FDA 对三星生物签发 483 检查观察报告，列出 4 项观察

2025年5月19日至27日，美国食品药品监督管理局（FDA）对三星生物（Samsung Biologics Co., Ltd.，FEI 3010479596，地址：韩国仁川广域市延寿区松岛国际大道300号）进行检查，签发 FDA 483 检查观察报告（Form FDA 483），列出 4 项观察：产品切换操作中防交叉污染的程序未遵守、质量部门职责与程序未遵守（涉及数据造假与匿名举报）、质量控制实验室程序与控制存在缺陷、未遵守已批准申请的变更报告与实施程序。如下：

FDA 483 检查观察报告（中英对照）

DEPARTMENT OF HEALTH AND HUMAN SERVICES

美国卫生与公众服务部

FOOD AND DRUG ADMINISTRATION

美国食品药品监督管理局（FDA）

DISTRICT OFFICE ADDRESS AND PHONE NUMBER：10903 New Hampshire Ave, Bldg71, Rm 5054, Silver Spring, MD 20993-0002, (240)402-9160

地区办公室地址及电话：马里兰州银泉市新罕布什尔大道10903号71栋5054室，邮编20993-0002，电话(240)402-9160

DATE(S) OF INSPECTION：05/19/2025 - 05/27/2025

检查日期：2025年5月19日 – 2025年5月27日

FEI NUMBER：3010479596

FEI 编号（企业识别号）：3010479596

NAME AND TITLE OF INDIVIDUAL TO WHOM REPORT IS ISSUED：John Rim, CEO

报告交付对象姓名及职务：John Rim，首席执行官（CEO）

FIRM NAME：Samsung Biologics Co., Ltd.

公司名称：三星生物（Samsung Biologics Co., Ltd.）

STREET ADDRESS：300 Songdoibaodae-Ro

街道地址：松岛国际大道300号

CITY, STATE AND ZIP CODE：Yeonsu Incheon 21987, Korea (the Republic of)

城市、州、邮政编码：韩国仁川广域市延寿区，邮编21987

TYPE OF ESTABLISHMENT INSPECTED：Drug Substance Manufacturer

被检查机构类型：药物活性成分生产商

This document lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations, and do not represent a final Agency determination regarding your compliance. If you have an objection regarding an observation, or wish to advise FDA of a plan to implement corrective action in response to an observation, you may discuss the objection or action with the FDA representative(s) during the inspection or submit this information to FDA at the address above. If you have any questions, please contact FDA at the phone number and address above.

本文件列出 FDA 代表在检查贵方设施期间提出的观察项。这些属于检查性观察，不代表 FDA 对贵方合规性的最终判定。如贵方对某项观察有异议，或希望告知 FDA 计划针对某项观察实施纠正措施，可在检查期间与 FDA 代表讨论该异议或措施，或将相关信息提交至上文地址的 FDA。如有任何疑问，请通过上文电话号码和地址联系 FDA。

DURING AN INSPECTION OF YOUR FIRM WE DESCRIBED:

在检查贵方工厂期间，我方观察到以下事项：

OBSERVATION 1

观察项 1

Procedures implemented to prevent cross-contamination of drug substances during product change over (PCO) operations were not followed.

未遵守为防止药品在切换生产（PCO）操作期间发生交叉污染而制定的程序。

Specifically, between 01OCT2018 to 21MAY2025, you routinely failed to change (b)(4) within the (b)(4) on the (b)(4) lines as part of change over between manufacturing of different drug substances within (b)(4) (as identified within deviations DEV-017954 and DEV-017965). This practice does not follow your current and historical procedures "SOP (b)(4)-00161, (ver. 2.0 - 14.0), Maintenance Procedure of (b)(4)" which requires that the (b)(4) be changed (b)(4) DS lot. You have manufactured, (b)(4) and (b)(4), the following drug substances (of which (b)(4) are within known expiry/retest dates) for manufacture of drug products (for U.S. and ROW markets) without having changed the (b)(4):

具体而言，在2018年10月1日至2025年5月21日期间，作为在(b)(4)内不同药品之间切换生产的一部分，贵方在(b)(4)生产线上通常未更换(b)(4)内的(b)(4)（如偏差 DEV-017954 和 DEV-017965 所述）。这一做法不符合贵方现行及历史的程序"SOP (b)(4)-00161（版本2.0–14.0）《(b)(4)维护程序》"，该程序要求每(b)(4)个药物活性成分（DS）批更换(b)(4)。贵方已生产(b)(4)和(b)(4)以下药品（其中(b)(4)在已知效期/复验期内），用于（美国和全球市场）药品生产，而未更换(b)(4)：

[表格] Drug Substance Product Code | Proprietary Name of Drug Product | Plant Number | Batches Released and Shipped

[表格] 药品产品代码 | 药品商品名 | 厂区编号 | 已放行并装运的批次数

（表格内容已涂黑，标注为 (b)(4)）

（表格内容已涂黑，标注为 (b)(4)，系 FDA 依据 FOIA 豁免条款第4类删除的商业机密信息）

Your investigation of the failure to change out (b)(4) did not include an adequate risk assessment in that you have not determined the impact of this failure on the various DS manufactured during the subject timeframe. Additionally, both deviations DEV-017954 and DEV-017965 were classified by quality as (b)(4). This classification does not follow section 8.3.2.2 of procedure SOP-QA-00037 (ver. 41.0) titled "Deviation Procedure," which states that a (b)(4) deviation is a (b)(4). Additionally, as deviation DEV-017954 was classified as a (b)(4) deviation, (b)(4) were not (b)(4).

贵方对未更换(b)(4)问题的调查未包含充分的风险评估，因为贵方未确定该问题对相关时间段内所生产的各种药物活性成分（DS）的影响。此外，两项偏差 DEV-017954 和 DEV-017965 均被质量部门定性为(b)(4)。该定性不符合程序 SOP-QA-00037（版本41.0）《偏差程序》第8.3.2.2节，该节规定(b)(4)偏差属于(b)(4)。此外，由于偏差 DEV-017954 被定性为(b)(4)偏差，(b)(4)未被(b)(4)。

OBSERVATION 2

观察项 2

The responsibilities and procedures applicable to the quality control unit were not followed.

未遵守适用于质量部门（QCU）的职责和程序。

Since 29SEP2021, 56 CAPAs and 74 change controls have been implemented to improve data integrity practices at your firm. However, since the conclusion of the previous agency inspection end dated 30JUL2024, data integrity deficiencies have continued as follows:

自2021年9月29日以来，贵方已实施56项纠正与预防措施（CAPA）和74项变更控制，以改善数据完整性管理。然而，自2024年7月30日结束的上一次 FDA 检查结束以来，数据完整性问题仍持续存在，具体如下：

DEV-017935 – Opened on 27FEB2025 (in support of deviation DEV-017965) for documenting changing of (b)(4) for product change over (PCO) within building (b)(4) during drug substance (b)(4) campaign (U.S. marketed product) without actual replacement of associated (b)(4). This was documented as Data Falsification on 20JAN2025. During the investigation, it was revealed that the falsification action was instructed by the manufacturing shift leader. Additionally, the investigation found that documentation of performance of preventative maintenance for (b)(4) of (b)(4) within building (b)(4) was also falsified during the period of 16FEB2025 to 18FEB2025.

DEV-017935（2025年2月27日发起，用于支持偏差 DEV-017965）：记录了在(b)(4)楼药品(b)(4)生产期间，为产品切换（PCO）更换(b)(4)，但实际未更换相应的(b)(4)。该行为于2025年1月20日被记录为数据造假（Data Falsification）。调查过程中发现，该造假行为系由生产班组长指示。此外，调查还发现，2025年2月16日至18日期间，(b)(4)楼(b)(4)的(b)(4)预防性维护执行记录也系伪造。

DEV-017546 – Opened on 10JAN2025 states that on 26DEC2024 the Quality Systems (QS) Director attempted to identify an employee who had anonymously reported a data integrity violation which was documented under DEV-017515, for falsification of (b)(4) testing data for (b)(4) for (b)(4) OOS for lot (b)(4) reported (b)(4) specification, (b)(4) tested 07SEP2023 and utilized for ROW drug substance manufacturing.

DEV-017546（2025年1月10日开启）载明：2024年12月26日，质量体系（QS）总监试图找出某位匿名举报数据完整性违规（记录于 DEV-017515）的员工。该违规涉及对批号(b)(4)的(b)(4)的(b)(4)检测数据造假，该批(b)(4)报告为(b)(4)规格，于2023年9月7日检测，并用于全球市场（ROW）药物活性成分生产。

DEV-017118 – Opened on 29NOV2024 states that in response to a transcription error within the batch record for drug substance product (b)(4) (U.S. marketed product) batch (b)(4) (incorrect lot number and serial number of (b)(4) documented during production), a shift supervisor instructed manufacturing operators to change the documented (b)(4) lot and serial number without verification that the changed lot and serial numbers were correct.

DEV-017118（2024年11月29日开启）载明：针对药品(b)(4)（美国上市产品）批号(b)(4)批记录中的转录错误（生产期间记录的(b)(4)批号和序列号不正确），一名班组长指示生产操作人员更改所记录的(b)(4)批号和序列号，而未确认更改后的批号和序列号是否正确。

OBSERVATION 3

观察项 3

Procedures and controls utilized within the Quality Control (QC) Laboratory in support of drug substance release and (b)(4) testing are deficient. The following was observed.

用于支持药物活性成分放行和(b)(4)检测的质量控制（QC）实验室程序和控制存在缺陷。观察到以下情况。

a) Your firm failed to adhere to established (b)(4) protocols for drug substance (DS) by not performing sample pulls and associated (b)(4) testing within defined protocol timeframes (SOP-QC-00067). The following issues were noted:

a) 贵方未能遵守既定的药物活性成分(b)(4)方案，未在方案规定的时间范围内进行取样和相应的(b)(4)检测（SOP-QC-00067）。注意到以下问题：

(b)(4) sample pulls were conducted outside the allowable time window specified in the protocol (DEV-012880). For example, the (b)(4) sample for (b)(4) DS batch (b)(4) was scheduled for pull on August 21, 2023, but the samples were pulled (b)(4) days outside the (b)(4) window defined by the stability protocol (b)(4)-02130.

(b)(4)取样超出了方案规定的允许时间窗（DEV-012880）。例如，(b)(4)药物活性成分（DS）批号(b)(4)的(b)(4)样品原定于2023年8月21日取样，但实际取样时间超出了稳定性方案(b)(4)-02130规定的(b)(4)时间窗(b)(4)天。

(b)(4) testing was not performed within the required (b)(4) timeframe after sample pull (DEV-013019), as defined by the (b)(4) protocol (b)(4)-02130 and SOP-QC-00067. For example:

(b)(4)检测未在取样后规定的(b)(4)时间范围内完成（DEV-013019），该时间范围由(b)(4)方案(b)(4)-02130和SOP-QC-00067规定。例如：

(b)(4) DS batch (b)(4) was due by September 20, 2023, but was not completed until (b)(4)

(b)(4)药物活性成分（DS）批号(b)(4)原应于2023年9月20日完成，但直到(b)(4)才完成。

(b)(4) DS batch (b)(4) under (b)(4), (b)(4) and (b)(4) conditions were delayed by (b)(4) past the expected testing window due to repeated assay failures, including standard curve issues regarding (b)(4)

在(b)(4)、(b)(4)和(b)(4)条件下的(b)(4)药物活性成分（DS）批号(b)(4)，因反复的检测失败（包括与(b)(4)相关的标准曲线问题）而延迟了(b)(4)，超出了预期检测时间窗。

(b)(4) DS batch (b)(4) test was reported OOS due to (b)(4) with an initial due date of November 24, 2023, and actual testing completed on (b)(4)

(b)(4)药物活性成分（DS）批号(b)(4)的检测因(b)(4)报告为超标（OOS），截止日期为2023年11月24日，实际检测完成于(b)(4)。

(b)(4) were not properly managed to ensure timely and valid execution of testing (DEV-017846). For which (b)(4) DS batch (b)(4) (b)(4) testing was initiated on time (February 7, 2025) but was invalidated due to a "(b)(4)," Contributing factors included delays in requalification of the (b)(4) reference standard and equipment error. As a result, valid testing was not completed until (b)(4) beyond the required testing timeframe.

(b)(4)未被妥善管理以确保检测的及时和有效执行（DEV-017846）。其中，(b)(4)药物活性成分（DS）批号(b)(4)的(b)(4)检测虽按时启动（2025年2月7日），但因"(b)(4)"而失效。促成因素包括(b)(4)标准品的重新确认延迟和设备错误。结果，有效检测直到超出规定检测时间范围(b)(4)后才完成。

b) Firm procedure SOP-QC-00083 (ver. 13.0) titled "Quality Control Laboratory Waste Disposal" was not followed in Plant (b)(4), Room (b)(4). Specifically,

b) 在(b)(4)厂区(b)(4)房间，未遵守公司程序 SOP-QC-00083（版本13.0）《质量控制实验室废弃物处置》。具体而言，

The (b)(4) for quality control laboratory waste disposal were labelled inconsistently (e.g., (b)(4) when (b)(4) is filled-up or (b)(4) within (b)(4), or no label, although either (b)(4) was used in each (b)(4)

用于质量控制实验室废弃物处置的(b)(4)标签标注不一致（例如，当(b)(4)装满时标注为(b)(4)，或(b)(4)内为(b)(4)，或未标注，尽管每个(b)(4)中使用了任一(b)(4)。

The QC lab waste was not disposed appropriately. (b)(4) were found in a (b)(4) labelled as (b)(4) and (b)(4) were found in a (b)(4) with a (b)(4)

QC 实验室废弃物未被妥善处置。在标注为(b)(4)的(b)(4)中发现(b)(4)，在带有(b)(4)的(b)(4)中发现(b)(4)。

OBSERVATION 4

观察项 4

Failure to follow established procedures for reporting and implementing changes to an approved application.

未遵守已批准申请的变更报告和实施程序。

a) Your firm implemented a revised version of the (b)(4) assay method (b)(4) – Determination of (b)(4) for the release and (b)(4) testing of drug substance (DS) batches for manufacturing (b)(4) prior to receiving FDA approval for the change and prior to completion of the required waiting period following submission of a CBE-30 supplement.

a) 贵方在获得 FDA 对该变更的批准之前、以及在提交 CBE-30 补充申请后规定的等待期届满之前，就实施了修订版的(b)(4)检测方法(b)(4)——《(b)(4)的测定》，用于生产(b)(4)的药物活性成分（DS）批次的放行和(b)(4)检测。

The revised assay method was used for release testing of (b)(4) DS batches (Batch numbers: (b)(4)) and for stability testing of (b)(4) DS batches (Batch numbers: (b)(4)). The batches including (b)(4) DS batches (b)(4) were released between 09JAN2024 and 22JAN2024, after implementation of the new method on 27OCT2023, even though the corresponding CBE-30 supplement (b)(4) was not submitted until 20MAR2024 and not approved until 10SEP2024.

该修订检测方法被用于(b)(4)药物活性成分（DS）批次（批号：(b)(4)）的放行检测，以及(b)(4)药物活性成分（DS）批次（批号：(b)(4)）的稳定性检测。包括(b)(4)药物活性成分（DS）批次(b)(4)在内的批次于2024年1月9日至22日期间放行，而此时新方法已于2023年10月27日实施，但相应的 CBE-30 补充申请(b)(4)直到2024年3月20日才提交、直到2024年9月10日才获批。

b) The approved protocol for qualifying new (b)(4) reference standards was not completely implemented, i.e., change was identified when comparing the information provided in Section 3.2.S.5 of an Annual Report with (b)(4) to that in the original BLA (b)(4)

b) 已批准的用于确认新(b)(4)标准品的方案未被完全实施，即：将年度报告 Section 3.2.S.5 中提供的信息与(b)(4)进行对比时，发现与原 BLA (b)(4)存在变更。

c) The data to support (b)(4) reference standard were not completely reported.

c) 用于支持(b)(4)标准品的数据未被完整报告。

EMPLOYEE(S) NAME AND TITLE (Print or Type)：Travis S. Bradley, Investigator; Peng Zhou, Investigator; Ze Peng, Biologist; Haimin Chu, Biologist

检查组成员姓名及职务：Travis S. Bradley，检查员；Peng Zhou，检查员；Ze Peng，生物学家；Haimin Chu，生物学家