论药品生产验证总计划(英文版)

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1、PHARMACY MANUFACTURING UNIT VALIDATION MASTER PLAN (VPM).General NotesAims of Qualification and ValidationAny 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

2、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 n

3、ormally 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

4、 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

5、).PurposeThe 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 stru

6、cture, 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

7、 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 SOPs, validation protocols, validation reports, and design plans.

8、A rationale for the inclusion or exclusion of validations, from the approach adopted should be included.VMP DocumentThe VMP template is attached for completion as appropriate the document should be cross-referenced with design specifications, design plans and other relevant documentation. Appendices

9、 should contain all the relevant documentation referenced or stated in the VMP.Company LogoCompany NameVALIDATION MASTER PLANDocument Reference:Reference NumberRevision:Draft Number or Revision NumberDate of Issue:_/_/_Page:3 of _Approved by:Name:Signature:Date:Production Team LeaderQuality Control

10、OfficerSenior EngineerCompiled byTitle:Name:Signature:Date:Validation EngineerCONTENTS1.0LIST OF ABBREVIATIONS52.0DOCUMENT REVISION HISTORY63.0VALIDATION STEERING COMMITTEE73.1Membership of Validation Steering Committee73.2Responsibilities83.2.1Pharmacy Production Team Leader83.2.2Pharmacy Senior Pr

11、oduction Technician83.2.3Trust Senior Engineer83.2.4Pharmacy Quality Control Officer83.2.5Validation Engineer84.0INTRODUCTION94.1Purposes of VMP94.2Overview of Project94.3Validation Philosophy95.0REGULATORY STANDARDS AND GUIDELINES106.0DESCRIPTION OF PRODUCTS AND PROCESSES116.1Introduction116.2Produ

12、ct Groups116.3Processes116.4Product Storage and Distribution117.0PROJECT DESCRIPTION127.1Site Location127.2Facility Design and Layout.127.3Production Suites127.3.1Zone 1, Non-Sterile Manufacturing127.3.2Zone 2, Preparation of Cytotoxic Products and Parental Nutrition Products128.0EQUIPMENT AND SERVI

13、CES TO BE VALIDATED148.1Impact Assessment148.2Risk Assessment148.3Validation Matrix149.0VALIDATION ACTIVITIES159.1Validation Activities159.1.1User Requirement Specification (URS)159.1.2Technical Specification159.1.3Impact Assessment159.1.4Design Review/Qualification159.1.5Factory Acceptance Tests159

14、.1.6Commissioning169.1.7Installation Qualification169.1.8Calibration169.1.9Operational Qualification179.1.10Standard Operating Procedures179.1.11Performance Qualification189.1.12Combined Qualifications (I/OQ & O/PQ)189.1.13Process Validation (PV)189.1.14Cleaning Validation189.1.15Analytical Method a

15、nd Laboratory Equipment Validation199.1.16Product Storage and Distribution Validation199.1.17Relocated Equipment199.1.18Computer Validation Testing209.1.19Computer Operational Qualification错误！未定义书签。9.2Validation Reports209.3Validation History File2010.0CHANGE CONTROL2110.1VMP Revisions2110.2Change C

16、ontrol Initiation2110.3Definition of Change2110.4Change Control Procedure2111.0QUALITY MANAGEMENT2212.0SCHEDULE OF STANDARD OPERATING PROCEDURES2313.0PREVENTATIVE MAINTENANCE2414.0SCHEDULE OF WORK PACKAGES2515.0TRAINING2616.0RESPONSIBILITIES AND APPROVAL OF PROTOCOLS AND DOCUMENTATION2716.1Protocol

17、Responsibility2716.2Approval of Protocols and Reports2716.3Approval Of Validation Documentation27APPENDICESANNEX 1CLEANING VALIDATION MASTER PLANANNEX 2ANALYTICAL METHOD VALIDATION MASTER PLAN1.0 LIST OF ABBREVIATIONSAHUAir Handling UnitNHSNational Health ServiceBPBritish PharmacopoeiaO & MOperation

18、 and MaintenanceBSBritish StandardOQOperational QualificationCFRCode of Federal RegulationsP&IDPiping and Instrumentation DiagramcGMPCurrent Good Manufacturing PracticePCAPatient Controlled AnalgesiaCIPClean In PlacePFDProcess Flow DiagramCIVACentralised Intravenous AdditivesPIDProportional Integral

19、 and Derivative Comm.CommissioningplcProgrammable logic controllerCPUCentral Processing UnitPQPerformance QualificationDCDirect CurrentPVProcess ValidationDCCDesign Change ControlQAQuality AssuranceDQDesign QualificationQCQuality ControlDRDesign ReviewQMSQuality Management SystemEDREnhanced Design R

20、eviewRARisk AssessmentEPEuropean PharmacopoeiaRev.RevisionEUEuropean UnionSATSite Acceptance TestFATFactory Acceptance TestSIP Sterilise/Sanitise In PlaceFDAFood and Drug AdministrationSOPStandard Operating ProcedureFDSFunctional; Design StatementSVASmall Volume AmpoulesGAGeneral ArrangementTPNTotal

21、 Parenteral NutritionGAMPGood Automated Manufacturing PracticeURSUser Requirement StatementGCPGood Cleaning PracticeVCCValidation Change ControlGEPGood Engineering PracticeVMPValidation Master PlanGLPGood Laboratory PracticeVSCValidation Steering CommitteeHACCPHazard And Critical Control PointVTFVal

22、idation Technical FileHS&EHealth Safety And EnvironmentWFIWater For InjectionHTMHealth Technical MemorandumHVACHeating, Ventilation and Air ConditioningIAImpact AssessmentIQInstallation QualificationISOInternational Standards OrganisationISPEInternational Society of Pharmaceutical EngineersLVFLarge

23、Volume FluidsMCAMedicines Control Agency2.0 DOCUMENT REVISION HISTORYRevisionDetailsDateAuthorDraft 1 Initial draft _/_/_Draft 2_/_/_Draft 3_/_/_Revision 00Original issue. _/_/_Revision 01_/_/_3.0 VALIDATION STEERING COMMITTEE3.1 Membership of Validation Steering CommitteeThis Validation Master Plan

24、 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

25、) 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 Vali

26、dation SpecialistAdditional members co-opted onto the VSC shall also sign below before undertaking any activities associated with this VMP.Name (Print)Position/CompanyInitialSignatureDate3.2 ResponsibilitiesWith respect to the activities outlined in this VMP and its Annexes, including cleaning, manu

27、facturing 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

28、with the minimum of delay, ideally within 2 working days, to facilitate the efficient operation of the facility3.2.1 Pharmacy Production Team LeaderThe pharmacy production team leader is responsible for: Ensuring that appropriately qualified personnel are appointed. Ensuring production processes are

29、 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.3.2.2 Pharmacy Senior Production TechnicianThe pharmacy operations

30、 representative is responsible for Completion of batch records. Operating procedures. Training of personnel.3.2.3 Trust Senior Engineer Ensuring that systems/equipment are appropriate for their purpose. Maintenance of systems/equipment. Maintenance procedures. Calibration policy and procedures. Revi

31、sion of O & M manuals for equipment/systems. Approval of validation protocols for content relating to engineering content.3.2.4 Pharmacy Quality Control Officer Ensuring appropriate Quality Control (QC) procedures are in place Provision and maintenance of auditable document storage systems. Approval

32、 of validation protocols for quality aspects. Approval of all working QC and production documents 3.2.5 Validation Engineer Identify and plan appropriate validation activities. Provide validation technical support and training. Ensure appropriate validation procedures are in place.4.0 INTRODUCTION4.

33、1 Purposes of the VMPThe 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 vali

34、dation activities that will be undertaken. Identify the methods by which these activities will be undertaken. Identify the documentation requirements to support the above activities.4.2 Overview of ProjectThis VMP relates to a new facility, to be known as the _. In line with current GMP standards th

35、e new pharmacy will provide aseptically dispensed intravenous products and manufactured sterile and non-sterile products to _ Hospital patients.4.3 Validation Philosophy The VMP is intended to be a live document that initially supports the design and construction of the facility and subsequently the

36、 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

37、 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 p

38、roduct 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 gr

39、oup headings: Quality Plan Design Reviews FAT/Commissioning Installation Qualification SAT/Operational/Performance Qualification Process Validation Cleaning Validation Analytical Method ValidationThe validation activities will be incorporated into project design, construction programs and production

40、 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.5.0 REGULATORY STANDARDS AND GUIDELINESThe following is a list of standa

41、rds 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 P

42、ractice 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

43、 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 025. MCA Rules and Guidance for Pharmaceutical Manufacturers and Distributors, 2002.6. A

44、S/NZS ISO14644.1:2002 : Cleanrooms and associated controlled environments Part 1: Classification and air cleanliness7. AS/NZS 14644.2:2002 : Cleanrooms and associated controlled environments Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644.18. AS/NZS ISO

45、 14644.4:2002 : Cleanrooms and associated controlled environments Part 4: Cleanrooms and associated controlled environments - Design, construction and start-up9. ISO EN 14644.5:2004, Cleanrooms and Associated Controlled Environments Part 5: Cleanroom Operations.10. ISO 14644-7:2004 : Cleanrooms and

46、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 Gu

47、ide Volume 3, Sterile Manufacturing Facilities14. ISPE Baseline Guide Volume 4, Water and Steam Systems15. ISPE Baseline Guide Volume 5, Commissioning and Qualification16. BS 5295 Environmental Cleanliness in Enclosed Spaces17. European Pharmacopeia18. British Pharmacopeia19. The Quality Assurance o

48、f Aseptic Preparation Services, 3rd edition, 2001.20. Good Automated Manufacturing Practice.21. Good Laboratory Practice.6.0 DESCRIPTION OF PRODUCTS AND PROCESSES6.1 IntroductionThe pharmacy produces and issues a large number of products to in-patients, out-patients and other group hospitals/clinics

49、.This VMP applies to all production processes in the pharmacy.6.2 Product GroupsProducts 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 differ

50、ences 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 Produc

51、ts (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 inclusio

52、n 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.6.3 ProcessesFor each product group, the manufacturing processes and the specific equipment utilised will be described in

53、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.6.4 Product Storage and DistributionGenerally for compound

54、ed 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 storag

55、e. 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, p

56、roducts 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

57、boxes will be used when a cold chain delivery is required.7.0 PROJECT DESCRIPTIONNote: All drawings referenced in this section are located in Appendix C.7.1 Site LocationThe new pharmacy is located on the site of the _. Its position with respect to other facilities on the same site is shown on layou

58、t drawing no. _.7.2 Facility 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

59、. _.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 gene

60、rator and control panels is situated in _. Please refer to drawing no. _.7.3 Production Suites7.3.1 Zone 1, Non-Sterile ManufacturingAll 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 un

61、dertaken in this area include: Non-sterile manufacture of creams, ointments, suppositories, oral suspensions, oral liquids and capsules. Extemporaneous preparation of creams, ointments and oral suspensionsPlease 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.