FDA对GSK德国马尔堡疫苗原液厂出具483，涉及原始记录被弃置、关键报警未评估与粒子监测中止复测

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受检机构/公司：GSK Vaccines GmbH

城市：Marburg, Hassia, 35041 Germany

类型：疫苗原液产品Vaccine Bulk Product

FEI号：3001314775

检查员：

Holly Brevig — 质量保证专家（Quality Assurance Specialist）

Massoud Motamed — 消费者安全官员（Consumer Safety Officer）

Shuang Tang — 研究生物学家（Research Biologist）

检查日期：2024年11月4日至12日

西门的吐槽：FDA最近每个工作日，都连续十几二十份的公布各类483，看不完，根本看不完……这份是前天公布的，应该时一个管线不同工厂，此前GSK的制剂厂子也有CSDI相关缺陷FDA483：某国际巨头药企生产设备配方管理失效且将未验证/错误配方用于疫苗制剂生产严重缺陷。总的来说，感觉是大外资这几年的一个缩影，集团化质量体系，上层文件扎实，中层确实都是国际级别的SME，但下面干活的不太理解博大精深的体系文件和目的……

在对你企业的检查过程中，我们观察到：

DURING AN INSPECTION OF YOUR FIRM (I) (WE) OBSERVED:

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观察项 1 / Observation 1

用于生物制品生产的厂房设施和设备维护存在缺陷。

1. Maintenance of facilities and equipment used in the manufacture of biologics are deficient.

a. — Shingrix（xxx 建筑）

用于生产 Shingrix 原液（xxx 建筑）的厂房设施和设备维护存在缺陷，不足以确保原液质量。2024年11月4日、11月5日和11月11日观察到以下情况：

a. The facility and equipment used in the manufacture of Shingrix (Building xxx) are deficiently maintained to ensure the quality of the bulk drug substance. On November 4, 2024, November 5, and November 11, 2024, the following conditions were observed:

i. 观察到有 xxx 液体从 xxx 泄漏，位于 xxx 房间，该房间为用于产品 xxx 的 xxx。

i. A xxx liquid was observed to be leaking from xxx in Room xxx which is a xxx used for product xxx.

ii. 在 xxx 上观察到 xxx 残留物，该 xxx 用于 Shingrix 下游生产，位于 xxx 房间。该 xxx 显示 xxx 残留物积累，提示物料从 xxx 外泄。该 xxx 为 xxx 原液。

ii. xxx residues were observed on the xxx which is used in downstream manufacturing of Shingrix and contained in Room xxx. This xxx shows accumulation of xxx residues suggestive of material egress from the xxx. This xxx is a xxx drug substance.

iii. 在用于 Shingrix 下游生产的 xxx（xxx 房间）上观察到 xxx 残留物。该 xxx 呈现 xxx 变色。xxx 呈现 xxx 色泽。xxx 存在 xxx 液体的积聚。

iii. xxx residues were observed on the xxx used in downstream manufacturing of Shingrix (Room xxx). The xxx displayed xxx discoloration. xxx displayed a xxx hue. xxx there was an accumulation of a xxx liquid.

iv. 在 xxx 房间内的 xxx 上观察到 xxx 残留物，该 xxx 用于 xxx 的在线清洁（CIP）和在线灭菌（SIP）。

iv. xxx residues were observed on the xxx in Room xxx which is used for clean-in-place (CIP) and steam-in-place (SIP) of the xxx.

v. 观察到 xxx 与 xxx 之间存在 xxx 残留物，位于 xxx 房间，该房间用于 xxx。此外，在 xxx 残留物下方观察到 xxx 条纹。

v. xxx residue was observed between xxx in Room xxx which is used for xxx. Further, xxx streaking was observed below the xxx residue.

vi. 在 xxx 房间内用于 xxx 的 xxx 上观察到 xxx 残留物。

vi. xxx residues were observed on xxx used to xxx in Room xxx.

vii. 在 xxx 上观察到 xxx 残留物，该 xxx 用于分别从 xxx 转移培养基，位于 xxx 房间。

vii. xxx residue was observed on the xxx that is used to transfer media from xxx, respectively, in Room xxx.

viii. 在 xxx 房间内连接于 xxx 的 xxx 上观察到 xxx 残余物。

viii. xxx remnants were observed on a xxx attached to xxx in Room xxx.

ix. 在用于 xxx 的 xxx 上观察到 xxx 残留物，位于 xxx 房间，用于下游纯化。

ix. xxx residues were observed on the xxx used to xxx in Room xxx utilized for downstream purification.

自2022年10月以来，同一生产区域内已报告了11起与设备泄漏或容器/设备滴漏相关的偏差。

Since October 2022, 11 deviations associated with equipment leaking or dripping vessels or equipment in the same manufacturing area have been reported.

自该区域最近一次预防性维护以来，已生产了 xxx 批原液。未对这些 xxx 批原液进行产品影响分析，也未对先前生产的批次进行回顾性分析。

Since the last preventive maintenance of the area, xxx drug substance lots have been manufactured. A product impact analysis of the xxx drug substance lots and a retrospective analysis of previous lots manufactured have not been performed.

b. — 麻疹（Measles）原液

用于生产麻疹原液（xxx 建筑）的厂房设施和设备未保持良好的维修状态。具体如下：

b. The facility and equipment used in the manufacture of Measles bulk drug substance (Building xxx) are not maintained in a good state of repair. Specifically,

i. 2024年11月7日，在用于生产麻疹原液的分级洁净区内观察到 xxx 劣化。具体而言，在 xxx 级区域（包括 xxx 房间）内，因 xxx 劣化导致 xxx 可见。

i. On November 07, 2024, deterioration of xxx was observed in the classified areas used to manufacture Measles bulk drug substance. Specifically, in Grade xxx areas (including Room xxx) the xxx were visible due to the deteriorated xxx.

ii. 2024年11月8日，在分级 xxx 房间内，用于修补的剥落的 xxx 后方观察到用于 xxx 的 xxx 发生损坏。

ii. On November 08, 2024, damage to a xxx used to xxx was observed behind the peeling xxx used for patching in classified Room xxx.

iii. 常规生产过程中不监测 xxx 的速度，也未按常规进行确认。

iii. The speed of the xxx is not monitored during routine production or verified on a routine basis.

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观察项 2 / Observation 2

用于 Shingrix 生产、作为产品 xxx 的关键公用设施 xxx 未得到充分确认，也未进行常规监测，以确保质量的稳定重现。具体而言，未对接收的 xxx 进行 xxx 质量控制检测，且未针对全厂范围内供应的这些公用设施建立常规监测计划。此外，在相关 xxx 的确认尚未完成的情况下，仍继续使用这些 xxx。

2. Critical utilities xxx utilized as product xxx in the manufacture of Shingrix are not adequately qualified or routinely monitored to ensure reproducible quality. Specifically, xxx quality control testing is not performed on the xxx received xxx and a routine monitoring program has not been established for these utilities that are supplied throughout the facility xxx. Further, the utilization of these xxx has continued in the absence of completed qualifications of the xxx.

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观察项 3 / Observation 3

未建立对支持生产设备、环境监测和生产系统（如过程控制系统）所捕获电子数据的质量监督及其完整性。例如：

3. Quality oversight and integrity of electronic data captured to support the manufacturing equipment, environmental monitoring, and manufacturing systems (e.g., Process Control System) has not been established. For example:

a. — 针对 xxx 的评估

a. For the xxx assessments:

i. 缺失2024年5月8日对 xxx 进行的 xxx 电子文件记录。

i. Electronic documentation of the xxx of the xxx, performed on May 8, 2024 is missing.

ii. 设备内部诊断自检分别于2024年10月29日和2024年6月17日被中止或失败，且无解释或文件记录。

ii. Self-tests for internal diagnostics of equipment were aborted or failed on October 29, 2024, and June 17, 2024, respectively, without explanation or documentation.

iii. 用于 xxx 仪器的 xxx 缺乏对相关检测和元数据进行质量监督的要求。

iii. xxx which is used for the xxx instruments, lacks a requirement for quality oversight of the associated testing and metadata.

b. — 程序 9000087546「SDOC – 环境监测」

b. For the xxx procedure 9000087546 titled SDOC – Environmental Monitoring, version 04 permits measurements to be interrupted [aborted] and repeated immediately for occurrences such as xxx. These interruptions are not subject to documented quality oversight. Aborted testing was observed in the xxx electronic audit trail. For example, particulate measurements of the classified areas used to manufacture Shingrix were aborted without contemporaneous quality review, and there is no record of an investigation, trending, or reporting the events aside from the audit trail (e.g., June 19, 2024, May 23, 2024, August 08, 2024).

对于编号为9000087546、名为「SDOC – 环境监测」的第04版 xxx 程序，允许在诸如 xxx 等情形下中断（中止）测量并立即重复测量。这些中断不受文件化的质量监督约束。在 xxx 电子审计追踪中观察到被中止的检测。例如，用于生产 Shingrix 的分级洁净区的粒子测量被中止，且无同步质量审核，除审计追踪外（例如2024年6月19日、2024年5月23日、2024年8月8日），没有任何调查、趋势分析或事件上报记录。

西门：FDA的审计指南，比如CPG7356.002m里，反复强调禁止test into compliance，任何中止的测试皆为异常，应该至少有评估，必要时上升。尤其时粒子监测，在全球范围内，FDA发现过很多异常的情况下。

c. — Shingrix 生产过程控制系统（PCS）

c. For the Process Control System (PCS) for the manufacture of Shingrix, critical alarms termed xxx are to be the subject of a documented investigation per SOP 9000056671 titled Alarm Management, version 16. A review of the PCS demonstrated the occurrence of xxx alarms that have not been investigated as mandated per the SOP. For example, deviations were not opened when different operators on March 22, 2024 and July 24, 2024 did not correctly xxx system following planned maintenance, which resulted in an upper limit xxx measurement and xxx upper alarm limit.

对于 Shingrix 生产过程控制系统（PCS），依照编号为9000056671、名为「报警管理」的第16版SOP，称为 xxx 的关键报警应成为文件化调查的对象。对 PCS 的审查表明，存在按该SOP要求本应调查却未调查的 xxx 报警。例如，2024年3月22日和2024年7月24日，不同操作员在计划维护后未正确 xxx 系统，导致上限 xxx 测量值和 xxx 高报限值，但未开启偏差。

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观察项 4 / Observation 4

偏差管理不足以证明对生产过程的质量监督，且未能充分识别、记录或调查对原液的影响。例如：

4. Deviation management is inadequate to demonstrate quality oversight of the manufacturing process, and does not adequately identify, document, or investigate the impact to drug substances. For example:

a. — 程序 9000075940-02「MZP：报警管理与审计追踪」

a. Procedure 9000075940-02, MZP: Alarm Management and Audit Trail defines critical xxx alarms (defined as xxx as xxx critical, xxx). Since October 09, 2024, there have been xxx critical xxx alarms that are xxx critical. Despite these xxx critical alarms, xxx has not reviewed, evaluated, or otherwise acknowledged these alarms since October 09, 2024 (as of November 09, 2024). Without xxx of these alarms, the production department continues to issue batch records for the manufacture of Shingrix drug substance per SOP 9000080766 version 4 titled eBR Execution and Review and has initiated manufacture of xxx batches of Shingrix drug substance without the evaluation of these xxx of alarms.

程序 9000075940-02「MZP：报警管理与审计追踪」将关键 xxx 报警（定义为 xxx 关键级、xxx）界定为 xxx 关键报警。自2024年10月9日以来，已发生 xxx 次属于 xxx 关键级别的 xxx 关键报警。尽管存在这些 xxx 关键报警，自2024年10月9日（截至2024年11月9日）以来，xxx 未对这些报警进行审核、评估或以其他方式确认。在未 xxx 处理这些报警的情况下，生产部门仍依照编号为9000080766、名为「eBR 执行与审核」的第04版SOP继续签发 Shingrix 原液生产批记录，并已在未评估这些 xxx 报警的情况下启动 xxx 批 Shingrix 原液的生产。

西门：报警应该全部被确认，被评估，很难，所以分类分级策略，但关键的话一般默认关联偏差了，偏差评估后才能带风险进行xxx，大概是这么个报警管理逻辑，最近比较流行。

b. — 高生物负载

b. High bioburden levels were discovered during a lifetime study of xxx. xxx has a xxx which was identified as a source of bioburden contamination to the Shingrix drug substance. Manufacture of Shingrix drug substance continues at risk with xxx. Correction of the equipment design is not scheduled until March 2025.

在 xxx 的寿命研究中发现高生物负载水平。xxx 存在 xxx，该 xxx 被确定为 Shingrix 原液的生物负载污染源。Shingrix 原液的生产在存在 xxx 的风险下继续进行。设备设计的纠正计划要到2025年3月才实施。

西门：原液生产的终极目的，就是低/无生物负载，虽然原液后面可能还有配制，还有除菌过滤，但是老外考虑原液如果生物负荷过高，会对细菌内毒素有影响，所以是希望控制的严格一点！这里一般C类比B管理。

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观察项 5 / Observation 5

缺乏充分的质量监督以确保 Shingrix 和麻疹原液具有其声称或所被代表的鉴别、规格、质量和纯度。例如：

5. There is inadequate quality oversight to assure that the Shingrix and Measles drug substances have the identity, strength, quality, and purity they purport or are represented to possess. For example:

a. — 寿命研究数据无效化

a. High bioburden levels were discovered during a lifetime study of xxx. Quality assurance invalidated this data during the lifetime study, albeit the data was considered valid data by quality control.

在 xxx 的寿命研究中发现高生物负载水平。质量保证部在寿命研究期间宣布该数据无效，尽管质量控制部认为该数据为有效数据。

西门：大公司的特色，感觉。

b. — 计划外维护缺乏质量监督

b. There is no quality oversight of unplanned maintenance events to assess the qualification/validation status and product impact. Specifically, procedure GUJ-9000055892-24 General Procedure of Preventive and Corrective Maintenance does not require the quality unit's approval for any unplanned maintenance or repairs to the facility.

对计划外维护事件缺乏质量监督，未评估确认/验证状态及产品影响。具体而言，程序 GUJ-9000055892-24《预防性和纠正性维护通用程序》不要求质量部门批准任何计划外维护或厂房设施维修。

西门：一个GMP流程悖论，GMP流程里带个QA肯定没错。

c. — 文件记录不规范

c. Documentation practices are insufficient. For example, xxx in classified Room xxx used to manufacture Measles bulk drug substance lacked supporting documentation.

文件记录做法不充分。例如，用于生产麻疹原液的 xxx（xxx 房间）缺少支持性文件记录。

d. — 原始文件被弃置

d. Signed and dated original documents pertaining to the xxx of materials used in the manufacture of Measles drug substance were found in the trash.

在垃圾中发现了与麻疹原液生产所用物料 xxx 相关的、经签署并注明日期的原始文件。

西门：最近披露了好几例外资垃圾桶被发现原始记录，当然这里只是物料相关，关键性没那么高。

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观察项 6 / Observation 6

缺乏数据证明 xxx 在用于疫苗生产前具备所需质量。xxx 在上游生产工艺使用前，未经检查和记录 xxx。

6. There is a lack of data to demonstrate the quality of the xxx prior to use for vaccine production. xxx the xxx have not been inspected and documented for xxx before use for the upstream manufacturing process.