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卓琦质量：专注质量，深耕质量，提高质量
随着中国制药的崛起，越来越多的中国原料药和制剂都走出了国门。但是，原料药和制剂的所有研究也并非仅由原料药企业和制剂企业来完成。基于研究设备、研究能力和研究效率的考虑，有部分研究，如晶型研究、元素杂质分析、基因杂质研究等，可能会委托第三方进行。根据延申检查规则，委托的第三方也需要接受官方检查。
相对原料药和制剂公司，第三方接受官方检查的经验比较少。分享一次FDA现场检查第三方公司的感受。
1.背景：
国内某制剂公司有一个仿制药申报美国上市，但该制剂的原料药公司没有晶型检测设备，需要委托有能力的第三方进行晶型检测。该第三方公司为一家研发公司。申报过程中，FDA发起了对该晶型检测的研发公司延伸现场检查。
2.检查准备：
在现场检查前，FDA检查官给研发公司发了一份要准备的资料清单（见FDA通用准备资料清单）。本次检查的研发公司仅是承接一项晶型检测。从这份清单中可以看出，部分资料不适用。
3.检查过程：
3.1首次会议：
该研发公司准备的首次会议PPT，除了FDA要求的内容外，还将晶型检测样品的接收、检测、报废的流程，原料药厂家与研发公司的沟通流程，晶型检测涉及的相关文件都详细的列在了PPT中。
从效果来看，非常符合检查官需求、很满意（个人理解：让检查官感觉企业质量管理的重点，不仅是企业自信的体现、也有助于检查官的检查快速和高效）。直接表示要打印这几页PPT，拿到实验室现场去。后面实验室现场的检查基本就是按照这几张PPT的内容检查的。
3.2实验室现场检查：
按照首次会议PPT中提到的样品相关的流程，检查官到现场去检查了相应的台账记录，询问了一些特殊情况的处理，如发现不合格如何处理。同时，台账上的一些异常情况也会引起检查官的注意。如，有一个批次的原料药在接收后，原料药公司临时中断了检测，在台账上体现了相关的信息。检察官就问了原料药公司与研发公司之间的信息如何传递等信息。
除了检查流程和相关记录外，现场操作也是FDA的检查重点。检查官围着晶型测定的设备看了好几圈，设备校验是重点。并要求操作人员现场操作是如何检测晶型的。基本上除了没有用样品外，完全是按照日常的检测流程来进行了一次无实物表演。这要求操作的人员一定要非常熟悉日常操作，否则很容易慌张，被检察官问住。
数据完整性是FDA必问的。针对该项目，主要问了审计追踪是否可以关闭等问题。
3.3软件检查：
围绕着晶型检测这个项目，查了测试方法文件、方法学验证文件、设备操作规程、偏差、OOS、变更等。其中关于晶型的结果判断，检查官对照图谱和标准的专利图谱进行了逐一核对，不放过每一个细节。在方法学验证和日常检测中，研发公司都是按照原料药公司提供的标准图谱去核对。检查官提出应定期使用标准品去核对。
对整个质量体系，基本是按照ICH Q10的要求来的。一般的质量要素，如：变更、偏差培训等，所有公司基本都已有建立。但对于研发公司，比较容易忽视的是质量手册。大家可以去看看ICH Q10的适用范围，是包括药物研发环节的。关于培训，检查官提出要每年都要培训GMP并要有考核。
个人体会：
1. 即使是研发公司，也要按照ICH Q10的要求建立完整的药品质量体系。ICH Q10，值得企业，特别是研发企业去研究。
2. 因为语言的关系，FDA检查官要求很多文件都需要翻译成英文。最好提前做好准备，同时现场要有及时响应翻译的能力，这样才能给检查官留下好印象。
3. 有些观点在CRO（contract research organization, 合同研发服务）或CDMO (contract development and manufacturing organization, 合同研发和生产业务)公司，有一定的借鉴作用。
延伸资料清单：
1. At the opening meeting provide a presentation (presentation copy for each of us) including at least :
a. Brief history of the company
b. Firm facilities overview including physical location and mailing addresses.
c. Firm Contact person and US Agent name, address, phone number(s), and email;
d. Description of manufacturing operations;
e. Management organizational structure with names and titles;
f. List of manufactured products intended/or approved for the US market including ANDA/NDA # and the application holder name and address;
g. List of manufacturing change for the API subject to the inspection;
h. List of batches shipped to the US market;
i. List of manufactured products not intended for the US market;
j. Facility description/layout (provide diagrams and square footage of each major area and the entire site) of the site inspected;
k. Manufacturing processes diagrams (identify QA/QC samples collection, major equipment, critical process parameters and critical quality attributes);
l. Processes flow charts, major equipment, critical process parameters, critical quality attributes;
m. QA/QC samples collection procedures.
2. Current company organizational charts. Including: quality assurance, quality control areas.
3. Quality Unit Responsibilities.
4. A summary description of the QC Department including its laboratories （Chemistry/ Microbiology /Stability）and locations as well as the amount of QC employees and managers.
5. Firm facilities overview including physical location and mailing addresses.
6. US Agent name, address ,number(s), and email.
7. Name and address of the distribution warehouses for USA products.
8. Indicate the operation schedules (hours/days) and amount of shift. Number of employees per group or division (e.g. QA, Production, QC, Materials, Administration).
9. Copy of the most current FDA drug registration; provide updated firm name, address, phone number, website, contact person(s); address of US Headquarters and/or US Affiliates.
10. Layout of the facility – each manufacturing area /building (provide diagrams and square footage) and flow of material and personnel around the site.
11. List of Annual Product Reports/Reviews for USA products (have the reports available for review).
12. List of the automated systems (software applications) used throughout the operations (Brand the Mode and for what it is used for), including production lines, if applicable.
13. Contract Manufacturers and Laboratories (if any), type of service, name and address.
14. List of field alert reports since the last inspection.
15. All field alerts and /or submitted to the agency since the last inspection.
16. List of the current SOP.
17. Training procedure – for all the employees narrative description of the current program).
18. Procedure for lot number assignment (narrative description of the lot numbering system with an example of the lot number).
19. Procedure for Recalls /List of recalls since the last inspection (include lots numbers/ investigations). Provide a narrative description of the recall procedure.
20. Procedure for returned goods (if applies) or list of returned products.
21. Specifications for final drug products.
22. Procedure of Change Controls.
23. List of change controls last 2 years- an excel electronic list containing the date, brief description of the change, the implementation date.
24. Procedure for consumer complaints (name/address of the office handling the complaints).
25. List of consumer complaints last 2 years – excel electronic list including the complaint number, receiving date, brief description of the claim, investigation conclusion, corrections and closing date.
26. List of complaints (last 2 years) to your current suppliers (vendors) and current SOP.
27. List of all stability batches -Excel electronic list including the product name, lot# and stability interval, investigation number, description and conclusion, corrections (if any).
28. List of finished and in-process lots rejected -Excel electronic list including the reasons for rejection and investigation number, description and conclusion (last 2 years).
29. Plant Investigation Procedures (events, deviations, investigations, non-conformances)- Narrative description of the current non-conformance process and indicate if a software is used to handle the non-conformances, complaints ,OOS, change control (example: Track Wise or other); when it was implemented the current version.
30. List of manufacturing discrepancies /deviations, last 2 years- Excel electronic list including product name, brief description, lots involved, conclusions and (corrections if any).
31. Laboratory OOS Investigations SOP-Narrative description of the current procedure.
32. List of out-of-specification (OOS) results, last 2 years -Excel electronic list including investigation description, lot numbers involved, and conclusions.
33. Copy of CAPA SOP.
34. Procedures for cleaning (validation) and sanitization for manufacturing equipment units.
35. List of manufacturing equipment units shared -by area.
36. Packaging area cleaning procedures -for bulk and summary of the packaging and labeling process as applicable to the scope of the inspection.
37. Labeling Inventory and Procedures for reconciliation and dispatch. Copies of labels for USA products.
38. List of the Approved Suppliers (and SOP for supplier qualification) – electronic list including the API material, component and the product in which these are used.
39. List of raw materials, in-process and finished products (API’s and /or finished products) with temperature and humidity requirements.
40. Diagram for the Water System- electronic copy.
41. Water Analyses （chemistry and micro） frequency and results, A narrative description of the water system (include a description of all filters by type, size, and manufacturer, maintenance /cleaning /sanitizing schedule). Description of the water treatment and monitoring program and trending of test results (past 2 years); tests conducted; alert/action limits or acceptance criteria.
42. Description concerning the use of wooden pallets; how these are handled and treated.
43. Corrections proposed and implemented to the observations or verbal discussion items cited during previous inspections, if applicable.
44. Provide the following documents:
a. A narrative summary of environmental monitoring program including the frequency of monitoring and limits /criteria.
b. Copy of last environmental monitoring trend report and a copy of the SOP.
“卓琦”团队致力于从事质量改进、传递质量兴趣。我们致力于建立一个解决问题的平台，让每个人既能发挥自身特长、又可相互学习。我们以“专注质量，深耕质量，提高质量”为宗旨；用科学指导质量，让习惯灌输日常，使兴趣创造思维。让质量回归质量！加入我们，一起合作，一起面对；传播正能量，持续改进你、我、他！
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