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2023.02.02-2023.02.10 FDA 6位检查员对CDMO 公司 AGC中一个DS业务板块进行了审计。
今天分享的是发现项5 主要针对QA职责
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检查员：Zhong Li，Charles Yuan-Chia Kuo ，Brain Janelsins，Teegan Dellibovi-Ragheb，Michael Araneta，Andrew “Drew” Haack
比较有趣的是，QA或者QU的职责具体是什么？我一直存疑，貌似RACI Responsible负责某行动？Accountable 负全责？Consultant 顾问？Inform 仅需要被通知？似乎都是又似乎都不是。我做过一段时间PQA 即项目QA，客户投诉一过来，无论怎么着，都是QA的错，都是QA监督不力，这个发现项，似乎就是这个的体现？
权限不受控？
设施设备清洁和维护
供应商审计
批记录审核慢了
标签管理
偏差管理中调查超期未关闭
放行管理描述不准确
投诉与召回管理不落地
某设备未经验证
所谓质量体系下的六大子系统，其实是相互纠缠的，这家公司给QU落了这么多发现项，相比背后发生了什么
OBSERVATION 5
Your firm's quality unit's oversight of your GMP manufacturing operations is inadequate.
Specifically,具体来说，
A.Your firm lacks security control to prevent the access of GMP utility and equipment by the unauthorized persons outside your facility. For example, the outdoor storage area of xxx and xxx tanks are not protected, rendering the process xxx control panels susceptible to manipulation by unauthorized personnel.您的公司缺乏安全控制，无法防止未经授权的外来人员使用GMP设施和设备。例如，xxx和xxx储罐的室外储存区未受到保护，导致工艺xxx控制面板容易受到未经授权人员的操纵。
B.The facility cleanliness and maintenance are inadequate for GMP grade manufacturing. Specifically,设施清洁度和维护不足以满足GMP级生产的要求。具体来说，
1.According to facility cleaning procedure, SEA-SOP-000087 version 46,“Facility Cleaning & Sanitization”, the facility cleaning is scheduled routinely from xxx for various sections of cGMP areas. The performance of facility cleaning in your firm is inadequate. For example, the xxx stuck with dust was observed throughout the Clean Corridor (ISO 8).根据设施清洁程序SEA-SOP-000087第46版“设施清洁和消毒”，cGMP区域各部分的设施清洁从xxx开始定期安排。贵公司的设施清洁工作做得不够好。例如，在整个清洁走廊（ISO 8）观察到粘有灰尘的xxx。
2.On February 6, 2023, we (ZL and CK) observed tape covered on mesh covers of multiple HEPA filters due to the missing bolts throughout the Clean Corridor and manufacturing suite2023年2月6日，我们（ZL和CK）观察到，由于整个清洁走廊和生产车间的螺栓丢失，多个HEPA过滤器的网盖上覆盖了胶带
西门的备注：ZL和CK是检查官的缩写
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3.On February 2, 2023, during the general walk through, multiple leaks underneath the xxx tank and pump were observed including an oil leak from CCA filter in the Clean Utilities room (Room xxx)2023年2月2日，在全面巡视期间，观察到xxx油箱和泵下方有多处泄漏，包括清洁公用设施室（xxx室）的CCA过滤器漏油
4.On February 2,2023, a chemical corrosion stain was observed around the top cover of the xxx tank for Line xxx (Room XXX and a rusty spot was observed around the pipe cover of the xxx generator in the same room.2023年2月2日，在xxx号线xxx号水箱（xxx室）的顶盖周围发现一处化学腐蚀斑，在同一室内的XXX发电机的管盖周围发现一处锈斑。
5.On February 10, 2023, during the general walk through in Building xxx we (ZL and CK) observed a white substance spilled on the floor inside xxx room,(Room xxx)2023年2月10日，我们（ZL和CK）在对xxx号楼进行全面检查时，发现xxx房间（xxx室）的地板上有白色物质溢出
C.Your quality unit does not fully exercise its responsibilities regarding the critical service contractor qualification. Specifically, your quality unit has not conducted any on-site audit of xxx who is responsible for HEPA certification in your Building xxx drug substance manufacturing facilities.您的质量部门没有充分履行其在关键服务商资质确认方面的职责。具体来说，贵公司的质量部门没有对负责HEPA认证的xxx进行任何现场审计。
西门：其实没有任何法规里对于单一设备提供商/服务商必须现场审计，这里其实我是存疑的，我大胆的猜测，这是个兑换项目。
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D.Your firm lacks timely quality review of batch records. For example, it took up to xxx from QA receipt to final sign-off of the MBR for commercial supply lot XXX (manufactured 15Sept2022). Similar trends were observed during review of the MBR for lot XXX (manufactured 1Jun2022). The process of QA batch record review is not clearly described in SEA-SOP-000130(Master Production Record and Laboratory Record Review). Delays is QA review and sign-off of batch records were routinely observed beyond the xxx target date for batch disposition. In addition, delays in QA review of batch records show inadequate quality oversight that can prevent appropriate actions from taking place to address issues during manufacturing operations. As an example, DEV-6918 (Exceeded mixing time xxx MBR-3064 step xxx was initiated after MBR review by QA Because review and approval of the MBR by QA took place 4 months after date of occurrence, no immediate action was taken in response to this issue.贵公司缺乏对批记录的及时质量审查。例如，从QA接收商业化批次xxx（2022年09月15日生产）的生产批记录到最终签署花费时长为XXX。在审查批次XXX（2022年6月1日生产）的MBR期间观察到类似的趋势。SEA-SOP-000130（主生产记录和实验室记录审查）中没有明确描述QA批记录审查的过程。在批次处置的xxx目标日期之后，经常观察到批次记录的QA审查和签核延迟。此外，批记录QA审查的延迟表明质量监督不足，这可能会妨碍采取适当的措施来解决生产过程中的问题。例如，DEV-6918（超过混合时间xxx MBR-3064步骤xxx）是在QA部审查MBR之后启动的，因为QA部门对MBR的审查和批准是在事件发生4个月后进行的，因此没有针对该问题立即采取措施。
西门的备注：
这里比较有意思的是，给出的发现项是，QA对批记录审核不及时。这里从偏差来看，批记录的审核和最终审核时理论上小余4个月，但也被认为是不合规的，QA没有执行自己的职责。我自己认为，质量体系的Metric 应该首重，按时执行。确保每个节点，准时完成。
另外，在完成批准生效后，或者如此例中批记录完成批准后，也是可以发起偏差的。质量不是一竿子打死，是continuous improve，如果当时没有这个knowledge或者认知是被认可的。
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E.DEV-14022 xxx Lot xxx SEA-MPR-000262, Product labels printed with incorrect lot number) was initiated after FDA investigators toured the Building xxx room and, upon review of the xxx drug substance lots located in a locked cage in the quarantine area of 2-8°C storage, noted that there was a discrepancy between the product label and the status tag (toe tag). The product label indicated lot xxx and the status tag indicated lot xxx both initialed and dated 1Feb2023. For such a critical deviation to occur, quality oversight failed at multiple steps in the processes defined by SEA-SOP-000105 (Assigning Lot Numbers and Issuing Manufacturing Batch Records) SEA-SOP-000071 xxx Fill),SEA-SOP-000248 (Line Clearance)and SEA SOP-000437 (Materials Control Procedure -Intermediates and API). all of which includes steps for verification of product labels. In addition, the discrepancy was not identified during either batch record verification or out-of-plant manufacturing review of MBR-3069 xxx. Deviation report DEV-14022 states that there have been other instances of incorrectly issued labels in the last 12 months. For example,DEV-10499 xxx lot# xxx SEA-MPR-000629, solution xxx lot number in record and on labels not matching) and DEV-10839 (Incorrect printed lot number on xxx sample labels).DEV-14022 xxx批次xxx SEA-MPR-000262，产品标签上印有不正确的批号）是在FDA调查人员参观了xxx大楼的房间后启动的，在审查了位于2-8°C储存隔离区上锁笼子中的xxx原料药批次后，发现产品标签和状态标签（临时标签）之间存在差异。产品标签显示批号xxx，状态标签显示批号xxx，均有姓名首字母缩写，日期为2023年2月1日。对于这种严重偏差的发生，质量监督在SEA-SOP-000105（分配批号和放行生产批次记录）、SEA-SOP-000071 xxx填充）、SEA-SOP-000248（生产线清理）和SEA SOP-000437（物料控制程序-中间体和原料药）规定的流程的多个步骤中失败。所有这些都包括验证产品标签的步骤。此外，在批次记录验证或MBR-3069 xxx的厂外生产审查期间，未发现差异。偏差报告DEV-14022指出，在过去的12个月中，还出现了其他错误放行标签的情况。例如，DEV-10499 xxx批号xxx SEA-MPR-000629，记录和标签上的溶液xxx批号不匹配）和DEV-10839（XXX样品标签上打印的批号不正确）。
西门的备注：看上去像标签管理不善
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F.The xxx manufacturing process and controls as described in the xxx application are not being followed. Change control CR-06479 was implemented to support the introduction of reprocessing at the xxx unit operation, and change control CR-05482 was implemented to support a xxx cycle of xxx and xxx purification unit operations) for commercial supply lot xxx. Furthermore, a new primary reference standard was implemented to the xxx process and control strategy during the xxx review period; this primary reference standard is intended to test commercial supply lot xxx (released by firm, but not by client) on stability and test other commercial supply lots at release and on stability (not yet released by firm and client). These changes are not part of the process and controls described in the xxx application, and xxx there are no written procedures in the change control reports or quality agreement or other provided documents that specifically state that these impacted lots cannot be released to the US market xxx没有遵循xxx申请中描述的xxx生产流程和控制。实施变更控制CR-06479，以支持在xxx装置操作中引入后处理；实施变更控制CR-05482，以支持商业供应批次xxx的xxx循环和xxx净化装置操作。此外，在xxx审查期间，对xxx流程和控制策略实施了新的主要参考标准；本主要参考标准旨在测试商业供货批次xxx（由公司放行，但不由客户放行）的稳定性，并测试其他商业供货批次的放行和稳定性（尚未由公司和客户放行）。这些变更不是xxx申请中描述的流程和控制的一部分，xxx在变更控制报告或质量协议或其他提供的文件中没有书面程序明确说明这些受影响的批次不能向美国市场xxx放行
西门的备注：产品放行
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G.Final product dispositions have been on hold due to pending investigations that were detected in 2021 and 2022. These deviations have not been closed nor have been completed.由于2021年和2022年发现的未决调查，最终产品批处置已被暂停。这些偏差既没有被关闭，也没有完成。
西门的备注：
1.老生常谈，质量的QRM，最后一环是回顾，不停回顾才能做好最后的防守，以及持续提升没错时间，时间一长，人员可能迭代，一朝天子一朝臣，后人不知前事，交接不可能百分百交接，从此又会有新的延误。而时间一长，owner部门以及质量部门，也会耗费大量时间，去回溯去跟踪，开会开会，现场再现场，资源被耗费在这一个个烂账上。时间一长，人员就会懈怠，身上的其他活儿也会越来越多越来越重，也就越来越难关闭这个异常。
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H.Your quality control unit failed to open a complaint and perform a risk assessment when notified by your customer of quality concern for product released by your firm. On 22Dec2022, your customer notified you that drug product manufactured at your facility, AGC lot xxx for product xxx was found to be out of specification for pH and identified that the root cause may be due to residual xxx carryover in bulk drug substance. While a deviation investigation was opened, no complaint or associated risk assessment, as detailed in SEA-SOP-000351 “Contract Manufacturing Client Product Complaints and Recalls” was performed.当客户通知您公司放行的产品存在质量问题时，您的质量控制部门未能提出投诉并进行风险评估。2022年12月22日，您的客户通知您，在您的工厂生产的药品（产品xxx的AGC批次xxx）被发现pH值不合格，并确定根本原因可能是原料药中残留的xxx残留物。尽管启动了偏差调查，但未执行SEA-SOP-000351“合同生产客户产品投诉和召回”中详述的投诉或相关风险评估。
西门的备注：这里提到了FDA现场检查必查的两点“投诉”与“召回”，这往往也是国内企业比较容易缺失的环节
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I.Your quality control unit has not ensured that all equipment used in drug substance testing has been qualified and is adequate for its intended use. On 3Feb2023, we (AKH, ZL and CK) observed microbial testing of xxx in laminar flow hood, BSC0324. This equipment had not undergone qualification to demonstrate that it suitable for its intended use.您的质量控制部门未能确保原料药测试中使用的所有设备都已通过资质审查，并且符合其预期用途。2023年2月3日，我们（AKH、ZL和CK）在BSC0324层流罩中观察了xxx的微生物测试。该设备未经确认，无法证明其适合预期用途。
*💡申明：以上为个人观点，不代表任何组织或个人，如果有其他意见可以讨论。
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