FDA对GSK Biologicals比利时瓦夫尔疫苗厂出具483，列配方管理与无菌工艺模拟等6项观察

本文中观点不代表任何公司和组织，如有觉得有冒犯的地方，请于后台联系，我会及时删除。所有分享案例都具有孤立性，仅供参考。

受检机构/公司：

GlaxoSmithKline Biologicals SA

城市：

Wavre, Brabant Wallon, 1300 Belgium

类型：

Vaccine Manufacturer

FEI号：

3003973577

检查员：

Shafiq Ahadi, Investigator

Thai D Truong, Investigator

检查日期：

2/09/2026(Mon), 2/10/2026(Tue), 2/11/2026(Wed), 2/12/2026(Thu), 2/13/2026(Fri), 2/16/2026(Mon), 2/17/2026(Tue), 2/18/2026(Wed), 2/19/2026(Thu), 2/20/2026(Fri), 2/23/2026(Mon), 2/24/2026(Tue), 2/25/2026(Wed), 2/26/2026(Thu), 2/27/2026(Fri)

西门的吐槽：吐槽下，一个月没披露，这两三天里披露了几十份483的FDA，其中就有几分GSK，看了下可能是同一个产品的PAI上市前检查。配方管理，说实话，难也不难，对于头部药企肯定有完善的详细的流程和高大上的系统。但是，这也是现实，所谓的集团化体系，还是会有各种集团和本地间的衔接理解不匹配，难落地的情况。不要觉得一家企业有这个情况，圈子里外企内资都这么吐槽，可能原先建文件写体系的一波人知其所以然也有自己意图，文件被local或者隔代人一抄，就不知道为啥了，就知道这么写的，再到执行层肯定也会打折……

关于配方管理，如需参考可以看前期文档：配方管理Recipe Management Part1

以下是原文和翻译

OBSERVATION 1

观察项 1

Input to and output from the computer and related systems of formulas are not checked for accuracy.

处方（配方）的计算机及相关系统的输入和输出未进行准确性核对。

Specifically,

具体而言：

A. Your firm utilizes electronic formats/recipes configured within the xxx systems to control critical manufacturing parameters for the drug products, including but not limited to fill volume. Your firm manufactured drug product batches using non-validated formats/recipes, as follows:

A. 贵企业使用在xxx系统中配置的电子格式/配方来控制药品的关键生产工艺参数，包括但不限于灌装体积。贵企业使用未经验证的格式/配方生产药品批次，具体如下：

Filling lines (xxx Wavre site)

灌装线（xxx 瓦夫尔厂区）

In addition, your firm used an incorrect format/recipe to manufacture and release commercial drug products. For example, during the manufacturing of SHINGRIX® Batch No. ASFLA026A, (Release date: September 1, 2025), your firm utilized a non-validated format/recipe identified as xxx in the xxx equipment system. However, the executed batch production record documents the use of the xxx format/recipe.

此外，贵企业使用错误的格式/配方生产并放行了商业药品。例如，在生产SHINGRIX®（欣安立适®）批号ASFLA026A（放行日期：2025年9月1日）期间，贵企业在xxx设备系统中使用了标识为xxx的未经验证格式/配方，而已执行的批生产记录记载使用的是xxx格式/配方。

B. Your firm implemented a new Format/Recipe, xxx in the xxx to manufacture SHINGRIX® drug product without subjecting the change to the firm's change control system. This change to the production control procedure was not drafted, reviewed, and approved prior to implementation. For example, your firm implemented the xxx Format/Recipe on filling line xxx to manufacture SHINGRIX® Lot No. ASFLA018A on xxx. The implementation of the xxx Format/Recipe, which controls critical parameters such as fill volume, was not documented, reviewed, and approved prior to implementation.

B. 贵企业在xxx中实施了新的格式/配方xxx来生产SHINGRIX®药品，但未将该项变更纳入企业的变更控制系统。这一生产控制规程的变更在实施前未经起草、审核和批准。例如，贵企业于xxx在xxx灌装线上实施了xxx格式/配方，用于生产SHINGRIX®批号ASFLA018A。该xxx格式/配方控制灌装体积等关键参数，其实施在实施前未经文件记录、审核和批准。

C. Your firm failed to adequately document process performance qualification (PPQ) batches to demonstrate that the process was validated under defined operating parameters. The PPQ batch record for SHINGRIX® Drug Product, Document No. xxx PPQ Report-xxx xxx" did not document which recipe or filling parameters were used during the validation batches. For example, the PPQ batch record for SHINGRIX® Lot No. ASFLA018A, manufactured on xxx lacks documentation of critical parameters such as the xxx Format/Recipe used to manufacture the batch. Without documentation of the correct Format/Recipe and filling parameters (e.g., fill volume) employed during PPQ, your firm cannot demonstrate that the validated process matches the commercial manufacturing process or that the process has been adequately validated under defined conditions.

C. 贵企业未能充分记录工艺性能确认（PPQ）批次，以证明工艺在规定的操作参数下得到了验证。SHINGRIX®药品的PPQ批记录（文件号xxx，PPQ报告-xxx xxx）未记录验证批次所用处方或灌装参数。例如，SHINGRIX®批号ASFLA018A（于xxx生产）的PPQ批记录缺少该批次生产所用xxx格式/配方等关键参数的记录。由于缺乏PPQ期间所用正确格式/配方及灌装参数（如灌装体积）的记录，贵企业无法证明经验证的工艺与商业生产工艺一致，也无法证明工艺在界定条件下得到了充分验证。

OBSERVATION 2

观察项 2

Your firm failed to establish written procedures for production and process controls designed to assure that the drug products have the identity, strength, purity, and quality that they are purported or represented to possess.

贵企业未建立生产和工艺控制的书面规程，以确保药品具有其声称或所代表的鉴别、含量、纯度和质量属性。

Specifically,

具体而言：

A. The Master Batch Record, MBR, No. xxx, and executed production batch records for SHINGRIX® specify the use of format/recipe xxx with a target fill volume of xxx xxx. However, actual manufacturing operations utilized format/recipe xxx with a target fill volume of xxx, representing a xxx deviation from the specified fill volume. Your firm failed to follow the batch record specifications during manufacturing for xxx lots of SHINGRIX® PFS-Pre-Filled Syringe drug products, of which xxx have been released since March 16, 2024. The actual fill volume and format/recipe used in production did not match the fill volume and format/recipe documented in the batch record. For example, your firm manufactured and released SHINGRIX® Batch No. ASFLA026A, release date September 1, 2025, on filling line xxx using format/recipe xxx with a fill volume of xxx. However, the MBR and production batch record reflect the use of format/recipe xxx with a target fill volume of xxx.

A. SHINGRIX®的主批记录（MBR，编号xxx）和已执行的批生产记录规定使用格式/配方xxx，目标灌装体积为xxx xxx。然而，实际生产操作使用了格式/配方xxx，目标灌装体积为xxx，与规定的灌装体积存在xxx偏差。在xxx批SHINGRIX®预充式注射器（PFS）药品的生产中，贵企业未遵循批记录的规定，其中xxx批自2024年3月16日起已放行。实际生产所用灌装体积和格式/配方，与批记录记载的灌装体积和格式/配方不一致。例如，贵企业在xxx灌装线上使用格式/配方xxx、灌装体积xxx生产并放行了SHINGRIX®批号ASFLA026A（放行日期2025年9月1日），而MBR和批生产记录记载使用的是格式/配方xxx、目标灌装体积xxx。

B. Filling parameters are modified and adjusted during production and process control in the xxx by the operator as needed. Your firm has not established procedures governing operator changes to filling parameters and there is no documentation of what changes were made or what fill volumes were actually used during manufacturing.

B. 在生产及工艺控制过程中，操作人员可按需在xxx中修改和调整灌装参数。贵企业未建立规范操作人员更改灌装参数的规程，也没有任何文件记录生产过程中更改了哪些参数或实际使用了什么灌装体积。

OBSERVATION 3

观察项 3

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile did not include adequate validation of the aseptic and sterilization process.

旨在防止标示为无菌的药品发生微生物污染的程序，未包括对无菌工艺和灭菌工艺的充分验证。

Specifically,

具体而言：

A. Your current APS (Aseptic Process Simulation) design does not challenge or represent worst-case conditions for routine commercial fill volumes and container sizes. Commercial products, such as Boostrix, Engerix, Havrix, Twinrix, Fluad, FluLaval, Infanrix, Kinrix, Pediarix, Rotarix, Shingrix, Synflorix, Penmenvy, Arexvy, and Hiberix are filled at volumes ranging from xxx syringe containers, xxx syringe containers, and xxx vial containers. However, your APS program uses only the xxx syringe container filled to a target volume of xxx for filling line xxx and xxx vial container filled to a target volume of xxx for filling line xxx.

A. 贵企业现行的APS（无菌工艺模拟）设计，未对常规商业灌装体积和容器规格构成挑战或代表最差条件。Boostrix、Engerix、Havrix、Twinrix、Fluad、FluLaval、Infanrix、Kinrix、Pediarix、Rotarix、Shingrix、Synflorix、Penmenvy、Arexvy和Hiberix等商业产品的灌装体积范围为xxx注射器容器、xxx注射器容器和xxx西林瓶容器。然而，贵企业的APS方案仅使用目标灌装体积为xxx的xxx注射器容器（用于xxx灌装线）和目标灌装体积为xxx的xxx西林瓶容器（用于xxx灌装线）。

B. Your LSOP 9000002087, version 17, "Validation of Aseptic Operations – Aseptic Process Simulation (APS)", section 6.2.5.2 requires justification and validation of the xxx media fill volumes for each container and validation of incubation conditions. Section 6.2.5.4 requires development and justification of a container xxx; otherwise, all container sizes must be xxx during xxx APS requalification. Section 6.2.5.4 further requires that when a single container size has more than xxx fill volume, xxx APS runs must be performed at the xxx fill volume.

B. 贵企业标准操作规程LSOP 9000002087第17版《无菌操作验证——无菌工艺模拟（APS）》第6.2.5.2节要求，对每种容器的xxx培养基灌装体积进行论证和验证，并对培养条件进行验证。第6.2.5.4节要求制定并论证容器xxx；否则，在xxx APS再确认期间，所有容器规格均须xxx。第6.2.5.4节进一步要求，当单一容器规格的灌装体积超过xxx时，须在xxx灌装体积下执行xxx次APS运行。

Your firm has not validated the xxx media fill volumes for each container, has not developed and justified a container xxx for syringe containers, and has not performed xxx runs at the xxx fill volume for syringe and vial containers with xxx fill volumes, as required by LSOP 9000002087.

贵企业未按LSOP 9000002087要求，对每种容器验证xxx培养基灌装体积，未制定并论证注射器容器的容器xxx，也未对具有xxx灌装体积的注射器和西林瓶容器在xxx灌装体积下执行xxx次运行。

OBSERVATION 4

观察项 4

Deviations from written production and process control procedures are not justified.

偏离书面生产和工艺控制规程的偏差未得到论证。

Specifically, your firm failed to evaluate unexpected events during drug product manufacturing to determine whether they constitute deviations from established procedures. There is no documentation demonstrating that your firm assessed these events or provided justification for why they were not classified and investigated as deviations. For example, your firm manufactured SHINGRIX® Lot No. ASFLA018A on xxx. During the manufacturing process, the operator detected a failure of the xxx, which monitors the Grade xxx filling line. This event was documented in the batch record as defect code xxx. However, your firm failed to evaluate whether this PEMS failure constituted a deviation from established procedures or requirements.

具体而言，贵企业未评估药品生产过程中的意外事件，以确定其是否构成对既定程序的偏离。没有任何文件证明贵企业评估了这些事件，或就这些事件为何未作为偏差进行分类和调查提供了论证。例如，贵企业于xxx生产SHINGRIX®批号ASFLA018A。生产过程中，操作人员发现监测xxx级灌装线的xxx发生故障。该事件在批记录中被记录为缺陷代码xxx。然而，贵企业未评估该PEMS故障是否构成对既定程序或要求的偏离。

OBSERVATION 5

观察项 5

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established, written and followed.

旨在防止标示为无菌的药品发生微生物污染的程序未建立、未形成书面文件且未得到遵守。

Specifically,

具体而言：

A. Inadequate Environmental Monitoring Following Planned and Unplanned Shutdowns

A. 计划性和非计划性停机后的环境监测不充分

Your xxx and xxx units are classified as Grade xxx (ISO xxx) during operations and declassified during shutdown. These Grade xxx areas are used for aseptic filling of drug substance (DS) and drug product (DP). Following both planned shutdowns (e.g., xxx shutdowns, preventive maintenance) and unplanned shutdowns (e.g., power failures, equipment malfunctions, loss of environmental controls), your firm performs cleaning and/or xxx xxx decontamination of these areas. However, your firm does not perform environmental monitoring, including viable and non-viable monitoring, to verify that the areas have been adequately restored to a state of environmental control prior to resuming manufacturing operations.

贵企业的xxx和xxx单元在运行期间被划分为xxx级（ISO xxx），在停机期间被降级。这些xxx级区域用于原液（DS）和药品（DP）的无菌灌装。在计划性停机（如xxx停机、预防性维护）和非计划性停机（如电力故障、设备故障、环境控制失效）之后，贵企业均对这些区域进行清洁和/或xxx xxx去污处理。然而，贵企业在恢复生产操作之前，未进行包括活性和非活性监测在内的环境监测，以验证这些区域已充分恢复至受控环境状态。

B. Inadequate Environmental Monitoring Following Action Limit Excursions

B. 行动限超标后的环境监测不充分

When environmental monitoring action limits are exceeded in your classified areas, including but not limited to the recovery of molds and atypical microorganisms in Grade xxx, Grade xxx direct and indirect areas, and Grade xxx classified areas, for example:

当贵企业分级区域的环境监测行动限被超出时（包括但不限于在xxx级、xxx级直接和间接区域以及xxx级分级区域中检出霉菌和非典型微生物），例如：

-Deviation UE 201159427, initiated on 27Jan2026 due to action limits exceeded for surface sample in Grade xxx room xxx.

-偏差UE 201159427，发起于2026年1月27日，原因：xxx级xxx房间表面样品超行动限。

-Deviation UE 201157043, initiated on 23Dec2025 due to action limits exceeded for surface xxx sample in Grade xxx room xxx.

-偏差UE 201157043，发起于2025年12月23日，原因：xxx级xxx房间表面xxx样品超行动限。

-Deviation UE 201108271, initiated on 29Jan2025 due to action limits exceeded for active air sample in Grade xxx room xxx.

-偏差UE 201108271，发起于2025年1月29日，原因：xxx级xxx房间浮游菌样品超行动限。

-Deviation UE 201125599, initiated on 20May2025 due to action limits exceeded for active air sample in Grade xxx room xxx.

-偏差UE 201125599，发起于2025年5月20日，原因：xxx级xxx房间浮游菌样品超行动限。

-Deviation UE 201095273 initiated on 29Oct2024 due to action limits exceeded for mold recovered in Grade xxx room xxx.

-偏差UE 201095273，发起于2024年10月29日，原因：xxx级xxx房间检出霉菌超行动限。

-Deviation UE 201076082, initiated on 03Jul2024 due to action limits exceeded for mold recovered in Grade xxx room xxx.

-偏差UE 201076082，发起于2024年7月3日，原因：xxx级xxx房间检出霉菌超行动限。

-Deviation UE 201061824, initiated on 16Apr2024 due to action limits exceeded for mold recovered in Grade xxx room xxx.

-偏差UE 201061824，发起于2024年4月16日，原因：xxx级xxx房间检出霉菌超行动限。

-Deviation UE 201046195, initiated on 29Jan2024 due to action limits exceeded for spore recovered in Grade xxx room xxx.

-偏差UE 201046195，发起于2024年1月29日，原因：xxx级xxx房间检出芽孢超行动限。

-Deviation UE 201037464, initiated on 05Dec2023 due to action limits exceeded for mold recovered in Grade xxx room xxx.

-偏差UE 201037464，发起于2023年12月5日，原因：xxx级xxx房间检出霉菌超行动限。

Your firm performs cleaning and/or decontamination of the affected areas. However, your firm does not verify the effectiveness of these corrective actions prior to resumption of manufacturing operations.

贵企业对受影响区域进行清洁和/或去污处理。然而，贵企业在恢复生产操作之前，未验证这些纠正措施的有效性。

In addition, you do not assess the impact on batches manufactured between the time of the environmental monitoring action limit excursion and subsequent verification that environmental control was restored.

此外，贵企业未评估从环境监测行动限超限到随后验证环境控制恢复期间所生产批次所受的影响。

OBSERVATION 6

观察项 6

Aseptic processing areas are deficient regarding the system for monitoring environmental conditions.

无菌生产区域的环境条件监测系统存在缺陷。

Specifically,

具体而言：

Your Grade xxx and Grade xxx classified areas, which provide direct and indirect support to Grade xxx aseptic processing operations, are not monitored for xxx via an environmental management system (e.g., xxx). Your firm monitors xxx in classified areas; however, xxx parameters are not monitored, recorded, trended, or evaluated in Grade xxx and Grade xxx areas.

为xxx级无菌生产操作提供直接和间接支持的xxx级和xxx级分级区域，未通过环境管理系统（如xxx）监测xxx。贵企业对分级区域监测xxx；然而，xxx级和xxx级区域的xxx参数未被监测、记录、趋势分析或评估。

Furthermore, your firm has not established a documented scientific justification demonstrating that the absence of routine xxx monitoring in these classified areas does not adversely impact aseptic processing conditions.

此外，贵企业未建立书面的科学论证，证明这些分级区域缺少常规xxx监测不会对无菌生产条件产生不利影响。