xx 的測試結果超標，結果為 xx%（驗收標準為 xx% 至 xx%）。貴公司的調查未能確定實驗室中的根本原因，由于無法找到原始樣品，因此繼續用其他瓶進行重復測試。新測試的樣品符合驗收標準，因此該批次被放行分發。

b. During the review of Out of Specification (OOS) Investigation OOS - AL2 - 23 - 0007, initiated on 06Jun2023 after xx test was out of specifications for 6 - month stability time point 25°C/60%RH xx batch). The Content of xx (%Label Claim) in sample (sample ID xx) was found to be xx %. The result for the xx (sample ID xx) for 6 Month stability timepoint, 25°C/60% was xx %. The reportable xx for the xx was xx %. Which is below the acceptance criteria of NLT xx %. Your firm could not identify a root cause for the OOS in the laboratory or in the documentation associated with the analysis, therefore, repeating the test with a new sample was authorized since the original sample solution was expired. During the review of raw data that supported this analysis and investigation the following I noted the OOS investigation was initiated on 29Jun2023, over three (3) weeks of the sample analysis therefore the original sample was not available. In addition, during the review of the raw data I observed that other results reported as passing for xx xx ng xx 6 - month 40°C/75RH % Lot: xx but individual results were xx % and xx %, however, because xx was over xx % xx %) it was accepted.
b. 在審查超標（OOS）調查 OOS - AL2 - 23 - 0007 時（該調查于 2023 年 6 月 6 日在 xx 測試在 25°C/60% 相對濕度 6 個月穩定性時間點超標后啟動，涉及 xx 批次）。樣品（樣品 ID xx）中 xx 的含量（標示含量百分比）為 xx% 。在 25°C/60% 相對濕度 6 個月穩定性時間點，xx（樣品 ID xx）的結果為 xx% 。xx 的可報告 xx 為 xx% ，低于不低于 xx% 的驗收標準。貴公司無法確定實驗室或與分析相關文件中 OOS 的根本原因，由于原始樣品溶液已過期，因此授權用新樣品重復測試。在審查支持該分析和調查的原始數據時，我注意到 OOS 調查于 2023 年 6 月 29 日啟動，此時距樣品分析已超過三周，因此原始樣品已不可用。此外，在審查原始數據時，我觀察到其他報告為合格的 xx xx ng xx 40°C/75 相對濕度 6 個月（批次：xx）的結果，但個別結果為 xx% 和 xx% ，然而，因為 xx 超過了 xx% xx%），所以結果被接受。

In addition, your firm analyzed other samples for xx xx ng xx 6 - month 25°C/60RH % Lot: xx in the same analytical run but because xx was NLT xx %, result was accepted. Your testing procedure does not indicate that this practice is acceptable.
此外，貴公司在同一分析運行中分析了 xx xx ng xx 25°C/60 相對濕度 6 個月（批次：xx）的其他樣品，但因為 xx 不低于 xx% ，結果被接受。貴公司的測試程序未表明這種做法是可接受的。

c. During the review of analytical raw data xx xx ng xx Lot: xx assay determination I observed an unidentified peak eluting at around xx of the chromatographic run. Your firm could not provide scientific evidence of what the unknown peak was as it was not observed during the establishing of standard testing procedure. Similarly, the peak was observed in other chromatographic runs for assay in stability samples. In addition, your firm confirmed that there is no procedure for investigating unknown peaks.

此外，貴公司在同一分析運行中分析了 xx xx ng xx 25°C/60 相對濕度 6 個月（批次：xx）的其他樣品，但因為 xx 不低于 xx% ，結果被接受。貴公司的測試程序未表明這種做法是可接受的。

OBSERVATION 8
觀察項 8

Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to assure that components and drug products conform to appropriate standards of identity, strength, quality and purity. Specifically,
實驗室控制未包括建立科學合理且適當的測試程序，以確保組分和藥品符合適當的屬性、效力、質量和純度標準。具體而言：

a. Your firm failed to establish a scientifically sound method to test related substances in xx Drug Substance. The method transfer of the Related Substance by HPLC method for xx was completed and effective on 03Aug2023, however, testing for xx Drug Substance batches (Batch No. xx, No. xx) used in the submission of xx was released by Quality Assurance in July 2022 and September 2022 for usage in submission batches manufactured on August 2022 and November 2022. Your testing of drug substances is conducted by a method that has not been implemented.
a. 貴公司未能建立科學合理的方法來測試 xx 原料藥中的有關物質。xx 的高效液相色譜（HPLC）法有關物質方法轉移于 2023 年 8 月 3 日完成并生效，然而，用于 xx 申報的 xx 原料藥批次（批號 xx、xx）的測試，已于 2022 年 7 月和 9 月由質量保證部門放行，用于 2022 年 8 月和 11 月生產的申報批次。貴公司對原料藥的測試所使用的方法并未得到實施。

b. In addition, as documented in Method Transfer of Related Substances by HPLC method for xx protocol TFR01 - 198RP - 21.00, the percentage of difference (%error) between the results for xx from your firm and the certificate of analysis from the vendor was xx % (Acceptance Criteria NMT xx %), nevertheless, the method was implemented by adjusting the acceptance criteria without a scientific sound justification.
b. 此外，如 xx 的 HPLC 法有關物質方法轉移協議 TFR01 - 198RP - 21.00 中所記錄，貴公司的 xx 結果與供應商分析證書之間的差異百分比（誤差百分比）為 xx%（驗收標準不超過 xx%），然而，在沒有科學合理依據的情況下，通過調整驗收標準實施了該方法。

OBSERVATION 9
觀察項 9

In - process samples are not representative. Specifically,
中間產品樣品不具代表性。具體而言，

Batch manufacturing record for xx Solution USP xx (Batch No. xx) requires that xx samples are collected for in - process testing xx by the manufacturing associates and xx samples are collected xx by quality assurances. The xx dated 22SEP2022, requires that xx samples are collected for in - process testing xx by the manufacturing associates and xx samples are collected xx by quality assurances. There is no assurance that the sampling approach is a statistically representative of each product and each lot and has a precise representation of the quality attributes purposed to have.

xx 美國藥典溶液 xx（批號 xx）的批次生產記錄要求，由生產人員采集 xx 樣品用于中間控制測試 xx，由質量保證人員采集 xx 樣品 xx。2022 年 9 月 22 日的 xx 要求，由生產人員采集 xx 樣品用于中間控制測試 xx，由質量保證人員采集 xx 樣品 xx。無法保證該抽樣方法在統計上能代表每種產品和每個批次，也無法精確體現預期的質量屬性。

OBSERVATION 10
觀察項 10

Control procedures are not established which validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in - process material and the drug product.

未建立控制程序來驗證那些可能導致中間物料和藥品特性出現變異性的生產工藝的性能。

Specifically,
具體而言，

According to the Operation Instruction of xx Machine (4.6.2018) xx in which “the machine must be stored or operated (mandatory)” included room quality requirements for the xx room “in which the front part of machine is positioned”. The requirements included xx. However, a review of your xx Log Book for Manufacturing Log Books revealed that the above xx controls including xx were not controlled to always meet the xx machine requirements in Room xx.
根據 xx 機器操作說明（4.6.2018）xx，其中 “機器必須存放或操作（強制性）” 包含了對 xx 房間（機器前部所在房間）的環境質量要求。這些要求包括 xx 。然而，對貴公司生產日志中的 xx 日志審查顯示，上述包括 xx 在內的 xx 控制措施并不能始終滿足 xx 房間內 xx 機器的要求。

According to the same logbooks xx during the period of August 2022 to January 2023 and on the days when the xx operations were performed for xx exhibit batches manufacturing xx were outside of the above xx control ranges. A review of xx mg xx exhibit batch assay testing OOS investigations (OOS number OOS - AL2 - 22 - 0002) revealed that you experienced aberration in the manufacturing process which caused variability in weight xx of the product xx.

根據同一批日志，在 2022 年 8 月至 2023 年 1 月期間，以及在進行 xx 展示批次生產的 xx 操作日，xx 超出了上述 xx 控制范圍。對 xx 毫克 xx 展示批次含量測試超標（OOS）調查（OOS 編號 OOS - AL2 - 22 - 0002）的審查顯示，生產過程中出現偏差，導致產品 xx 的重量 xx 出現變異性。

OBSERVATION 11
觀察項 11

Procedures for corrective and preventive action have not been adequately established.

糾正和預防措施程序未得到充分建立。

Specifically,
具體而言，

Investigation Report for Device Malfunction for xx Solution USP, xx Complaint Number A - PC2024 - 001 opened on 01/11/2024 is deficient. The investigation was initiated after complaint was received due to xx malfunction. During your investigation report, you didn't identify a root cause associated to manufacturing process. However, your investigation failed to mention that previously, investigations INV - NC - 018 - 015, INV - NCAL - 018 - 001, INV - NCAL - 019 - 004 and DEV - 19 - 013, were initiated for malfunction of the xx during the submission batches manufactured in 2018. It was identified a potential root cause as xx of xx to the bottles prior to filling may disrupt the xx however, after changes to the process were implemented, your firm has received over a hundred (100) of complaints for xx malfunction. The corrective and preventive actions implemented were inadequate in that the condition for the malfunction of the xx was not corrected before the batches were released for distribution.
2024 年 1 月 11 日開啟的關于 xx 美國藥典溶液的設備故障調查報告（投訴編號 A - PC2024 - 001）存在缺陷。在收到因 xx 故障的投訴后展開調查。在貴公司的調查報告中，未確定與生產工藝相關的根本原因。然而，貴公司的調查未提及此前在 2018 年生產的提交批次中，曾針對 xx 故障發起過 INV - NC - 018 - 015、INV - NCAL - 018 - 001、INV - NCAL - 019 - 004 和 DEV - 19 - 013 等調查。已確定一個潛在根本原因，即在灌裝前對瓶子進行 xx 的 xx 操作可能會干擾 xx，然而，在對工藝進行變更后，貴公司仍收到了一百多起關于 xx 故障的投訴。所實施的糾正和預防措施并不充分，因為在批次放行分發前，xx 故障的狀況并未得到糾正。