PIC/S更新备忘录：与包装相关的GMP检查

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1月19日，国际药品检查组织(PIC/S)更新了四篇检查相关的备忘录：

• 公用系统检查备忘录PI 009-4 Aide Memoire on Utilities
• 生物技术检查备忘录PI 024-3 Aide Memoires on Biotech
• 包装检查备忘录PI 028-2 Aide Memoire on Packaging
• 评估QRM实施备忘录PI 038-2 Aide Memoire on Assessment of QRM Implementation
  

以下是包装检查备忘录的内容，供参考：

1. 文档历史

Adoption by Committee  31 October 2008

Entry into force 1 March 2009

委员会通过: 2008年10月31日

生效: 2009年3月1日

2. 介绍

2.1. The process of packaging of medicinal products is listed among the risk factors that may affect the quality of the finished medicinal products and may also cause mix-ups.

对于可能会影响成品制剂质量并可能造成混淆的风险因素，需要将药品包装工艺列在其中。

2.2. The increased number of the defects of medicinal products occurred due to deficiencies in the process of labelling and packaging has drawn inspectors’ attention towards the need for identifying and clarifying the critical aspects of this specific stage of inspection, in order to have a uniform interpretation of the provisions of the current GMP guide concerning packaging of medicinal products and prevention of mix-up.

由于贴标和包装工艺中的缺陷而导致的药品缺陷数量增加，这引起了检查员的关注，即需要识别和澄清这一特定检查阶段的关键方面，以便对当前GMP指南中有关药品包装和防止混淆的规定有一个统一的解释。

2.3. In the light of technological progress, considering the wide variety of medicinal products developed, the 2005 PIC/S Seminar (Bucharest, Romania) was dedicated to the GMP inspection of the final stage of manufacturing process (primary and secondary packaging, labelling).

鉴于技术进步，考虑到所开发的多种药品，2005 PIC/S研讨会（罗马尼亚布加勒斯特）讨论GMP检查，专门致力于生产工艺的最后阶段（内包装和次级包装、贴标）。

The first version of the Aide-Memoire is the outcome from the 2005 PIC/S Seminar with the latest version providing updated cross-reference to the PIC/S GMP Guide PE 009-14.

备忘录的第一版是2005年PIC/S研讨会的成果，最新版本提供了对PIC/S GMP指南PE 009-14的更新交叉引用。

3.目的

3.1. The purpose of this document is to provide guidance for GMP inspectors in preparation for inspections. This document aims to define the minimal requirements acceptable for an inspector as well as the requirements that provide maximum safety for the finished product (“best practices”).

本文档的目的是为GMP检查员准备检查提供指南。本文档旨在界定检查员可接受的最低要求，以及为最终产品提供最大安全性的要求（“最佳实践”）。

3.2. The Aide-Memoire should enable the inspector to assess the GMP compliance of the packaging process using the quality risk management tools.

备忘录使得检查员能够使用质量风险管理工具，评估包装工艺的GMP符合性。

4. 范围

4.1 The following Aide-Memoire describes different areas which could be evaluated during the GMP inspection of packaging and labelling process. However, the Aide- Memoire should be considered as a non-exhaustive list of areas to be looked at during an inspection.

针对包装和贴标工艺的GMP检查，以下备忘录介绍了其中可以评估的不同区域。但是，备忘录应视为检查期间要检查的区域的非详尽列表。

4.2 At the time of issue, this document reflected the current state of the art. It is not intended to be a barrier to technical innovation or the pursuit of excellence. The advice in this Aide-Memoire is not mandatory for industry. However, industry should consider PIC/S recommendations and Aide-Memoires as appropriate.

在发布时，该文档反映了当前的最新状态。它无意成为技术创新或追求卓越的障碍。本备忘录中的建议并非行业必需的。但是，行业应酌情考虑PIC/S建议和备忘录。

5.  备忘录

1.1 Quality and purchasing 质量与采购

Notes:

• purchasing from approved suppliers;

• auditing the manufacturing sites of suppliers of primary packaging materials for sterile products (vials, rubber stoppers, syringes, etc.) and of printed materials;

• compliance with specifications;

• up-dating the documents (quality specifications), in accordance with the marketing authorization and any subsequent variations;

• delivery from supplier made such as to preserve the quality (to prevent contamination).

关注点：

•从批准的供应商处采购；

•对无菌产品（小瓶、橡胶塞、注射器等）内包装材料和印刷材料供应商的生产场所，进行审计；

•符合质量标准；

•根据上市许可和任何后续变更更新文件（质量标准）；

•供应商交货方式可以确保质量（防止污染）。

Crucial questions:

• What is the policy for suppliers’ approval?

• Show me the audit report

• Do the primary materials specifications comply with the Pharmacopoeial parameters and limits?

关键问题：

•批准供应商的政策是什么？

•给我展示：审计报告

•内包材质量标准是否符合药典参数和限度？

1.2 Receipt 接收

Notes:

• quality documents: certificates of analysis;

• checking the conditions for packages shipment and handling;

• integrity checks and identification of each batch of primary packaging material or printed material received;

• de-dusting and cleaning of packages on the outside (separate area).

关注点：

•质量文件：分析证书；

•检查运输和处理条件；

•对收到的每批内包材或印刷材料，进行完整性检查和鉴别；

•在外部（分开的区域）对包装进行除尘和清洁。

Crucial questions:

• Show me the records and SOPs which apply when receiving primary packaging materials or printed materials

• Describe internal labelling system

关键问题：

•给我展示：接收内包材或印刷材料时适用的记录和SOP

•描述内部贴标系统

1.3 Storage areas 储物区

Notes:

• adequate capacity, order and organization, location plan available;

• the cleaning status, procedure and records;

• physically separated areas for “quarantine”, “approved”, “rejected/recalled” materials or a system that provides similar safety;

• secured conditions (physically separated areas, controlled, authorised access) for storage of primary and secondary printed materials (cartons, labels, leaflets);

• storage of one batch per pallet – when the number of recipients allows -, without mixing batches on the same pallet ;

• storage conditions adequate to each category of materials (qualification of the ventilation, air conditioning unit, critical parameters monitoring – temperature, humidity);

• existence of an efficient system to prevent entrance of rodents, insects or other animals;

• adequate control over destruction of materials.

关注点：

•有充分的容量、次序和组织，有位置图；

•清洁状态、程序和记录；

•有物理上分开的区域，用于“隔离”、“批准”、“拒绝/召回”材料或提供类似安全性的系统；

•储存内包材和印刷材料（小盒、标签、说明书单）的安全条件（物理上分开的区域，受控的授权访问）；

•在接收数量允许时，每个货盘存储一批货物，不得在同一货盘上混合批次；

•适合每种材料类别的存储条件（通风条件、空调设备、关键参数监控–温度，湿度）；

•存在有效系统，防止啮齿动物、昆虫或其他动物进入；

•对于材料破坏，有充分控制。

Crucial questions:

• Show me the seasonal/annual trends and results of temperature and humidity monitoring

• Show me the location plan and records concerning these activities

关键问题：

•向我展示：温度/湿度监测的季节性/年度趋势和结果

•向我展示：这些活动的位置图和记录

1.4 Quality control 质量控制

Notes:

• sampling plan and conditions, according to the material being sampled;

• specific laboratory equipment for the testing of packaging materials;

• testing of packaging materials/packages in accordance with the methodology approved in the marketing authorization (functionality tests according to the manufacturer specification and tests according to current edition of relevant pharmacopoeia);

• integrity testing for primary packaging, differentiated for each category of finished products (when applicable);

• in-process controls with relevance for the quality of the primary packages used (weight, filling level, blister scan, leak test, verification of the printing of labels, bar code reader challenges);

• assessment of the integrity for a sterile product packaging.

关注点：

•根据所取样的材料，制定取样计划和条件；

•用于测试包装材料的专用实验室设备；

•按照上市许可中批准的方法，对包装材料/包装进行测试（根据生产商质量标准进行功能测试，以及根据当前版本的相关药典进行测试）；

•对内包装进行完整性测试，针对每种成品类别进行区分（适用时）；

•与内包装装质量相关的过程控制（重量、灌装水平、泡罩扫描、泄漏测试、标签打印确认、条形码读取器挑战）；

•评估无菌产品包装的完整性。

Crucial questions:

• Show me the sampling plan and records for primary packaging materials (including labels)

• Show me the approved specification and current results from internal testing

• Show me the certificates issued by QC for one or more of these materials / packages used for primary packaging

关键问题：

•向我展示：内包装材料（包括标签）的取样计划和记录

•向我展示：批准的质量标准和内部测试的最新结果

•向我展示：QC签发的用于内包装的一种或多种材料/包装的报告单

1.5 Manufacturing premises (packaging area) 生产场所（包装区域）

Notes:

• designed and built-up to minimise the risk of contamination and mix-up - enough space, logical positioning of packaging equipment, separation of each and every primary and secondary packaging line (different cleanliness levels);

• qualification (IQ, OQ, PQ) of utilities (HVAC, PW, WFI, sterile steam, inert gases used, if applicable);

• monitoring of environmental conditions based upon the nature of the product (sterile or non-sterile).

关注点：

•设计和建立以下方面，以最大程度地减少污染和混淆的风险-足够的空间、包装设备的合理放置、每条内包装和外包装线的分隔（不同的洁净度）；

•公用系统（HVAC、PW、WFI、无菌蒸汽、所用惰性气体——如适用）的确认（IQ、OQ、PQ）；

•根据产品的性质，监控环境条件（无菌或非无菌）。

Crucial questions:

• Show me the qualification (IQ, OQ, PQ) of utilities used inside the primary packaging area

• Show me the results of environmental monitoring (especially for primary packaging of sterile products)

• How is the access ensured for products/ materials and personnel to production areas?

关键问题：

•向我展示：内包装区域内使用的公用系统的确认（IQ、OQ、PQ）

•向我展示：环境监测的结果（尤其是无菌产品的内包装）

•对于产品/材料和人员进入生产区域，如何进行保障？

1.6 Packaging equipment and process 包装设备及工艺

Notes:

• high performance, qualified and well-maintained equipment, able to ensure the control during the primary/secondary packaging;

• line clearance (working area, packaging lines, label printing machines and other equipments should be clean and free from any other products, materials or documents previously used);

• content of adequate level of details on the checklist for line clearance;

• line cleaning;

• cleaning of dust extractors

• checking of the type of label used and its attachment on the primary package;

• the presence of safety elements of the package (to prevent the counterfeit);

• validation of the packaging process (critical process operation) – protocol, report and records;

• adequate functioning of electronic devices to establish identity, such as barcode or RFID readers.

• waste handling

关注点：

•高性能、已确认且维护良好的设备，能够确保在内/外包装工艺中的控制；

•生产线 清场（工作区域、包装线、标签印刷机和其他设备应保持清洁，且没有任何其他先前使用过的产品、物料或文件）；

•检查清单上足够详细的内容，以确保生产线清场；

•生产线清洁；

•除尘器清洁

•检查所用标签的类型，及其在内包装上的粘贴；

•包装中有安全元件（以防假冒）；

•验证包装工艺（关键过程操作）–方案、报告和记录；

•电子设备（例如条形码或RFID读取器）具有足够的功能，以进行鉴别。

•废物处理

Crucial questions:

• Show me the SOP and records of the line clearance

• Show me the checklist used for line clearance

• IQ, OQ, PQ and CQ

• Show me the qualification/validation of the packaging equipment/process

• Show me the calibration and maintenance records for the packaging line

• Show me the SOP and program for mix-up prevention

关键问题：

•向我展示：生产线清场SOP和记录

•向我展示：用于生产线清场的清单

•IQ、OQ、PQ和CQ

•向我展示：包装设备/工艺的确认/验证

•向我展示：包装线的校准和维护记录

•向我展示：防止混淆的SOP和程序

1.7 Documents 文档

Notes:

• batch packaging records (BPR) – on paper or electronic form (attention paid to level of access, electronic signature, etc.) for every batch or sub-batch manufactured;

• SOPs and instructions for reconciliation, especially for the printed materials (including investigation of any discrepancy noticed and solving before batch release);

• defined and adequate action limits regarding reconciliation;

• adequate control of return in storage area of excess packaging materials;

• adequate and documented investigation of packaging process deviations.

关注点：

•批包装记录（BPR）–每生产一批或亚批的纸质或电子形式（注意访问级别、电子签名等）；

•物料平衡的SOP和指导，特别是印刷材料（包括对发现的任何差异进行调查，并在批放行之前解决）；

•关于物料平衡的已规定且适当的行动限；

•对于多余包装材料的退货存放区，进行充分控制；

•对包装工艺中的偏差，进行充分的书面调查。

Crucial questions:

• How do you ensure the security of the data entry in the electronic BPR?

• Show me the records of investigation of any discrepancies noticed during reconciliation?

• How did you investigate the packaging process deviations?

• Show me the SOP for handling the obsolete or damaged printed packages

关键问题：

•您如何确保电子BPR中数据输入的安全性？

•向我展示：对于物料平衡期间发现的任何差异，其调查记录

•您如何调查包装工艺中的偏差？

•向我展示：处理过时或损坏的印刷包装的SOP

1.8 Personnel 人员

Notes:

• adequate in terms of qualification and training regarding hygiene practices, clothing and operation on particular packaging equipments;

• knows and applies the procedures regarding the activity performed;

• performs operation reliably and with no impact on the quality of the product;

• training of maintenance personnel and contractors.

关注点：

•在卫生习惯、更衣和特定包装设备操作方面的资质和培训方面，是充分的；

•了解并应用有关所进行活动的程序；

•可靠地执行操作，而不影响产品质量；

•有关维护人员和合同的培训。

Crucial questions:

• Show me the records of medical checks for operators working in primary packaging area.

• Observe and discuss with personnel involved in the packaging process, to see the level of their knowledge on the operations they perform

• Show me the records of training on line clearance SOP

关键问题：

•向我展示：在内包装区域工作的操作员的医疗检查记录。

•观察并与包装工艺中涉及的人员进行讨论，以了解他们对所执行操作的了解程度

•向我展示：现场清场SOP的培训记录

1.9 Quality assurance 质量保证

Notes:

• Quality policy, risk management, risk assessment

• self inspection system (frequency based on the critical aspects of packaging materials/ processes, taking into account the number and gravity of the quality defects and taking the appropriate preventive and corrective measures);

• investigation of complaints to identify the package/ packaging related cause;

• assessment of the change control impact on the package/packaging of the finished product, during the whole shelf life of the product;

• release procedure on printed and primary packaging materials;

关注点：

•质量方针、风险管理、风险评估

•自检系统（基于包装材料/工艺的关键方面的频率，考虑到质量缺陷的数量和严重程度，并采取适当的预防和纠正措施）；

•调查投诉，确定包装的相关原因；

•在产品的整个有效期期内，评估变更控制对成品包装的影响；

•印刷和内包装材料的放行程序；

Crucial questions:

• Show me the self inspection plan and outcome

• How did you investigate the complaints related to packaging?

关键问题：

•向我展示：自检计划和结果

•您如何调查与包装有关的投诉？

Ref.: PI 028-2 Aide Memoire on Packaging. PIC/S. 19 January 2021

baixuedajie

感谢分享，多谢！

张杨1

感谢分享，多谢！！