上海煜品

一、 目的：

      当前药用一次性使用系统广泛应用于上游加工，同时下游加工和最终灌装也逐步扩大应用，因此终端用户必须充分了解和验证其与生物制药溶液和最终药物产品的相互作用。为确保产品质量，制药行业在工艺开发的初期以及在工艺监测和质量控制的范围内进行全面的分析测试,以证明药品的纯度、功效和安全性。产品安全评估研究是在设计和开发一次性生产过程中进行的。这些验证研究需要对浸出物进行完全的定量、识别和毒理学评估，浸出物是指药液和药用一次性使用系统相互作用而存在于药液中的物质。浸出物是可从药用一次性使用系统中提取的可提取物的子集，可提取物使用的提取溶剂和提取条件比通常的使用条件更加剧烈。本指南的目的是提供最糟糕情况下可提取物的数据，以支持工艺开发人员和毒理学家验证研究。

     药用一次性使用系统中最为常见的一次性使用多层共挤袋的安全性问题一直是众多制药企业最为担心的，特别是袋子和液体料液的兼容性问题。针对这类次性使用的袋子，国内外暂没有官方政策法规对此进行规范约束。参考国外原材料供应商的技术资料、国内CDE已经发布的相容性研究技术指导原则(国内已有《化学药品注射剂与药用玻璃包装容器相容性研究技术指导原则(试行)》、《化学药品注射剂与塑料包装材料相容性研究技术指导原则〈试行)》、《化学药品与弹性体密封件相容性研究技术指导原则(试行)》;中国食品药品国际交流中心在2017年11月出版了《一次性使用系统应用及技术指南》)、SUS相关组织制定的技术指导原则、美国药典委员会USP<665>和USP<1665>等制定出合理的一次性袋子溶出物测试方案。

药用一次性使用系统潜在的溶出物质,可能来自塑料加工过程中的表面活性剂、润滑剂和添加剂等，也可能来自材料结构的原材料及低聚物单体的脱落等。本研究报告总结了药用一次性使用系统主要参考USP<665>指导文件，在3种模拟溶剂中元素和有机化合物(不挥发性化合物、半挥发性和挥发性化合物、小分子挥发物)的可提取物信息。元素由电感耦合等离子体-质谱仪(ICP-MS)和电感耦合等离子体-发射光谱仪(ICP-OES)进行检测、不挥发性化合物由超高效液相质谱仪(LC-MS/MS)和超高液相色谱仪（HPLC)进行检测，半挥发性和挥发性化合物由气相色谱仪-质谱仪(GC-MS)进行检测，小分子挥发物由顶空进样-气相色谱仪–质谱仪(HS-GC-MS)进行检测。 

二、 毒理学

在测试前,需对分析评价阈值(AET)进行了确认,根据产品质量研究协会(PQRI指导原则的建议，AET为一个阈值，当某个化合物的浓度超过该阈值时，化学家应对该化合物进行鉴定、定量和报告，并且可能提交到毒理学家进行毒理评估。AET根据合适的安全评估阈值(SCT)或者毒理关注阈值(TC）等并结合产品的给药剂量转换而来，当某个可提取物的浓度低于该阈值时，可认为该化合物的含量非常低，不会对人体产生危害。

三、 USP 665介绍

Pharmaceutical and biopharmaceutical manufacturing processes are the sum of the steps that convert starting raw materials

into a biopharmaceutical drug substance (DS) or a pharmaceutical or biopharmaceutical drug product (DP). Manufacturing processes use components and parts that may be fully or partially constructed from plastic materials. Plastic components will likely contact one or more manufacturing process streams, from starting materials to the DP. Such contact between the process stream and the manufacturing component could lead to the release of extractables, heretofore referred to as process equipment-related leachables (PERLs), into the process stream where they could alter the effectiveness or efficiency of subsequent processing operations. Furthermore, should the PERLs persist in the process stream through the entire manufacturing process, they would accumulate in the DP, where they could potentially have an adverse effect on DP quality and/or patient safety.

To ensure that plastic materials and components used in manufacturing operations are suitable for their intended use, they should be:

• Composed of components that are suitable for use and compatible with biopharmaceutical DSs, pharmaceutical or biopharmaceutical DPs, and all process intermediates and/or process streams

• Functional (out of chapter scope)

四、 USP 1665介绍

A manufacturing process is the sum of the steps required to convert starting raw materials into a manufactured

biopharmaceutical drug substance (DS) or a pharmaceutical or biopharmaceutical drug product (DP). Manufacturing processes are performed utilizing manufacturing systems which are the sum of the components that together comprise the equipment that converts starting raw materials into biopharmaceutical DSs or pharmaceutical or biopharmaceutical DPs.

Manufacturing systems can be partially or completely constructed from plastic materials. Plastics used in manufacturing systems possess a range of molecular weights and contain plastic additives such as antioxidants, stabilizers, lubricants, plasticizers, and colorants. Several factors dictate the types of plastics that are used in manufacturing components, the types and amounts of additives and polymeric resins that are used in plastic materials and the processes used to convert the plastic materials into components or systems.

The process stream, production intermediates, DS, or the DP itself could directly come in contact, and potentially interact, with one or more plastic components of the manufacturing system at some point during the manufacturing process. During contact, substances could leach from a manufacturing component and become incorporated into the process stream. If these substances persist in the process stream through subsequent process operations, they could accumulate in either a DS or DP as process equipment-related leachables (PERLs). If they are present in the DP, PERLs have the potential to alter critical quality attributes of the DP, such as safety, efficacy, and stability.

Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products á665ñ addresses these interactions by providing a risk-based means for chemically characterizing and qualifying plastic components used to manufacture biopharmaceutical DSs and pharmaceutical and biopharmaceutical DPs. That chapter provides guidance on qualification procedures applicable to manufacturing components and systems that are within its

unicates the key concepts behind and provides additional information and guidance regarding

the applicability and the application of á665ñ.

五、实验涉及文献

1. USP<665>PLASTIC MATERIALS,COMPONENTS,AND SYSTEMS USED IN THE

MANUFACTURING OF PHARMACEUTICAL DRUG PRODUCTSAND

BIOPHARMACHEUTICAL DRUG sUBSTANCESAND PRODUCTS

2. USP<1665>CHARACTERIZATION OF PLASTIC MATERIALS,COMPONENTS,AND

SYSTEMS USED IN THE MANUFACTURING OF PHARMACEUTICAL DRUG PRODUCTS

AND BIOPHARMACEUTICAL GRUG SUBSTANCESAND PRODUCTS

3. BPOG Best Practices Guide for Evaluating Leachables Risk in Biopharmaceutical Single-Use Systems

4. BioPhorum best practices guide for extractables testing of single-use components

5. ICH Q3D(R1)元素杂质指导原则

6. ICH M7(R1)评估和控制药物中DNA反应性(致突变）杂质以限制潜在致癌风险

7.一次性使用系统应用及技术指南

链接USP<665>塑料材料、组件和系统医药药品的制造和生物制药药物种类及产品

链接USP<1665>塑料材料、部件和用于药品制造的系统和生物制药原料和产品