引言：近日，美国食品药品监督管理局（FDA）公布了对印度某实验室有限公司一处制剂工厂为期九天的现场检查结果，并签发Form FDA 483表格。本次检查揭示了企业在偏差（OOS）调查、设备变更控制、清洁验证、分析方法及物料取样等多个核心质量环节存在的需要改进的观察项。下面将对本次检查中发现的问题进行分析。

备注：（b4）表示敏感信息或不方便对外透露的信息

观察项一：OOS调查不充分

1. 溶出度OOS调查：针对2025年4月两批产品的溶出度OOS结果，第一阶段调查未确定根本原因。基于“桨叶未放置”的假设进行复测并放行批次，但后续复核原始记录（检查表）显示该假设缺乏证据支持。涉及成品已发运至美国市场。

2. 未知峰偏差调查：针对2025年1月一批产品的溶出度色谱未知峰，调查后推断为滴管污染导致，但未提供确凿证据。同样基于复测合格结果将初始结果无效化并放行批次，该成品也已发运。

3. 市场投诉调查：对于收到的药片印记错误投诉，在涉事批次不属于已知召回活动的情况下，未对投诉批次本身展开调查，而是假设为药房端的混淆。

观察项二：设备变更后未进行再确认

2024年3月，压片线关键部件(b)(4)发生故障并被更换为另一台制造商和型号皆不同的设备。截至检查日（2025年12月），该压片机与新(b)(4)组成的组装体未进行性能再确认。企业理由是新旧设备“工作原理相同”，但未提供支持此结论的评估或数据。该生产线用于生产多种供应美国市场的产品。

观察项3：设备变更后清洁验证未更新

2020年完成的清洁验证是基于包含原(b)(4)（PR034）的设备组。2024年该部件被更换为PR182后，未对包含新部件的设备组重新进行清洁验证。企业提及新部件表面积更大，但未能提供原部件的表面积计算数据，因此无法评估变更对清洁效果的影响。

观察项4：分析方法验证与人员资质确认存在不足

1. 分析方法验证：企业现行程序要求含量测定方法需对每个制备样品进行(b)(4)次测定，但实际验证时仅进行了单次测定。用于建立方法线性的各浓度点也仅进行了单次测定。该方法已用于申报批次的检测。

2. 目视检查员资质确认：现行程序未明确资质确认用测试套件中缺陷药片的类型和数量，实际使用的评估表格也未记录合格药片的数量。企业虽已制定新程序，但在检查时尚未实施，且未备有符合要求的测试套件。期间持续收到与外观缺陷相关的市场投诉。

观察项5：原料药取样工具不符合程序

企业程序规定应使用特定工具(b)(4)进行原料药取样，但实际操作中使用了无菌药勺和勺子等工具。检查发现，多批成品的有关物质OOS结果与使用这些不合规工具取样的原料药批次相关联。

FDA483：中英对照

OBSERVATION 1
观察项 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.
未能彻底审查任何无法解释的差异，以及某一批次或其任何成分未达到其质量标准的情况，无论该批次是否已分销。

A. On 4/28/2025, you recorded non-conformances 310028189 and 310028200 for (b)(4) (b)(4) for Dissolution by HPLC. The OOS results were recorded for (b)(4) Batch No's. (b)(4) (OOS No. 310028189) and (b)(4) (OOS No. 310028200). Both the batches failed the dissolution test for Tablet Unit (b)(4) % (Batch No. (b)(4) and (b)(4) % (Batch No. (b)(4) against the Specification NLT (not less than) (Q) of the labeled amount of (b)(4) dissolved in (b)(4).
A. 2025年4月28日，贵公司记录了HPLC溶出度检测中，对于(b)(4)的(b)(4)不符合项310028189和310028200。OOS结果针对(b)(4)批次号(b)(4)（OOS编号310028189）和(b)(4)（OOS编号310028200）。两个批次在片剂单位(b)(4)溶出度测试中均未达到质量标准，实测值分别为(b)(4)%（批号(b)(4)）和(b)(4)%（批号(b)(4)），而质量标准要求不低于（NLT）标示量的(b)(4)%在(b)(4)时间内溶出。

The above two batches were analyzed in a set of three batches, Batch No's. (b)(4) (b)(4) in that order) by the same analyst (b)(4). In Phase I, you confirmed the OOS result via Re-Measurement Testing. No root cause was identified in Phase I. You assumed that "OOS result might be the cause of paddle not placed for subjected unit (Unit (b)(4) Based on this hypothesis, you repeated the analysis with fresh sample preparation and based on the passing results (DS (b)(4) % for Batch No. (b)(4) DS (b)(4) % for Batch No. (b)(4) you invalidated the initial OOS results and released the batch.
上述两个批次与第三个批次（批号依次为(b)(4)）由同一分析员(b)(4)作为一组进行分析。在第一阶段调查中，贵公司通过复测确认了OOS结果，但未确定根本原因。贵公司假设“OOS结果可能是由于桨叶未放置于受试单元（单元(b)(4)）所致”。基于此假设，贵公司使用新制备的样品重复分析，并根据合格结果（批次(b)(4)溶出度为(b)(4)%，批次(b)(4)溶出度为(b)(4)%）将初始OOS结果判定为无效，并放行了该批次。

You carried out Phase II Manufacturing investigation only to verify the various process parameters. Your Site QA Head stated that the (b)(4) test and (b)(4) batch or (b)(4) batch whichever is earlier is tested for description, assay, and KF. You stated that the (b)(4) for the subject batches Batch No’s (b)(4) and (b)(4) were 2nd and 3rd batches for 2025 and did not need testing.
贵公司进行的第二阶段生产调查仅限于验证各种工艺参数。贵公司现场质量负责人表示，(b)(4)测试及(b)(4)批次或(b)(4)批次（以较早者为准）会进行性状、含量和水分检测。贵公司说明，相关批次(b)(4)和(b)(4)是2025年的第2和第3批，因此无需进行(b)(4)测试。

On 12/9/2025, your analyst (b)(4) reviewed FORM-FS01-QC-0358 Version 4.0, Check List for the Dissolution Analysis for the dissolution test for the implicated batches and confirmed that the paddles were placed as per the numbering. The analyst also confirmed in the Check List that Tablets were disintegrated completely at the end of the run. These recorded information by the analyst (at the time of analysis) in the Check List does not support the root cause and retesting.
2025年12月9日，贵公司分析员(b)(4)复核了相关批次溶出度测试的检查表FORM-FS01-QC-0358第4.0版，确认桨叶已按编号放置。分析员还在检查表中确认片剂在运行结束时已完全崩解。分析员（在分析时）记录于检查表中的这些信息，并不支持“桨叶未放置”的根本原因假设及后续的复测决定。

The (b)(4) Batch No’s (b)(4) and (b)(4) were used to manufacture (b)(4) Batch No’s (b)(4) (Mfg. date 4/6/2025 and Expiry date (b)(4) and (b)(4) (Mfg. date 4/15/2025 and Expiry date (b)(4) respectively. You shipped a total of (b)(4) bottles ((b)(4) tablets) of the above batches to the US market.
原料药批次(b)(4)和(b)(4)被用于生产制剂批次(b)(4)（生产日期2025年4月6日，有效期(b)(4)）和(b)(4)（生产日期2025年4月15日，有效期(b)(4)）。贵公司已将上述批次总计(b)(4)瓶（(b)(4)片）发运至美国市场。

B. On 1/23/2025, you recorded a major deviation, DV2000020047 for (b)(4) mg for Dissolution by HPLC. The deviation was recorded for Batch No. (b)(4) when an extraneous peak at (b)(4) was recorded for Tablet Unit-(b)(4) % against to standard area response, Specification NMT (b)(4)%. Remeasurement of the Same vial confirmed the extraneous peak, but this peak was missing from the Benck top solution. Phase I investigation did not reveal any assignable root cause. You concluded that the dropper (that was used to transfer the test solution into the HPLC vial) could be the most probable cause for the extraneous peak. You then made new sample and based on the passing dissolution test values, you invalidated the initial results and released the batch.
B. 2025年1月23日，贵公司记录了(b)(4)mg规格产品HPLC溶出度检测的重大偏差DV2000020047。偏差发生在批次(b)(4)，其片剂单位(b)(4)的色谱图在(b)(4)处出现一个未知峰，响应值为标准品响应的(b)(4)%，超出标准规定的不高于（NMT）(b)(4)%。对同一小瓶的复测确认了该未知峰，但该峰在对照品溶液中未出现。第一阶段调查未发现任何可归因的根本原因。贵公司推断，用于转移测试溶液至HPLC小瓶的滴管可能是未知峰的最可能原因。随后，贵公司制备了新样品，基于合格的溶出度测试结果，将初始结果判定为无效并放行了该批次。

The (b)(4) Batch No. (b)(4) was used to manufacture (b)(4) Batch No. (b)(4) (Mfg. date 1/11/2025 and Expiry date (b)(4) You shipped a total of (b)(4) bottles ((b)(4) tablets) of the above batches to the US market.
原料药批次(b)(4)被用于生产制剂批次(b)(4)（生产日期2025年1月11日，有效期(b)(4)）。贵公司已将上述批次总计(b)(4)瓶（(b)(4)片）发运至美国市场。

C. You have received multiple market complaints for (b)(4) and made several markets recalls on a select campaign batches. You unsubstantiated the Market Complaints for the (b)(4) batches that were not part of this campaign. E. g. on 1/28/2025 you received a Market Complain # 200433853 for (b)(4) Batch No's. (b)(4) and (b)(4) The pharmacy reported, "One tablet with the incorrect imprint on it which matches the (b)(4) strength however the color of the tablet is correct as similar to other tablets." These two batches were not part of the campaign that were implicated for the market recall. You assumed that the tablets from a "recall batch" were mixed at the pharmacy.
C. 贵公司收到多起关于(b)(4)的市场投诉，并对特定活动批次进行了多次市场召回。对于不属于此召回活动的(b)(4)批次的市场投诉，贵公司未经充分调查即予以否认。例如，2025年1月28日，贵公司收到关于(b)(4)批次号(b)(4)和(b)(4)的市场投诉#200433853。药房报告称，“一片药片上的印记错误，印记与(b)(4)规格相符，但药片颜色与其他药片一致且正确。”这两个批次并非涉及市场召回的活动批次。贵公司假设是“召回批次”的药片在药房发生了混淆。

OBSERVATION 2
观察项 2

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.
未能建立控制程序，以验证那些可能导致中间体和成品特性波动的生产工序的性能。

Specifically, you qualified your Tablet Compression Machine ID # PR034 and (b)(4) ID # PR034 in Room (b)(4) as per the Performance Qualification Report FTS1PRPR034-01 (Effective date 8/8/2013). On 3/16/2024 the (b)(4) ID # PR034 underwent breakdown during the manufacturing of (b)(4) Batch No. (b)(4) You replaced (b)(4) ID # PR034 with a different (b)(4) ID # PR182 and continued with the manufacturing of (b)(4) Batch No. (b)(4) As of 12/12/2025, you have not requalified your Tablet Compression Machine ID # PR034 and (b)(4) ID # PR182 assembly in Room (b)(4) The make and model of the (b)(4) ID’s # (b)(4) are different. Your Head of Production (b)(4) stated that the working principles for (b)(4) are same thus requalification is not needed.
具体而言，贵公司曾依据性能确认报告FTS1PRPR034-01（生效日期2013年8月8日）对压片机PR034和(b)(4)室(b)(4)中的(b)(4)PR034进行了确认。2024年3月16日，(b)(4)PR034在生产批次(b)(4)时发生故障。贵公司将其更换为另一台(b)(4)PR182，并继续生产批次(b)(4)。截至2025年12月12日，贵公司尚未对压片机PR034与(b)(4)PR182在(b)(4)室重新组成的组装体进行再确认。两台(b)(4)的制造商和型号不同。贵公司生产负责人(b)(4)表示，两者的工作原理相同，因此不需要再确认。

You manufacture multiple drug products on Tablet Compression Machine ID # PR034 and (b)(4) ID # PR182 in (b)(4) for the US market. E. g. (b)(4) (b)(4) (b)(4) (b)(4) (b)(4), and (b)(4) (b)(4) (b)(4) (b)(4).
贵公司在(b)(4)室使用压片机PR034和(b)(4)PR182为美国市场生产多种药品，例如(b)(4)等。

OBSERVATION 3
观察项 3

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.
未能为用于药品生产、加工、包装或储存的设备（包括器具）的清洁和维护建立书面程序。

Specifically, you practice cleaning validation for equipment trains for the worst-case molecule. The cleaning validation for your Tablet Compression Machine ID # PR034 and (b)(4) ID # PR034 in (b)(4) was conducted in an equipment train for (b)(4) Tablet as the worst-case molecule as reported in Cleaning Validation Report for (b)(4) Tablets VALRP-FS01-000310 (Effective date 10/6/2020). On 3/16/2024 the (b)(4) ID # PR034 underwent breakdown during the manufacturing of (b)(4) Batch No. (b)(4) You replaced (b)(4) ID # PR034 with a different (b)(4) ID # PR182. After changing the equipment, you did not re-validate the cleaning of the new equipment train. Your Head of Production (b)(4) stated that the surface area of PR182 (b)(4) is higher than PR034 (b)(4). After multiple requests, you were unable to provide surface area calculations for the (b)(4) ID # PR034 for verification.
具体而言，贵公司对设备组按最差条件分子进行清洁验证。根据(b)(4)片剂的清洁验证报告VALRP-FS01-000310（生效日期2020年10月6日），压片机PR034和(b)(4)室(b)(4)中的(b)(4)PR034的清洁验证是以(b)(4)片剂作为最差条件分子在设备组中进行的。2024年3月16日，(b)(4)PR034在生产批次(b)(4)时发生故障。贵公司将其更换为另一台(b)(4)PR182。更换设备后，贵公司未对新的设备组重新进行清洁验证。贵公司生产负责人(b)(4)表示，PR182的表面积(b)(4)高于PR034的表面积(b)(4)。经多次要求，贵公司未能提供(b)(4)PR034的表面积计算数据以供核实。

OBSERVATION 4
观察项 4

Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the final specifications prior to release.
药品的检测和放行分销，未能在放行前通过适当的实验室检测确定其符合最终质量标准。

A. Section 5.10.6 of your procedure, SOP-GLOB-QC-0085 Version 13.0 Good Analytical Practices (Effective date 7/25/2025) requires (b)(4) measurements from each preparation for assay test methods by HPLC. However, you have validated the assay test methods by HPLC from a single measurement from each preparation. E. g.

A.贵公司规程 SOP-GLOB-QC-0085 第13.0版《良好分析实践》（生效日期2025年7月25日）第5.10.6条要求，高效液相色谱法-含量测定方法需对每个供试品溶液制备进行(b)(4)次测定。然而，贵公司验证HPLC含量测定方法时，对每个制备样品仅进行了单次测定。

B. Your procedure SOP-FS01-PR-0067 Version 14.0 Production Procedure and Controls (Manufacturing + Packing) (Effective date 12/13/2023) does not ensure that the visual inspectors are adequately qualified. Section 5.2.30 requires taking (b)(4) units of good tablets and add defective tablets. These tablets are mixed and used as test kit to qualify the visual inspectors. There is no information about the type of defects and the number of defective tablets in the test kit. Review of an inspector evaluation form, FORM-FS01-PR-0328 Version 2.0 executed on 10/11/2025 for an Inspector (b)(4) confirmed that defective tablets were added and were identified by the Inspector However, the form did not have information about the number of good tablets used in the test kit. Your Production Head confirmed that it was the standard practice to qualify the Visual Inspectors. Your Production Manager also stated that the firm has created a new procedure to qualify the visual inspector, SOP-FS01-QA-0025 Version 1.0 Inspection Evaluation Process (Effective date 12/7/2025). As of 12/11/2025, you have not implemented the procedure, and you also did not have the test kit.
B. 贵公司规程SOP-FS01-PR-0067第14.0版《生产规程与控制》（生效日期2023年12月13日）未能确保目视检查员得到充分资质确认。第5.2.30条要求取(b)(4)片合格药片并加入缺陷药片，混合后用作资质确认的测试套件。但规程未规定测试套件中缺陷的类型和数量。查阅一份于2025年10月11日为检查员(b)(4)执行的评估表FORM-FS01-PR-0328第2.0版，确认其中添加了缺陷药片且被检查员识别，但该表格未记录测试套件中使用的合格药片数量。贵公司生产负责人确认此即为目视检查员资质确认的常规做法。生产经理同时说明，公司已制定新规程SOP-FS01-QA-0025第1.0版《检查评估流程》（生效日期2025年12月7日）用于资质确认。但截至2025年12月11日，新规程尚未实施，且测试套件也未配备。

You have recorded multiple market complaints for defective tablets, capsules, and commingled products. E. g. Market Complaint No's. 200434402 (physical defects in capsules), 200434810 (foreign products), 200425820 (comingled tablets), 200436426 (discolored tablets with black spots), 200433853 (tablet is the correct color, but the imprints match the (b)(4) strength).
贵公司已记录多起因药片缺陷、胶囊缺陷及产品混杂引起的市场投诉。例如投诉号200434402（胶囊物理缺陷）、200434810（异物）、200425820（药片混杂）、200436426（药片变色带黑点）、200433853（药片颜色正确，但印记与(b)(4)规格相符）。

OBSERVATION 5
观察项 5

Written procedures are not followed for the sampling of drug substance and excipients.
未遵循关于原料药和辅料取样的书面程序。

Specifically, your sampling practices are not scientifically sound and appropriate to ensure that your raw materials conform to established standards of quality and purity. Section 5.5.2.1 of your SOP-GLOB-QC-0113 Version 15.0 Sampling and Testing of Raw Materials (Effective date 5-Nov-2025) requires use of (b)(4) to collect samples from (b)(4) of the containers or bags. You use sterile scoop (b)(4) cm) and (b)(4) spoons to collect the samples for the active pharmaceutical ingredients (APIs). You have recorded multiple OOS results for drug products for related substances where APIs were sampled with sterile scoops and spoons.
具体而言，贵公司的取样实践不具备科学性和适当性，无法确保原材料符合既定的质量和纯度标准。贵公司规程SOP-GLOB-QC-0113第15.0版《原料取样与检测》（生效日期2025年11月5日）第5.5.2.1条要求使用(b)(4)从(b)(4)容器或袋子中取样。而贵公司使用无菌药勺（(b)(4) cm）和(b)(4)勺来采集原料药样品。贵公司已记录多起因使用无菌药勺和勺子取样原料药而导致的成品有关物质OOS结果。

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