- pharmaceutical water monitoring, control & sampling · 2018. 4. 4. · - pharmaceutical water...

- Pharmaceutical water monitoring, control & sampling制药水监控和采样

- Austar critical utilities case study.- 奥星关键实用案例研究。

Sanjay KolawaleTechnical DirectorLiquid & Bio Process Systems29th March 2018

2/21

INTRODUCTION 导论

Working as a Technical director of Austar Liquid & Bioprocessing department. 担任奥星流体以及生物部门技术总监

• Engineering Design and Trunkey project management expert, has Over 15 years rich experience in design and project management of Pharmaceutical facility, equipment’s and clean utilities Industries in various dosages i.e. Injectable, Oral solid dosage, Liquid & Biotec

• 工程设计和 Trunkey 项目管理专家，已有超过 15 年丰富的设计和项管理经验制药厂，设备和清洁公用事业行业各种剂量，即可注射，口服固体剂量，液体和生物科技

Graduated in Mechanical engineering from Shivaji University and post graduation in Environmental management from AIIMAS本科于希瓦吉大学完成机械工程专业研究生与于AIIMAS进修环境管理毕业

Worked with for design and Project management 设计以及管理工作经历 STILMAS Sun Pharma Ltd. Sanofi LUPIN Pharma ltd. Doshion Veolia water solutions.

3/21

PHARMACEUTICAL WATER SYSTEM 制药水系统

PLC

HMI

Field Instruments

4/21

PW SYSTEM– REGULATIONS REQUIREMENTS 纯化水系统法规要求

Attribute USP EP JP

Production Method生产方法 Suitable 合适的 Suitable合适的

Distillation, ion-exchange, UF or combination蒸馏，离子交换，超滤相结合

Source Water 水源US, EU, Japan, WHO, drinking water 饮用水

Human consumption 饮用水

JP water specification 日本规格水

Total aerobic (CFU/ml)总需氧量 100 100 100Conductivity (µS/cm)电导率 1.3 @25°C 5.1 @25°C 2.1 @25°CTOC (ppm)总含碳量 500 500 500Bacterial Endotoxins内毒素 - - -Nitrates (ppm)硝酸盐 - 0.2 -Heavy Metals (ppm)重金属 - 0.1 -

Appearance 表面 -Clear, colorless 洁净，无颜色

Clear, colorless, odor free 洁净，无色，无味

5/21

WFI SYSTEM – REGULATIONS REQUIREMENTS纯化水系统法规要求

USP 38 JP 16 EP 8 EP 9 (Draft)

Feed Water原水

Drinking water according US, EU, Japanese or WHO guidelines. Contains no added substances.根据美国，欧盟，日本或世界卫生组织的指导方针饮用水。不含添加物质。

Water after applying some adequate pre-treatment such as IX, RO or from PW在应用一些适当的预处理如IX，RO或PW之后进行水处理

Complies with the regulations on water intended for human consumption laid down by competent authorities or PW符合主管部门或私营部门制定的供人类用水的规定

Complies with the regulations on water intended for human consumption laid down by competent authorities or PW符合主管部门或私营部门制定的供人类用水的规定

Production Method生产方法

Distillation or a production process that is equivalent or superior to distillation in the removal of chemicals and microorganisms在去除化学物质和微生物方面等同或优于蒸馏的蒸馏或生产过程

Distillation or by reverse osmosis and/or ultrafiltration (cut-off 6000 MW)蒸馏或通过反渗透和/或超滤（截止6000MW）

Distillation with an effective device to prevent the entrainment of droplets用有效的装置蒸馏以防止夹带液滴

Distillation or reverse osmosis, coupled with other suitable techniques such as deionisation and/or ultrafiltration蒸馏或反渗透，以及其他合适的技术如去离子和/或超滤

Description描述

None无

Clear, colorless, no odor洁净，无色，无味

None无

None无

Conductivity电导率

6/21

Pharmaceutical water systems is a complex system :制药用水-复杂系统

• composed by different operation units• 由不同的运营单位组成• all those operation units are contributing to achieve the final product.• 所有这些运营单位都在为实现最终产品作出贡献。

These systems must be well understood, quality of water must be monitored after each step for correct performance.这些系统必须被很好地理解，在每个步骤之后必须监控水的质量以获得正确的性能。

PHARMACEUTICAL WATER – Complex System制药用水-复杂系统

7/21

Pretreatment预处理

Storage and Distribution储存分配

Intermediate Treatment中间处理

Final treatment最终处理

PHARMA WATER SYSTEM

制药水系统

1

2 3

4

PHARMACEUTICAL WATER – Complex System制药用水-复杂系统

8/21

PRETREATMENT CONTROL前处理控制

Filtration 过滤

Purpose 目的

remove solid contaminants (organic & inorganic) from feed water to improvePerformance of intermediate and final treatment system.去除进水中的固体污染物（有机和无机）以改善中级和最终处理系统的性能。

Variables to be controlled 变量控制

• pressure 压力

• Flow 流速

• Temperature 温度

• chlorine content 氯含量

• pH 酸碱度

9/21


Filtration 过滤

Control & monitor program 控制和监控步骤

• Backwashing analyzing pressure drop• 反冲洗分析压降

• sanitizing periodically• 定期消毒

• analyzing temperature in incoming and microbial load• 分析进入和微生物负荷的温度

• replacing filtering media• 更换过滤介质

• Replace frequently the dosing chemicals.• 经常更换剂量化学品。

10/21


SOFTNER 软化Purpose 目的

Water softeners through cation-exchange resins removewater-hardness ions, such as calcium and magnesium.通过阳离子交换树脂去除水软化剂水 - 硬度离子，如钙和镁。


• Pressure 压力• Flow 流速• temperature 温度• Inlet chlorine content 进口铝含量• outlet hardness 出口硬度• resins particles 树脂颗粒

11/21


SOFTNER 软化


• Appropriate regeneration step analyzing Hardness and Time.• 适当的再生步骤分析例如硬度和时间。

• sanitize periodically columns (once per month)• 定期清理罐（每月一次）

• analyzing temperature in incoming and microbial load• 分析进入和微生物负荷的温度

• replacing resins periodically• 定期更换树脂

• Implement solutions to recirculate water during periods of low water use in order to avoid stagnation

• 在低用水量期间实施再循环水解决方案，以避免停滞

12/21

INTERMEDIATE TREATMENT中间处理

Reverse Osmosis 反渗透

Purpose 目的

Reverse osmosis (RO) is based on semipermeable membranes with the proper controls, ROmembranes can achieve chemical and microbial, quality improvement..反渗透（RO）基于具有适当控制的半渗透膜，反渗透膜可实现化学和微生物质量改善。


* Differential pressure 不同压力 * temperature 温度 * recovery rate 回收率* pollutants in incoming (i.e. hardness, chlorine) 污染物进入例如：硬度和氯* microbial count (in/out) 微生物进入和排出 * conductivity电导率 * TOC含碳量* SDI

13/21

INTERMEDIATE TREATMENT中间处理

Reverse Osmosis 反渗透系统


• Daily log filling with all the relevant RO parameters 日志包括所有的反渗透关键参数

• Incoming temperature and chlorine control.进入的温度和氯的控制

• Check microbial and sanitize whenever necessary检查微生物并在必要时进行消毒

• Flush & keep in recirculation the system when is not in use当不用时，冲洗并保持系统循环

• Use as much as possible the equipment尽可能多的使用设备

14/21

FINAL TREATMENT终处理

Multiple Effect 多重效果

Purpose 目的

Distillation units provide chemical and microbial purification via thermalvaporization.蒸馏装置通过热量提供化学和微生物净化汽化。

The purification capability is depend on incoming water quality; 净化能力取决于进水水质


• Each Effect Temperatures 每个温度影响• Blow down flow rate降低流速• Industrial Steam Pressure / Temperature工业蒸汽压力/温度• Feed water flow rate 进水流量• Feed water quality (i.e. conductivity, hardness etc.) 原水水质例如：电导率硬度• Cooling water flow rate 冷却水流量• Cooling water temperature 冷却水温度

15/21

FINAL TREATMENT终处理

Multiple Effect 多重效果


• For automatic product regulation , ensure the level of tanks set properly to avoid frequent start –stop and lose of energy.

• 对于自动产品调节，确保正确设置储罐的液位，以避免频繁起动关闭和失去能量。

• Check pretreatment and intermmidiate treatment parameters and flow to provide constant quality of feed water to WFI generation unit.

• 检查预处理和中间处理参数和流量，为WFI生产设备提供恒定的给水质量。

• Adjust daily blow down as per feed water quality.• 根据给水量调整每日排污量

• periodic maintenance of the heat exchangers for mainiain efficency and avoid scaling.

• 定期维护热交换器以保持效率并避免结垢。

16/21

STORAGE & DISTRIBUTION SYSTEM储存分配系统

Storage & Distribution System 储存分配系统

Purpose 目的

Distribution system should guarantee the correct quantity of water at the correct pressure to the user in a controlled and safe condition;

分配系统应在受控和安全的条件下，以正确的压力向用户保证正确的水量;

The storage tank is included in water distribution systems to optimize processingequipment capacity.

储水箱包含在分配系统中以优化处理设备容量。

The system should recirculate the water continuously in an auto-sanitization status in order to keep under control biofilm growth; this means recirculation under turbulence condition and under controlled temperature.

为了控制生物膜的生长，系统应该在自动化状态下持续循环水; 这意味着在湍流条件下和受控温度下再循环。

17/21



• Pressure on loop return 循环回水压力 * Loop temperature 进出口温度• * Conductivity 电导率• Minimum Flowrate 最低流速 * Tank Temperature 罐体温度

* Filter temperature 呼吸器温度• * TOC 总含碳量


18/21


Control & monitor program 控制监控步骤

• Guarantee continuous recirculation under turbulent condition• 保证在湍流状态下的连续再循环• Take sampling from each point of sampling routinely• 从每个采样点例行抽样• Vent filter integrity check – Vent filter temperature check• 空气过滤器完整性检查 – 空气过滤器温度检查• Spray coverage; tank is critical point because no turbulence• 喷雾覆盖; 罐是关键点，因为没有湍流• Periodic valves diaphragm check and change• 定期阀门隔膜检查和更换• Periodic sanitization. 定期清洁• Drain the system when in maintenance . 在维修时系统排空• Check the temperature 温度检测


19/21

PHARMA WATER SAMPLING制药用水取样

20/21

PURPOSE OF SAMPLING取样的目的

3. Technical, Investigational or Diagnostic Purposes (T )技术研究或者诊断的目的

2. Process Control

Purposes (P)工艺控制目的

Sampling

?Purpose?取样目的

Defined in Three classifications定义分为三类

1. QualityControlPurposes(Q)

质量目的Q

21/21

To duplicate the quality of the water used for manufacturing:为了重复复制制造用水的质量

• Monitor quality at Point Of Use (POU) for manufacturing.• 监视制造业使用点（POU）的质量。

• Sample exactly the same way as the water is used in production (e.g. flush, time, sanitation, use of same hose, gasket etc. related

• to SOP)• 采样与生产中使用的水完全相同（例如冲洗，时间，卫生，使用相同的软管，垫圈

等到SOP）

Define Action- and Alert levels定义行动和警报级别

Sampling and analysis: 取样和分析Chemical: In-line, On-line, At-line and/or Off-line 化学品：In-line, On-line, At-line and/or Off-line Microbial / Endotoxin: Off-line (so fare Off-line is only reliable method)微生物/内毒素：离线（目前为止离线只是可靠的方法）

QUALITY CONTROL PURPOSE (Q)质量控制目的

22/21

The purpose is to monitor the system performance and ensure proper control:目的是监视系统性能并确保适当的控制：

Done by Test of Sample Point (SP) e.g.通过采样点（SP）的测试完成例如• End of distribution loop, 分配循环的点• Outlet of distribution storage tank or 储罐分配排水点• All Pre-Treatment purification steps (e.g. RO) 所有预处理纯化步骤例如反渗透

To test, what is inside the system rather than the condition of the SP itself为了测试，系统内部是什么，而不是SP本身的状况

PROCESS CONTROL PURPOSE (P)工艺控制目的

23/21

• The knowledge of Process control sampling, incl. defining actions and alert limits, may support awareness and system robustness. The more active use of knowledge / history / trending, the better possibility to create system robustness• 过程控制采样知识，包括定义行为和警报限制，可以支持意识和系统稳健性。更积极地使用知识/历史/趋势，创建系统健壮性的可能性就越大

PROCESS CONTROL PURPOSE (P)工艺控制目的

24/21

Examples: 案例

• Technical: Drain valve on a pump or in a distribution loop. Purpose is for maintenance or other intervention

• 技术：排放泵上或分配回路上的阀门。• 目的是为了维护或其他干预

• Investigation / Diagnostic: Sample valves at outlet of EDI and inletto distribution Storage tank

• 调查/诊断：EDI和进口出口处的取样阀配送储罐

TECHNICAL ,INVESTIGATIONAL OR DIAGNOSTIC PURPOSES (T)技术调查以及诊断目的

25/21

Are all Quality Attributes uniformly distributed?所有质量属性是否均匀分布？

• Chemical attributes (e.g. nitrates, dissolved metals, conductivity and TOC) are considered uniformly / homogeneously distributed

• 化学属性（例如硝酸盐，溶解的金属，电导和TOC）被认为是均匀/均匀分布的

• Biological attributes (e.g. bacteria, endotoxin) are to be consideredheterogeneously / not uniformly distributed

• 生物属性（如细菌，内毒素）应予以考虑非均匀/不均匀分布

QUALITY ATTRIBUTES – THE IMPURITIES WE TEST FOR 质量属性 - 我们测试的杂质

26/21

Authority Rules: “Routine sampling must be sufficient” 权威规范：“例行抽样必须足够”

1. USP general chapter : "Water systems should be monitored at a frequency that is sufficient to ensure that the system is in control, and continues to produce water of acceptable quality" 1. USP总则：“应监测水系统的频率，以确保系统处于可控状态，并继续生产质量合格的水”

2. FDA “Guide to Inspection of High Purity Water Systems” (1993). Statement for PQ3 (1 year): “For WFI systems samples should be taken daily from a minimum of one POU, with all POU tested weekly”2. FDA“高纯水系统检验指南”（1993年）。 PQ3声明（1年）：“对于WFI系统，每天应至少从一个POU采集样本，每周测试一次POU”

SAMPLE PLANS取样计划

27/21

• Design for quality” => ”Quality by Design” i.e. continuous ensurethat the process is in control

• 质量设计“=>”按设计质量“即连续确保该过程处于控制之中

• Plan sampling during Design, Installation and C&Q• 在设计，安装和C＆Q期间计划抽样

• Before Basic Design, make total analysis of the Supply Water• 在基本设计之前，对供水进行全面分析

• Focus on good sample conditions (access, cross contamination risk, etc.)

• 注重良好的样本条件（接触，交叉污染风险等）

DESIGN & “UNOFFICIAL SAMPLE PLAN设计与“非正式样本计划”

28/21

• During installation, make “Line-walks” to secure the physical installation before end of installation.

• 在安装过程中，在安装结束之前请使用物理安装“线路走线”来确保安全。

• Commissioning: Make a sample plan (”unofficial”). Start asap. to getlearning, data, control i.e. inputs for the PQ-sample plans. Sample min. 1-5 days for Pre-Treatment, Final treatment and Distribution

• 调试：制定一个样本计划（“非正式”）。尽快开始。以得到学习，数据，控制，即PQ样本计划的输入。样品分钟数。预处理，最终处理和分配1-5天

• Validation: Make QA approved PQ-strategy. Risk based sample plans for PQ (PQ1, PQ2 og PQ3) incl. rationales

• 验证：通过QA批准的PQ策略。基于风险的样本PQ计划（PQ1，PQ2和PQ3）理由

• Think “Worst case scenarios” and possible ”special scenarios” e.g. max/min capacity and perhaps power failure etc.

• 认为“最糟糕的情况”和可能的“特殊情况”，例如最大/最小容量和可能的电源故障等。

DESIGN & “UNOFFICIAL SAMPLE PLAN设计与“非正式样本计划”

29/21

• The valve must be of sanitary type e.g. diaphragm valve, but othertypes also exists阀门必须是卫生型的，例如隔膜阀等，其他类型也存在卫生型要求

• Often unsanitary sampling vales are seen in the Pre-Treatment systems, but if test for CFU is interesting, unsanitary samplingvalves are not recommended

• 不可思议在预处理系统中经常会看到不卫生的取样值，但如果CFU 的检测，则不建议采用不卫生的取样阀

• Beside the sampling valves the design of the installation itself is extremely important和取样阀相比安装本身的设计非常重要

DESIGN OF SAMPLE POINTS样本点设计

30/21

• Sanitary design – incl. Pre-Treatment SP• 卫生设计 - 包括。预处理SP

• Secure drain ability (~drying). Avoid capillary effect• 安全排水能力（〜干燥）。避免毛细管效应

• Be aware of hoses, fittings, adaptors, limitations, drain conditions,water mist, splash, humidity, condensate, good access incl. samplebottles, personal security

• 注意软管，接头，适配器，限制，排水条件，水雾，飞溅，潮湿，冷凝水，良好的通道，样品瓶子，个人安全

• SP at a sink must be sampled as user is using it• 必须根据用户使用的接收器对接收器上的SP进行采样

• SOP is needed for Sampling - handling, cleaning, sanitization etc. • 采样 - 处理，清洁，消毒等需要SOP。

DESIGN OF SAMPLE POINTS样本点设计

31/21

Case Study

32/21

▪ A global pharmaceutical and biopharmaceutical producer.

▪ 全球制药和生物制药生产商。

▪ The GMP production workshop includes the Perfusion production workshop and the Fed Batch production workshop.

▪ GMP生产车间包括灌注生产车间和批量生产车间。

▪ Very short time for delivery of project.▪ 极短的交付日期

PROJECT BACKGROUND工程背景

33/21

3D LAYOUT三维布局图

34/21

WHAT WE BUILT我们建造了什么

Turnkey Water system consisting of the following: 总包水系统项目组成如下

35 m³/hr X 2 common Pretreatment for process & Utilities. 35 m³/hr X 2 一般性工艺和公用事业的预处理。

20 m³/hr PWG X 2 Qty. 20 m³/hr 纯化水机两套

20 KL X 2 PW Storage & Distribution. 20 KL X 2 纯化水储存和分配

4 m³/hr MWS X 1 Qty & 8 m³/hr MWS X 2 Qty.

35/21

WHAT WE BUILT我们建造了什么

Turnkey Water system consisting of the following: 总包水系统项目组成如下

25 KL X 2 WFI Storage & Distribution. 25 KL X 2 注射水储存和分配

2000 Kg/hr Pure steam production X 2 Qty. 2000 Kg/hr 纯蒸汽发生器2套

ASME BPE piping for PW, WFI ,PS,PA & N2 distribution. ASME BPE 标准的分配管道（纯化水，注射水，工业蒸汽，氮气）

36/21

SITE INSTALLATION – GENERATION SYSTEMS现场安装—— 生产系统

37/21

SITE INSTALLATION – STORAGE AND DISTRIBUTION SYSTEM现场安装—— 储存分配系统

38/21

WHAT UNIQUELY DELIEVERED我们独特的地方

Basic & Detailed engineering for water generation and distribution system. 一次和二次设计工程师为水生产分配系统做设计

Water room beautification.水机工艺区美化

The pretreatment system for mutual standby.预处理系统相互备用

The distribution pump of PW&WFI Storage & Distribution system for mutual standbyPW和WFI水系统的循环一用一备

Use point of PW & WFI Distribution system design as recommended by ISPE & ASME –BPE根据ISPE和ASME-BPE的推荐使用PW和WFI分配系统设计点

39/21

PA system by using the loop.工艺气体系统通过使用循环

Many point of use in one Sub Loop of WFI Storage & Distribution system .WFI存储和分配系统的一个子回路中有许多使用点。

Single point of contact for engineering, Procurement, execution of all PW, WFI ,PS,PA & N2 piping and equipment.工程，采购，执行所有PW，WFI，PS，PA＆N2管道和设备的单点联系人。

Project in compliance to GAMP5, SCADA & remote monitoring.符合GAMP5，SCADA和远程监控的项目。

WHAT UNIQUELY DELIEVERED我们独特的地方

幻灯片编号 1幻灯片编号 2Field Instruments幻灯片编号 4幻灯片编号 5幻灯片编号 6幻灯片编号 7幻灯片编号 8幻灯片编号 9幻灯片编号 10幻灯片编号 11幻灯片编号 12幻灯片编号 13幻灯片编号 14幻灯片编号 15幻灯片编号 16幻灯片编号 17幻灯片编号 18幻灯片编号 19幻灯片编号 20幻灯片编号 21幻灯片编号 22幻灯片编号 23幻灯片编号 24幻灯片编号 25幻灯片编号 26幻灯片编号 27幻灯片编号 28幻灯片编号 29幻灯片编号 30幻灯片编号 31幻灯片编号 32幻灯片编号 33幻灯片编号 34幻灯片编号 35幻灯片编号 36幻灯片编号 37幻灯片编号 38幻灯片编号 39幻灯片编号 40

- pharmaceutical water monitoring, control & sampling · 2018. 4. 4. · - pharmaceutical water...

Documents