PFS manufacturing process for biotech生物制剂用预灌封注射器 制造工艺

Alessandro Morandotti, Product Manager Syringes欧璧注射器产品经理 Alessandro Morandotti

CNPPA，2016 年 9 月 9 日

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Outline大纲

• Market overview (up to date and in the next 5 years)市场概览（最新及未来 5 年）

• Market evolution 市场发展• Syringe Segmentation 注射器细分• Injectable trend 注射剂趋势

• PFS and sensitive drugs:预灌封注射器和敏感药物：

• Existing technical challenges aspect to be considered during development of PFS:预充针开发过程中要考虑的现有技术难题：

• Silicone treatment (silicone quantity and components selection)硅化处理（硅油量和配件选择）

• Autoinjectors integration 自动注射笔适配组装

• New option for high sensitive drugs 高敏感药物的新选择

• State of the art manufacturing process and control strategy尖端制造工艺与控制策略

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Trends: injectables blockbuster趋势：注射剂迅速发展

注射剂需求至2018年均复合增长率达4%-7%

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Worldwide Market Trend on Injectable Drugs注射剂药物全球市场趋势

PFS are widely used for administering vaccines, heparin, biotech drugs

预充针广泛用于疫苗、肝素和生物技术药物给药

Responsibilities are transferred to Patient or Caregiver

(easy-of use and compliance as consequence)

职责转移至患者或看护人员（易于使用并且

符合法规）

Increasing standards are driving demand for high quality products also in

emerging markets越来越多的标准正在推动高质量产品进入新兴市场

的需求

Self-Administration自我给药

+3 bn of PFS on the

market市面现有

+30 亿 预充针

More safety更加安全

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Focus on Prefilled Syringes对预灌封注射器的关注

Source: Roots Analysis 2013数据来源：Roots Analysis 2013

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NEEDLE TYPE

针头类型

MATERIAL材料

Plastic,0,5%塑料预充针，0.5%

Glass 99,5%玻璃预充针99.5%

Bulk,10%普通未灭菌，10%

Sterile90%无菌90%

Luer Lock,30%鲁尔式无针注射器 30%

Staked Needle70%带针注射器70%

BULK/RTU未灭菌/预充针（无菌）

3BN Units30亿件

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Injectable Delivery Trend注射剂给药趋势

Prefilled Syringes and Cartridges, both sterile and Ready to fill, are the fast growingcontainers for injectable drugs.

预灌封注射器和卡式瓶（无菌、预灌封）是快速增长的注射剂药包材。

1980sInsulin:

First biologicdrug

上世纪 80 年代胰岛素：首个生物药物

201450% of new

molecules in researchare biotech

201450% 新研究分子为

生物技术

2020

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PFS and AI预灌封注射器和自动注射笔

Before: Complement of the PFS过去：预充针为后期备选

Today:AI introduced in early stage现在：在早期引入 AI

研发

筛选包材

量产

研发

筛选包材

量产

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Small Molecules Drug Vs Biologics小分子药物 Vs 生物制药

Small molecule drugs小分子药物

Biological drugs生物制药

Size大小

- Small (single molecule)- 小（单分子）- Low molecular weight- 低分子量

- Large (mixture of related molecules)- 大（相关分子混合）- High molecular weight- 高分子量

Structure结构

Simple, well defined, independent of manufacturing process简单，充分定义，独立于制造工艺

Complex (heterogeneous), defined by the exact manufacturing process复杂（不同），由具体制造工艺定义

Modification修改

Well defined充分定义

Many options多种选择

Manufacturing制造

- Produced by chemical synthesis- 通过化学合成生产- Predictable chemical process- 可预测化学流程- Identical copy can be made- 可以制造相同副本

- Produced in living cell culture- 在活体细胞组织中生产- Difficult to control from starting material to final API- 从起始原料到最终 API 难以控制- Impossible to ensure identical copy- 无法确保相同副本

Characterisation特点

Easy to characterise completely容易完全确定特性

Cannot be characterised completely the molecular composition and heterogenicity无法完全确定分子组成和异质性

Stability稳定性

Stable稳定

Unstable, sensitive to external conditions不稳定，对外界条件敏感

Immunogenicity免疫性

Mostly non-immunogenic多数不免疫

Immunogenic免疫

Examples of marketedproducts上市产品示例

• Lovenox依诺肝素• Imigran英明格• Metotraxate• Sumatriptan舒马曲坦• Diluent for Lyo冻干用稀释剂

• Enbrel依那西普• Humira单抗• Copaxone克帕松• Actemra安挺乐• Praluent

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Superior gliding performance优秀的滑动性能

More proactive quality management更加主动的质量管理

Increase Auto-Injector compatibility增加与自动注射笔适配性

Minimizing risk of false rejects of filled syringes减少装填注射器误注射风险

Increase compatibility between drug and container增加药物和包材的相容性

Ensuring successful and timely launch

for novel and existing drug.

确保成功及时推出新药和现有药物。

Minimizing Total Cost of Ownership

via superior reliability

通过卓越的可靠性降低总体开发成本

Regulatory Expertise to support launch of new products法规专业知识支持推出新产品

Syringes | Benefits expected注射器 | 可以预见的优势

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Manual Injection手动注射

Auto Injection自动注射

Easy to manage, less parameters to check

便于管理，要检查的参数更少

More parameters to manage,More experience required

要控制的参数更多，需要的经验更多

ISO

A big challenge挑战

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Some AI’s use the shoulder as a contact point for assembly & the functionality of the system一些自动注射笔将肩部作为系统组装和功能的接触点

This is becoming a critical part of the syringe barrel and for this reason must be characterized for the dimensional point of view 这成为注射器针筒的一个关键部件，因此必须注明尺寸

Syringe注射器

DAI™: Disposable Auto injector with RNSDAI™：带硬质护帽的一次性自动注射器

Shoulder Interaction肩部配合

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ISO 11040-4 does not specify shoulder areaISO 11040-4 未规定肩部区域

The shape and the stability of the syringe shoulder depends on the forming process & ease of inspection.

注射器肩部的形状和稳定性取决于成形工艺和检验控制方式。

Traditionally cartridge barrels have some additional dimensional parameters to better specify the area of interaction with the device

传统针筒具有一些其他尺寸参数，能够更好地指定设备交互区域

Shoulder Interaction肩部配合

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Silicone treatment characterization硅化处理特性

Autoinjector mediated drug delivery is a complex phenomenon, involving multipleparameters.自动注射笔给药是一种复杂方式，涉及多个参数。

Inner siliconization on glass barrel 玻璃注射器针筒内部硅化

In this system the power unit provides a constant motion but not a constant force, having a uniform siliconecoverage is a fundamental requirement on the final product. This can help maintaining a reliable maximuminjection time over product shelf-life.在此系统中，动力装置提供恒定运动而非恒定力，实现均匀硅油覆盖是产品合格的基本要求。这样有助于在产品有效期内维持可靠最大注射时间。

Shape and coating of plunger胶塞形状和涂层

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Silicone treatment – Fixed Nozzles硅化处理 – 固定喷嘴式

• Quantity delivered: less than 0.7 mg/syringe (1 ml Long syringebarrel)

• 硅化量：不到 0.7 mg/只（1 ml 细长型）

• Coverage: difficult to obtain specific silicone oil profile(inhomogeneous distribution)

• 硅油分布：难以获得理想特定硅油分布（不均匀分布）

Only for reference仅供参考

• Suitable for manual injection• 适合手动注射

• AI use depending on the filling volume and drug viscosity能否适配自动注射笔取决于灌装量和药物粘稠度

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Silicone treatment – Movable Nozzles硅化处理 – 可移动喷嘴式

• Quantity delivered could be decreased than fixed platform: 0.5mg±0.2mg/syr or less (1 ml Long Syr Barrel)硅油量可以比固定值更少：0.5 mg±0.2mg/只 或更少（比如1 ml 细

长型）

• Coverage: uniform (possible to create specific silicone oil profile)硅油分布：均匀（可以形成特定硅油分布）

• Only for reference• 仅供参考

• Suitable for manual and autoinjector application适合手动和自动注射笔应用

• Could challenge AI use also with high drug viscosity可以挑战将自动注射笔用于高粘稠度药物

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EZ-fill syringes Process steps预灌封注射器工艺步骤

Washing清洗

•Multiple washing steps with purified or WFI water•用纯水或WFI注射用水多次清洗步骤

•Final Rinsing with WFI •用WFI注射用水最终冲洗

Drying干燥

•Syringe barrel flushing with filtered compressed air for drying•用过滤压缩空气冲洗注射器针筒进行干燥

Siliconization硅化

•Siliconization of the glass barrel (based on specific recipe)•硅化玻璃针筒（根据特定/定制化需求）

•Siliconization of the needle (if present)•硅化针头（针对带针注射器）

Closure assembly组件装配

•Assembling of the specified closure (e.g. RNS; NS etc.)•组装指定配件（例如 RNS；NS 等）

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Silicone Trials硅化试验

Ompi and a leading AI company have studied these parameters on a bench unit system combining a matrix of 25 different tests.欧璧和一家顶尖自动注射笔公司正在试验台系统上研究这些参数，包括 25 个不同检测。

Some key elements:一些关键要素：

• 25 different tests conditions25 个不同检测条件

• 9000 syringes produced生产 9000 个注射器

• Tests used for characterization:用于确定特性的检测：

– Silicone quantity determined with 5 digits scale用 5 位数尺度确定硅化量

– Test on freshly sprayed syringes to verify silicone coverage在新喷涂的注射器上检测，检验硅油覆盖分布

– Gliding test on empty syringes在空注射器上进行滑动力检测

– Injection time on syringes filled with high viscosity solution在灌有高粘稠度溶液的注射器上的注射用时间

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Process Parameter Variations工艺参数变化

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Various process parameter influencing the silicone distribution inside the barrel影响针筒内硅化分布的各个工艺参数

Test n.1: More silicone on the flange检测 1： 卷边处更多硅油

Test n.18: More silicone on the shoulder

检测 18：肩部更多硅油

Test n.25: Uniform Distribution on the barrel

检测 25：针筒上均匀分布

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Silicone treatment characterization: the starting point硅化处理特性：起点

What kind of instruments should be used to deeper characterize silicone distribution?应使用哪种仪器更深入确定硅化分布特性？

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

1 2 3 4 5 6 7 8 9 10

mg/

syri

nge

Number of Cycle

Batch EZ1500107

Nozzle 1

Nozzle 2

Nozzle 3

Nozzle 4

Nozzle 5

Nozzle 6

Weight Test on single syringe, to determine cycle to cycle difference 单只注射器重量检测，确定循环之间差异

Glide Force with different speed to measure product performances with empty and filled containers.不同速度进行滑动力测试，测量空针管和灌装之后滑动力表现。

Standard Instruments标准仪器

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Silicone treatment characterization: other options硅化处理特性：其他选择

Rap-Id technique to determine silicone thickness on the barrelRap-Id 技术，确定针筒上的硅化层厚度

Heat Map with ZebraSci instrument to detect silicone coverageZebraSci 仪器热图，检测硅化分布

Good Coverage. Red = 100% coverage分布良好。红色 = 100% 覆盖

Bad Coverage. Blue = Lack of silicone (Dry spots)覆盖差。蓝色 = 缺少硅胶（干点）

Nice to have instruments became a must for deeper detail on silicone distribution仪器成为深入研究硅油分布的必要工具

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Our path towards a brand product portfolio通往品牌化组合产品的道路

Optimized for parenterals

为注射用药物优化

Best in class for your most demanding products

在要求最严苛产品中同类最佳

Taking Drug Delivery to a New World将给药方式提高到新境界

Ready-to-use containers即用型包装容器

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Video视频

Video 2 –Ompi EZ-fill® Syringes Process视频 2 – 欧璧 EZ-fill® 注射器工艺

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Conclusions结论

Thanks for the Attention谢谢！