FDA对Lonza朴茨茅斯基地出具Form 483，列出10项无菌操作与数据完整性观察项

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：Lonza Portsmouth, Inc.

城市：美国新罕布什尔州朴茨茅斯市 03801

类型：药品（制剂）生产企业

FEI号：

3001451441

检查员：

Xiuju Lu，首席消费者安全官、主检查员

Massoud Motamed，消费者安全官

Kinjal Patel，生物审评员

Timothy Kamaldinov，生物审评员

Athena Russell，工作人员研究员

检查日期：

2025年6月2日（周一）至6月6日（周五）

西门的吐槽：

Lonza 的朴茨茅斯（Portsmouth）基地并非 Lonza 从零开始自建，而是通过收购获得的。以下是该基地的历史沿革：

关键历史节点

1. 最初建立（1980年代）：该基地最初由 Celltech 建立。Celltech 是英国的一家早期生物技术公司，于 1980 年代在美国新罕布什尔州朴茨茅斯建立了这个生物制药生产基地。

2. 第一次收购（2004年）：UCB（优时比） 收购了 Celltech，朴茨茅斯基地随之并入 UCB，成为其生物制药生产网络的一部分。

3. Lonza 收购（2006年）：2006 年，Lonza 集团从 UCB 手中收购了朴茨茅斯基地。这次收购是 Lonza 战略转型的重要一步——从传统精细化工和特殊化学品业务，向高附加值的生物制药 CDMO（合同研发生产组织）领域扩张。

现状

自 2006 年以来，该基地一直由 Lonza 全资拥有和运营，是其全球生物制药网络中历史最悠久、经验最丰富的哺乳动物细胞培养生产基地之一。它专注于临床和商业化阶段的生物制剂原液（Drug Substance）生产，服务全球客户。

这也就是说，这家公司已经完全是LONZA体系，不存在，大外资新购某家药企，企业体系未完成切换的情况。此外，这个483里提到的药物CASGEVY，是全球首个获批的 CRISPR-Cas9 基因编辑疗法，Vertex Pharmaceuticals Incorporated（福泰制药）是 CASGEVY 的 MAH，该药定价极高（美国定价约 220万美元/疗程），被称为"史上最贵药物"之一。

DURING AN INSPECTION OF YOUR FIRM WE OBSERVED:

本次对贵企业检查期间，我们观察到：

OBSERVATION 1

观察项 1

Aseptic processing of CASGEVY drug product is deficient. Through review of closed-circuit television (CCTV) footage on June 04, 2025, during the processing for batch xxx on May 26, 2025, the following was observed:

CASGEVY药品的无菌生产工艺存在缺陷。经2025年6月4日对闭路电视（CCTV）录像的回看审查，在2025年5月26日xxx批次的生产过程中，观察到以下情况：

西门的吐槽：CCTV保存期限要控制好，公司内要审核审查，以及要及时把过期的按生命周期销毁……国外法规暂无CCTV为正式GMP电子记录要求……纯吐槽

a. Throughout aseptic processing, Grade xxx operators routinely change sterile xxx in the Grade xxx area where manufacturing is conducted. It was observed that an operator, on multiple occasions, proceeded to perform manufacturing activities following xxx changes without xxx of the xxx. Per procedure USPO-15643 titled "Gowning and Personnel Movement for Cell Therapy," xxx changes should be conducted in the xxx. Similarly, operators routinely adjusted xxx including the xxx in direct proximity to open manufacturing activities, as opposed to utilizing the xxx as mandated by the aforementioned procedure.

a. 在整个无菌生产过程中，xxx级操作人员在实施生产的xxx级区域内常规性地更换无菌xxx。现场观察到，一名操作人员多次在更换xxx后、未经xxx xxx，即继续进行生产活动。依据题为《细胞治疗更衣及人员流动》的规程USPO-15643，xxx的更换应在xxx内进行。同样，操作人员经常在开口的生产活动直接邻近处调整xxx（包括xxx），而未按上述规程要求使用xxx。

b. Throughout aseptic processing, a Grade xxx operator on multiple occasions reached into the Grade xxx biological safety cabinet (BSC) without taking special precautions xxx as prescribed by procedure USPO-16621 titled "Operation of the Biosafety Cabinet in Cell Therapy" to prevent contamination.

b. 在整个无菌生产过程中，一名xxx级操作人员多次伸手进入xxx级生物安全柜（BSC），而未按照题为《细胞治疗生物安全柜操作》的规程USPO-16621所规定的xxx特殊防护措施来防止污染。

c. Throughout aseptic processing, multiple Grade xxx operators rested/leaned their upper body against a xxx an aseptic operation. The person on a xxx can be seen rolling in a circular motion throughout a portion of the Grade xxx room flanking the BSC where aseptic processing occurs. No xxx occurred prior to returning to manufacturing operations.

c. 在整个无菌生产过程中，多名xxx级操作人员将上半身倚靠/斜靠在一只xxx上——这一无菌操作行为。可以看到，坐在xxx上的人员在发生无菌生产的生物安全柜一侧的xxx级房间区域内呈圆周状滚动。在返回生产操作之前，未进行任何xxx。

d. Your firm's BSC operators xxx (without any subsequent manufacturing activities) immediately prior to performing xxx.

d. 贵企业的生物安全柜操作人员在即将执行xxx之前，进行了xxx（其后无任何后续生产活动）。

OBSERVATION 2

观察项 2

Cleaning of Grade xxx areas used in the manufacture of CASGEVY drug product is deficient. For example, during an evaluation of cleaning conducted on xxx of rooms xxx respectively, the following deficiencies were noted:

用于生产CASGEVY药品的xxx级区域清洁存在缺陷。例如，在xxx对xxx房间分别进行的清洁评估中，发现以下缺陷：

a. During xxx cleaning operations, a cleaning operator retrieved an item from the Grade xxx floor with their xxx hands, and proceeded to operation without xxx as prescribed in procedure USPO-15643 titled "Gowning and Personnel Movement for Cell Therapy".

a. 在xxx清洁操作期间，一名清洁操作人员用其xxx（未戴防护手套的）手从xxx级地面捡拾物品，且未按题为《细胞治疗更衣及人员流动》的规程USPO-15643规定的xxx进行操作。

b. xxx and BSC were largely omitted as a part of cleaning. These areas appeared to be inaccessible to cleaning staff.

b. xxx和生物安全柜（BSC）在很大程度上被排除在清洁范围之外。这些区域似乎为清洁人员无法进入。

c. Cleaning throughout the rooms failed to apply xxx as described in the corresponding work instruction USPO-16065 titled "Cleaning of Grade xxx".

c. 整个房间的清洁未能按照相应操作说明书USPO-16065《xxx级区域清洁》所述的要求施加xxx。

d. During the cleaning of Room xxx, a dirty mop was left on a multi-use cart, and subsequently removed without disinfecting the multi-use cart.

d. 在xxx房间的清洁过程中，一只脏拖把被遗留在多用途推车上，随后在未对多用途推车进行消毒的情况下被取走。

e. Cleaning activities are xxx without verification of cleaning activities by your firm.

e. 清洁活动为xxx，贵企业未对清洁活动进行核实。

OBSERVATION 3

观察项 3

The following practices that are inconsistent with Good Documentation Practices were observed:

现场观察到以下不符合良好文件记录规范（Good Documentation Practices，GDP）的做法：

a. Your firm uses xxx to instruct quality control analysts to review/revise environmental monitoring records. On June 05, 2025, xxx encompassing review comments were observed on a laboratory record and in the trash can to the xxx (Room xxx). For example, one xxx reads xxx.

a. 贵企业使用xxx指示质量控制（QC）分析人员审核/修订环境监测记录。2025年6月5日，在xxx（xxx房间）的一份实验室记录上及垃圾桶内，观察到含有审核意见的xxx。例如，一份xxx写道xxx。

b. Five original xxx were identified in the aforementioned trash.

b. 在上述垃圾桶中发现了五份原始xxx。

c. The authenticity of documents cannot be established. Specifically, the comment on page 48 of xxx of batch records for lot xxx indicates that spreadsheet was reprinted for clarity on December 18, 2024. The performer's signature dated October 4, 2024, for Step 10.3 was crossed out and replaced with the reviewer's signature dated December 18, 2024. The original excel spreadsheet was not attached to the batch records and remains missing.

c. 文件的真实性无法确认。具体而言，xxx批次批记录xxx第48页上的批注表明，该电子表格已于2024年12月18日为清晰起见而重新打印。步骤10.3执行人日期为2024年10月4日的签名被划掉，并替换为审核人日期为2024年12月18日的签名。原始Excel电子表格未附于批记录，至今仍缺失。

d. Your firm failed to establish documentation, validation, and control of spreadsheets utilized for tracking of xxx. For example, uncontrolled spreadsheets is used to track the xxx. Separate uncontrolled spreadsheet is used by SOP USP-6090 "Handling and Tracking of Returned Materials for Further Investigation" to xxx. There is no defined user accountability, nor adequate controls to prevent uncontrolled modifications to the spreadsheets.

d. 贵企业未建立用于追踪xxx的电子表格的文件记录、验证和控制体系。例如，使用了不受控的电子表格来追踪xxx。另一份不受控的电子表格被SOP USP-6090《退回物料处理与追踪以供进一步调查》用于xxx。电子表格既无明确的用户责任机制，也没有足够的控制措施来防止未经控制的修改。

西门的吐槽： no defined user accountability 我理解未权限不可控，以及可追溯可确保每个数据被追溯到个人。计算用电子表格唯一的出路，我个人觉得只有被干掉，因为计算很重要，而且现在不是十几二十年前了，任意的应用都有很丰富的计算能力，比如empower自定义或者eln做入计算等。

如果无奈，必须使用计算用excel，除了控制好副本不满天飞，也要考虑新的指南要求，无论按模板控制和下发，以及每次计算打印pdf保存供追溯等。

可以在我往期的excel指南里翻找

OBSERVATION 4

观察项 4

Heating, ventilation, and air conditioning maintenance and controls are inadequate. For example:

暖通空调（HVAC）系统的维护和控制不充分。例如：

a. There have been repeated losses in differential pressure within the Grade xxx areas for extended periods of time (e.g., July 11, 2024, August 19, 2024, October 08, 2024, October 14, 2024). These events were not deemed deviations, and no root cause or corrective and preventive actions (CAPA) were identified. The pressure differentials within the Grade xxx areas are completely lost. Upon retrospective evaluation in response to FDA request, your firm tabulated that a repeated xxx of the respective fan unit led to the loss of pressure differentials. Nevertheless, you failed to holistically identify or rectify the cause of the xxx.

a. 在xxx级区域内多次出现长时间的压差丧失（例如2024年7月11日、2024年8月19日、2024年10月8日、2024年10月14日）。这些事件未被认定为偏差，也未确定根本原因或纠正与预防措施（CAPA）。xxx级区域内的压差完全丧失。应FDA要求进行回顾性评估时，贵企业汇总得出：相应风机单元的反复xxx导致了压差丧失。尽管如此，贵企业未能整体性地识别或纠正该xxx的原因。

b. Grade xxx areas to Cell Therapy contain HEPA air supply vents adjacent to xxx which lack installation of a xxx.

b. 细胞治疗车间xxx级区域内的HEPA送风口邻近xxx，但缺少xxx的安装。

OBSERVATION 5

观察项 5

Areas designed to xxx in a biological safety cabinet are deficient regarding characterization and mapping of the areas and operations for aseptic processing of drug products. Specifically,

用于在生物安全柜内xxx的区域，在药品无菌生产工艺的区域和操作特征描述及映射方面存在缺陷。具体而言：

a. Turbulent upward airflow was observed in Grade xxx rooms when operators opened xxx in xxx.

a. 操作人员在xxx内打开xxx时，观察到xxx级房间内出现湍流上升气流。

b. During operations in the BSC, turbulent airflow was observed in the prevailing Grade xxx environment near the operator's xxx.

b. 在生物安全柜内操作期间，观察到操作人员xxx附近的xxx级主环境出现湍流气流。

c. Worst-case operations were not challenged during the full dynamic smoke study supporting operations in the BSC, including maximum number of xxx xxx.

c. 在支持生物安全柜操作的完整动态烟雾研究中，未对最差条件操作进行挑战，包括最大数量的xxx xxx。

d. During the processing for batch xxx on May 26, 2025, a waste bucket was introduced into the BSC xxx in a manner that does not appear slow or deliberate. Your firm failed to emulate similar operations as a part of your dynamic smoke studies.

d. 在2025年5月26日xxx批次的生产过程中，一只废物桶以看似不够缓慢或不够谨慎的方式被放入生物安全柜xxx内。贵企业未将类似操作作为动态烟雾研究的一部分进行模拟。

OBSERVATION 6

观察项 6

Management of deviations and anomalous events is inadequate to identify root causes and appropriate corrective actions. For example:

偏差和异常事件的管理不充分，无法确定根本原因并采取适当的纠正措施。例如：

a. Deviations are cancelled without documented justification. Furthermore, upon cancellation of deviations, your firm deletes the associated deviation information and context from the applicable electronic system, xxx. For example, On June 3, 2025, your firm failed to provide adequate reasoning for cancellation of the following deviations:

a. 偏差在无书面论证的情况下被取消。此外，在取消偏差时，贵企业从相应的电子系统xxx中删除了相关的偏差信息和背景。例如，2025年6月3日，贵企业未能为取消以下偏差提供充分的理由：

b. The repeated deviations are not escalated and adequately investigated to prevent re-occurrence. For example:

b. 重复发生的偏差未被升级并充分调查以防止再次发生。例如：

i. Three similar repeated deviations were initiated in three consecutive xxx for CASGEVY drug product related to the presence of xxx xxx were identified in 50% of the vials in the three runs xxx. The deviations were not escalated, and no further investigation was conducted to implement appropriate CAPAs.

i. 针对CASGEVY药品，连续三次xxx各发起了一项相似的重复偏差，均与xxx xxx的存在相关——三次运行中50%的西林瓶被检出xxx xxx。这些偏差未被升级，也未开展进一步调查以实施适当的纠正与预防措施（CAPA）。

ii. There have been repeated deviations for personnel who exceed the xxx for remaining in the Grade xxx area before xxx is required, as established in USPO-15643 titled "Gowning and Personnel Movement for Cell Therapy." These deviations were documented in records 1254029 (opened October 03, 2024), 1255104 (opened October 07, 2024), 1262110 (opened October 22, 2024), and 1354895 (opened May 22, 2025). However, despite recurrence of these deviations, the deviation classification was not escalated, and an applicable CAPA has not been identified or implemented.

ii. 对于在需要xxx之前超过在xxx级区域内停留时限xxx的人员，已出现多次重复偏差——该时限依据题为《细胞治疗更衣及人员流动》的USPO-15643确定。这些偏差分别记录于1254029（2024年10月3日发起）、1255104（2024年10月7日发起）、1262110（2024年10月22日发起）和1354895（2025年5月22日发起）。然而，尽管这些偏差反复发生，偏差分类未被升级，也未确定或实施适用的纠正与预防措施（CAPA）。

c. You fail to open deviations in response to non-conforming events documented as comments on your production batch records. For example:

c. 贵企业未针对记录在生产批记录批注中的不合格事件发起偏差。例如：

i. During execution of xxx

i. 在执行xxx期间

1) xxx

2) xxx

3) xxx

4) xxx

5) xxx

6) xxx

ii. xxx batch xxx

ii. xxx批次xxx

iii. xxx appeared to have a puncture in one of the xxx and had to be replaced on xxx for batch xxx

iii. xxx的一只xxx出现破损，xxx批次于xxx不得不更换该xxx

OBSERVATION 7

观察项 7

Environmental monitoring and control are deficient. For example:

环境监测和控制存在缺陷。例如：

a. The non-viable particulate monitoring on xxx exceeded the prospective allowable limits. Nonetheless, your firm deemed the results in specification. The determination that the results were in specification was based on an assignment of an xxx status despite no ongoing manufacturing operations.

a. xxx的非活性粒子（尘埃粒子）监测结果超出了预设允许限度。然而，贵企业仍判定结果符合标准。该"符合标准"的判定是基于在并无进行中的生产操作的情况下，为其赋予了xxx状态。

b. Procedure USPO-1637 titled "Remedial Action for Environmental, Water, Clean Steam, and Gas Monitoring Data" stipulates xxx.

b. 题为《环境、水、纯蒸汽和气体监测数据的补救措施》的规程USPO-1637规定xxx。

xxx.

xxx。

xxx.

xxx。

Thus, your response to xxx does not include the appropriate scrutiny and follow-up to address the potential problem.

因此，贵企业对xxx的应对未包括针对该潜在问题的适当审查和后续处理。

OBSERVATION 8

观察项 8

Your firm routinely downgrades Grade xxx suites intended for commercial CASGEVY manufacturing xxx xxx to Grade xxx environmental status for the purposes of personnel training. The procedures followed to restore Grade xxx status are inadequate to ensure purported safety of products manufactured in xxx and xxx. The following deficiencies were observed:

贵企业出于人员培训目的，经常将拟用于商业生产CASGEVY的xxx级洁净室套间xxx xxx降级为xxx级环境状态。用于恢复xxx级状态的程序不充分，无法确保在xxx和xxx中生产的产品的既定安全性。观察到以下缺陷：

a. USPO-5217 indicates that xxx.

a. USPO-5217规定xxx。

However, the limits applied to the EM data collected, were set at Grade xxx limits, as opposed to xxx limits as required per USPO-5217. The total particulates (per m³) data collected for xxx xxx xxx did not meet the prospective acceptance limits for the xxx Grade xxx classification. Specifically, xxx instances of total particulates exceeding the alert level of xxx should have triggered alert level excursions.

然而，对收集到的环境监测（EM）数据所应用的限度设定为xxx级限度，而非USPO-5217所要求的xxx限度。针对xxx xxx xxx收集的总粒子数（每立方米）数据，未达到xxx xxx级分类的预设可接受限度。具体而言，有xxx次总粒子数超出xxx警戒水平，本应触发警戒水平超限。

b. You utilize xxx to downgrade Grade xxx suite to Grade xxx status. The instructions of the form indicate to conduct activities in accordance xxx xxx. However, xxx does not exist in xxx and your firm failed to explain what document and section were reviewed to enable return to service.

b. 贵企业使用xxx将xxx级套间降级为xxx级状态。该表格的说明要求按照xxx xxx开展活动。然而，xxx并不存在于xxx，且贵企业未能说明为恢复使用状态而审核了哪份文件的哪个章节。

c. You provided Environmental Monitoring data package collected on May 17, 2025, used to restore the Grade xxx status of xxx. However, the EM data contained numerous samples with "N/A" readings which lacked applicable testing results.

c. 贵企业提供了2025年5月17日收集的环境监测数据包，用于恢复xxx的xxx级状态。然而，该环境监测数据包含大量读取值为"N/A"的样品，这些样品缺少相应的检测结果。

d. Control of electronic data captured on the xxx computerized system supporting restoration of Grade xxx is deficient. For example:

d. 支持xxx级状态恢复的xxx计算机化系统所捕获电子数据的控制存在缺陷。例如：

i. xxx

i. xxx

ii. xxx

ii. xxx

OBSERVATION 9

观察项 9

Each batch of drug product purporting to be sterile and/or pyrogen-free is not adequately tested to determine conformance to such requirements. Specifically, sterility samples of CASGEVY drug product are stored frozen under liquid nitrogen per procedure USPO-30461 titled "xxx Analytical Testing - QC Monograph for xxx Product Samples", and shipped in liquid nitrogen prior to sterility testing.

声称无菌和/或无热原的每一批药品，均未经过充分检验以确定其是否符合上述要求。具体而言，依据题为《xxx分析检验——xxx产品样品的QC专论》的规程USPO-30461，CASGEVY药品的无菌检查样品在液氮下冷冻储存，并在无菌检查之前于液氮中运输。

OBSERVATION 10

观察项 10

Pest control program is deficient. The pest control trending report for Q1 2025 indicated numerous incidences of insects (same type) in xxx and Grade xxx storage room xxx, which are xxx corridor and Grade xxx corridor, respectively. The same insect species was reported to be persistently seen in the facility with incidences varying seasonally. No source for the insect entry has been identified, and no deviation has been initiated.

虫害控制方案存在缺陷。2025年第一季度虫害控制趋势报告显示，在xxx和xxx级储存室xxx（分别为xxx走廊和xxx级走廊）中，有多起同类型昆虫发生事件。据报告，同一昆虫种类持续在厂区内出现，发生频率随季节变化。昆虫进入的来源未被识别，也未发起任何偏差。