8月1日，FDA连续发布了8封涉嫌违反GMP的警告信，包括2封美国本土药企和6封国外药企（主要是印度药企）的警告信，如下：
Intas Pharmaceuticals Limited
英塔斯制药公司
Iso-Tex Diagnostics, Inc.
Baxter Healthcare Corporation
百特医药有限公司（印度工厂）
Medgel Private Limited
Centaur Pharmaceuticals Private Ltd.
Avlon Industries, Inc.
Jamol Laboratories, Inc.
LXR Biotech, LLC
部分警告信缺陷翻译如下：
Warning Letter 320-23-18
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Baxter Pharmaceuticals India Pvt. Ltd., 3004610460, at Village Vasana Chacharwadi, Taluka Sanand, Ahmedabad, India, from January 19 to January 27, 2023.
FDA于 2023 年 1 月 19 日至 1 月 27 日检查了你们的药品制造工厂，位于印度艾哈迈达巴德塔卢卡萨南德瓦萨纳瓦迪村的百特制药印度有限公司。
This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).
本警告信总结了药物制剂严重违反CGMP法规的情况。请参阅联邦法规 21 CFR第 210 和 211 部分。
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).
由于你们的制造、加工、包装或保存方法、设施或控制不符合 CGMP，你们的药品按照《联邦食品、药品和化妆品法案》（FD&C法案）第 501（a）（2）（B） 条（21 U.S.C. 351（a）（2）（B） 为掺假。
We reviewed your February 17, 2023 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
我们详细审查了你们于 2023 年 2 月 17 日对我们 FDA 483 表格的回复，并确认收到你们的后续信件。
During our inspection, our investigators observed specific violations including, but not limited to, the following.
在我们的检查过程中，我们的检查人员观察到的具体的违规行为，包括但不限于以下：
1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
贵公司未能彻底调查批次或其任何组分的任何无法解释的差异或不符合其任何标准的情况，无论该批次是否已放行（21 CFR 211.192）。
You failed to conduct adequate investigations into endotoxin testing and your 100% automated visual inspection system. You conducted investigations that were not thorough, expanded to an appropriate scope, or based on scientifically supported root cause(s). You did not identify and implement appropriate corrective actions and preventive actions (CAPA). Specifically,
你们未能对内毒素检测和100%自动灯检系统进行充分调查。你们进行了不彻底、未能扩展到适当范围或基于科学支持的根本原因的调查。你们没有确定并实施适当的纠正措施和预防措施（CAPA）。具体说来：
Your firm invalidated multiple endotoxin tests for finished products upon discovery of particulate matter in one or more wells used to perform the kinetic-turbidimetric assay (KTA) method. You failed to characterize the particulate matter and attributed the particulates to environmental and laboratory conditions, such as air ducts and activities being performed by personnel in the immediate vicinity of the analysis. You did not definitively identify the source or sources of the particulate matter, define the scope of potentially impacted operations (including potential manufacturing causes), and implement scientifically justified CAPA in a timely manner.
贵公司在用于执行动力学比浊测定（KTA）方法的一个或多个孔中发现颗粒物后，判定多个成品的内毒素测试无效。你们未能确认这些颗粒物，并将颗粒归因于环境和实验室条件，例如空气管道和检测（区域）附近人员正在进行的活动。你们没有明确确定颗粒物的来源，定义可能受影响的范围（包括潜在的生产原因），并及时实施科学合理的 CAPA。
In a previous inspection (May 2022), FDA cited your firm for inadequate investigations into these and other similar out-of-specification (OOS) endotoxin testing that you invalidated due to uncharacterized particulate contamination in one or more wells during KTA analyses. Prior to and during an October 5, 2022 regulatory meeting with your firm, we requested you perform a retrospective assessment of investigations associated with OOS endotoxin results or endotoxin testing deviations. During the current inspection, your personnel explained that these investigations were not reopened or otherwise reassessed. Although you retained a third-party consultant to perform a retrospective assessment of endotoxin investigations associated with OOS endotoxin result investigations, you did not provide the third-party consultant with an investigation cited during the May 2022 inspection. You also did not ensure the assessment included approximately 20 invalidated laboratory tests generated in 2021 and 2022 (including multiple investigations since the May 2022 inspection).
在之前的检查（2022 年 5 月）中，FDA 引用了贵公司对这些和其他类似的不合格 （OOS） 内毒素测试的调查不充分，这些测试在 KTA 分析期间一个或多个孔中存在未表征的颗粒污染被判定无效。在 2022 年 10 月 5 日与贵公司举行监管会议之前和期间，我们要求你们对与 OOS 内毒素结果或内毒素检测偏差相关的调查进行回顾性评估。在本次检查期间，你们的人员解释说，这些调查没有重新开始或以其他方式重新评估。尽管你们聘请了第三方顾问对与 OOS 内毒素结果调查相关的内毒素调查进行回顾性评估，但你们没有向第三方顾问提供 2022 年 5 月检查期间引用的调查。你们也没有确保评估包括 2021 年和 2022 年产生的大约 20 项无效实验室测试（包括自 2022 年 5 月检查以来的多项调查）。
Your firm did not adequately investigate failures of the (b)(4) automatic inspection machine to detect known defects, including particulate matter in injectable drug products. Despite the data indicating significant deficiencies in the machine’s ability to detect known defects during its use, you continued to employ the (b)(4) automatic inspection machine to inspect commercially distributed products (e.g., several batches of (b)(4) injection (b)(4) mg/mL USP). Notably, you fully relied on this automated visual inspection system to detect various defects including particulate contamination for an extended period and did not perform a 100% manual visual inspection for all defects.
贵公司未能充分调查（b）（4）自动灯检机未能检测已知缺陷的失败，包括注射用药品中的颗粒物。尽管数据表明机器在使用过程中检测已知缺陷的能力存在严重不足，但你们仍继续使用（b）（4）自动灯检机检测商业产品（例如，多批（b）（4）注射用（b）（4）mg /mL USP）。值得注意的是，你们完全依靠这种自动灯检系统来检测各种缺陷，包括颗粒污染，并且没有对所有缺陷进行 100% 的手动目视检查。
Challenges with defect kits indicated failing rejection rates or other deficiencies. For example, an October 2022 challenge excluded the use of(b)(4) particles despite their lower detectability than other “dark” particles in (b)(4) mL amber glass vials. The challenge also used a highly detectable particle range of (b)(4) μm, but still indicated detection and capability issues. Similar challenges to the (b)(4) automatic inspection machine utilized commercial inspection parameters. You did not initiate adequate investigations into these detection issues. You lacked adequate assurance that sterile injectable drug batches visually inspected with the (b)(4) automatic inspection machine were free from visible particulates.
缺陷组合的挑战表明剔除率失败或其他缺陷。例如，2022 年 10 月的一项挑战踢出了（b）（4） 颗粒的使用，尽管在（b）（4） mL 琥珀色玻璃瓶中的可检测性低于其他“深色”颗粒 。该挑战还使用了（b）（4）μm范围的高可检测性颗粒，但仍表明检测和能力问题。与（b）（4）自动灯检机类似的挑战是使用商业检测参数。你们未能对这些检测问题进行充分调查。你们没有足够的保证确保使用（b）（4）自动灯检机检查的无菌注射剂批次没有可见颗粒。
Your response is inadequate. Your firm previously committed to evaluate and implement improvements to your procedures and practices associated with the conduct of investigations following the conclusion of the July 27 to August 4, 2017, inspection of this facility and in response to the warning letter sent to your firm on July 5, 2018. You also reported significant CAPA activities to address the frequency of endotoxin testing OOS results and deviations following the October 5, 2022, regulatory meeting.
你们的回复不充分。贵公司此前承诺，在2017年7月27日至8月4日结束对该设施的检查以及回复2018年7月5日发给贵公司的警告信后，评估和实施与调查相关的程序和操作的改进。在 2022 年 10 月 5 日监管会议之后，你们还报告了重要的 CAPA 活动以解决内毒素检测 OOS 结果的频率和偏差。
In your February 17, 2023, response to the Form FDA 483 issued at the conclusion of the most recent inspection, you commit to further revisions of your investigation procedures.
在 2023 年 2 月 17 日对最近一次检查结束时发布的 FDA 483 表格的回复中，你们还承诺进一步修订你们的调查程序。
However, you do not adequately address your failure to conduct timely investigations into recurring and persistent issues. Your response did not adequately address the use of insufficiently qualified(b)(4) equipment for 100% visual inspection of injectable drug products for approximately five years (until October 2022) and the excessive number of samples contaminated with endotoxins or particles in your laboratory.
但是，你们没有充分解决未能及时调查反复出现和持续存在的问题的缺陷。你们的答复没有充分解决使用不合格的（b）（4）设备对注射药品进行100%目视检查约五年（至2022年10月）以及实验室中被内毒素或颗粒污染的样品数量过多的问题。
We encourage the use of automated visual inspection for particulates to augment the 100% manual visual inspection program. Automated methods should be rigorously studied for their capability and robustness under various conditions, machine settings, container-closure sizes, defect types, and other variables. In addition, any use of automated particulate inspection does not supplant the need for 100% manual visual inspection for various other attributes (e.g., cracks).
我们鼓励对颗粒物使用自动目视检测，以增强100%人工目视检测程序。应严格研究自动化方法在各种条件下的能力和稳健性、机器设置、容器尺寸、缺陷类型和其他变量。此外，任何使用自动灯检都不能取代对各种其他属性（例如裂缝）进行100%手动目视检测的需要。
2. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).
贵公司未能建立并遵循适当的书面程序来清洁和维护设备（21 CFR 211.67（b））。
An FDA investigator observed white spots at the bottom of a(b)(4) L bulk solution holding tank used to supply a non-dedicated filling machine despite the vessel being documented as clean. You subsequently analyzed and identified the white spots as (b)(4) (the product previously processed on this equipment) at levels of up to (b)(4) parts per million (ppm). Your limit for post-cleaning residues is not more than (b)(4) ppm.
FDA检查人员观察到（b）（4）L散装溶液储罐底部有白点，该罐用于供应非专用灌装机，尽管该罐被记录为已清洁。随后，你们分析并确定了白点（b）（4）（先前在此设备上加工的产品），其水平高达（b）（4）ppm。清洁后残留物的限值不超过 （b）（4） ppm。
Your response is inadequate. Although you revised your cleaning procedure to require vessels to be dry before conducting the visual inspection for cleanliness and implemented visual verification of the vessel interior via a sight glass following the cleaning and(b)(4) activities, you did not provide scientific justification for your use of visual inspection to verify the removal of residues to levels as low as (b)(4) ppm. Your response noted (b)(4) injection, not (b)(4) injection, is the “worst-case product” processed in this vessel, but you did not provide a comprehensive investigation to assess the impact of this cleaning deviation on products previously manufactured on this and other non-dedicated equipment. You also did not propose a systemic assessment of your equipment cleaning program.
你的回复是不充分的。尽管你们修改了清洁程序，要求在进行清洁度目视检查之前对容器进行干燥，并在清洁和 （b）（4） 活动后通过视镜对容器内部进行了目视确认，但你们没有提供科学依据来验证残留物去除到低至 （b）（4） ppm 的水平。你们的答复指出，（b）（4）注射剂，而不是（b）（4）注射剂，是该容器处理的“最差情况产品”，但你们没有提供全面的调查来评估这种清洁偏差对以前在此和其他非专用设备上生产的产品的影响。你们也没有对你们的设备清洁程序进行系统评估。
3. Your firm failed to establish adequate written procedures for production and process control designed to assure that drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess, and to follow all of your written production and process control procedures (21 CFR 211.100(a) and (b)).
贵公司未能为生产和工艺控制建立适当的书面程序，以确保你们生产的药品具有其特性、含量、质量和纯度，并符合你们的所有书面生产和工艺控制程序（21 CFR 211.100（a） 和 （b））。
Your program for the visual inspection of sterile injectable drug products does not provide adequate assurance that finished products manufactured at your facility possess their purported quality attributes, including that they are free from particulate matter. For example,
你们的无菌注射药品目视检查程序未能充分保证你们的工厂生产的成品具有其所谓的质量属性，包括它们不含颗粒物。例如
Personnel performed 100% manual visual inspection of sterile injectable units for less than the minimum amount of time required by your written procedures.
人员对无菌注射单元进行100%手动目视检查，时间少于你们的书面程序要求的最短时间。
You lacked scientific justification for removing vials containing (b)(4) particles from the defect kits used to qualify visual inspection processes. For example, although (b)(4) particles were more difficult to reproducibly detect than (b)(4) stopper particles in the (b)(4) mL amber vials, you elected to only use the (b)(4) stopper particles in the defect kits.
你们缺乏科学依据从用于确认目视检查过程的缺陷套件中踢出含有 （b）（4） 颗粒的瓶子。例如，尽管在（b）（4） mL 琥珀色样品瓶中的 （b）（4） 颗粒比 （b）（4） 瓶胶塞颗粒更难重现检测，但你们仍选择在缺陷套件中仅使用 （b）（4） 胶塞颗粒。
Your response is inadequate. You commit to using a “pacing device” during the 100% manual visual inspections and requiring a supervisor to periodically verify the inspection times. You did not provide a description of the pacing device or commit to requalify operators following implementation of the pacing device. Additionally, you did not commit to evaluate operator performance throughout a(b)(4).
你们的回复是不充分的。你们承诺在 100% 手动目视检查期间使用“限速设备”，并要求主管定期确认检查时间。你们没有提供限速设备的描述，也没有承诺在实施限速设备后重新确认操作人员。此外，你们没有承诺在整个 （b）（4） 中评估操作人员的性能。
You also state a successful qualification program does not evaluate “… an inspector’s ability to differentiate and identify various types and morphologies of particles.” However, it is critical to be able to reproducibly detect particulate defects of different types, morphologies, and sizes.
你们还声明成功的确认程序不会评估“......检查人员区分和识别各种类型和形态的颗粒的能力。然而，能够可重复地检测不同类型、形态和大小的颗粒缺陷至关重要。
4. Your firm failed to use equipment in the manufacture, processing, packing, or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance (21 CFR 211.63).
贵公司未能在制造、加工、包装或保存药品时使用适当设计、规格和安装的设备以适合其预期用途的操作以及清洁和维护（21 CFR 211.63）。
Equipment used in the manufacture of terminally sterilized drugs at your facility is not designed or maintained appropriately. Our inspection revealed instances of damaged metal and plastic parts, open vials exposed to worn bolt threading, and process flow that required employees to duck underneath the sterile processing line conveyer in order to perform interventions near open vials (e.g., stopper addition on the(b)(4) filling line).
在你们的工厂中用于制造最终灭菌药物的设备设计或维护不当。我们的检查发现了损坏的金属和塑料部件、暴露于磨损螺栓螺纹的未加塞瓶子以及要求员工弯身在无菌加工线输送机下方以便在未加塞瓶子附近进行干预的工艺流程（例如，在 （b）（4） 灌装线上添加胶塞）。
Your response is inadequate. Although you commit to replacing the threaded bolt(b)(4) on the (b)(4) filling line with a different part that will not expose a threading over open vials, you did not commit to evaluate production rooms and production equipment for wear, damage, or poor design that may lead to the generation of particulate matter in the vicinity of open vials. You also plan to install a (b)(4) conveyor at the capping machine outfeed, and merge filling and capping areas, for two filling lines ((b)(4) and (b)(4)), but you did not commit to perform a comprehensive assessment of your facility’s production lines to ensure they are appropriately designed and controlled.
你们回复是不充分的。尽管你们承诺将 （b）（4） 灌装线上的螺纹螺栓 （b）（4） 更换为不会暴露开口小瓶上的螺纹的不同部件，但你们并未承诺评估生产车间和生产设备是否存在可能导致在未加塞瓶子附近产生颗粒物质的磨损、损坏或设计不良。你们还计划在轧盖机出口处安装（b）（4）输送机，并合并两条灌装线（（b）（4）和（b）（4）的灌装和轧盖区域），但你们没有承诺对工厂的生产线进行全面评估，以确保它们得到适当的设计和控制。
