论药品生产验证总计划(英文版).doc

1 32 2 32 PHARMACY MANUFACTURING UNIT VALIDATION MASTER PLAN VPM General Notes Aims of Qualification and Validation Any significant changes to premises equipment or processes which may affect the quality of the final product directly or indirectly should be qualified and validated The key elements of a qualification and validation program should be clearly defined and documented in a Validation Master Plan The process should establish and provide documentary evidence that premises supporting utilities equipment and processes have been designed in accordance with the requirements of GMP This normally constitutes the Design Qualification or DQ and includes confirmation that the premises supporting utilities and equipment have been built and installed in compliance with their design specifications this constitutes Installation Qualification or IQ and that they operate in accordance with their design specifications this constitutes Operational Qualification or OQ A specific process will consistently produce a product meeting its predetermined specifications and quality attributes this constitutes Process Validation or PV The term Performance Qualification or PQ may be used also Purpose The VMP is intended to be a live document that supports the design and construction of any production facility its subsequent operation maintenance and changes to the facility for its life span The VMP should present an overview of the entire validation operation its organisational structure its content and planning The core of the VMP is the list inventory of items to be validated and the planning schedule The VMP should provide your organisation with the basis for validation and quality system activities required for cGMP compliance This will enable any sterile or non sterile medicinal product that is produced processed stored or distributed by the manufacturing unit to be validated under the control of an appropriate quality system The VMP should provide a cross reference to other documents such as SOP s validation protocols validation reports and design plans A rationale for the inclusion or exclusion of validations from the approach adopted should be included VMP Document The VMP template is attached for completion as appropriate the document should be cross referenced with design specifications design plans and other relevant documentation Appendices should contain all the relevant documentation referenced or stated in the VMP 3 32 Company Logo Company Name VALIDATION MASTER PLAN Document Reference Reference Number Revision Draft Number or Revision Number Date of Issue Page 3 of Approved by Name Signature Date Production Team Leader Quality Control Officer Senior Engineer Compiled by Title Name Signature Date Validation Engineer 4 32 CONTENTS 1 0LIST OF ABBREVIATIONS 5 2 0DOCUMENT REVISION HISTORY 6 3 0VALIDATION STEERING COMMITTEE 7 3 1MEMBERSHIP OF VALIDATION STEERING COMMITTEE 7 3 2RESPONSIBILITIES 8 3 2 1Pharmacy Production Team Leader 8 3 2 2Pharmacy Senior Production Technician 8 3 2 3Trust Senior Engineer 8 3 2 4Pharmacy Quality Control Officer 8 3 2 5Validation Engineer 8 4 0INTRODUCTION 9 4 1PURPOSES OF VMP 9 4 2OVERVIEW OF PROJECT 9 4 3VALIDATION PHILOSOPHY 9 5 0REGULATORY STANDARDS AND GUIDELINES 10 6 0DESCRIPTION OF PRODUCTS AND PROCESSES 11 6 1INTRODUCTION 11 6 2PRODUCT GROUPS 11 6 3PROCESSES 11 6 4PRODUCT STORAGE AND DISTRIBUTION 11 7 0PROJECT DESCRIPTION 12 7 1SITE LOCATION 12 7 2FACILITY DESIGN AND LAYOUT 12 7 3PRODUCTION SUITES 12 7 3 1Zone 1 Non Sterile Manufacturing 12 7 3 2Zone 2 Preparation of Cytotoxic Products and Parental Nutrition Products 12 8 0EQUIPMENT AND SERVICES TO BE VALIDATED 14 8 1IMPACT ASSESSMENT 14 8 2RISK ASSESSMENT 14 8 3VALIDATION MATRIX 14 9 0VALIDATION ACTIVITIES 15 9 1VALIDATION ACTIVITIES 15 9 1 1User Requirement Specification URS 15 9 1 2Technical Specification 15 9 1 3Impact Assessment 15 9 1 4Design Review Qualification 15 9 1 5Factory Acceptance Tests 15 9 1 6Commissioning 16 9 1 7Installation Qualification 16 9 1 8Calibration 16 9 1 9Operational Qualification 17 9 1 10Standard Operating Procedures 17 9 1 11Performance Qualification 18 9 1 12Combined Qualifications I OQ Design StatementSVASmall Volume Ampoules GAGeneral ArrangementTPNTotal Parenteral Nutrition GAMPGood Automated Manufacturing Practice URSUser Requirement Statement GCPGood Cleaning PracticeVCCValidation Change Control GEPGood Engineering PracticeVMPValidation Master Plan GLPGood Laboratory PracticeVSCValidation Steering Committee HACCPHazard And Critical Control PointVTFValidation Technical File HS EHealth Safety And EnvironmentWFIWater For Injection HTMHealth Technical Memorandum HVACHeating Ventilation and Air Conditioning IAImpact Assessment IQInstallation Qualification ISOInternational Standards Organisation ISPEInternational Society of Pharmaceutical Engineers LVFLarge Volume Fluids MCAMedicines Control Agency 7 32 2 0DOCUMENT REVISION HISTORY RevisionDetailsDateAuthor Draft 1 Initial draft Draft 2 Draft 3 Revision 00Original issue Revision 01 8 32 3 0VALIDATION STEERING COMMITTEE 3 1Membership of Validation Steering Committee This Validation Master Plan has been compiled by a Validation Steering Committee VSC who will also manage its execution The members of the VSC are listed below and by their signatures acknowledge their responsibilities to ensure that all validation activities are carried out as described in this Validation Master Plan VMP and its annexes It is recommended that the members of the VSC should include but is not limited to the following areas of responsibility and expertise Pharmacy Production Team Leader Pharmacy Senior Production Technician Trust Senior Engineer Pharmacy Quality Control Officer cGMP Consultant Validation Specialist Additional members co opted onto the VSC shall also sign below before undertaking any activities associated with this VMP Name Print Position CompanyInitialSignatureDate 9 32 3 2Responsibilities With respect to the activities outlined in this VMP and its Annexes including cleaning manufacturing practices and analytical methods the responsibilities of key VSC members are outlined below Their responsibilities with respect to the overall operation are included where this may have an impact upon validation activities Approval of new or amended documentation should be accomplished with the minimum of delay ideally within 2 working days to facilitate the efficient operation of the facility 3 2 1Pharmacy Production Team Leader The pharmacy production team leader is responsible for Ensuring that appropriately qualified personnel are appointed Ensuring production processes are in accordance with cGMP requirements Facilitating validation activities Training and management of personnel Approval of user functional aspects of validation protocols Approval of working production documents for overall content 3 2 2Pharmacy Senior Production Technician The pharmacy operations representative is responsible for Completion of batch records Operating procedures Training of personnel 3 2 3Trust Senior Engineer Ensuring that systems equipment are appropriate for their purpose Maintenance of systems equipment Maintenance procedures Calibration policy and procedures Revision of O M manuals for equipment systems Approval of validation protocols for content relating to engineering content 3 2 4Pharmacy Quality Control Officer Ensuring appropriate Quality Control QC procedures are in place Provision and maintenance of auditable document storage systems Approval of validation protocols for quality aspects Approval of all working QC and production documents 3 2 5Validation Engineer Identify and plan appropriate validation activities Provide validation technical support and training Ensure appropriate validation procedures are in place 10 32 4 0INTRODUCTION 4 1Purposes of the VMP The purposes of the VMP are to Identify the members of the Validation Steering Committee Identify Regulatory requirements Identify and describe the facility systems and equipment to be validated Identify and describe products and processes to be validated Identify the validation activities that will be undertaken Identify the methods by which these activities will be undertaken Identify the documentation requirements to support the above activities 4 2Overview of Project This VMP relates to a new facility to be known as the In line with current GMP standards the new pharmacy will provide aseptically dispensed intravenous products and manufactured sterile and non sterile products to Hospital patients 4 3Validation Philosophy The VMP is intended to be a live document that initially supports the design and construction of the facility and subsequently the operation maintenance and change of the facility for its entire life It will provide the basis for validation and quality system activities required for cGMP compliance This will enable the validated production processing storage and distribution of a range of sterile and non sterile medicinal products under the control of an appropriate quality system The VMP may be revised as appropriate to incorporate changes and or additions to the facility and or products Using current pharmaceutical industry guidelines the validation steps and activities will be designed to address all critical product attributes and process steps whilst minimising un necessary work This will be achieved by employing techniques such as Impact Assessment and risk assessment in order to focus validation activity onto those systems critical to product quality The validation process will follow these basic group headings Quality Plan Design Reviews FAT Commissioning Installation Qualification SAT Operational Performance Qualification Process Validation Cleaning Validation Analytical Method Validation The validation activities will be incorporated into project design construction programs and production schedules The objective of this is to integrate similar activities e g SAT with OQ and thus reduce duplication of tests and checks to a minimum Appendix D illustrates the relationship between project and validation stages 11 32 5 0REGULATORY STANDARDS AND GUIDELINES The following is a list of standards and guidelines deemed to be appropriate for this project This list is not exhaustive and further regulations and guidelines will be used where appropriate The list will be reviewed and revised as necessary whenever a new revision of the VMP is issued 1 New Zealand Code of Good Manufacturing Practice for Manufacture and Distribution of Therapeutic Good Part 1 Manufacture of Pharmaceutical Products 1993 2 New Zealand Code of Good Manufacturing Practice for Manufacture and Distribution of Therapeutic Good Part 3 Compounding and Dispensing 1993 3 New Zealand Code of Good Manufacturing Practice for Manufacture and Distribution of Therapeutic Good Part 3 Annex 1 Compounding of Sterile Pharmaceutical Products 1995 4 PIC S Guide to Good Manufacturing Practice for Medicinal Products 15th Jan 02 5 MCA Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2002 6 AS NZS ISO14644 1 2002 Cleanrooms and associated controlled environments Part 1 Classification and air cleanliness 7 AS NZS 14644 2 2002 Cleanrooms and associated controlled environments Part 2 Specifications for testing and monitoring to prove continued compliance with ISO 14644 1 8 AS NZS ISO 14644 4 2002 Cleanrooms and associated controlled environments Part 4 Cleanrooms and associated controlled environments Design construction and start up 9 ISO EN 14644 5 2004 Cleanrooms and Associated Controlled Environments Part 5 Cleanroom Operations 10 ISO 14644 7 2004 Cleanrooms and associated controlled environments Part 7 Separative devices clean air hoods gloveboxes isolators and mini environments 11 AS NZS 4273 INT 1995A1 Guidelines for the design installation and use of pharmaceutical isolators 12 Pharmaceutical Isolators 1st edition 2004 13 ISPE Baseline Guide Volume 3 Sterile Manufacturing Facilities 14 ISPE Baseline Guide Volume 4 Water and Steam Systems 15 ISPE Baseline Guide Volume 5 Commissioning and Qualification 16 BS 5295 Environmental Cleanliness in Enclosed Spaces 17 European Pharmacopeia 18 British Pharmacopeia 19 The Quality Assurance of Aseptic Preparation Services 3rd edition 2001 20 Good Automated Manufacturing Practice 21 Good Laboratory Practice 12 32 6 0DESCRIPTION OF PRODUCTS AND PROCESSES 6 1Introduction The pharmacy produces and issues a large number of products to in patients out patients and other group hospitals clinics This VMP applies to all production processes in the pharmacy 6 2Product Groups Products with similar characteristics and or manufacturing processes have been placed into seven groups A general process flow diagram PFD has been generated for each group found in Annex A Where significant differences occur within a group these are identified in sub sections within the PFD for the group The seven product groups are Cytotoxics dispensed unlicensed manufacture TPN dispensed unlicensed CIVA dispensed unlicensed Terminally sterilised products licensed manufacture Non Sterile Products unlicensed manufacture Repacking dispensed Other unlicensed manufacture Please refer to schedule of products product group descriptions and associated process flow charts located in appendix A Whenever new products are to be processed by the pharmacy then each will be assessed for inclusion into an existing group Where this is inappropriate e g a significant new process is introduced then a new group will be added with supporting PFD and process descriptions 6 3Processes For each product group the manufacturing processes and the specific equipment utilised will be described in detail Specifically these will include all processes critical to product quality Processes that involve standard operation of equipment e g weighing of product materials may be simply listed and referenced to appropriate equipment SOPs 6 4Product Storage and Distribution Generally for compounded products product storage time is relatively short as most products are manufactured to meet prescription orders and in some cases have a short shelf life When batch production is employed batch size is managed to meet anticipated short term demand and hence avoid the need for long term storage Batch products with a prolonged expiry raw materials and repacked products will be stored in a quarantine area before release for use which will be a designated site in the cold room or storage area that is inaccessible Products will be stored within a dedicated storage area Where necessary products will be stored in refrigerators or a cold room There is a paper system for Inventory control Products are delivered by a variety of routes dependant upon product and intended use Generally they will be delivered in small lots carried by hand trolley etc to the end user Returnable cold boxes will be used when a cold chain delivery is required 13 32 7 0PROJECT DESCRIPTION Note All drawings referenced in this section are located in Appendix C 7 1Site Location The new pharmacy is located on the site of the Its position with respect to other facilities on the same site is shown on layout drawing no 7 2Facility Design and Layout The facility consists of a Please refer to drawing no The facility contains the production area This is divided into 2 discrete clean room production suites termed zones 1 2 and 3 according to the HVAC zoning Zone 1 Please refer to drawing no There is a walk on ceiling level above the clean rooms within which piped services HVAC ducting and electrical services are located The plant room within which equipment such as Air Handling Units AHUs Water for Injections WFI generation storage and circulation equipment clean steam generator and control panels is situated in Please refer to drawing no 7 3Production Suites 7 3 1Zone 1 Non Sterile Manufacturing All rooms classified GMP grade D Please refer to schedule of room data sheets located in Appendix C Served by HVAC zone 1 Please refer to drawing no Processes undertaken in this area include Non sterile manufacture of creams ointments suppositories oral suspensions oral liquids and capsules Extemporaneous preparation of creams ointments and oral suspensions Please refer to process flow diagrams located in Appendix A The zone is divided into 3 discrete areas and accessed by dedicated personnel change airlock number Hazardous non sterile product manufacture including Dithranol Coal Tar flammables and cytotoxics Prep 1 2 and 3 Non sterile product manufacture non hazardous Equipment and bottle wash area Pass boxes provide access for materials to local storage areas within preparation areas Please refer to typical personnel material product and waste flow diagrams located in Appendix A 7 3 2Zone 2 Preparation of Cytotoxic and Parental Nutrition Products Rooms classified EU grades B C and D served by HVAC zone 2 Additionally there is a small equipment store Please refer to schedule of room data sheets located in Appendix C and to drawing no Processes undertaken in this area include Aseptic dispensing of parenteral nutrition products and aseptic dispensing of other parenteral items 14 32 Aseptic dispensing of cytotoxic chemotherapy Aseptic manufacture of cytotoxic chemotherapy Please refer to process flow diagrams located in Appendix A The zone is divided into 4 discrete areas Grade D cytotoxic compounding area Accessed by dedicated personnel change airlock number Compounding of Cytotoxic products in grade A isolator Grade D cytotoxic materials disinfection and final check area access etc Grade D check and disinfection area serving grade B compounding room Personnel access via Materials access via corridor and trolley transfer airlock Grade B area for compounding of Total Parenteral Nutrition TPN products in grade A laminar flow cabinet Personnel access via cascading grade B change Materials access via hatch Please refer to typical personnel material product and waste