冻干机验证方案

2024年2月7日发(作者：)

冷冻干燥机验证计划

增加冷冻干燥机项目

Freeze-dryer Extension Project

Author:

Reviewed by:

Approved by:

Approved by:

SSPC WUXI

VALIDATION PLAN

Freeze Dryer

(GLZ 12)

…………………………………… Xin Juxaing, Validation Team Leader

…………………………………… Bertil Boman/Lu Xiaoan, Project Managers

…………………………………… Chen Yueyun, Production Manager

…………………………………… Ma Tao, QA Manager

Freeze Drying System

冷冻干燥机验证计划

Freeze-dryers Extension Project

增加冷冻干燥机项目

List of Contents

Page

1

INTRODUCTION ....................................................................................................................... 2

2

BACKGROUND .......................................................................................................................... 3

3

BRIEF DESCRIPTION OF THE FREEZE DRYER .............................................................. 3

3.1

3.2

3.3

3.4

3.5

3.6

3.7

3.8

3.9

3.10

3.11

3

CHAMBER

DOORS ...................................................................................................................................... 3

PRODUCT

SHELVES ................................................................................................................................... 3

HEAT

TRANSFERRING

UNIT ...................................................................................................................... 4

ICE

CONDENSER ........................................................................................................................................ 4

MAIN

VALVE ............................................................................................................................................. 4

VACUUM

4

REFRIGERATING

UNIT ............................................................................................................................... 4

HYDRAULIC

STOPPERING ......................................................................................................................... 4

CIP

&

SIP

SYSTEM ................................................................................................................................ 4

CONTROL

SYSTEM ................................................................................................................................. 5

4

SCOPE .......................................................................................................................................... 5

5

VALIDATION TEAM ................................................................................................................ 5

6

INSTALLATION QUALIFICATION ...................................................................................... 6

6.1

6.2

6.3

6.4

CHECK OF THE

P&ID

6

CALIBRATION OF THE

INSTRUMENTS ....................................................................................................... 6

CHECK OF

UTILITIES ................................................................................................................................. 6

DOCUMENTATION ..................................................................................................................................... 6

7

OPERATION AND PERFORMANCE QUALIFICATION .................................................. 6

7.1

7.2

7.3

7.4

7.5

7.6

7.7

7.8

LEAKING

RATE

CHECK ............................................................................................................................. 6

HEAT

DISTRIBUTION

TEST ........................................................................................................................ 6

CIP

TEST .................................................................................................................................................... 6

SIP

TEST .................................................................................................................................................... 6

CAPACITY BY

WATER

TEST ...................................................................................................................... 6

SEALING

CHECKING

AFTER

STOPPERING ................................................................................................ 6

FREEZE

DRYING

CYCLE

TEST .................................................................................................................. 6

PLACEBO

PROCESS

VALIDATION

(ONLY

VITAMIN

C

+

GLYCINE

) ........................................................ 6

8

PRODUCT VERIFICATION .................................................................................................... 7

8.1

PRODUCTION

VALIDTION ......................................................................................................................... 7

9

APPENDIX .................................................................................................................................. 7

1 Introduction概述

This Validation Plan (VP) describes the validation intentions for the Freeze Drying machine at the facility of

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15 November 2010

Freeze Drying System

冷冻干燥机验证计划

Freeze-dryers Extension Project

增加冷冻干燥机项目

SSPC SVP Freeze Dryer Extension Project, as described in Validation Master Plan 400-VMP-P1. It is written

to cover the validation requirements and includes a description of the equipment, process and key functions.

There are two sets freeze dryers of type GLZ-12, made by Beijing Tianli Cryogenic Process Equipment Co.

Led will be introduced during freeze dryer extension project. Validation work will be performed separated

and there will be validation document number respectively, which is the binder No. 402 and 403.

This VP covers the product of Soluvit N.

A specific Validation Team, has been formed to co-ordinate the joint validation work carried out by the

existing plant.

A rough description of the planned tests is described with a time table.

2 Background背景

The process takes place on the first floor in hygienic class B area. The water solution of Vitamin is freezed

first. Then the ice is sublimated under very high vacuum during the drying steps.

The whole freeze drying process is controlled by a computerised control system.

The validation work for the freeze dryer covers all the process that including of the main steps as below:

--IQ and OQ

--Media & product filling

--Cassette transfer and loading and unloading

--Freeze-drying process including freezing, primary drying, second drying, pressure rise test, filling N2,

stoppering device

--Defrosting

--CIP & SIP

3 Brief Description of the Freeze Dryer冷干机简述

The freeze-dryers will be equipped, which type of GLZ-12 mainly consists of the following units:

3.1 Chamber腔室

The chamber is a welded fabrication of rectangular section manufactured from AISI 316L stainless steel

optimized to provided adequate access to components within the chamber whilst minimizing dead volumes.

The internal corners of the chamber have a radius >30 mm, a validation flange is fitted to the top of the

chamber.

3.2 Chamber Doors腔室门

The chamber main maintenance door is rectangular and fabricated from AISI 316 stainless steel. Hinged on

the left side when viewed form the machine room. There are two DN200 viewing windows mounted in the

door. A rectangular slot door is located on the opposite clean room side of the chamber to enable product to

be loaded.

3.3 Product Shelves 产品架

There are 9 product support shelves and one compensation (radiation) shelf in the chamber. Each shelf is

975mm wide X 1420 mm deep. The shelves, 24mm thick, are suspended vertically to create a stack with 110

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Freeze Drying System

冷冻干燥机验证计划

Freeze-dryers Extension Project

增加冷冻干燥机项目

mm vertical clearance between each shelf.

3.4 Heat Transferring Unit 热交换单元

The circuit comprises a series of cooling and heating exchangers and circuit pumps. The medium passes

through shelves to effect heat transfer to the product. The temperature deviation between each shelves is±1℃. The capacity of this system may be cooled from +20℃ to -40℃ within 60 minutes without load and

heated at a rate of not less than 1℃/min.

3.5 Ice Condenser 冰凝结器

The cylindrical condenser vessel is mounted vertically behind the chamber. The vessel is fabricated from

AISI 316 stainless steel by a pair of dished ends welded to each end of a cylinder. There is manway of

400mm diameter on top of condenser. The total condensing surface area is 12.5 m2, providing a total capacity

for condensed ice of 240 kg. The refrigeration system provides sufficient capacity to the condense 240kg of

ice within 24 hours. Achieve an ultimate minimum temperature of –70℃ and cool the condenser from

+20℃ to -40℃ within 30 minutes.

3.6 Main Valve 主阀

The automatically actuated butterfly valve, which is fixed on the 400mm diameter vapour duct enable the

chamber and condenser to be isolated from one another.

3.7 Vacuum System 真空系统

The vacuum necessary for the freeze drying process is created by use of two 2-stage, oil sealed, rotary vane

pumps equipped with gas ballast and exhaust oil mist filters. The Pirani vacuum gauges that equipped at

main vacuum pipe and the chamber each will provide signals to vacuum measurement recording and control.

3.8 Refrigerating Unit 冷却单元

The three individual refrigeration circuits are configured to be able to serve either condenser or shelves

cooling duties as required during the various stages of the process.

3.9 Hydraulic Stoppering

A hydraulic cylinder is mounted above the chamber, it can provide with adjustment for stoppering pressure

and safety devices to prevent excessive force being generated. Operation of the hydraulic system is

interlocked to prevent the shelves being operated with the chamber door open.

3.10 CIP & SIP System

The CIP system comprised a series of self-draining, fixed and rotary spray nozzles mounted on the

distributing mainifolds positioned within the chamber and condenser. Some fixed nozzles and one rotary

nozzle are employed. The CIP process is initiated through the LyoManager control system and is operated

automatically by the PLC.

3 times pre-vacuum steam impulse process is employed during SIP. The chamber and condenser are designed

and fabricated as pressure vessels to enable sterilization of the temperature to be achieved 130℃. The SIP

process is initiated through the LyoManager control system and is operated automatically by the PLC. It is

base on the temperature of the chamber drain. When the sterilization finish, a water ring pump is use for

removal steam and moisture from the system. After this, nitrogen is filled until the pressure in the chamber

and condenser achieved to preset point.

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Freeze Drying System

冷冻干燥机验证计划

Freeze-dryers Extension Project

增加冷冻干燥机项目

3.11 Control System 控制系统

The control system consists of a PC, control panel with a set of PLC, printer and recorder.

Vacuum sensors and temperature sensor are the main input process signal. (for further details, see Technical

Specification)

The general layout of freeze- dryer as below

注射用水纯蒸汽CIP罐液压系统N2过滤器N2真空计CIP泵去2号干燥机真空计冷凝室真空泵真空泵硅油箱冷冻水出冷冻水进硅油循环泵电加热器压缩机

4 Scope 范围

The purpose of this VP is to describe a study to determine whether the system as described in the

background:

 satisfies the GMP requirements of the Regulatory Authorities: People’s Republic of China, the EU GMP

and internal standards of SSPC and Fresenius-Kabi.

 is properly constructed, installed, operated and maintained.

 is suitable for its intended use and capable of consistently producing products that meets their pre

determined specifications and quality attributes.

This VP covers the freeze-drying process of Soluvit N. Raw materials dispensing, formulation, vials washing

and sterilization, filling of solution are excluded, and because of they have been validated before and work

well for many years.

5 Validation Team

The Validation Team members will be from the following departments:

Validation Team member Responsibility

Project Group:

Bertil Boman

Lu Xiaoan

Project responsible

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Freeze Drying System

冷冻干燥机验证计划

Freeze-dryers Extension Project

增加冷冻干燥机项目

Production Department:

Zhu Wei

Xu Hongliang

Xin Juxiang

Receiving department

QA representative

Validation Team leader

Quality Assurance:

Validation Group:

6 Installation Qualification 安装确认

These IQ tests will provide documented evidence that the equipment was installed to meet all cGMP, safety

requirements and technical specification. The IQ protocol was supplied and executed in local factory by

vender and SSPC technical staff together, and most tests are covered by the FAT document and IQ protocol.

Anyhow, the IQ protocol and test results should be reviewed by SSPC Validation Master Team, and some

tests will be added as below during re-assembling:

6.1 Check of the P&ID Drawing 检查流程图

6.2 Calibration of the Instruments 效核仪表

6.3 Check of Utilities 检查公用介质

6.4 Documentation 检查文件

7 Operation and Performance Qualification 运行与性能确认

These OQ tests will provide documented evidence that the equipment operated to meet all cGMP, safety and

designed specification. The OQ protocol was supplied and executed in local factory by vender and SSPC

technical staff together, and most tests are covered by the FAT document and OQ protocol. Anyhow, the OQ

protocol and test results should be reviewed by SSPC Validation Master Team, and some of the tests will be

re-executed as below during start up:

7.1 Leaking Rate Check 泄漏率检查

7.2 Heat Distribution Test 热分配试验

7.3 CIP Test 在线清洁试验

7.4 SIP Test 在线消毒试验

7.5 Capacity by Water Test

最大捕水能力测试

7.6 Sealing Checking After Stoppering 压盖后密封试验

7.7 Freeze Drying Cycle Test 冷干周期试验

7.8 Placebo Process Validation (only Vitamin C + Glycine

)

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Freeze Drying System

冷冻干燥机验证计划

Freeze-dryers Extension Project

增加冷冻干燥机项目

8 Product Verification 产品验证

8.1 Production Validation

Test to verify that the correct quality attributes and requirements are fulfilled. It includes production of at

least three consecutive batches of the following:

“Soluvit N” Product

PV will additionally include verifying that the total processing up to a finished product fulfils the product

specification.

9 Appendix附录

Process Flow Drawing of Freeze Dryer

Production Process of “Soluvit N”

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7 Appendix 9.1

Appendix 9.2