嘉峪检测网 2025-05-22 13:16
导读：近日，ECA 发布了新的《GMP审计/检查参考手册》，这是一份关于GMP（良好生产规范）审计的指导手册，旨在为 GMP/GDP审计人员提供参考和指导，促进制药行业的 GMP/GDP 规范的协调统一。
近日，ECA 发布了新的《GMP审计/检查参考手册》，这是一份关于GMP（良好生产规范）审计的指导手册，旨在为 GMP/GDP审计人员提供参考和指导，促进制药行业的 GMP/GDP 规范的协调统一。附件3涉及审计的内容及标准，包括质量管理体系、设备设施、公用系统、仓库和物流、厂房、洁净室、产品管理、工艺、质量控制等内容。翻译如下：
ECA Good Practice Guide –GMP Auditors Reference Handbook
Attachment 3: Audit Areas and Criteria
ECA 《GMP审计/检查参考手册》
附件 3：审计内容及标准
A. Pharmaceutical Quality System
药品质量体系
B. Equipment / Utilities / Systems
设备 / 公用设施 / 系统
C. Warehouse and Logistics
仓库与物流
D. Premises
厂房
E. Environmental Conditions
环境条件
F. Handling of Goods
产品处理
G. Processes
工艺
H. Quality Control
质量控制
I. Microbiology
微生物学
J. Evaluating Testing Process & Methods
检测流程与方法评估
K. Evaluating major Equipment and Instruments
主要设备与仪器评估
L. Utilities
公用设施
M. Maintenance
维护
N. Non-sterile and sterile Solid Dosage Forms Production Area
非无菌及无菌固体制剂生产区
O. Particulars for sterile Dosage Forms
无菌制剂细则
P. Water and Sanitisers
水与消毒剂
Q. How to audit a medical Cannabis Grower
医用大麻种植者审计指南
R. Preparing Audits for Cell and Gene Therapies (CGT) based Advanced Therapy Medicinal Products (ATMPs)
基于细胞与基因治疗（CGT）的先进治疗药品（ATMPs）审计准备
1.ATMP-specific Challenges
ATMPs 特定挑战
2.How to audit ATMPs - managing the Complexities of allogenic CGT Manufacturing
如何审计 ATMPs - 管理异基因 CGT 生产的复杂性
2.1. The Challenges of the Supply Chain
供应链挑战
2.2. Where to start at the Manufacturer
从制造商处的审计起点
2.3. ATMP OOS Batches being used
使用中的 ATMP 超标批次
2.4. QP Certification of ATMP and Import
ATMPs 的 QP 认证与进口
Transport and Storage of ATMPs
ATMPs 的运输与储存
A. Pharmaceutical Quality System（A. 药品质量体系）
A company’s pharmaceutical quality system (PQS) should describe the procedures and controls in place to ensure reliable operations across the organisation.
公司的药品质量体系（PQS）应明确相应程序和管控措施，以确保整个组织运营可靠。
The PQS should ensure all operations follow current GMP requirements and local regulatory expectations and comply with licensing requirements.
PQS 应确保所有操作遵循现行药品生产质量管理规范（GMP）要求、当地监管规定，并符合许可要求。
Audits of the PQS are detailed in various guidelines, but especially in chapter one of the EU - GMP guidelines. Examples of what to look for when auditing the PQS are indicated in this chapter.
PQS 的审计在各类指南中有详细阐述，尤其是欧盟 GMP 指南第一章。本章列举了审计 PQS 时需关注的要点。
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
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Structure of the PQS （PQS 的架构）
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Consistency across the process? （整个流程是否具有一致性？） |
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Are all processes clearly defined? （所有流程是否都有清晰定义？） |
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Are elements of the PQS reviewed and approved by management and the Quality Unit? （PQS 的各项要素是否经管理层和质量部门审核批准？） |
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Are responsibilities clearly defined? （职责是否明确界定？） |
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Regulatory status （监管状况） |
Is the company operating within its authorised licences? （公司是否在获批许可范围内开展经营活动？） |
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Company organisation （公司组织架构）
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Is an organisational diagram in place illustrating roles and responsibilities of key roles? （是否有组织结构图来明确关键岗位的职责？） |
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Is the company staffed appropriately? （公司人员配备是否合理？） |
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Is the Quality Control Unit operating independently of production? （质量控制部门是否独立于生产部门运作？） |
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Release system （放行系统）
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Who is responsible for batch confirmation, certification and release? （谁负责批次确认、认证和放行？） |
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Who actually performs batch confirmation, certification, and release, and can decisions be made independently of other management functions? （实际执行批次确认、认证和放行的是谁，其决策能否独立于其他管理职能？） |
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Is all relevant documentation and information related to each batch available at the point of review, confirmation, certification and release? （在审核、确认、认证和放行环节，与每批产品相关的所有文件和信息是否都可获取？） |
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Are the functions involved appropriately resourced to ensure a full overview? （相关职能部门是否具备充足资源以实现全面把控？） |
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Deviation handling （偏差处理）
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Is there a clear definition of a deviation and how deviations are classified (e.g. incident, minor, major, critical)? Note: different organisations may use different terms when referring to these processes, and this is acceptable as long as the definitions are clear and all processes are covered. （是否对偏差有明确定义，以及偏差是如何分类的（如事件、轻微、重大、关键）？注：不同组织在提及这些流程时可能使用不同术语，只要定义清晰且涵盖所有流程，都是可以接受的。） |
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Who is responsible for investigating and reporting deviations? （谁负责调查和报告偏差？） |
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
|---|---|
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Deviation handling（偏差处理）
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Who is responsible for reviewing and approving the investigation report? （谁负责审核和批准偏差调查报告？） |
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Who assesses the impact of the deviation on the final batch before confirmation, certification and release? （在批次确认、认证和放行前，谁评估偏差对最终批次的影响？） |
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Are flow charts available for associated processes? （相关流程是否有流程图？） |
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What actions are taken when serious deviations are reported, and how are actions justified and documented? （当报告严重偏差时采取何种行动，以及如何证明这些行动合理并记录？） |
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Are all personnel trained in the processes? （所有人员是否都接受过相关流程的培训？） |
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How many deviations are overdue, and how are they treated (deviation, extension, etc.)? （有多少偏差逾期，以及如何处理（如偏差处理、延期等）？） |
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Corrective and Preventive Action (CAPA)（纠正和预防措施）
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Are there clear definitions of the terms used (e.g. corrections, corrective actions and preventive actions)? （所用术语（如纠正、纠正措施和预防措施）是否有明确定义？） |
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Are CAPAs defined when needed? And if no CAPA is opened, how is this justified /documented? （必要时是否定义了纠正和预防措施？若未启动纠正和预防措施，如何证明其合理性并记录？） |
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How are effectiveness checks realised? （如何进行有效性检查？） |
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Is the Quality Unit involved in defining, closing and approving CAPAs? （质量部门是否参与定义、结束和批准纠正和预防措施？） |
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Are all personnel trained in the processes? （所有人员是否都接受过相关流程的培训？） |
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Root cause analysis (RCA)（根本原因分析）
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Is the RCA process clearly defined in a procedure? （根本原因分析流程在程序中是否有明确定义？） |
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Has the organisation defined and provided useful RCA tools? （组织是否定义并提供了有用的根本原因分析工具？） |
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Are RCA processes logical and scientifically sound, and have the potential root causes and contributing factors been identified? （根本原因分析流程是否逻辑合理、科学可靠，是否已确定潜在根本原因和影响因素？） |
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Are the defined CAPAs based on root causes? （所定义的纠正和预防措施是否基于根本原因？） |
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How is the Quality Unit involved in defining, closing and approving an RCA? （质量部门如何参与定义、结束和批准根本原因分析？） |
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Are all personnel trained in the processes? （所有人员是否都接受过相关流程的培训？） |
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Are there any repeated RCAs (e.g. 'human error') reported with no clear corrective action to resolve the issue? （是否有报告的重复根本原因分析（如 “人为错误”）且没有明确的纠正措施来解决问题？） |
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Change Control（变更控制）
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Are types of changes and relevant responsibilities defined? （是否定义了变更类型和相关职责？） |
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Is the process /are further batches halted until the change is fully implemented (when appropriate)? （在变更完全实施前（如适用），流程 / 后续批次是否暂停？） |
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Is an impact analysis available for the change and each action that leads to the change, and is there a requirement for an effectiveness check for each change /action? If not, how is this justified? （是否有针对变更及导致变更的每项行动的影响分析，是否要求对每项变更 / 行动进行有效性检查？若没有，如何证明其合理性？） |
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
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Change Control（变更控制）
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for an effectiveness check for each change /action? If not, how is this justified? （对每项变更 / 行动是否有有效性检查要求？若没有，如何说明其合理性？） |
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How many changes are overdue? How are they handled (deviation or extension, etc.)? （有多少变更逾期？如何处理（如偏差处理或延期等）？） |
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Is the Quality Unit involved in closing and approving a change? （质量部门是否参与变更的结束和批准环节？） |
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Are all personnel trained in the processes? （所有人员是否都接受过相关流程的培训？） |
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Supplier management（供应商管理）
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Does the audit programme define the frequency of audits? A company may use a risk - based approach, as described in chapter 3 of this guide. An auditor should check this approach and the associated documentation. （审计计划是否明确规定了审计频率？公司可能采用基于风险的方法，如本指南第 3 章所述。审计人员应检查该方法及相关文件。 ） |
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Are the audits performed as defined in the programme? （是否按照审计计划进行审计？） |
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Are the audits performed by trained auditors? （审计工作是否由经过培训的审计人员执行？） |
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How is supplier performance monitored and linked to the qualification? （如何监控供应商绩效并将其与供应商资质挂钩？） |
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Do the responsible positions (QP, Purchasing) have access to relevant data and audit reports? Are they aware of possible deficiencies and the corrective actions agreed upon? （相关责任岗位（质量受权人、采购人员）能否获取相关数据和审计报告？他们是否了解可能存在的缺陷以及已商定的纠正措施？） |
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Is there a formal assessment of the impact on product quality when serious deficiencies are reported? （当报告严重缺陷时，是否有对产品质量影响的正式评估？） |
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Are quality agreements in place for every outsourced activity? Is the Quality Unit involved (e.g. in review and approval)? （每项外包活动是否都有质量协议？质量部门是否参与（如审核和批准环节）？） |
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Training system培训系统）
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Is there a GMP / GDP training programme for new employees? （是否有针对新员工的药品生产质量管理规范 / 药品经营质量管理规范培训计划？） |
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Is training recorded, and is it possible to track staff training to the tasks they performed? （培训是否有记录，能否将员工培训情况与他们执行的任务关联起来？） |
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How is training realised (online, classroom, shop floor)? （培训如何开展（在线、课堂、车间现场等方式）？） |
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Who trains, and what are the requirements to become a trainer? （谁负责培训，成为培训师有哪些要求？） |
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How are effectiveness checks done and documented? （如何进行有效性检查并记录？） |
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How are personnel disqualified for processes, if necessary? How is disqualification recorded and communicated? （如有必要，如何取消人员参与相关流程的资格？取消资格的情况如何记录和传达？） |
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Internal audits（自检）
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Is there an SOP in place to describe the IA process? （是否有标准操作规程来描述内部审计流程？） |
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Is there an annual plan /schedule in place? （是否有年度计划 / 时间表？） |
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
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Internal audits（自检）
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Does the company adhere to the schedule, and how are overdue IAs addressed? （公司是否遵守时间表，逾期的内部审计如何处理？） |
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Who is performing IAs and how are the auditors trained? （谁执行内部审计，审计人员如何接受培训？） |
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Are the actions arising incorporated into the Corrective and Preventive Action (CAPA) system? （产生的措施是否纳入纠正和预防措施（CAPA）系统？） |
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Document management（文件管理）
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Is there a version control for each GMP-relevant document including unique number and version number? （每个与药品生产质量管理规范（GMP）相关的文件是否有版本控制，包括唯一编号和版本号？） |
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Are documents distributed and tracked appropriately? （文件的分发和追踪是否恰当？） |
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Is the documentation hierarchy clear, and are documents structured? （文件层级是否清晰，文件是否有结构？） |
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Are the documents reviewed periodically as defined in the Document Management procedure, or earlier if required? （文件是否按照文件管理程序定期审核，或在需要时提前审核？） |
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Is there a link between the Change Control and Document Management procedures to ensure documents are reviewed and updated if impacted by a change? （变更控制和文件管理程序之间是否有联系，以确保文件在受变更影响时得到审核和更新？） |
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Quality Risk Management (QRM)（质量风险管理）
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Is there a QRM procedure in place, and is it applied appropriately? （是否有质量风险管理程序，且应用得当？） |
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Which QRM tools are used, and are they appropriate? （使用哪些质量风险管理工具，是否适用？） |
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Are all personnel trained in the processes? （所有人员是否都接受过相关流程培训？） |
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Management review（管理评审）
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Does the management review process follow ICH Q10 requirements? （管理评审流程是否遵循国际人用药品注册技术协调会（ICH）Q10 要求？） |
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Is the management review conducted regularly based on a pre-defined agenda covering all relevant quality-related activities of the organisation? （管理评审是否基于预先定义的议程定期进行，涵盖组织所有相关质量活动？） |
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Are key personnel involved? （关键人员是否参与？） |
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Is the protocol /report signed off by management? （方案 / 报告是否由管理层签署？） |
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Are the actions arising incorporated into the CAPA system? （产生的措施是否纳入纠正和预防措施（CAPA）系统？） |
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Product Quality Review (PQR)/ Annual Product Review (APR)（产品质量回顾 / 年度产品回顾）
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Are Quality Reviews in place, and are they conducted regularly? （是否进行质量回顾，是否定期进行？） |
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How is the QP involved? （质量受权人（QP）如何参与？） |
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Is the protocol /report signed off by management? （方案 / 报告是否由管理层签署？） |
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Are the actions arising incorporated into the corrective and preventive action (CAPA) system? （产生的措施是否纳入纠正和预防措施（CAPA）系统？） |
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Recall system（召回系统） |
Is there an SOP in place to describe the recall system? （是否有标准操作规程（SOP）来描述召回系统？） |
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
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Recall system（召回系统）
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Are roles and responsibilities in a recall process clearly defined? （召回过程中的角色和职责是否明确定义？） |
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Who makes the final decision on a recall? （谁对召回做出最终决定？） |
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In case of a recall, who is informed, including the local regulatory authority? （在召回情况下，通知哪些方，包括当地监管机构？） |
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How are the activities documented? （这些活动如何记录？） |
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Complaint handling（投诉处理）
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How are complaints received by the company? （公司如何接收投诉？） |
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Are they investigated appropriately (see deviations, RCA, CAPA, etc.)? （是否对投诉进行适当调查（参照偏差处理、根本原因分析、纠正和预防措施等）？） |
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Are appropriate actions taken (CAPA)? （是否采取适当措施（纠正和预防措施）？） |
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How is feedback provided to the complaint provider? （如何向投诉方提供反馈？） |
B. Equipment / Utilities / Systems
（B. 设备 / 公用设施 / 系统）
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
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Qualification（确认）
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How is equipment designed, qualified, monitored and maintained? （设备如何设计、确认、监控和维护？） |
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Is equipment qualified before use and re-qualified after any significant changes or repairs? （设备在使用前是否经过确认，在重大变更或维修后是否重新确认？） |
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Is equipment identified unambiguously? （设备标识是否明确无误？） |
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How are cleaning processes defined, and are they validated? （清洁流程如何定义，是否经过验证？） |
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Maintenance（维护）
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Is a maintenance programme in place? （是否有维护计划？） |
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Are maintenance plans (for individual equipment) in place? （是否有（针对单个设备的）维护计划？） |
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Are pre-defined frequencies complied with? （是否遵守预先设定的维护频率？） |
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Logbooks（日志）
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Are logbooks available? （是否有日志？） |
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Are they regularly checked by personnel who can draw conclusions and, for example, adapt maintenance plans? （是否由能够做出判断（例如调整维护计划）的人员定期检查？） |
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Outsourcing（外包） |
Are maintenance and /or calibration activities outsourced, and are contracts in place? （维护和 / 或校准活动是否外包，是否签订合同？） |
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
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Status labelling（状态标识）
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Do external partners have to comply with the auditees’ SOPs, and, if so, how are they kept up-to-date? （外部合作伙伴是否必须遵守被审计方的标准操作规程（SOPs）？若需遵守，如何使其保持更新？ ） |
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Is the status (clean /to be cleaned) clearly identified? （设备状态（清洁 / 待清洁）是否明确标识？ ） |
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Are holding times for clean /dirty equipment defined? （清洁 / 脏污设备的存放时间是否有规定？ ） |
C. Warehouse and Logistics
（C. 仓库与物流）
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
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Storage（储存）
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How are the product and its components stored before, during and after the process? （产品及其组件在生产前、生产中及生产后如何储存？ ） |
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What are the storage time limits and conditions for each stage? （每个阶段的储存时限和条件是什么？ ） |
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How are the storage areas controlled and monitored? （储存区域如何进行控制和监控？ ） |
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Transport（运输）
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How are the personnel, material, waste and product flows managed in each area? （每个区域的人员、物料、废弃物和产品流动如何管理？ ） |
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What are the transportation methods and routes used for each item (unidirectional flow)? （每种物品使用何种运输方式和路线（单向流）？ ） |
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How are the transportation conditions controlled and monitored? （运输条件如何进行控制和监控？ ） |
D. Premises
（D. 厂房）
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
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Warehouse（仓库）
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How is access controlled? （出入如何控制？ ） |
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What is the status and maintenance condition of the facility (holes and cracks in walls and floors, broken windows, rusty equipment, etc.)? （设施的状况和维护情况如何（墙壁和地板上的孔洞和裂缝、破损的窗户、生锈的设备等）？ ） |
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Are there water or solvent stains that might be caused by incoming water during the rainy season or leakages in pipes /vessels? （是否存在可能由雨季进水或管道 / 容器泄漏导致的水渍或溶剂污渍？ ） |
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What is the overall quality of starting materials (missing labels, rusty or damaged drums, insufficient sampling and quality control tests)? （起始物料的整体质量如何（标签缺失、生锈或损坏的桶、采样和质量控制测试不足）？ ） |
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Is a status labelling of materials defined and adhered to? （物料的状态标识是否有规定并得到遵守？ ） |
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Are cleaning processes in place and controlled? （是否有清洁流程并得到控制？ ） |
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
|---|---|
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Warehouse（仓库） |
Are there API drums from third parties which might just be re - labelled? （是否存在可能仅重新贴标的第三方原料药桶？） |
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Are areas, rooms, and key equipment qualified and key processes validated? （区域、房间和关键设备是否经过确认，关键流程是否经过验证？） |
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Are medicinal products stored directly on the ground (making sufficient cleaning impossible)? （药品是否直接存放在地面上（导致无法充分清洁）？） |
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Is there adequate separation between the receipt, dispatch and storage areas? （收货区、发货区和储存区之间是否有足够的分隔？） |
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Is there a defined room capacity for cool rooms, and is this qualified and controlled? （冷藏室是否有规定的房间容量，是否经过确认和控制？） |
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Outer premises（外部场所） |
Is there a fence or other protective measures against unauthorised access? （是否有围栏或其他防止未经授权进入的防护措施？） |
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How are visitors registered? （访客如何登记？） |
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Is there CCTV coverage of the outer area? （外部区域是否有闭路电视监控？） |
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How are incoming and outgoing trucks registered? （进出的卡车如何登记？） |
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Is there any outside storage or stacking of materials, and if so, how is it justified and controlled? （是否有物料在室外储存或堆放，若有，如何证明其合理性并进行控制？） |
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External (contracted) premises（外部（外包）场所） |
Do contracted premises exist? （是否存在外包场所？） |
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Do contracted premises have their own certification? （外包场所是否有自己的认证？） |
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How are these premises qualified and monitored? （这些场所如何进行确认和监控？） |
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Are transportation activities between sites validated and monitored? （场所之间的运输活动是否经过验证和监控？） |
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Pest control（虫害控制） |
Is there an adequate system in place? （是否有足够的虫害控制系统？） |
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Is there an unregulated usage of biocides? （是否存在未经规范使用的杀虫剂？） |
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What happens if animals are caught? （如果捕获到动物会如何处理？） |
E. Environmental Conditions
（E. 环境条件）
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
|---|---|
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Storage conditions（储存条件） |
How are storage conditions maintained in different climatic conditions (heat in summer, cold periods in winter, rain periods)? （在不同气候条件下（夏季高温、冬季寒冷期、雨季）如何维持储存条件？ ） |
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Are seasonal variations taken into consideration during qualification and validation activities? （在确认和验证活动中是否考虑了季节变化？ ） |
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Is the equipment used to control or monitor environmental conditions calibrated at defined intervals based on a risk assessment? （用于控制或监测环境条件的设备是否根据风险评估按规定间隔进行校准？ ） |
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How are (temperature) deviations managed? （如何处理（温度）偏差？ ） |
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Mapping（温度分布测绘 ） |
Was an initial temperature mapping carried out before the warehouse was put into use? （仓库投入使用前是否进行了初始温度分布测绘？ ） |
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Was temperature mapping performed under representative conditions (experience extreme fluctuations)? （温度分布测绘是否在具有代表性的条件下进行（经历极端波动）？ ） |
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Are temperature monitoring devices located according to the results of the mapping exercise (positioned in the areas that experience extreme fluctuations)? （温度监测设备是否根据温度分布测绘结果放置（放置在经历极端波动的区域）？ ） |
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Is the mapping exercise repeated according to the results of a risk assessment or whenever significant modifications are made to the facility or the temperature controlling equipment? （是否根据风险评估结果或设施、温度控制设备发生重大变更时重复进行温度分布测绘？ ） |
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Have all relevant areas been mapped? （所有相关区域是否都进行了温度分布测绘？ ） |
F. Handling of Goods
（F. 货物处理 ）
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
|---|---|
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Returned goods（退货） |
If returned to stock, has it been demonstrated by the customer that products have been transported, stored and handled in compliance with their specific storage requirements? （若退货重新入库，客户是否证明产品在运输、储存和处理过程中符合其特定储存要求？ ） |
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If returned to stock, have they been examined and assessed by a sufficiently trained and competent person authorised to do so? （若退货重新入库，是否由经过充分培训且具备资质的授权人员进行检查和评估？ ） |
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Dispensing and intermediate storage areas（配料和中间储存区 ） |
Are there multi-purpose drums for internal transport and storage? （是否有用于内部运输和储存的多用途桶？ ） |
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Is there a risk of mix - ups (labelling of raw materials and intermediates)? （是否存在混淆风险（原材料和中间体的标识）？ ） |
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How is (cross -) contamination of drums avoided (dust, multiple use, cleaning)? （如何避免桶的（交叉）污染（灰尘、多次使用、清洁方面）？ ） |
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Storage of solvents（溶剂储存 ） |
Which solvents are used and how are they stored (focus on toxic solvents)? （使用哪些溶剂，如何储存（重点关注有毒溶剂）？ ） |
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How are tanks and pipes identified /labelled? （储罐和管道如何标识？ ） |
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How is the recovery and testing of solvents performed? （如何进行溶剂的回收和检测？ ） |
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How is (cross -) contamination of storage tanks avoided? （如何避免储罐的（交叉）污染？ ） |
G. Processes
（G. 工艺 ）
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Aspect |
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（评估维度） |
Possible details to evaluate （可评估的具体细节） |
|---|---|
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Qualification and validation（确认与验证 ） |
Is there a list of critical equipment? （是否有关键设备清单？ ） |
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Is there a validation master plan (VMP)? （是否有验证主计划（VMP）？ ） |
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Is the company’s approach to qualification and validation correctly described? （公司对确认和验证的方法是否有准确描述？ ） |
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Are there proper documentation requirements for the risk assessment, validation plan, protocol, report? （风险评估、验证计划、方案、报告是否有适当的文件记录要求？ ） |
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How often is re - qualification realised, and how is it justified? （重新确认多久进行一次，如何证明其合理性？ ） |
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Are worst - case and bracketing approaches applied and justified? （是否应用了最坏情况和分组方法，并证明其合理性？ ） |
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Are deviations treated appropriately in the various systems? （在各种系统中偏差是否得到适当处理？ ） |
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Is there a process in place to disqualify equipment, etc.? （是否有使设备等丧失资格的流程？ ） |
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Is there a possibility to use non - validated equipment /processes? （是否可能使用未经验证的设备 / 工艺？ ） |
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How are the qualification and validation results recorded and analysed? （确认和验证结果如何记录和分析？ ） |
H. Quality Control
（H. 质量控制）
Auditing a quality control laboratory involves evaluating various areas such as, but not limited to, the laboratory facility, including stability chambers, sample management, equipment calibration and maintenance, result creation and reporting, OOS/OOE/OOT investigations and storage of reagents and reference substances.
审计质量控制实验室涉及评估多个方面，包括但不限于实验室设施，如稳定性试验箱、样品管理、设备校准与维护、结果重现与报告、超标 / 趋势外 / 预期外（OOS/OOT/OOE）调查以及试剂和对照品的储存。
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Aspect（评估维度） |
Possible details to evaluate （可评估的具体细节） |
|---|---|
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Laboratories（实验室） |
How are the rooms classified, qualified and maintained? （实验室房间如何分类、确认和维护？ ） |
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How is the equipment classified, qualified, calibrated and maintained? （设备如何分类、确认、校准和维护？ ） |
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Is there sufficient space for the preparation of samples and reagent with good labelling control /documentation practices? （是否有足够空间用于样品和试剂制备，且标签管理 / 文件记录规范良好？ ） |
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How are waste and leftovers dealt with? （如何处理废弃物和剩余物？ ） |
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Are equipment logbooks available, and do they include entries on at least the following: operations performed (including product), maintenance (planned /breakdown/calibration), checks and verifications, and cleaning? （是否有设备日志，且日志中是否至少记录以下内容：执行的操作（包括产品相关）、维护（计划 / 故障 / 校准）、检查与核查以及清洁？ ） |
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Equipment calibration（设备校准） |
In - house calibration（内部校准）
（人员是否经过培训（培训计划和记录应清晰）？ ） （所用标准的可追溯性 ） |
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External calibration（外部校准）
（服务提供商是否具备资质 / 获得批准？ ）
（设备如何运输？ ）
（承包商如何运输和储存标准品？ ） （所用标准的可追溯性 ） |
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Does the calibration certificate include the following?
（校准证书是否包含以下内容？ ）
（设备标识 ）
（结果（通过 / 不通过）—— 包括规格 ）
（测量不确定度 ）
（与国际测量标准的可追溯性 ）
（使用限制（如有） ）
（校准日期 ）
（若外包，接受校准公司的签名 ） （下次校准到期日 ） |
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Does the calibration label include the following?
（校准标签是否包含以下内容？ ）
（设备标识 ）
（校准执行日期 ）
（有效期至 / 下次校准日期 ） （校准执行者 ） |
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Are out of limit /specification results investigated according to an SOP, including notification /information and an impact assessment on prior tests /results? （超标结果是否按照标准操作规程进行调查，包括通知 / 信息传达以及对先前测试 / 结果的影响评估？ ） |
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Reference substances /standards (RS)（对照品） |
Are reference substances /standards correctly labelled, have an expiry date and indicate purity on the label or CoA? （对照品标签是否正确，是否有有效期，并在标签或分析证书上标明纯度？ ） |
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From where do RS originate? （对照品来源何处？ ） |
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Is there a certificate for each RS? （每个对照品是否都有证书？ ） |
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Are storage conditions for the RS adhered to? （是否遵守对照品的储存条件？ ） |
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Is there a usage log for each RS? （每个对照品是否有使用日志？ ） |
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Out of specification, out of trend and out of expectation results (OOS, OOT, OOE)（超标、趋势外、预期外结果） |
How are expiry dates handled? （如何处理有效期？ ） |
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Do processes comply with GMP requirements and instructions / SOPs? （流程是否符合药品生产质量管理规范（GMP）要求以及相关说明 / 标准操作规程？ ） |
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How are such results investigated, recorded and reported? （如何调查、记录和报告此类结果？ ） |
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Was all glassware and instrumentation retained in the state it was used until results were deemed acceptable to report? （在结果被认为可报告之前，所有玻璃器皿和仪器是否保持使用时的状态？ ） |
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Is re - measurement only allowed using the approved protocol which specifies the purpose and intent of the test? It should not be used to "fix" the result. （是否仅允许按照已批准的方案进行重新测量，该方案应明确测试目的和意图？不得用于 “修正” 结果 ） |
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Is re - testing only allowed after both laboratory and production investigations have been completed and both have been deemed inconclusive? （是否仅在实验室和生产部门的调查均完成且均无结论时才允许重新测试？ ） |
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Is re - sampling only allowed if evidence is available indicating that the original sample was not taken correctly or compromised before analytical testing started? This should be done following the same procedure as the original sample. （是否仅在有证据表明原始样品在分析测试开始前采集不正确或已受影响时才允许重新采样？应按照与原始样品相同的程序进行 ） |
I. Microbiology
（I. 微生物学）
When auditing microbiological laboratories, it is essential to ensure that processes and methods comply with marketing authorisation and meet necessary standards and requirements.By following a systematic approach and thoroughly examining key areas such as laboratory facilities, documentation, personnel, sample management, culture media, reference cultures, sterilisation indicators, method validation, major equipment, environmental monitoring and record keeping, auditors can ensure the laboratory's quality management system is well-established and meets necessary requirements.
在审计微生物实验室时，必须确保流程和方法符合上市许可要求，并满足必要的标准和规定。通过系统的审计方法，全面检查实验室设施、文件记录、人员、样品管理、培养基、参考培养物、灭菌指示器、方法验证、主要设备、环境监测和记录保存等关键领域，审计人员可以确保实验室的质量管理体系健全且符合必要要求。
Note: this is a highly specialised subject, therefore the auditor conducting a full audit of these facilities should have adequate knowledge of microbiology and microbiological test methods or consult with / bring an expert.
注：这是一个高度专业化的领域，因此进行全面审计的审计人员应具备微生物学和微生物测试方法的足够知识，或咨询 / 聘请专家。
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
|---|---|
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Sample receipt（样品接收） |
Is there a dedicated area assigned for receipt of samples? （是否有专门用于接收样品的区域？） |
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How does the company prevent sample mix - ups? （公司如何防止样品混淆？） |
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Are storage conditions observed where necessary? Sample receipt may require adherence to defined storage requirements and may include frozen (-80°C) or cold (5°C), a defined time before cold storage and adherence to correct labelling. （必要时是否遵守储存条件？样品接收可能需要遵循规定的储存要求，可能包括冷冻（-80°C）或冷藏（5°C）、冷藏前的规定时间以及正确的标识。） |
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Do sampling processes comply with GMP requirements and instructions / SOPs? How is it documented (at minimum are the lot number, expiry date, storage conditions and the test (s) required)? （采样流程是否符合药品生产质量管理规范（GMP）要求以及相关说明 / 标准操作规程？如何记录（至少包括批号、有效期、储存条件和所需测试）？） |
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How are the samples labelled? （样品如何标识？） |
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How is traceability ensured? （如何确保可追溯性？） |
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Where are the samples stored? （样品存放在何处？） |
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Sample preparation（样品制备） |
Do processes comply with GMP requirements and instructions / SOPs? How are they documented? （流程是否符合药品生产质量管理规范（GMP）要求以及相关说明 / 标准操作规程？如何记录？） |
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Are balances checked regularly within appropriate ranges and masses, ensuring that they are situated on stable platforms, are clean and unaffected by environmental conditions? （天平是否定期在合适的量程和质量范围内进行检查，确保其放置在稳定平台上，干净且不受环境条件影响？） |
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Is volumetric glassware of the correct grade used, washed and stored? （是否使用、清洗和储存正确等级的量器？） |
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Documentation（文件记录） |
Are laboratory notebooks assigned to specific individuals, version controlled and appropriately stored and archived? （实验室笔记本是否指定给特定人员，是否有版本控制，并妥善存储和归档？） |
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Are results sheets pre - printed, and what is the procedure for this? What is the reconciliation process of pre - printed sheets? （结果表是否预先印制，相关程序是什么？预先印制表格的核对流程是什么？） |
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Are specifications consistent with the dossier and /or quality agreement? （规格是否与档案文件和 / 或质量协议一致？） |
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Data and reporting（数据与报告） |
How is raw data defined? （原始数据如何定义？） |
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Are test results independently checked to ensure there are no errors? （测试结果是否经过独立检查以确保无错误？） |
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Is system suitability testing performed before the start of the test? （在测试开始前是否进行系统适用性测试？） |
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How are reports reviewed and approved? （报告如何审核和批准？） |
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Who has the authority to approve reports, and how is this defined? （谁有权批准报告，如何界定？） |
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How is data transferred to the certificate of analysis (CoA)? （数据如何传输到分析证书（CoA）？） |
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How is it ensured that CoAs meet customer requirements /specifications? （如何确保分析证书符合客户要求 / 规格？） |
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Are IT, computer system validation and data integrity requirements being met? （是否满足信息技术、计算机系统验证和数据完整性要求？） |
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Microbiology laboratory tour（微生物实验室参观） |
How are access, gowning and changing rooms managed and checked? （进入通道、更衣室如何管理和检查？） |
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Is the size, housekeeping and cleanliness of the laboratory adequate? （实验室的面积、卫生和清洁状况是否达标？） |
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Are there dedicated areas for sample and culture media preparation, incubation, reference microbial cultures, bio - hazardous waste collection, endotoxin and sterility testing, sampling and material storage (e.g. freezers)? （是否有专门区域用于样品和培养基制备、培养、参考微生物培养物、生物危险废物收集、内毒素和无菌测试、采样以及物料储存（如冰箱）？） |
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Is equipment labelled, qualified and maintained? Are logbooks available, and do they confirm these activities? （设备是否标识、确认和维护？是否有日志，日志是否记录这些活动？） |
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Personnel（人员） |
How is protective gowning practised, including hygienic hand washing (e.g. the use of antimicrobial soap and duration), disinfection and drying? （如何进行防护着装，包括卫生洗手（如使用抗菌肥皂及洗手时长）、消毒和干燥？） |
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Are garments for the laboratories and the micro lab fresh and sterilised, non - shedding and with no external pockets? Do garments for sterility testing (sterile zone) include closed footwear, a hair net, gloves, a mask and goggles? （实验室和微生物实验室的工作服是否干净、经过灭菌、不脱落纤维且无外部口袋？无菌测试（无菌区）的工作服是否包括封闭式鞋履、发网、手套、口罩和护目镜？） |
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Sample management（样品管理） |
How are contaminated biohazardous samples, used culture media, containers, plates and tubes decontaminated? （受污染的生物危害样品、用过的培养基、容器、培养皿和试管如何进行消毒？） |
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How is it ensured that the correct media is used for testing? （如何确保使用正确的培养基进行测试？） |
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
|---|---|
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Culture media, including reference and working cultures（培养基，包括参考培养物和工作培养物 ） |
Is there an SOP for media preparation, and how are the processes validated? （是否有培养基制备的标准操作规程，流程如何验证？ ） |
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Have heat /cold shock studies for assessment of media transportation been performed? （是否进行过评估培养基运输的热 / 冷冲击研究？ ） |
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Which tests are run for identity and purity (genotypic analysis)? （进行哪些测试以确定身份和纯度（基因型分析）？ ） |
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How is identity and purity confirmed for incoming cultures? （如何确认新到培养物的身份和纯度？ ） |
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How long can the working culture be used under the defined storage condition, and how was this defined? （工作培养物在规定储存条件下可使用多久，这是如何界定的？ ） |
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Indicators for sterilisation /biological indicators (BI)（灭菌指示剂 / 生物指示剂 ） |
Which BI is used, and from where was it purchased? （使用哪种生物指示剂，从何处购买？ ） |
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Is the supplier qualified and regularly audited, and did the supplier audit cover the verification of the D - value claimed by the supplier? （供应商是否具备资质并定期接受审计，供应商审计是否涵盖对供应商声称的 D 值的验证？ ） |
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Is the bacterial population (and purity) confirmed for every BI lot? （是否对每个生物指示剂批次的细菌数量（和纯度）进行确认？ ） |
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Review procedure on microbial identification（微生物鉴定审查程序 ） |
Are standard solutions of strains suitable, available and controlled? （菌株标准溶液是否合适、可用且受控？ ） |
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Is the database suitable (with representative organisms used within the lab facility)? （数据库是否合适（在实验室设施内使用有代表性的生物体）？ ） |
J. Evaluating Testing Process & Methods
（J. 评估测试流程和方法 ）
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
|---|---|
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Sterility testing（无菌测试 ） |
Are procedures for testing and transferring sterility samples and media into the test environment in place (including media usage, incubation time, closure integrity), and do they comply with requirements? （是否有将无菌样品和培养基测试并转移到测试环境中的程序（包括培养基使用、培养时间、密封完整性），这些程序是否符合要求？ ） |
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What actions are taken after a sterility failure? （无菌测试不合格后采取什么措施？ ） |
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Bacterial endotoxin testing（细菌内毒素测试 ） |
Are there procedures in place for preparation of a standard endotoxin stock solution and for preparation of test solutions? （是否有制备标准内毒素储备液和测试溶液的程序？ ） |
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Is the test method validated appropriately, and how often is validation /re - validation checked? （测试方法是否经过适当验证，验证 / 重新验证的检查频率如何？ ） |
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How is test sensitivity confirmed with a new LAL reagent lot? （如何用新的鲎试剂批次确认测试灵敏度？ ） |
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Microbial limit testing（微生物限度测试 ） |
Is there a procedure in place for a growth promotion test? （是否有进行促生长试验的程序？ ） |
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Is media use effective (media should not only recover the target microorganism, but also other inhibitors)? （培养基使用是否有效（培养基不仅应能回收目标微生物，还应能抑制其他微生物）？ ） |
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Is the incubation process sufficient (correct temperature, duration and conditions)? How are the conditions defined? （培养过程是否充分（正确的温度、时长和条件）？条件如何界定？ ） |
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
|---|---|
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Is media use effective (media should not only recover the target microorganism, but also other inhibitors)? （培养基的使用是否有效（培养基不仅应能回收目标微生物，还应能抑制其他微生物）？ ） |
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Is the incubation process sufficient (correct temperature, duration and conditions)? How are the conditions defined? （培养过程是否充分（正确的温度、时长和条件）？条件是如何界定的？ ） |
K. Evaluating major Equipment and Instruments
（K. 评估主要设备和仪器）
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
|---|---|
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Autoclave（高压灭菌器） |
Is the sterilisation autoclave separated from the decontaminating autoclave? （灭菌用高压灭菌器与去污用高压灭菌器是否分开？ ） |
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Is the autoclave qualified, including calibration of sensors, a timer, type of thermocouples, etc.? （高压灭菌器是否经过确认，包括传感器校准、计时器、热电偶类型等方面？ ） |
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Are sterilisation processes validated? （灭菌过程是否经过验证？ ） |
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Incubator（培养箱） |
Is air equally distributed (incl. during the heat-up phase)? （空气是否均匀分布（包括升温阶段）？ ） |
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How are details like door opening (causing a temperature drop) handled and documented? （诸如开门（导致温度下降）这类细节是如何处理和记录的？ ） |
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Is there a log for temperature /humidity excursions? （是否有温度 / 湿度波动记录？ ） |
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Is the incubator qualified, including temperature /humidity sensors, a timer, a gas supply and an alarm? （培养箱是否经过确认，包括温度 / 湿度传感器、计时器、气体供应和警报装置？ ） |
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Was mapping performed for the location of the probes? （是否对探头位置进行过测绘？ ） |
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Water bath（水浴锅） |
How is the water level monitored? （如何监测水位？ ） |
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What quality of water is used (only distilled water should be acceptable)? （使用何种水质（只应使用蒸馏水）？ ） |
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How is closure integrity of samples controlled? （如何控制样品的密封完整性？ ） |
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How are samples labelled? （样品如何标识？ ） |
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How are samples cleaned after removing them from the water bath and before testing? （从水浴锅中取出样品后，在测试前如何清洁样品？ ） |
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How are the samples dried? （如何干燥样品？ ） |
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Biosafety cabinet（生物安全柜） |
Where is it placed, and how is cabinet seal integrity controlled? （放置在何处，如何控制柜体密封完整性？ ） |
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How are filter integrity tests and glove integrity tests performed? （如何进行过滤器完整性测试和手套完整性测试？ ） |
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Is the decontamination process appropriate (including frequency, monitoring, verification)? （去污过程是否合适（包括频率、监测、核查）？ ） |
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
|---|---|
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How is the decontamination agent chosen, controlled and verified? （如何选择、控制和核查去污剂？ ） |
L. Utilities
（L. 公用设施）
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
|---|---|
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Air and gas quality（空气和气体质量） |
How are specifications for the quality of the gases used defined? （所用气体质量规格如何定义？ ） |
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How is the air and gas quality ensured in each area? （如何确保每个区域的空气和气体质量？ ） |
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Air supply（空气供应） |
Do air supply systems provide adequate filtration, ventilation, humidity, temperature control, air speed, number of air exchanges per hour and unidirectional flow (in laminar flow compartments)? （空气供应系统是否提供足够的过滤、通风、湿度、温度控制、风速、每小时换气次数以及单向流（在层流隔间中）？ ） |
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Do they meet the microbial and particulate limits for each grade? （它们是否符合每个等级的微生物和颗粒限度要求？ ） |
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Do they have regular testing and (re -) validation? （是否定期进行测试和（重新）验证？ ） |
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Compressed air（压缩空气） |
How is the compressed air quality ensured for pneumatic purposes? （如何确保用于气动目的的压缩空气质量？ ） |
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Does it meet the requirements for purity, dryness, pressure and flow rate? （它是否符合纯度、干燥度、压力和流速要求？ ） |
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Does it have regular testing and validation? How were the specifications set? （是否定期进行测试和验证？规格是如何设定的？ ） |
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Steam（蒸汽） |
How is the steam quality ensured for sterilisation purposes? （如何确保用于灭菌的蒸汽质量？ ） |
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Does it meet the requirements for purity, dryness, pressure and temperature? （它是否符合纯度、干燥度、压力和温度要求？ ） |
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Does it have regular testing and validation? How were the specifications set? （是否定期进行测试和验证？规格是如何设定的？ ） |
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Other gases (N2, etc.)（其他气体（氮气等）） |
How are other gases used in the process quality controlled? （过程中使用的其他气体如何进行质量控制？ ） |
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Do they meet the requirements for purity, dryness, pressure and flow rate? （它们是否符合纯度、干燥度、压力和流速要求？ ） |
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Do they have regular testing and validation? How were the specifications set? （是否定期进行测试和验证？规格是如何设定的？ ） |
M. Maintenance
（M. 维护）
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
|---|---|
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Maintenance and repair（维护与修理） |
Are rooms maintained properly, employing suitable cleaning and disinfection agents and procedures? （房间是否通过使用合适的清洁和消毒剂及程序进行妥善维护？ ） |
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Are rooms qualified before use and re - qualified after any significant changes or repairs? （房间在使用前是否经过确认，在任何重大变更或修理后是否重新确认？ ） |
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Equipment maintenance（设备维护） |
Is there a procedure in place describing what the company expects from preventive maintenance? （是否有程序描述公司对预防性维护的期望？ ） |
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Who is authorised to realise it, and how is it documented? （谁被授权执行预防性维护，如何记录？ ） |
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Is there a clear definition for replacement parts and final assessment /review of the impact of any parts? Is there a handover process from an engineer to the laboratory? （对于更换部件以及对任何部件影响的最终评估 / 审查是否有明确定义？是否有从工程师到实验室的交接流程？ ） |
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How is it ensured that the equipment is performing as before and if its validated status is maintained? （如何确保设备性能如前且其验证状态得以维持？ ） |
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Is there a clear description of what parts are in the programme and how often? （是否清楚描述了计划中包含哪些部件以及维护频率？ ） |
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Are personnel qualified to perform the tasks in question? （人员是否具备执行相关任务的资质？ ） |
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How is the glassware washer maintained (drains check, sieve, signs of wear, cleaning of trolleys and jet nozzles)? （玻璃器皿清洗机如何维护（检查排水、筛网、磨损迹象、清洁推车和喷嘴）？ ） |
N. Non - sterile and sterile Solid Dosage Forms Production Area
（N. 非无菌和无菌固体剂型生产区域）
Solid dosage forms come in various styles such as powders, granules, tablets, capsules and suppositories. Each form has its own unique characteristics and administration methods. Therefore, it is important to consider these characteristics when auditing facilities involved in the manufacture and testing of such products.
固体剂型有多种形式，如粉末、颗粒、片剂、胶囊和栓剂。每种形式都有其独特的特性和给药方法。因此，在对涉及生产和测试这些产品的设施进行审计时，考虑这些特性非常重要。
Sterile dosage forms are products that are intended to be administered bypassing the patient’s digestion system, making them a potentially life-threatening source of infections if they are contaminated with microorganisms and pyrogens. Usually they are administered by injection, infusion, implantation or inhalation. To ensure the quality and safety of these products (sterility), auditors need to ask key questions and focus on certain areas during an audit.
无菌剂型是指绕过患者消化系统给药的产品，如果它们受到微生物和热原污染，可能会成为潜在的感染源。通常通过注射、输注、植入或吸入给药。为确保这些产品的质量和安全性，审计人员需要关注某些关键领域。
When auditing the production of these dosage forms, it is important to pay attention to the specific requirements relating to the product. This includes ensuring that the raw materials used in production meet the required specifications, the processes follow the established validated processes and that the finished product is fully produced (and tested) in line with the Marketing Authorisation (MA) and cGMP requirements.
在对这些剂型的生产进行审计时，重要的是要关注与产品相关的具体要求。这包括确保生产中使用的原材料符合规定的规格，工艺遵循已建立的验证流程，成品按照上市许可（MA）和药品生产质量管理规范（cGMP）要求进行充分生产（并测试）。
If an auditor hasaccess tothe relevant technical sections(Module2,3) oftheproduct MarketingAuthorisation(MA),theauditorcancheckthemanufacturingdocumentation against these documents to identify any non-compliance issues.
如果审计人员可以查阅产品上市许可（MA）的相关技术部分（模块 2、3），则可以对照这些文件检查生产文件，以识别任何不符合项。
Toreviewthemanufacturingprocess,theauditormayselectabatchbasedononeofthe following:
为审查生产过程，审计人员可基于以下情况选择一批产品：
A batch that was reported in a non-compliance investigation or a deviation / complaint / OOS, etc.
曾在不符合项调查、偏差 / 投诉 / 超标（OOS）等情况中被提及的批次。
A batch that was impacted by significant change (equipment, procedures, layout, etc.)
受重大变更（设备、程序、布局等）影响的批次。
A re-processed or reworked batch
重新加工或返工的批次。
A rejected batch
被拒收的批次。
Other considerations (new product, volume, specificity, etc.)
其他考虑因素（新产品、产量、特性等）。
Or simply selection of one of the last three batches manufactured recently.
或简单选择最近生产的三批产品中的一批。
Alternatively, auditors can review a proposed batch by the auditee, but this may not guarantee a representative document. Auditors should check if there is a system controlling the 'blank' batch records and check if that is controlled by the change control procedure. The auditor can then check the compliance of this template with the validation documentation or MA. Then the selected batch record should be checked to ensure the process is followed correctly.
或者，审计人员可以审查被审计方提议的批次，但这可能无法保证文件具有代表性。审计人员应检查是否有系统控制 “空白” 批次记录，并检查其是否与变更控制程序相关联。然后，审计人员可以检查该模板的合规性以及验证文件或上市许可（MA）。接着，应检查所选批次记录，以确保生产过程得到正确执行。
When auditing without having access to the MA, auditors can use process validation as a starting point. If there is no access to the MA and the process validation, an auditor can review the manufacturing process as per the evaluation focus areas.
在无法获取上市许可（MA）进行审计时，审计人员可以将工艺验证作为起点。如果无法获取上市许可和工艺验证相关内容，审计人员可以根据评估重点领域审查生产过程。
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
|---|---|
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Audit with Marketing Authorisation (MA)（依据上市许可（MA）进行审计） |
Does process validation (batch size, scale up, yield) follow the defined master formula? （工艺验证（批次规模、放大生产、产量）是否遵循既定的主配方？ ） |
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Do executed batch records correspond to the master batch records (including packaging)? （已执行的批次记录是否与主批次记录（包括包装）相符？ ） |
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Do critical IPC test results and acceptance limits match with pre-defined IPC checks and acceptance limits? （关键的中间产品控制（IPC）测试结果和可接受限度是否与预先设定的 IPC 检查和可接受限度一致？ ） |
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Do QC test methods, incl. IPC, comply with validated methods? （质量控制（QC）测试方法，包括 IPC 测试方法，是否符合经过验证的方法？ ） |
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Do QC test results comply with product specifications? （QC 测试结果是否符合产品规格？ ） |
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Is the holding time of bulk product (s) documented and justified? （散装产品的存放时间是否有记录并说明理由？ ） |
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Was the equipment used for manufacturing also used during validation (type, model, including packaging)? （用于生产的设备在验证过程中是否也被使用（类型、型号，包括包装设备）？ ） |
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Are listed suppliers of starting materials qualified? （列出的起始物料供应商是否具备资质？ ） |
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Audit without marketing authorisation (MA)（无上市许可（MA）时的审计） |
Process validation in comparison with master batch records
（与主批次记录对比的工艺验证）
（生产工艺流程）
（设备和房间） （起始 / 原材料 ） ・Sampling （采样） ・IPC checks （中间产品控制检查） ・Acceptance criteria （验收标准） ・Environmental conditions （环境条件） ・Cleaning process （清洁流程） |
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
|---|---|
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Audit without Marketing Authorisation (MA) or process validation（无上市许可（MA）或工艺验证时的审计） |
Check overall GMP compliance （检查总体药品生产质量管理规范合规情况） |
O. Particulars for sterile Dosage Forms
（O. 无菌剂型的特殊要点）
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
|---|---|
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Room design（房间设计） |
Are rooms designed to follow a clean room cascade, preventing contamination from lower-grade areas to higher-grade areas? （房间设计是否遵循洁净室等级顺序，防止低等级区域的污染进入高等级区域？ ） |
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How are the (air over-) pressure cascades established and controlled? Do they prevent the ingress of contaminants from lower-grade areas to higher-grade areas? Do they account for the different activities and operations in each area? （（空气）压力梯度如何建立和控制？它们是否能防止污染物从低等级区域进入高等级区域？是否考虑了每个区域的不同活动和操作？ ） |
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How are the rooms classified, qualified and maintained? （房间如何分类、确认和维护？ ） |
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Do they comply with the relevant standards and regulations, such as Annex 1 and the US FDA aseptic guide? （是否符合相关标准和法规，如欧盟药品生产质量管理规范附录 1 和美国食品药品监督管理局无菌指南？ ） |
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Are rooms easy to clean and disinfect? （房间是否易于清洁和消毒？ ） |
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Are the rooms free from drains in grade A and B areas (as they can be a source of microbial contamination)? （A 级和 B 级区域的房间是否没有排水装置（因为排水装置可能是微生物污染的来源）？ ） |
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Monitoring（监测） |
Are the rooms monitored regularly for microbial and particulate counts using appropriate methods and locations? （是否使用合适的方法和位置定期对房间进行微生物和颗粒计数监测？ ） |
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How are rooms, environment, surfaces monitored? （如何对房间、环境、表面进行监测？ ） |
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What methods and instruments are used for monitoring? （使用什么方法和仪器进行监测？ ） |
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How often and where are the samples taken? （采样频率是多少，在哪些位置采样？ ） |
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How are the results recorded and analysed? （结果如何记录和分析？ ） |
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Contamination control（污染控制） |
How is contamination and degradation of the product and its components prevented? （如何防止产品及其成分受到污染和降解？ ） |
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Are there adequate cleaning and sterilisation processes and procedures in place? （是否有足够的清洁和灭菌流程及程序？ ） |
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
|---|---|
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Are cleaning and sterilisation processes validated? （清洁和灭菌流程是否经过验证？） |
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Personal hygiene（个人卫生） |
How are personnel adequately monitored and controlled? （如何对人员进行充分的监测和管控？） |
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Do personnel follow strict hygiene and gowning requirements for each area and perform their tasks correctly and consistently following standard operating procedures (SOPs) based on applicable GMPs? How is this ensured? （人员是否遵循每个区域严格的卫生和着装要求，并按照基于适用药品生产质量管理规范（GMP）的标准操作规程（SOP）正确且始终如一地执行任务？如何确保这一点？） |
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Do personnel undergo regular media fill tests to demonstrate their aseptic skills? （人员是否定期进行培养基灌装测试以证明其无菌操作技能？） |
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When (i.e. based on which criteria) are qualified personnel dis - qualified to continue working in the aseptic environment? （具备资质的人员在何时（即基于哪些标准）会被取消在无菌环境中工作的资格？） |
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How is it ensured that personnel minimise their interventions and movements in critical areas where aseptic operations take place? （如何确保人员在进行无菌操作的关键区域尽量减少其干预和活动？） |
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Aseptic process simulation（无菌工艺模拟） |
How are media fills performed to simulate the aseptic filling process according to specifications and instructions? （如何根据规格和说明进行培养基灌装以模拟无菌灌装过程？） |
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What are the media fill methods, materials and frequency used for each product type and container size? （针对每种产品类型和容器规格，所用的培养基灌装方法、材料和频率是什么？） |
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How are the media fill results recorded and analysed? （培养基灌装结果如何记录和分析？） |
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Filling（灌装） |
How is the product filled into the final containers, and does it comply with GMP requirements and instructions / SOPs? （产品如何灌装到最终容器中，是否符合药品生产质量管理规范（GMP）要求及相关说明 / 标准操作规程（SOP）？） |
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Are filling processes validated appropriately and re-validated after any significant changes or modifications? （灌装流程是否经过适当验证，在任何重大变更或修改后是否重新验证？） |
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What are the filling methods, equipment and parameters used for each product type and container size? Do they comply with GMP requirements, process validation and MA? （针对每种产品类型和容器规格，所用的灌装方法、设备和参数是什么？是否符合药品生产质量管理规范（GMP）要求、工艺验证和上市许可（MA）？） |
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How are the filling accuracy, uniformity and sterility ensured and verified? （如何确保和验证灌装的准确性、均匀性和无菌性？） |
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Are filling processes simulated using media fills to demonstrate aseptic performance? （是否通过培养基灌装模拟灌装流程以证明无菌操作性能？） |
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Lyophilisation（冻干） |
How is the product lyophilised, and does it comply with GMP requirements and instructions / SOPs? （产品如何进行冻干，是否符合药品生产质量管理规范（GMP）要求及相关说明 / 标准操作规程（SOP）？） |
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What are the lyophilisation methods, equipment, and parameters used for each product type and container size? Do they comply with GMP requirements, process validation, and MA? （针对每种产品类型和容器规格，所用的冻干方法、设备和参数是什么？是否符合药品生产质量管理规范（GMP）要求、工艺验证和上市许可（MA）？） |
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How are the lyophilisation cycle, temperature, pressure, and duration controlled and measured? （冻干周期、温度、压力和时长如何控制和测量？） |
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
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How are the lyophilised product characteristics, such as appearance, moisture content and reconstitution time, ensured and verified? （如何确保和验证冻干产品的特性，如外观、水分含量和复溶时间？） |
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Crimping and container closure integrity (CCI)（压盖和容器密封完整性） |
Do the processes employed comply with GMP requirements and instructions / SOPs? （所采用的流程是否符合药品生产质量管理规范（GMP）要求及相关说明 / 标准操作规程（SOP）？） |
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What are the crimping methods, equipment and parameters used for each product type and container size? Do they comply with GMP requirements, process validation and MA? （针对每种产品类型和容器规格，所用的压盖方法、设备和参数是什么？是否符合药品生产质量管理规范（GMP）要求、工艺验证和上市许可（MA）？） |
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How are the crimping quality, uniformity and integrity ensured and verified? （如何确保和验证压盖质量、均匀性和完整性？） |
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How is the container closure integrity (CCI) tested and validated for each product type and container size? （针对每种产品类型和容器规格，如何测试和验证容器密封完整性（CCI）？） |
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Sterile filtration（无菌过滤） |
Do filtration processes comply with GMP requirements and instructions / SOPs? （过滤流程是否符合药品生产质量管理规范（GMP）要求及相关说明 / 标准操作规程（SOP）？） |
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What are the filtration methods, equipment and materials used for each product type and container size? （针对每种产品类型和容器规格，所用的过滤方法、设备和材料是什么？） |
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How are the filter integrity, efficiency and compatibility ensured and verified? （如何确保和验证过滤器的完整性、效率和兼容性？） |
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Sterilisation（灭菌） |
Do sterilisation processes comply with GMP requirements and instructions / SOPs? （灭菌流程是否符合药品生产质量管理规范（GMP）要求及相关说明 / 标准操作规程（SOP）？） |
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What are the sterilisation methods, equipment and materials used for each product type and equipment? （针对每种产品类型和设备，所用的灭菌方法、设备和材料是什么？） |
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How are the sterilisation efficacy, uniformity and compatibility ensured and verified? （如何确保和验证灭菌效果、均匀性和兼容性？） |
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Sterilisation of containers（容器灭菌）
注：大多数公司会提到 “除热原”，此时 “容器灭菌” 的目标是除热原。除热原是玻璃容器在进行灭菌热处理时会发生的过程。容器可能 “无热原”，但这并不一定意味着它们是无菌的。 |
Do the sterilisation processes used comply with GMP requirements and instructions / SOPs? （所用的灭菌流程是否符合药品生产质量管理规范（GMP）要求及相关说明 / 标准操作规程（SOP）？） |
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What are the sterilisation methods, equipment and materials used for each item? （针对每个物品，所用的灭菌方法、设备和材料是什么？） |
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How are the sterilisation efficacy, uniformity and compatibility ensured and verified? （如何确保和验证灭菌效果、均匀性和兼容性？） |
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Visual inspection（目视检查） |
Do visual inspection processes comply with GMP requirements and instructions / SOPs? （目视检查流程是否符合药品生产质量管理规范（GMP）要求及相关说明 / 标准操作规程（SOP）？） |
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What are the visual inspection methods, equipment and materials used for each product type and container size? （针对每种产品类型和容器规格，所用的目视检查方法、设备和材料是什么？） |
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How are the visual inspection results recorded and analysed? （目视检查结果如何记录和分析？） |
P. Water and Sanitisers
（P. 水与消毒剂 ）
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
|---|---|
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Water（水） |
What quality of water is used for which purpose? （不同用途使用何种质量的水？ ） |
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How are the water samples taken (where and when; rationale)? （如何采集水样（在何处、何时采集；理由是什么）？ ） |
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Where are the sampling points (rationale)? （采样点位于何处（理由是什么）？ ） |
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Which sample containers are used (glass, sterilised, labelled, identified; rationale)? （使用何种采样容器（玻璃材质、是否灭菌、是否贴标签、是否标识；理由是什么）？ ） |
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What is the max. time of storage prior to testing? Is it controlled? （测试前最长储存时间是多少？是否加以控制？ ） |
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Sanitiser（消毒剂） |
What sanitisers are used and for what purpose (type and temperature)? （使用哪些消毒剂，用途是什么（类型及适用温度）？ ） |
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How are sanitising solutions prepared, approved and stored? （消毒溶液如何制备、批准和储存？ ） |
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How is effectiveness checked and verified? （如何检查和验证消毒效果？ ） |
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How are contact time and drying method and time controlled? （如何控制接触时间、干燥方法和干燥时间？ ） |
Q. How to audit a medical Cannabis Grower
如何审核医用大麻种植者
Principles and Background
原则与背景
Auditing a medical cannabis grower introduces several new concepts at the edges of GMP such as hydroponic cultivation systems, good agricultural collection practice (GACP) and increased demand for site and product security measures. Some authorities inspect both GACP and GMP, but others solely inspect GMP. The scope here is mainly limited to GMP considerations.
对医用大麻种植者进行审核，会引入一些处于药品生产质量管理规范（GMP）边缘的新概念，如水培种植系统、良好农业采集规范（GACP），以及对场地和产品安全措施日益增长的需求。一些监管机构会同时检查 GACP 和 GMP，但另一些仅检查 GMP。此处的范围主要局限于对 GMP 的考量。
Some authorities regard cannabis flowers as APIs, whereas others treat them as intermediate products and some as finished products. This is an evolving area and the inspector needs to know the intended markets current requirements.
一些监管机构将大麻花视为原料药（APIs），而另一些将其视为中间产品，还有一些视为成品。这是一个不断发展的领域，审核人员需要了解目标市场当前的要求。
Laboratory testing of cannabis products frequently needs several test laboratories, and these are often contractors. Testing facilities at growing sites are often absent or very basic.
大麻产品的实验室检测通常需要多家检测实验室，且这些实验室往往是外包机构。种植场地的检测设施通常不存在或非常基础。
Relevant sections of Eudralex Vol 4 should be followed and include non-sterile production topics plus relevant annexes such as Annex 7 (Herbals), Annex 11 (Computers) and Annex 15 (Validation).
应遵循欧盟药品法规第四卷（Eudralex Vol 4）的相关章节，包括非无菌生产主题以及相关附录，如附录 7（草药）、附录 11（计算机）和附录 15（验证）。
Most sites have sophisticated plant monitoring measures to satisfy narcotics regulations. However there is still a potential for mix-ups, as some sites grow plants from seed, others may purchase plants and others may clone plants. Normal GMP principles of segregation, identification and labelling should be included in the inspection.
大多数场地都有精密的植物监测措施以满足麻醉品法规要求。然而，仍存在混淆的可能性，因为有些场地从种子开始种植植物，有些可能购买植物，还有些可能克隆植物。检查中应包含 GMP 中关于隔离、识别和标识的常规原则。
Annex 7 refers to the Guideline on Good Agricultural and collection practice for starting materials of herbal origin. The inspector is recommended to read this document before a GMP inspection. Annex 7 provides advice on the borderlines between GACP and Part I and Part II of Eudralex Vol 4. The document reference is EMEA/HMPC/246816/2005.
附录 7 指的是草药起始原料的良好农业和采集规范指南。建议审核人员在进行 GMP 检查前阅读该文件。附录 7 就 GACP 与欧盟药品法规第四卷第一部分和第二部分之间的界限提供了建议。文件编号为 EMEA/HMPC/246816/2005。
Some products may be irradiated, with current examples being some products exported from Canada. Practices differ within the EC. The inspector may examine results and certification from a contracted irradiation facility. Annex 12 is useful in this case. The effects of irradiation on the multiple components of cannabis, such as terpenes, is the subject of debate. If products are irradiated, the inspector should ensure that the recipient is notified of this.
一些产品可能会经过辐照处理，目前的例子是一些从加拿大出口的产品。欧盟内部的做法各不相同。审核人员可以检查来自外包辐照设施的结果和认证。在这种情况下，附录 12 会有所帮助。辐照对大麻多种成分（如萜烯）的影响存在争议。如果产品经过辐照，审核人员应确保接收方得到通知。
Products may not be the subject of QP release due to their current status. In addition, QC staff at these sites may be less experienced than those in mainstream pharmaceutical factories. Cannabis products can present substantial patient risks from finished product ochratoxin and microbial contaminants. Inspectors should ensure that the finished product specification is appropriate and results are being adequately monitored.
由于目前的状况，产品可能不经过质量受权人（QP）放行。此外，这些场地的质量控制（QC）人员可能不如主流制药厂的人员经验丰富。大麻成品中的赭曲霉毒素和微生物污染物可能会给患者带来很大风险。审核人员应确保成品质量标准恰当，并对检测结果进行充分监控。
Prior to inspection of these sites, and especially for inspectors new to this topic, it is recommended that preparation is started early so that any questions can be answered before commencing the inspection.
在检查这些场地之前，特别是对于初次接触该主题的审核人员，建议尽早开始准备工作，以便在检查开始前解答任何疑问。
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
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Preparation（准备工作） |
What is the sites determined cut-off between GACP and GMP? （场地如何界定中药材生产质量管理规范（GACP）和药品生产质量管理规范（GMP）的界限？） |
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Is there a formal QMS for GACP? （是否有正式的针对 GACP 的质量管理体系（QMS）？） |
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Are plants bought in, or grown at the site? （植物是采购的还是在场地内种植的？） |
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Is the site activity limited to flower growing, or are there additional activities such as extraction and formulation? （场地内的活动是否仅限于花卉种植，还是有诸如提取和配制等其他活动？） |
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What narcotics licences are held or applied for? （持有或申请了哪些麻醉品许可证？） |
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Does the company use hydroponics or soil growing? （公司采用水培法还是土壤种植法？） |
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What laboratories are used for chemical and microbial testing? （用于化学和微生物检测的实验室有哪些？） |
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Is there 24/7 security with manned presence and a security plan? （是否有每周 7 天、每天 24 小时有人值守的安保措施以及安保计划？） |
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Goods received and storage（货物接收与储存） |
Are growth media received with suitable certification? （接收的培养基是否有合适的认证？） |
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Are chemical nutrients suitably labelled and stored to prevent degradation? （化学营养物质是否有合适的标签并妥善储存以防止变质？） |
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Do the company adequately address TSE risks in all potential product-contact items? （公司是否充分应对所有可能接触产品的物品中的传染性海绵状脑病（TSE）风险？） |
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Are any printed materials received and suitably checked and securely stored? （收到的印刷材料是否经过适当检查并安全储存？） |
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Facility design（设施设计） |
Are rooms classified to expected GMP standards for non-steriles? （房间是否按照非无菌产品预期的 GMP 标准进行分类？） |
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Are suitable pressure cascades maintained and monitored? （是否维持并监测合适的压力梯度？） |
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Are air inlets and outlets located to achieve suitable sweeping and absence of stagnant areas? （进风口和出风口的位置是否能实现合适的气流吹扫并避免出现气流停滞区域？） |
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What filtration standards are applied to both incoming and recirculated air? （对进风与循环风分别应用何种过滤标准？） |
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Is a suitable area provided for cleaning equipment and solutions? （是否有合适的区域用于清洁设备和溶液？） |
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Clothing（工作服） |
Is a suitable changing area provided with adequate space and washing facility? （是否有合适的更衣室，具备足够空间和洗涤设施？） |
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What measures are in place to protect workers and inspectors from light radiation - eye protection, special clothing and sunscreen? （采取了哪些措施保护工人和检查人员免受光辐射 —— 如护眼措施、特殊服装和防晒霜？） |
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Are any external laundry facilities audited and approved? （外部洗衣设施是否经过审计和批准？） |
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Fertigation controls（施肥灌溉控制） |
Is there an automated system controlling key parameters such as solution preparation, irrigation, temperatures, light and gas levels? （是否有自动化系统控制诸如溶液制备、灌溉、温度、光照和气体浓度等关键参数？） |
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Has the system been formally validated and approved? （该系统是否经过正式验证和批准？） |
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Request and examination calibration records of key sensors. （要求并检查关键传感器的校准记录。） |
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What controls are in place to stop unauthorised changes or optimisation? （采取了哪些控制措施防止未经授权的更改或优化？） |
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Pest controls and fungus risks（虫害控制与真菌风险） |
What pest control measures are in place and how is their efficacy challenged? （采取了哪些虫害控制措施，如何验证其效果？） |
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What measures are in place to reduce/discourage fungal growth?（ 采取了哪些措施减少 / 抑制真菌生长？） |
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Harvesting, drying, trimming and curing（收获、干燥、修剪和熟化） |
How is flowering monitored to determine a suitable and consistent point for harvesting? （如何监测开花情况以确定合适且一致的收获时机？） |
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Are machines used for bucking and trimming? （是否使用机器进行破碎和修剪？） |
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Is there sufficient instrumentation on automatic machines? （自动机器上是否有足够的仪器装置？） |
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Is there an adequate procedure for cleaning and sanitising machinery? （是否有适当的机器清洁和消毒程序？） |
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Packaging and labelling（包装与贴标） |
Is the packing process manual or is machinery required? （包装过程是手动的还是需要机器？） |
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What containers are used for the product - are these bought in or is a local pouch produced? （产品使用何种容器 —— 是采购的还是本地生产的包装袋？） |
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Is there any use of nitrogen in the packing process and, if so, is this subject to point-of-use filtration? （包装过程中是否使用氮气，若使用，是否在使用点进行过滤？） |
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Are suitable in-process checks conducted during packing? （包装过程中是否进行适当的过程中检查？） |
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Aspect （评估维度） |
Possible details to evaluate （可评估的具体细节） |
|---|---|
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If pouches are used, what checks are carried out for pinholes and integrity of the seal? （如果使用包装袋，如何检查针孔和密封完整性？ ） |
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Are product labels printed fully in house, or just variable data such as the batch number and expiry date added locally? （产品标签是全部在厂内印刷，还是仅在当地添加诸如批号和有效期等可变数据？ ） |
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QC testing（质量控制检测） |
Are the water sources evaluated for pesticides, heavy metals and micro levels? （是否对水源进行农药、重金属和微生物含量评估？ ） |
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Is there an adequate environmental monitoring programme in place? （是否有适当的环境监测计划？ ） |
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Does the company check for the absence of aspergillus in the finished product? （公司是否检查成品中是否存在曲霉菌？ ） |
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Does the company monitor and trend levels of aflatoxins and ochratoxins in the finished product? （公司是否监测并追踪成品中黄曲霉毒素和赭曲霉毒素的含量水平？ ） |
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Is there a requirement for the absence of salmonella and E.coli in the product? （是否要求产品中不得含有沙门氏菌和大肠杆菌？ ） |
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Are cannabinol levels in the finished product controlled and evaluated? （成品中大麻酚含量是否得到控制和评估？ ） |
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Are the qualifications and experience of the releasing officer or QP adequate? （放行人员或质量负责人的资质和经验是否足够？ ） |
R. Preparing Audits for Cell and Gene Therapies (CGT) based Advanced Therapy Medicinal Products (ATMPs)
R. 基于细胞和基因疗法（CGT）的先进治疗药物（ATMPs）审核准备
Background
背景
The European Commission has published a separate regulation for Advanced Therapeutic Medicinal Products (ATMPs) which lays down specific rules concerning the authorisation, supervision and pharmacovigilance of ATMPs (Regulation 1394/2007). The regulation defines three types of ATMPs: gene therapy medicines, somatic cell medicines and tissue engineered medicines.
欧盟委员会已针对先进治疗药物（ATMPs）发布了单独的法规，该法规制定了有关先进治疗药物的授权、监管和药物警戒的具体规则（法规 1394/2007）。该法规定义了三种类型的先进治疗药物：基因治疗药物、体细胞治疗药物和组织工程药物。
This article is mainly focused on ATMP based cell and gene therapies (CGT). CGTs can be described as therapies that offer personalised and targeted treatments for a number of rare and chronic diseases. These therapies are classified into two main types: autologous and allogenic.
本文主要关注基于先进治疗药物的细胞和基因疗法（CGT）。细胞和基因疗法可以被描述为为多种罕见和慢性疾病提供个性化靶向治疗的疗法。这些疗法主要分为两种类型：自体和异体。
Autologous CGTs involve using the patient’s own cells, which are collected, modified and then reintroduced into the patient. This personalised approach minimizes the risk of immune rejection.
自体细胞和基因疗法涉及使用患者自身的细胞，这些细胞被采集、改造，然后重新输回患者体内。这种个性化的方法将免疫排斥风险降至最低。
Allogenic CGTs, on the other hand, use cells from a donor. These therapies can be produced in larger quantities and administered to multiple patients, but they carry the risk of immune response and require careful matching of donor and recipient.
另一方面，异体 细胞和基因疗法使用供体的细胞。这些疗法可以大量生产并用于多个患者，但它们存在免疫反应风险，需要仔细匹配供体和受体。
1 ATMP-specific Challenges
1 ATMP 特定挑战
Due to the specific nature of ATMPs, new challenges need to be addressed. These new challenges and difficulties regarding sterility, out - of - specification handling, batch release and EU import test are situated throughout the entire manufacturing process.
由于先进治疗药物（ATMPs）的特殊性质，需要应对新的挑战。这些与无菌性、超标处理、批次放行以及欧盟进口检测相关的新挑战和难题贯穿于整个生产过程。
One of the major challenges is the aseptic risk associated with the ATMP manufacturing. ATMP administration requires injection, infusion or transplantation of the medicinal product. Therefore, the ATMP product needs to be manufactured under aseptic conditions. Unlike traditional small molecule medicinal products, sterile filtration or terminal sterilisation is in most cases impossible, either because these methods impede the product’s structure or function, or because cells are simply too large to pass through the pore size of the filter. As stated in Part IV of the EU GMPs (Good Manufacturing Practice), all processes related to aseptic processing need to be validated before entering clinical phase I trials. The combination of growing requirements, clean room qualification and validation of these aseptic processes by the media fill and a validated sterility test method needs to ensure the sterility of the product and, therefore, requires specific attention during an audit according to Annex 1, as applicable.
主要挑战之一是与先进治疗药物生产相关的无菌风险。先进治疗药物的施用需要对药品进行注射、输注或移植。因此，先进治疗药物产品需要在无菌条件下生产。与传统的小分子药物不同，在大多数情况下，无菌过滤或终端灭菌是不可能的，要么是因为这些方法会破坏产品的结构或功能，要么是因为细胞太大而无法通过过滤器的孔径。如欧盟药品生产质量管理规范（EU GMPs）第四部分所述，所有与无菌加工相关的工艺在进入临床一期试验前都需要进行验证。不断增长的要求、洁净室鉴定以及通过培养基灌装和经过验证的无菌测试方法对这些无菌工艺进行验证，这些共同作用需要确保产品的无菌性，因此，在审核时需要根据适用的附录 1 给予特别关注。
2 How to audit ATMPs - managing the Complexities of allogenic CGT Manufacturing
2 如何审核先进治疗药物 —— 应对异体细胞和基因疗法生产的复杂性
2.1. The Challenges of the Supply Chain
2.1 供应链的挑战
The creation of a CGT based ATMP involves the collection or “donation” from an individual. The donated material is then generally modified, engineered or manufactured into a therapy product for delivery to the patient. This complex manufacturing and delivery model is known as the “vein - to - vein supply chain”.
基于细胞和基因疗法（CGT）的先进治疗药物的生产涉及从个体采集或 “捐赠”。捐赠的材料通常随后会被修饰、加工或制造成治疗产品，以交付给患者。这种复杂的生产和交付模式被称为 “静脉到静脉供应链”。
CGTs have not yet adapted on a large scale, due to a combination of clinical, regulatory and cost - related hurdles. At present, supply chains are necessarily bespoke and costly. However, given the potential presented by CGTs and the current focus on developing them, it seems likely that they will form an integral part of future therapies. As they become more prevalent, ensuring the ongoing integrity of their supply chains will be of paramount importance. This also includes the storage and transport of them.
由于临床、监管和成本相关的障碍，细胞和基因疗法尚未大规模应用。目前，供应链必然是定制化且成本高昂的。然而，鉴于细胞和基因疗法所具有的潜力以及当前对其研发的关注，它们很可能会成为未来治疗方法的重要组成部分。随着它们变得更加普遍，确保其供应链的持续完整性将至关重要。这也包括它们的储存和运输。
Right from cell collection to the delivery of the therapy product, each step involves several processes which bring their own risks and require controls.
从细胞采集到治疗产品交付，每一步都涉及多个过程，这些过程都有各自的风险且需要管控。
During the collection process (via apheresis, etc.), preparing and monitoring the patient and equipment to yield the appropriate quality raw material is essential.
在采集过程（通过单采等方式）中，准备和监测患者及设备以获取合适质量的原材料至关重要。
The raw material and drug products can get affected by factors such as timing, temperature, microbiological basic load, packaging, etc. and therefore need to be handled, packed and transported with care. Obtaining a sterile starting material can be a challenge.
原材料和药品可能会受到时间、温度、微生物基础负荷、包装等因素的影响，因此需要小心处理、包装和运输。获取无菌起始原料可能是一项挑战。
Certain complex manipulations and activities are performed during the manufacturing process and are crucial if the end product is to meet specifications. These are often performed manually and require great skill and consistency.
在生产过程中会进行某些复杂的操作和活动，对于最终产品符合规格要求而言，这些操作和活动至关重要。它们通常是手工完成的，需要高超的技能和一致性。
Understanding the GMP requirements, equipping the team with the necessary skills and rigorous training is critical.
理解药品生产质量管理规范（GMP）要求，为团队配备必要的技能并进行严格培训至关重要。
Lot genealogy, including chain of identity (COI) and chain of custody (COC), are two critical data sets that maintain the record of all the materials, processes, testing and outputs of a batch to ensure that patients are treated with the specific product meant for them.
批次谱系，包括身份链（COI）和保管链（COC），是两组关键数据集，用于记录批次的所有物料、工艺、检测和产出，以确保患者接受专为其准备的特定产品治疗。
It must be ensured that the qualification and performance of vendors meet the required standards, especially since many of them do not operate in a GMP environment.
必须确保供应商的资质和表现符合要求的标准，尤其是因为许多供应商并非在药品生产质量管理规范（GMP）环境下运营。
Standardised processes and controls ensure that the products are safe and fit for the intended use and comply with regulatory requirements.
标准化的工艺和控制措施可确保产品安全、适用于预期用途并符合法规要求
Risks have to be identified, and mitigation measures established using an integrated process for both quality and risk management.
必须识别风险，并通过质量和风险管理的综合流程制定缓解措施。
Continuous improvement has to be set up through monitoring of processes and performance, track and trend investigations, root cause and CAPA (Corrective and Preventive Action) analysing of supply chain performance and managing risks.
必须通过监控工艺和绩效、追踪和趋势调查、对供应链绩效进行根本原因分析以及采取纠正和预防措施（CAPA）并管理风险，来建立持续改进机制。
A robust audit process is critical for ensuring patient safety, mitigating risks, reducing failure and increasing operational efficiency
健全的审核流程对于确保患者安全、降低风险、减少失误以及提高运营效率至关重要。
2.2. Where to start at the Manufacturer
2.2 从制造商处入手的要点
When manufacturing an ATMP, it is important to pay attention to the choice of raw materials used. These materials influence the entire process, from clinical development to market authorisation. GMP guidelines contain important considerations. This requires specialist expertise, with careful consideration and impact assessment undertaken, which is not routinely available as the dense supplier management needed. Agreements with suitable suppliers such as blood centres are required to facilitate delivery of these specialist materials to be of suitable specified quality. Audits and continuing oversight arrangements should confirm the technical quality and suitability of the services documented in a quality and technical agreement.
在生产先进治疗药物（ATMP）时，关注所用原材料的选择非常重要。这些原材料会影响从临床开发到上市许可的整个过程。药品生产质量管理规范（GMP）指南包含重要的考量因素。这需要专业知识，要进行仔细考量和影响评估，而这并非常规操作，因为需要密集的供应商管理。需要与合适的供应商（如血站）达成协议，以确保这些专业材料能以合适的规定质量交付。审核和持续监督安排应确认质量和技术协议中记录的服务的技术质量和适用性。
Therefore, when auditing manufacturers, an essential focus should be on raw material supplier management.
因此，在审核制造商时，一个关键重点应放在原材料供应商管理上。
2.3. ATMP OOS Batches being used
2.3 正在使用的先进治疗药物（ATMP）超标批次
Due to a higher variability and the quality of raw materials, a higher level of deviations and OOS (Out - of - Specification) results are more likely. In case of an OOS result, there is the possibility to release the batch and administer it to the patient. This contrasts with traditional medicinal products, where a product which does not comply with the specifications cannot be certified and released.
由于原材料的更高变异性和质量问题，出现更高程度的偏差和超标（OOS）结果的可能性更大。在出现超标结果的情况下，存在放行该批次产品并将其用于患者的可能性。这与传统药品形成对比，传统药品中不符合规格的产品无法获得认证和放行。
During an audit the following should be checked with regard to OOS documentation:
在审核时，应就超标（OOS）文件检查以下内容：
A description of the OOS with a risk analysis by the manufacturer on the impact on the following:
对超标的描述，以及制造商对以下方面影响的风险分析：
The quality of the product, including the percentage of batches that is OOS on the total of commenced productions and a reflection on the production process (root cause analysis and CAPAs (Corrective Action and Preventive Action)),
产品质量，包括超标（OOS）批次在已开始生产的总批次中所占的比例，以及对生产过程的分析（根本原因分析和纠正预防措施（CAPAs））。
Role of the QP
质量受权人（QP）的职责
The safety and efficacy of the product in relation to the patient;
产品与患者相关的安全性和有效性。
There should also be a feedback loop in place to the critical quality attributes (CQAs), which have been identified during the quality target product profile (QTTP) process to define the quality, safety and efficacy attributes of the desired final product during the risk - based process development (e.g. quality by design).
还应建立一个反馈循环，针对在质量目标产品概况（QTTP）过程中确定的关键质量属性（CQAs），以便在基于风险的工艺开发（如质量源于设计）过程中定义所需最终产品的质量、安全性和有效性属性。
A confirmation by the physician to the manufacturer to accept the product;
医生向制造商确认接受该产品。
A declaration from the MAH (marketing authorisation holder) as to whether or not the product has been administered.
上市许可持有人（MAH）声明该产品是否已被使用。
A Q&A document on how to handle an OOS for authorised batches was first published by the EMA in April 2019.
欧洲药品管理局（EMA）于 2019 年 4 月首次发布了关于如何处理已批准批次超标情况的问答文件。
2.4. QP Certification of ATMP and Import
2.4. ATMP 的 QP 认证与进口
According to EU directive 2001/83/EC, a registered qualified person (QP) is responsible for the certification of medicinal products prior to their release. This and the applicable responsibilities of a QP do not differ for ATMPs. However, the difficulties which might be faced by a QP are different throughout the entire manufacturing process.
根据欧盟指令 2001/83/EC，注册质量受权人（QP）负责在药品放行前对其进行认证。对于先进治疗药物（ATMPs）而言，质量受权人的这一职责及相关适用职责并无不同。然而，质量受权人在整个生产过程中可能面临的困难有所不同。
A QP cannot certify an OOS ATMP batch, the release of these batches is based on a documented request by a treating physician.
质量受权人不能对超标（OOS）的先进治疗药物批次进行认证，这些批次的放行基于主治医生的书面申请。
The QP needs to assure that verification according to GMP Part Ⅳ - 11.27 has been performed. Prerequisites to release the OOS batch are mentioned in GMP Part Ⅳ - 11.5.
质量受权人需要确保已按照药品生产质量管理规范（GMP）第四部分 - 11.27 进行核查。放行超标批次的前提条件在 GMP 第四部分 - 11.5 中有提及。
As a reminder, QP certification is a written signed statement that the manufacture and testing of a batch has been conducted in accordance with GMP and the relevant approved marketing authorisation or clinical trial application before the batch can be released.
需提醒的是，质量受权人认证是一份书面签字声明，表明在批次放行前，该批次产品的生产和检测是按照药品生产质量管理规范（GMP）以及相关获批的上市许可或临床试验申请进行的。
The obligation to perform import testing in case a medicinal product is manufactured in a third country, does not always apply to ATMPs (e.g. for ATIMPs, import waiver). There are exemptions from EU batch retesting laid down in paragraph 11.17 of GMP Part Ⅳ. In case of exemptions, the manufacturing of the ATMP needs to be performed according to EU GMPs. This implies that an audit prior to first importation is required. As the QP takes on the responsibility of certifying this batch from a third country, the audit is preferably performed by the QP. A Q&A document on the exemption from batch controls carried out on ATMPs imported into the European Union from a third country was published first by the EMA in July 2019.
对于在第三国生产的药品进行进口检测的义务，并不总是适用于先进治疗药物（例如对于某些先进治疗药物，可豁免进口检测）。欧盟药品生产质量管理规范（GMP）第四部分第 11.17 段规定了欧盟批次重新检测的豁免情况。在豁免情况下，先进治疗药物的生产需按照欧盟 GMP 进行。这意味着在首次进口前需要进行审核。由于质量受权人承担着对来自第三国的该批次产品进行认证的责任，因此审核最好由质量受权人进行。欧洲药品管理局（EMA）于 2019 年 7 月首次发布了关于对从第三国进口到欧盟的先进治疗药物免除批次控制的问答文件。
2.5.Transport and Storage of ATMPs
2.5. 先进治疗药物（ATMPs）的运输与储存
Much of the discussion in the ATMP industry today focuses on the complexity of manufacturing. However, the ultimate success of an ATMP rests on the ability to deliver a viable, potent product to the patient.
如今，先进治疗药物行业的诸多讨论聚焦于生产的复杂性。然而，先进治疗药物的最终成功取决于能否向患者交付有活性且有效的产品。
In order to ensure that this “living” drug is delivered to the right patient at the right time, location and temperature is essential to patient safety and product effectiveness and therefore should not be forgotten when auditing.
为确保这种 “活性” 药物能在合适的时间、地点，以合适的温度交付给合适的患者，这对患者安全和产品有效性至关重要，因此在审核时不应忽视。
The logistics of these types of medicines are complex, due to specific requirements regarding temperature, reliability and traceability. For example:
由于对温度、可靠性和可追溯性的特定要求，这类药物的物流运作十分复杂。例如：
Frozen storage requirements: Cryogenic storage and distribution capabilities are established for many ATMPs. Distribution in deep - frozen or cryogenic conditions needs specialist shippers, to keep the temperature stable and track the location and conditions during the shipment.
冷冻储存要求：许多先进治疗药物需要低温储存和配送能力。在深度冷冻或低温条件下配送需要专业的托运商，以保持温度稳定，并在运输过程中追踪位置和条件。
Short shelf lives — ATMP or their starting materials may have an extremely short shelf life. This could even mean that not all test results are available at the time points of release or even administration. A risk assessment, risk mitigation and processes (e.g. what happens if a specification is not met) need to be in place.
保质期短 —— 先进治疗药物或其起始原料可能保质期极短。这甚至可能意味着在放行或给药时，并非所有检测结果都已得出。需要进行风险评估、风险缓解并制定相关流程（例如，若不符合规格该如何处理）。
Any deviation from storage, distribution or traceability requirements has the potential to impact the quality of the ATMP and, therefore, the safety of patients. Storage and distribution under GMP and good distribution practice (GDP) guidelines are applicable for CGTs, too.
任何偏离储存、配送或可追溯性要求的情况，都可能影响先进治疗药物的质量，进而影响患者安全。按照药品生产质量管理规范（GMP）和良好分销规范（GDP）指南进行储存和配送，同样适用于细胞和基因疗法（CGTs）。
The challenges of CGT for pharma logistics are as followed:
细胞和基因疗法在医药物流方面面临的挑战如下：
Delays due to inspection and compliance checks
因检查和合规核查导致的延误
Complexity calls for experienced logistics partners
复杂性要求有经验丰富的物流合作伙伴
Limited visibility in logistics because of low quantity
由于数量少，物流可视性有限
Scalability of transport methods
运输方式的可扩展性
Unforeseen disruptions in supply chains
供应链中难以预见的中断
来源：Internet
关键词： GMP审计
