相信任何药企都不会希望收到FDA发出的Warning Letter，德斯特团队的同事们根据以往的FDA检查经验及翻阅历年的FDA警告信总结出了以下的警告信重点内容供各位制药同仁参考，从FDA警告信的重点内容可以看出FDA检查过程中容易出现的缺陷，便于各位制药同仁在工作中避免出现同样的错误。

1.Quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP.

质量控制部门未能履行其职责，确保生产的药品符合CGMP的要求。

1.1.Quality Assurance (QA) and production departments failed to provide adequate oversight and ensure the reliability of data related to the quality of finished drug products manufactured at the facility. Visual inspectors manipulated particle and other defect counts on manual visual inspection records in many instances, in order to keep the finished product batches within rejection limits. More specifically, the investigation found that operators manipulated the defect quantities “to keep the category wise rejections within limits to avoid a deviation and investigation.”

质量保证 （QA） 和生产部门未能提供足够的监督，并确保与工厂生产的成品药质量相关的数据的可靠性。目视检查员在许多情况下在手动目视检查记录上操纵颗粒和其他缺陷计数，以将成品批次保持在剔除范围内。更具体地说，调查发现，运营商操纵了缺陷数量，“以将类别的剔除率保持在限制范围内，以避免偏差和调查。”

1.2.Some records, filled out by multiple operators, had an identical number of defects listed for all drug product defect categories.

一些记录由多个操作员填写，所有药品缺陷类别列出的缺陷数量相同。

1.3.Production managers including, but not limited to, front line supervisors failed to ensure reliable data, leading to significant data integrity deficiencies in your production records.

生产经理（包括但不限于一线主管）未能确保数据的可靠性，导致生产记录中存在严重的数据完整性缺陷。

1.4.In addition, there was a lack of QA department review and oversight of visual inspection records. These findings indicated that QA department was not exercising its basic responsibilities including, but not limited to, oversight and control over the adequacy and reliability of all CGMP data at the facility.

此外，缺乏 QA 部门对目视检查记录的审查和监督。这些发现表明，质量保证部门没有履行其基本职责，包括但不限于监督和控制工厂中所有CGMP数据的充分性和可靠性。

1.5. In particular, lack a comprehensive review of the management of your operations, including but not limited to ineffective supervision and governance in your production department (i.e., encompassing frontline supervisors through top operations managers).

特别是，缺乏对运营管理的全面审查，包括但不限于生产部门（即从一线主管到高层运营经理）的监督和治理效率低下。

Recommended measure建议性措施：

A comprehensive assessment and remediation plan to ensure QA department is given the authority and resources to effectively function. The assessment should also include, but not be limited to:

全面的评估和补救计划，以确保QA部门获得有效运作的权力和资源。评估还应包括但不限于：

1.5.1.A determination of whether procedures used by are robust and appropriate.

确定使用的程序是否稳健和适当。

1.5.2.Provisions for QA oversight throughout your operations to evaluate adherence to appropriate practices.

在整个运营过程中提供QA监督，以评估是否遵守适当的做法。

1.5.3.A complete and final review of each batch and its related information before the QA disposition decision.

在作出QA处置决定之前，对每批及其相关信息进行完整的最终审查。

1.5.4.Oversight and approval of investigations and discharging of all other QA duties to ensure identity, strength, quality, and purity of all products.

监督和批准调查并履行所有其他QA职责，以确保所有产品的特性、强度、质量和纯度。

1.5.5.Describe how supports QA and reliable operations, including but not limited to, timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.

描述如何支持QA和可靠运营，包括但不限于及时提供资源，以主动解决新出现的制造/质量问题，并确保持续的控制状态。

1.5.6.A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates documentation practices to ensure retain contemporaneous, attributable, legible, complete, original, and accurate records throughout your operation.

对整个制造和实验室操作过程中使用的文档系统进行全面评估，以确定文档实践不足之处。包括一份详细的CAPA计划，全面修正文件实践，以确保在整个运营过程中保留同期、可归因、清晰、完整、原始和准确的记录。

1.5.7.Describe plans to prevent manipulation and enhance control of all CGMP records. Specifically, describe reconciliation and integrity improvements for all CGMP records that may be in loose form or otherwise vulnerable to manipulation. Based on an independent review by a qualified consultant, provide a gap analysis and specific CAPA measures will take to safeguard integrity of records (e.g., recording data in logbooks, pre-paginated documents, and validated electronic systems).

描述防止操纵和加强对所有CGMP记录的控制的计划。具体来说，请描述对所有CGMP记录的对账和完整性改进，这些记录可能形式松散或容易被操纵。根据合格顾问的独立审查，提供差距分析和将采取的具体CAPA措施，以保障记录的完整性（例如，记录日志中的数据、预先分页的文件和经过验证的电子系统）。

1.5.8.Corrective action and preventive action (CAPA) plan to implement routine, operations management oversight of facilities and equipment. This plan should include, at a minimum:

纠正措施和预防措施（CAPA）计划对设施和设备实施日常运营管理监督。该计划至少应包括：

1.5.8.1.Improved production management oversight that ensures prompt detection of equipment, facility, and process performance issues.

改进生产管理监督，确保及时发现设备、设施和过程性能问题。

1.5.8.2.Timely upgrades to equipment and facilities.

及时升级设备和设施。

1.5.8.3.Adherence to appropriate preventive maintenance schedules.

遵守适当的预防性维护计划。

1.5.8.4.Effective execution of repairs.

有效执行维修。

1.5.8.5.Allocation of appropriate resources, staffing, and competencies.

分配适当的资源、人员和能力。

1.5.8.6.Appropriately qualified production supervisors and managers.

合格的生产主管和经理。

1.5.8.7.Improved systems for ongoing management review.

改进了持续管理审查的系统。

1.5.8.8.A provision(s) that appropriate actions are taken throughout the company network.

在整个公司网络中采取适当行动的规定。

2.A thorough evaluation and risk assessment that addresses the suitability of equipment for its intended use. Include an evaluation whether equipment is of appropriate design and ongoing control and maintenance program is effective.

全面的评估和风险评估，以确定设备是否适合其预期用途。包括评估设备是否具有适当的设计以及持续控制和维护计划是否有效。

3.Failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications.

未能彻底调查批次或其任何组件不符合其任何规格的任何无法解释的差异或故障

3.1.Lacked investigations into visual inspection failures and non-viable particulates (NVP) exceeding your action levels.

缺乏对目视检查失败和超出行动水平的非活性颗粒物（NVP）的调查。

3.2.There was no characterization of the particulates found in the batch to determine if they were intrinsic, extrinsic, or inherent to the product.

没有对批次中发现的颗粒物进行表征，以确定它们是内在的、外在的还是产品固有的。

3.3.In addition, there was no documented breakage of vials in the filling batch record. Closed the investigation without identifying the root cause or identifying the source of the white or glass particles.

此外，灌装批次记录中没有记录到西林瓶破损的记录。未确定根本原因或确定白色或玻璃颗粒的来源的情况下关闭了调查。

Recommended measure建议性措施：

3.3.1.It is important that any visible particulate contamination is appropriately evaluated and investigated. Visible particulates in injectable products should be avoided through appropriate preventive measures built into your design and production controls. When categorizing any visible particles, extrinsic or foreign matter should receive special attention, as it may indicate possible microbial contamination. Extrinsic or foreign particulate contamination should occur very infrequently, and be thoroughly investigated and appropriate CAPA implemented.

重要的是，对任何可见的颗粒物污染进行适当的评估和调查。注射产品中可见的颗粒物应通过设计和生产控制中内置的适当预防措施来避免。在对任何可见颗粒进行分类时，应特别注意外在或异物，因为它可能表明可能存在微生物污染。外来或外来颗粒物污染应很少发生，并应进行彻底调查并实施适当的CAPA。

3.3.2.A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification (OOS) results, and failures. Provide a detailed action plan to remediate this system. Action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality assurance oversight, and written procedures.

对整个系统进行全面、独立的评估，以调查偏差、差异、投诉、不合格 （OOS） 结果和故障。提供详细的行动计划来修正此系统。行动计划应包括但不限于调查能力、范围确定、根本原因评估、CAPA 有效性、质量保证监督和书面程序的重大改进。

3.3.3.An independent, retrospective evaluation of all ISO 5 NVP deviations, root causes, and a relevant CAPA plan.

对所有 ISO 5 NVP 偏差、根本原因和相关 CAPA 计划进行独立的回顾性评估。

4.Failed to establish adequate written procedures for production and process controls designed .

未能建立足够的生产和过程控制书面程序

4.1.Failed to provide adequate challenge test set vials

未能提供足够的挑战测试集小瓶

4.2.Quality unit personnel have not maintained a defect library for training purposes or reference.

质量单位人员没有维护缺陷库以供培训或参考。

4.3.Failed to adequately validate the manufacturing process for tablets.

未能充分验证片剂的制造工艺。

4.4.The process validation study, and commercial manufacturing data, did not provide sufficient assurance of that process consistency is maintained throughout production batch operations.

工艺验证研究和商业制造数据未能充分保证在整个批量生产操作中保持工艺一致性。

Recommended measure建议性措施：

Comprehensive risk assessment of all contamination hazards with respect to aseptic processes, equipment, and facilities, including an independent assessment that includes, but is not limited to:

关于无菌工艺、设备和设施的所有污染危害的全面风险评估，包括独立评估，包括但不限于：

4.4.1.All personnel interactions within the ISO 5 area.

ISO 5区域内的所有人员互动。

4.4.2.Equipment placement and ergonomics.

设备放置和人体工程学。

4.4.3.Air quality in the ISO 5 area and surrounding room.

ISO 5区域和周围房间的空气质量。

4.4.4.Facility layout.

设施布局。

4.4.5.Personnel Flows and Material Flows (throughout all rooms used to conduct and support sterile operations).

人员流动和物质流动（在用于进行和支持无菌操作的所有房间内）。

4.4.6.A detailed remediation plan with timelines to address the findings of the contamination hazards risk assessment. Describe specific tangible improvements to be made to aseptic processing operation design and control.

详细的补救计划和时间表，以解决污染危害风险评估的结果。描述无菌处理操作设计和控制的具体具体改进。