FDA向印度迈兰实验室签发483检查观察记录，列出六项缺陷

近日，FDA发布了迈兰实验室有限公司的483缺陷报告，核心发现指向数据完整性全线失守：批生产记录被篡改批号与重量、操作员销毁称重打印件、分析天平审计追踪记录被批量删除；同时，2026年2月14日工厂火灾导致全厂停产，公司处置不当。如下：

Name and Address of Establishment: Mylan Laboratories Limited, F-4 & F-12, Pune Nashik Road, MIDC, Malegaon, Sinnar, Nashik Dist., Maharashtra, PIN: 422113, India

公司名称与地址：迈兰实验室有限公司（Mylan Laboratories Limited），印度马哈拉施特拉邦纳西克县 Sinnar 镇 Malegaon MIDC，浦那-纳西克路 F-4 & F-12 地块，邮编 422113

FEI Number: 3005587313

FEI 编号：3005587313

Inspection Dates: 05/04/2026 through 05/15/2026

检查日期：2026 年 5 月 4 日至 2026 年 5 月 15 日

Type of Establishment: Finished Drug Product Manufacturer

公司类型：制剂成品生产商（口服固体制剂）

Investigators: Pratik S. Upadhyay (Investigator); Unnee Ranjan (Investigator)

检查员：Pratik S. Upadhyay（检查员）；Unnee Ranjan（检查员）

Date Issued: 05/15/2026

签发日期：2026 年 5 月 15 日

Issued To: Dr. Abhijit Deshmukh, Head of Global Non Sterile Operations

签发给：Abhijit Deshmukh 博士，全球非无菌运营负责人

观察项 1

OBSERVATION 1

The responsibilities and procedures applicable to the quality control unit are not fully followed. [21 CFR 211.22]

质量控制单元的适用职责和程序未得到完全遵守。〔21 CFR 211.22〕

A. 质量部门对确保生产记录完整性和产品质量缺乏监管。

A. Quality Unit lacks oversight into ensuring integrity of manufacturing records and product quality.

1. On 11-May-2026, evaluation of raw data relating to (b)(4) stages of batch manufacturing revealed altering of the batch number and weights or omitting the weight printouts from the Batch Manufacturing Records (BMRs) for (b)(4) Tablets and (b)(4) Capsules.

1. 2026 年 5 月 11 日，对与 (b)(4) 个批次生产工序相关的原始数据的评估发现：(b)(4) 片剂和 (b)(4) 胶囊的批生产记录（BMR）中存在篡改批号和重量、或省略重量打印条的情况。

On 12-May-2026, firm initiated Incident Investigation PR ID: 4134254 to investigate “balance printouts taken from View Batch History of Analytical balances not matching with respective BMR Prints” and suspended batch manufacturing and batch release from their site as a result. However, no Field Alert Report was submitted to USFDA to notify potential impact on drug product quality and US market supply.

2026 年 5 月 12 日，公司启动事件调查（PR ID: 4134254），调查“分析天平‘查看批次历史’中的打印条与相应 BMR 打印条不匹配”一事，并因此暂停了本厂的批生产和批放行。然而，公司未向美国 FDA 提交现场警示报告（Field Alert Report），以通报其对药品质量和美国市场供应的潜在影响。

Examples:

实例：

a. Audit trail history log (“View Batch History”) for analytical balances displayed same date and time stamp with same individual weight of (b)(4) tablets for (b)(4) different batches and varying Nominal weights on the balance printouts (e.g. tablet weight (b)(4) mg). There was no justification provided for altering balance printouts (meta data) depicting the weighing activities that were conducted for (b)(4) different batches at the same date and time along with the reason for changing the Nominal weights.

a. 分析天平审计追踪历史日志（“查看批次历史”）显示：(b)(4) 个不同批次出现了完全相同的日期时间戳和完全相同的 (b)(4) 片剂单粒重量，而打印条上的标称重量各不相同（如片重 (b)(4) mg）。公司对篡改反映称量活动的天平打印条（元数据）——即在同一日期和时间对 (b)(4) 个不同批次进行的称量——以及更改标称重量的原因，均未提供任何解释。

b. Missing weight printouts either in audit trail history log or in respective BMRs.

b. 审计追踪历史日志或相应 BMR 中存在重量打印条缺失的情况。

c. Balance weight printouts in BMRs showed weight entries in “mg” whereas same entries were in “g” in the balance audit trail history log for individual weight of capsules. Additionally, two balances ESD0087 and ESD0115 displayed same date and time stamp for the same individual weight of (b)(4) capsules for (b)(4) different batches.

c. BMR 中胶囊单粒重量的天平打印条单位为“mg”，而同一数据在天平审计追踪历史日志中单位为“g”。此外，两台天平 ESD0087 和 ESD0115 对 (b)(4) 个不同批次的相同 (b)(4) 胶囊单粒重量，显示了相同的日期时间戳。

2. On 05-May-2026, evaluation of Incident Investigation PR ID: 3606933 (Date opened: 12-Sep-2024) revealed that Production Operator (b)(6) destroyed balance printouts dated 10-Sep-2024 by tearing into pieces and disposed torn pieces into leftover (b)(4) of batch (b)(4) – in attempt of destroying evidence of weighing activities per the incident investigation. The investigation is deficient:

2. 2026 年 5 月 5 日，对事件调查（PR ID: 3606933，开启日期 2024 年 9 月 12 日）的评估发现：生产操作人员 (b)(6) 将 2024 年 9 月 10 日的天平打印条撕成碎片，并丢弃到批次 (b)(4) 的残余 (b)(4) 中——试图销毁称量活动的证据。该调查存在缺陷：

a. “Product Impact/Conclusions” section of the investigation indicated no impact upon review of Trackwise history for preceding 12 months for Production Operator (b)(6). However, evaluation of BMR for (b)(4) stages revealed that Production Operators (b)(6) potentially changed balance printout at a later date. Assessment of balance printouts for legibility of ink color and fonts revealed notable differences – printout dated 10-Sep-2024 (relating to weight of (b)(4) tablets) appeared to have dark blue color ink whereas printouts time stamped (b)(4) (relating to weight of (b)(4) tablets) and others appeared to have printouts in light blue color ink. The evaluation of verification record of analytical balance logbook revealed the legibility of balance printout for ink color and font remained consistent i.e. dark blue ink on 09-Sep-2024 to 11-Sep-2024. This ruled out the possibility of using a different printer.

a. 调查的“产品影响/结论”部分在仅回顾了生产操作人员 (b)(6) 此前 12 个月的 Trackwise 历史后，即判定无影响。然而，对 (b)(4) 个工序 BMR 的评估显示：生产操作人员 (b)(6) 可能在事后更换了天平打印条。对天平打印条墨色和字迹清晰度的评估发现了显著差异——2024 年 9 月 10 日（对应 (b)(4) 片剂称重）的打印条为深蓝色墨，而时间戳为 (b)(4)（对应 (b)(4) 片剂称重）及其他打印条为浅蓝色墨。对分析天平日志验证记录的评估显示，2024 年 9 月 9 日至 9 月 11 日期间打印条的墨色和字体保持一致（即深蓝）。据此排除了更换打印机的可能。

b. On 07-May-2026, Site Operation Head indicated that the Operator may have changed ribbon of balance printout causing differences in ink colors. However, no indication the printer ribbon was changed since color of fonts remained consistent between print dated 10-Sep-2024 to printout taken on 11-Sep-2024 using the subject balance ID: ESD1770.

b. 2026 年 5 月 7 日，现场运营负责人表示操作人员可能更换了打印条色带，从而导致墨色差异。然而，由于使用涉案天平（编号 ESD1770）在 2024 年 9 月 10 日打印的条与 9 月 11 日打印的条之间字体颜色保持一致，并无更换打印色带的迹象。

c. Production Supervisor (b)(6) stated that the balance ID ESD1770 and its printer among other equipment cannot be taken out of the manufacturing room and other similar equipment cannot be brought inside during manufacturing to avoid cross-contamination. Therefore, no possibility of changing the printer for balance ID: ESD1770.

c. 生产主管 (b)(6) 表示，为避免交叉污染，天平（编号 ESD1770）及其打印机等设备不能搬出生产间，其他同类设备在生产期间也不能搬入。因此，天平（编号 ESD1770）不存在更换打印机的可能。

d. Firm has no balance usage logbook for analytical balances used in weighing drug products (tablets/capsules) at different stages of manufacturing activities.

d. 公司没有用于在各生产工序称量药品（片剂/胶囊）的分析天平的使用日志。

The firm reopened the above investigation on 08-May-2026 after a period of approximately 1.5 years.

公司在约 1.5 年之后，于 2026 年 5 月 8 日重新开启了上述调查。

B. 质量部门缺乏支持质量控制检测完整性的原始数据或元数据。

B. Quality Unit has no raw data or metadata to support the integrity of QC testing.

1. On 04-May-2026, there was no documented record of testing relating to material weighed (balance printout), preparation, lot number, manufacturer details for chemical and reagents used along with record of preparation per stepwise instructions in test procedures (finished products, swab samples, raw materials (API + Excipients), packaging materials). Firm found raw data worksheets for Finished Products lacking provision for documenting testing details per STPs; worksheets for active residue (swab and rinse) analyses also deficient; deficiencies also observed for APIs, excipients, packaging materials worksheets. Firm simply revised worksheets (Change Control 3615818) to align with STPs. No Risk Assessment performed to evaluate impact of previous practices on integrity of testing, product quality and patient safety.

1. 2026 年 5 月 4 日，检查发现：没有关于所称量物料（天平打印条）、配制、批号、所用化学品和试剂的生产商信息，以及按检验规程逐步操作配制记录的书面检测记录（涉及成品、擦拭样品、原辅料（原料药＋辅料）、包装材料）。公司发现成品原始数据记录缺少按标准检验规程（STP）记录检测信息的规定；活性残留（擦拭和淋洗）分析记录也有缺陷；原料药、辅料、包装材料记录同样存在缺陷。公司仅通过变更控制（Change Control 3615818）修订了记录以符合 STP。未开展风险评估以评价既往做法对检测完整性、产品质量和患者安全的影响。

2. On 05-May-2026, additional worksheets for APIs and excipients lacking individual samples testing info; worksheets had provision for only (b)(4) samples out of (b)(4); sample testing details for remaining samples missing. Revised (b)(4) out of (b)(4) worksheets via CAPA 4052216 (opened 03-Feb-2026). No Risk Assessment. QC Analysts continuing to use unrevised worksheets routinely.

2. 2026 年 5 月 5 日，进一步发现原料药和辅料记录缺少单个样品的检测信息；记录仅能记录 (b)(4) 个样品中的 (b)(4) 个，其余样品的检测信息缺失。公司通过 CAPA 4052216（2026 年 2 月 3 日开启）修订了 (b)(4) 个中的 (b)(4) 个记录。未开展风险评估。QC 检验员仍在日常使用未修订的记录。

3. No documented records of testing for (b)(4) Test (Chemical Analysis, FTIR, (b)(4) test). Deficiencies identified through FDA inspection of sister facilities 06/14-26/2024. Quality Unit initiated Change Control (PR ID 3541324, 29-Jun-2024) to revise worksheets. No risk assessment. Firm reported “Complies” for testing of batches analyzed without raw data and metadata.

3. 没有 (b)(4) 检测（化学分析、FTIR、(b)(4) 检测）的书面检测记录。这些缺陷在 2024 年 6 月 14 日至 26 日对其姊妹设施的 FDA 检查中已被发现。质量部门启动了变更控制（PR ID 3541324，2024 年 6 月 29 日）以修订记录。未开展风险评估。公司对在无原始数据和元数据情况下分析的批次，报告了“符合”。

观察项 2

OBSERVATION 2

Appropriate controls are not exercised over computers or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel. [21 CFR 211.68]

未对计算机或相关系统实施适当的控制，以确保对主生产和控制记录或其他记录的更改仅由授权人员进行。〔21 CFR 211.68〕

Analytical balances in production blocks lack adequate controls.

生产区的分析天平缺乏充分的控制。

A.OHAUS EX224 ((b)(4) balances) and EX225AD ((b)(4) balances) used in weighing drug products at in-process stages have user level access privileges to turn “On and Off” – “Date and Time”, “Balance ID”, “Balance Name”, “User Name”, “Sample Name”, “Sample ID”, “Project Name”, “Header”, “Batch ID”, “Result”, “Gross”, “Net”, “Tare”, “Information”, “Application Name” etc. in SQC Mode assigned to Production Operators and Supervisors.

用于在中控工序称量药品的奥豪斯（OHAUS）EX224（(b)(4) 台）和 EX225AD（(b)(4) 台）天平，具有在 SQC 模式下由生产操作人员和主管开关“日期和时间”“天平编号”“天平名称”“用户名”“样品名称”“样品编号”“项目名称”“表头”“批号”“结果”“毛重”“净重”“去皮”“信息”“应用名称”等功能的用户级访问权限。

On 06-May-2026, Production Supervisor (b)(6) demonstrated “On and Off” functionalities stating Operators and Supervisors are assigned SQC access privileges through which they can turn “On and Off” different functionalities and they can verify weight of tablets without generating printout at different stages by turning off “Result” function. Indicated it is normal to turn “On and Off” different functionalities to see tablet weights without generating printout and the printout could be reprinted at a later time. No controls established for reprinted balance printout to ensure weight info remains unchanged and no misuse of reprinted printout which may affect integrity of manufacturing data.

2026 年 5 月 6 日，生产主管 (b)(6) 演示了“开/关”功能，称操作人员和主管被赋予 SQC 访问权限，可开关不同功能，并可关闭“结果”功能在不生成打印条的情况下查看不同工序的片重。其表示，开关不同功能以查看片重而不生成打印条是“正常的”，打印条可以在事后补打。公司对补打的天平打印条未建立任何控制，无法确保重量信息保持不变，也无法防止补打打印条的滥用对生产数据完整性造成影响。

B.On 07-May-2026, SOP-000485434 “Operation and Cleaning of Balances” Version 20.0 has stepwise instructions for deleting data and controlling results generation:

2026 年 5 月 7 日，SOP-000485434《天平操作与清洁》版本 20.0 包含删除数据和控制结果生成的分步说明：

a. Sections (b)(4) indicate stepwise instructions for “Delete All Records” by turning this option “On” in SQC Mode.

a. 第 (b)(4) 节载明了在 SQC 模式下开启该选项以“删除全部记录”的分步说明。

b. Sections (b)(4) indicating stepwise instructions for controlling generation of results by pressing “On or Off” in SQC Mode.

b. 第 (b)(4) 节载明了在 SQC 模式下按“开或关”以控制结果生成的分步说明。

No oversight of Quality Unit in controlling/monitoring Operators and Supervisors practices of deleting records and results from OHAUS EX224 and EX225AD balances. IT Administrator stated the balances can save last ten (10) weighing entries in internal memory under audit trail history log “View Batch History”. However, evaluation of “View Batch History” revealed weighing activities were deleted from (b)(4) out of (b)(4) OHAUS model analytical balances used in Production Blocks. Evaluation of “View Batch History” log for (b)(4) balances on 11-May-2026 revealed missing weighing entries in between multiple weights along with altered weights and batch numbers (refer OBSERVATION 1 A (1)).

质量部门对操作人员和主管删除奥豪斯 EX224 和 EX225AD 天平记录与结果的行为缺乏控制和监管。IT 管理员称，天平内部存储器在审计追踪历史日志“查看批次历史”中只能保存最后 10 条称量记录。然而，对“查看批次历史”的评估显示，生产区所用 (b)(4) 台奥豪斯分析天平中有 (b)(4) 台的称量活动被删除。2026 年 5 月 11 日对 (b)(4) 台天平“查看批次历史”日志的评估发现，多条重量记录之间存在缺失的称量条目，且重量和批号被篡改（参见观察项 1 A(1)）。

观察项 3

OBSERVATION 3

Failure to thoroughly review any unexplained discrepancy and failure of a batch or any of its components to meet any of its specifications. [21 CFR 211.192]

未能彻底审查任何无法解释的差异，以及批次或其任何组分不符合其规格的情况。〔21 CFR 211.192〕

A.Laboratory Investigations PR 3717477 (opened 20-Jan-2025) and PR 3802187 (opened 15-Apr-2025) for product (b)(4) Tablets USP (b)(4) mg – deficient for annual stability batches with (b)(4) shelf life, OOS for Organic Impurity by HPLC.

针对产品 (b)(4) 片剂 USP (b)(4) mg 的实验室调查 PR 3717477（2025 年 1 月 20 日开启）和 PR 3802187（2025 年 4 月 15 日开启）——其年度稳定性批（货架期 (b)(4)）的 HPLC 有机杂质检测出现超标结果（OOS），调查存在缺陷。

PR 3717477: Batch (b)(4), LT (25°C/60%RH) at 18 months.

PR 3717477：批次 (b)(4)，长期条件（25°C/60%RH）18 个月。

PR 3802187: Batch (b)(4), LT (25°C/60%RH) at 24 months.

PR 3802187：批次 (b)(4)，长期条件（25°C/60%RH）24 个月。

Content of (b)(4) Impurity found (b)(4)% (OOS); Specification NMT (b)(4)% w/w.

检出的 (b)(4) 杂质含量为 (b)(4)%（超标）；规格为不得过 (b)(4)% w/w。

Final classification: Invalid OOS.

最终判定：无效 OOS。

Investigations extended to Global Quality Investigation (GQI) Team.

调查延伸至全球质量调查（GQI）团队。

Phase 1 (laboratory), Phase 2A (manufacturing), Phase 2B (extended laboratory) identified no root cause. Firm extended OOS investigation to R&D and determined composition of HPLC column containing (b)(4) content as root cause.

第一阶段（实验室）、第二阶段A（生产）、第二阶段B（扩展实验室）均未找出根本原因。公司将 OOS 调查延伸至研发（R&D），并将含 (b)(4) 成分的 HPLC 色谱柱组成确定为根本原因。

Deficient reasons:

存在缺陷的原因：

1. Firm switched chromatographic systems from HPLC ID: IQC305 (original analyses) to IQC264 (Analyst 1) and IQC98 (Analyst 2) during retest analyses. Column used in original analyses contained (b)(4) content whereas retest analyses performed using columns containing (b)(4) content. No scientific justification for changing HPLC systems along with columns that potentially may impact accuracy of test results.

1. 公司在复测分析中将色谱系统从 HPLC（编号 IQC305，原分析所用）更换为 IQC264（分析员 1）和 IQC98（分析员 2）。原分析所用色谱柱含 (b)(4) 成分，而复测分析所用色谱柱含 (b)(4) 成分。对于更换 HPLC 系统及其色谱柱（可能影响检测结果准确度）这一做法，缺乏科学论证。

2. No re-qualification of the analytical method performed after changing the HPLC column (accuracy, precision, LOD, LOQ, linearity).

2. 更换 HPLC 色谱柱后，未进行分析方法再确认（准确度、精密度、检测限、定量限、线性）。

3. OOS investigations were closed with significant delays. PR 3717477 was closed after approximately 8 months while PR 3802187 after approximately 4 months. Furthermore, CAPA initiated during OOS investigation PR 3717477 was closed on 23-Mar-2025, however, the associated Change Control PR 4036996 opened on 22-Jan-2026 is still not closed.

3. OOS 调查关闭严重拖延。PR 3717477 约 8 个月后才关闭，PR 3802187 约 4 个月后关闭。此外，OOS 调查 PR 3717477 期间启动的 CAPA 已于 2025 年 3 月 23 日关闭，但与之相关的变更控制 PR 4036996（2026 年 1 月 22 日开启）至今仍未关闭。

4. Based on R&D recommendation MLLRDAVL/BHC/INS/069R/25-00 (approved 10-Jun-2025), firm started using columns containing (b)(4) content instead of columns with (b)(4) content to overcome the issue of higher impurity generation. The change in column composition could potentially produce significantly lower results, however, the firm did not report this change to the USFDA.

4. 基于 R&D 建议 MLLRDAVL/BHC/INS/069R/25-00（2025 年 6 月 10 日批准），公司开始使用含 (b)(4) 成分的色谱柱替代含 (b)(4) 成分的色谱柱，以“克服较高杂质生成问题”。该色谱柱组成变更可能产生显著偏低的检测结果，但公司未向美国 FDA 报告这一变更。

B.PR 3624563 (original analyses 29-Sep-2024, investigation 01-Oct-2024): (b)(4) Tablets (b)(4) mg assay OOS (Inj1 (b)(4)%, Inj2 (b)(4)%, average (b)(4)%; specification (b)(4)-(b)(4)%). Invalid OOS.

PR 3624563（原分析 2024 年 9 月 29 日，调查 2024 年 10 月 1 日）：(b)(4) 片剂 (b)(4) mg 含量 OOS（进样 1 (b)(4)%，进样 2 (b)(4)%，平均 (b)(4)%；规格 (b)(4)–(b)(4)%）。判定为无效 OOS。

1. Hypothetical investigation with no root cause. HPLC IQC300 had no pressure fluctuations, no retention time drift, system suitability met, other batches in same sequence met. However, firm invalidated original results attributing to instrument malfunction and retested using IQC176 and IQC184 by two different analysts and obtained passing results (18-Oct-2024).

1. 调查为假设性、无根本原因。HPLC（编号 IQC300）无压力波动、无保留时间漂移、系统适用性合格、同序列其他批次均合格。但公司以“仪器故障”为由作废原结果，随后改用 IQC176 和 IQC184 由两名不同分析员复测，得到合格结果（2024 年 10 月 18 日）。

2. OOS investigation cited precision test failure ((b)(4) µL injection, results (b)(4)%; limit (b)(4)%) attributing to V3 valve malfunction of HPLC IQC300 during calibration (“V3 valve might have closed partially and because of that less injection volume drawn by syringe during intermittent injection that led to failure in precision test”). However, no assessment performed of impact of “less injection volume” on accuracy and reliability of results of drug products tested using IQC300 during previous calibration period.

2. OOS 调查引用了精密度测试失败（进样 (b)(4) µL，结果 (b)(4)%；限度 (b)(4)%），归因于 HPLC（编号 IQC300）校准期间 V3 阀故障（“V3 阀可能部分关闭，导致间歇进样时注射器吸取的进样量偏少，从而造成精密度测试失败”）。然而，未评估“进样量偏少”对上一校准周期内使用 IQC300 检测的药品结果准确性和可靠性的影响。

C.PR 3525929 (original analyses 12-Jun-2024, investigation 13-Jun-2024): (b)(4) Tablets (b)(4) mg 24-month long-term stability assay OOS. Invalid OOS.

PR 3525929（原分析 2024 年 6 月 12 日，调查 2024 年 6 月 13 日）：(b)(4) 片剂 (b)(4) mg 24 个月长期稳定性含量 OOS。判定为无效 OOS。

1. Invalidated original results attributing to suspected extraction error without clear justification.

1. 以“怀疑提取错误”为由作废原结果，但无明确依据。

2. LIMS worksheet and STP (FPPACP096R-06) sonication extraction step: (b)(4) for (b)(4) Tablets to ensure complete dissolution. Firm did not justify the adequacy of extraction power of the method while control batches prepared by the same method in the same sequence met using HPLC method.

2. LIMS 记录和标准检验规程（STP FPPACP096R-06）的超声提取步骤：对 (b)(4) 片剂超声 (b)(4) 次以确保完全溶解。公司未论证该方法提取能力的充分性，而同一序列中用相同方法制备的对照批经 HPLC 法检测合格。

D.Production Operators adjusted equipment parameters after collection of samples and some samples were tested approximately (b)(4) hours later, while some were tested within (b)(4). Reasons for machine adjustments were neither documented nor investigated. Production Operators stated they checked the average tablet weight and adjusted the machine if there was deviation, but no records of change rationale, no record of tablet weight checks, and no explanation why machine was adjusted after sampling. Multiple tablet products. No assurance that in-process testing data is representative of actual manufacturing conditions. Multiple examples ((b)(4) parameters adjusted for (b)(4) out of (b)(4) samples before testing).

生产操作人员在取样后调整设备参数，部分样品约 (b)(4) 小时后才检测，部分在 (b)(4) 内完成。调机原因既无记录也无调查。生产操作人员称其检查平均片重、有偏差即调机，但无变更原因的记录、无片重检查记录、也无法解释为何在取样后调机。涉及多个片剂品种。无法保证中控检测数据代表实际生产状态。存在多个实例（(b)(4) 个样品中有 (b)(4) 个在检测前调整了 (b)(4) 个参数）。

The firm has distributed approximately (b)(4) batches of (b)(4) Tablets for the U.S. market.

公司已向美国市场分销了约 (b)(4) 批 (b)(4) 片剂。

E.Equipment breakdowns during batch processing not adequately investigated. For (b)(4) Tablets, during (b)(4) of approximately (b)(4) batches, equipment malfunctions occurred resulting in unloading of (b)(4). Initial assessments stated (b)(4) were discharged into drums and kept covered during maintenance activities. Hence no impact on product quality. However, no evaluation was carried out to assess impact of unplanned discharge on product quality. Furthermore, (b)(4) out of (b)(4) batches of (b)(4) Tablets that were unloaded as part of unplanned maintenance exhibited atypical dissolution or OOS assay results and were rejected. Despite these OOS results, no CAPAs initiated to improve assessment of quality impact when work orders raised during in-process manufacturing.

批处理期间的设备故障未得到充分调查。对于 (b)(4) 片剂，在约 (b)(4) 批中有 (b)(4) 批在 (b)(4) 阶段发生设备故障，导致卸料 (b)(4)。初步评估称 (b)(4) 被卸入桶中并在维护期间保持覆盖，因此“对产品质量无影响”。然而，未开展任何评估以评价非计划卸料对产品质量的影响。此外，作为非计划维护而卸料的 (b)(4) 批 (b)(4) 片剂中，有 (b)(4) 批出现异常溶出或含量 OOS 结果并被拒收。尽管出现这些 OOS 结果，仍未启动任何 CAPA 以改进对中控生产期间提报工单时质量影响的评估。

F.Operators observed frequently altering machine parameters; however, verification of (b)(4) was not performed following these adjustments. (b)(4) results from previous tests were found to be borderline with respect to specification limits, and impact of machine adjustments on batch quality was not evaluated. According to SOP-000486284 “In-Process Parameters Monitoring”, (b)(4) units tests are to be performed (b)(4).

操作人员被观察到频繁调整机器参数；然而，调整后未对 (b)(4) 进行确认。此前检测的 (b)(4) 结果处于规格限的边缘，且未评估调机对批质量的影响。根据 SOP-000486284《中控参数监控》，应执行 (b)(4) 个单位测试 (b)(4)。

On 18-Apr-2025, tablets observed borderline (b)(4) at (b)(4) while (b)(4) was (b)(4). Operator increased (b)(4) to (b)(4); however, (b)(4) test not performed following adjustment.

2025 年 4 月 18 日，观察到片剂 (b)(4) 处于边缘值 (b)(4)，此时 (b)(4) 为 (b)(4)。操作人员将 (b)(4) 调高至 (b)(4)；然而，调整后未执行 (b)(4) 测试。

At (b)(4), the (b)(4) was reduced to (b)(4). IPQA performed (b)(4) testing at (b)(4) which yielded passing results. However, no testing performed to verify whether (b)(4) met specifications while (b)(4) remained at (b)(4) during approximately (b)(4) of (b)(4) operation.

在 (b)(4) 时，(b)(4) 被调低至 (b)(4)。IPQA 在 (b)(4) 处执行了 (b)(4) 测试，结果合格。然而，在 (b)(4) 保持在 (b)(4) 的约 (b)(4) 的 (b)(4) 运行期间，未执行任何测试以验证 (b)(4) 是否符合规格。

观察项 4

OBSERVATION 4

Equipment and utensils are not cleaned and maintained at appropriate intervals to prevent malfunctions and contamination that would alter the safety, identity, strength, quality, or purity of the drug product. [21 CFR 211.67]

设备和器具未按适当间隔进行清洁和维护，以防止可能改变药品安全性、特性、含量、质量或纯度的故障和污染。〔21 CFR 211.67〕

On 04-May-2026:

2026 年 5 月 4 日：

a. The cover of the discharge chute of the (b)(4) (Equipment No. ESD1082) was observed to have (b)(4) residue, and the protective (b)(4) cover was found to be damaged. This non-dedicated equipment was cleaned and inspected on 01-Apr-2026 with a record of “OK” and was previously used to manufacture (b)(4) Tablets (non-US market batches).

a. 观察到 (b)(4)（设备编号 ESD1082）的卸料溜槽盖有 (b)(4) 残留，且防护 (b)(4) 盖破损。该非专用设备于 2026 年 4 月 1 日清洁并检查，记录为“OK”，此前曾用于生产 (b)(4) 片剂（非美国市场批）。

b. The cover of the discharge chute of the (b)(4) (Equipment No. ESD1117) was observed to have (b)(4) residue, and the protective (b)(4) cover was found to be damaged. This non-dedicated equipment was cleaned and inspected on 13-Apr-2026 with a record of “OK” and was previously used to manufacture (b)(4) Tablets (US market batches).

b. 观察到 (b)(4)（设备编号 ESD1117）的卸料溜槽盖有 (b)(4) 残留，且防护 (b)(4) 盖破损。该非专用设备于 2026 年 4 月 13 日清洁并检查，记录为“OK”，此前曾用于生产 (b)(4) 片剂（美国市场批）。

观察项 5

OBSERVATION 5

Written stability program is not followed. [21 CFR 211.166]

书面稳定性方案未被遵守。〔21 CFR 211.166〕

SOP-003041575 “Stability Program” requires a minimum of (b)(4) batches per year to be placed on long-term stability to cover the shelf life. However, no annual stability batches were placed for the 2024 manufactured batches of (b)(4) Tablets, (b)(4) mg. The firm has distributed (b)(4) batches of (b)(4) mg to the U.S. market.

SOP-003041575《稳定性方案》要求每年至少放置 (b)(4) 批于长期稳定性以覆盖货架期。然而，2024 年生产的 (b)(4) 片剂 (b)(4) mg 未放置年度稳定性批。公司已向美国市场分销 (b)(4) 批 (b)(4) mg 产品。

观察项 6

OBSERVATION 6

The applicant fails to submit a Field Alert Report (FAR) within three working days of receipt of information concerning any failure of one or more distributed batches of a drug product to meet the specification established for it in the application. [21 CFR 314.81(b)(1)(ii)]

申请人未能在收到关于已分销的一个或多个药品批次不符合其申请中规定规格的信息后三个工作日内提交现场警示报告（FAR）。〔21 CFR 314.81(b)(1)(ii)〕

The firm failed to submit a Field Alert Report (FAR) for the fire incident that occurred on 14-Feb-2026 which resulted in complete shutdown of the plant. The incident investigation PR 4063221 (fire incident) showed significant impact to manufacturing and testing (number of affected analysis, commercial batches, Exhibit/Scale-up batches). Additionally, during the inspection, manufacturing in (b)(4) blocks was suspended. (b)(4) blocks were started approximately 10 days before the beginning of the inspection. The firm acknowledged the fire affected stability samples, finished product and distribution, but did not provide any explanation for the potential quality impact on distributed US market drug products with incomplete stability testing.

公司未就 2026 年 2 月 14 日发生的、导致全厂停工的火灾事故提交现场警示报告（FAR）。事件调查 PR 4063221（火灾事故）显示其对生产和检测有显著影响（受影响的分析数量、商业批、展示批/放大批）。此外，检查期间 (b)(4) 个生产区处于停产状态；(b)(4) 个生产区在检查开始前约 10 天才启动。公司承认火灾影响了稳定性样品、成品和分销，但未就稳定性检测不完整的已分销美国市场药品的潜在质量影响提供任何说明。