冻干机验证方案

Freeze-dryer Extension ProjectSSPC WUXIVALIDATION PLANFreeze Dryer(GLZ 12)Author: …………………………………… Xin Juxaing, Validation Team LeaderReviewed by: …………………………………… BertilBoman/Lu Xiaoan, Project ManagersApproved by: …………………………………… Chen Yueyun, Production ManagerApproved by: …………………………………… Ma Tao, QA ManagerList of Contents Page1INTRODUCTION 32BACKGROUND 33BRIEF DESCRIPTION OF THE FREEZE DRYER 3 3.1C HAMBER 33.2C HAMBER D OORS 33.3P RODUCT S HELVES 43.4H EAT T RANSFERRING U NIT 43.5I CE C ONDENSER 43.6M AIN V ALVE 43.7V ACUUM S YSTEM 43.8R EFRIGERATING U NIT 43.9H YDRAULIC S TOPPERING 43.10CIP & SIP S YSTEM 43.11C ONTROL S YSTEM 54SCOPE 55VALIDATION TEAM 66INSTALLATION QUALIFICATION 66.1C HECK OF THE P&ID D RAWING 66.2C ALIBRATION OF THE I NSTRUMENTS 66.3C HECK OF U TILITIES 66.4D OCUMENTATION 67OPERATION AND PERFORMANCE QUALIFICATION 67.1L EAKING R ATE C HECK 67.2H EAT D ISTRIBUTION T EST 67.3CIP T EST 67.4SIP T EST 67.5C APACITY BY W ATER T EST 67.6S EALING C HECKING A FTER S TOPPERING 77.7F REEZE D RYING C YCLE T EST 77.8P LACEBO P ROCESS V ALIDATION (ONLY V ITAMIN C + G LYCINE) 78PRODUCT VERIFICATION 78.1P RODUCTION V ALIDTION 79APPENDIX 71 Introduction概述This Validation Plan (VP) describes the validation intentions for the Freeze Drying machine at the facility of 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 & SIP3 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 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 theproduct. 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 SystemThe CIP system comprised a series of self-draining, fixed and rotary spraynozzles 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.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 below4 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 andFresenius-Kabi.* is properly constructed, installed, operated and maintained.* is suitable for its intended use and capable of consistently producingproducts that meets their pre determined specifications and qualityattributes.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 TeamThe Validation Team members will be from the following departments: Validation Team member ResponsibilityProject Group: Bertil Boman Project responsibleLu XiaoanProduction Department: Zhu Wei Receiving departmentQuality Assurance: Xu Hongliang QA representativeValidation Group: Xin Juxiang Validation Team leader6 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 andOQ 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)　8 Product Verification　产品验证8.1 Production ValidationTest 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” ProductPV 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 Appendix 9.1 Production Process of “Soluvit N” Appendix 9.2。