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3. Validation (and Qualification)

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  1. Basic Principles of GMP 3. Validation (and Qualification)

  2. Validation, Qualification Two phylosophies: • Validation, qualification (and calibration) are different, although interrelated activities (e.g. EU GMP) • Qualification and also calibration belong to validation activities (e.g. WHO GMP)

  3. Terms Qualification or validation? • A system/equipment must be qualified to operate in a validated process • Qualify a system and/or equipment • Validate a process • Qualification versus validation, e.g. you qualifythe autoclave, while you validate the whole sterilization process • (and calibrate a measuring instrument!)

  4. Validation Introduction Three basic principles of Quality Assurance: • Quality, safety, efficacy • Cannot inspect quality into a product • Processes must be under control (for this, they should be validated, whether they can be under control!

  5. Validation Objectives • To review the definition and types of validation • To understand the requirements for documentation and key stages in the process of validation • To consider models for process validation

  6. Validation Definition Validation is the documented act of proving that any procedure, process, equipment, material, activity or system actually leads to the expected result

  7. Validation Qualification and validation work require: • Collaboration of experts • Budget • Meticulous and careful planning A Validation Master Plan helps the manufacturer and inspectorate

  8. Validation Essential Part of GMP • Predetermined protocols • Written reports • Processes and procedures • Periodic revalidation • Specific attention: • processingprocess validation • testinganalytical method validation • cleaningcleaning validation

  9. Validation Types of Manufacturing Process Validation • Experimental approach • Prospective validation • Concurrent validation • Analysis of historical data • Retrospective validation • Revalidation • Periodic revalidation • Revalidation after change

  10. Prospective validation • Before starting a new manufacturing process (or after its significant change), or revalidation: • Manufacturing 3 batches only for validation purposes, all data documented. Reason: to see that the process is under control • As a rule, these batches are not marketed later, except special decision to do that

  11. Concurrent validation • In case of rarely produced medicines (e.g. 2 batches per year: no reason to produce 3 „validation” batches) • Concurrent validation: during the manufacture of „normal” batches to be marketed • Strict documentation!

  12. Retrospective validation • This validation means the assessment of data generated during previous batch manufacturing • Only for established technologies, the GMP is strictly applied, defects are rare • Assessment of data of 10-30 batches, including defective ones (their data are very valuable to see how the process can run out of control!)

  13. Qualification Types (Stages) of Qualification • Design qualification (DQ) • Installation qualification (IQ) • Operational qualification (OQ) • Performance qualification (PQ)

  14. Design qualification DQ • E.g. of a manufacturing equipment • Before purchasing! • Collection of data about the similar equipments available on the market, assessing our needs, resources to buy and to operate, space and maintenance they would need, etc. • Making the decision

  15. Installation Qualification IQ • E.g. of a manufacturing equipment • After purchasing (or critical repair) • Put it on its intended place, connect with other equipments, electric power, material flow devices • Collect its documents incl. Operation Manual, etc. • Its formal „release”: it is ready for working with

  16. Operational Qualification OP • E.g. of a manufacturing equipment • „Model manufacturing” experiments with model materials, similar to those to be used in the real manufacture • E.g. qualifying an autoclave we use culture-media • Permit the acceptable fluctuations of parameters, even set the „worst conditions”

  17. „Worst conditions” • say, an equipment must be operated within the limits of • temperature: 20 and 35 oC • pressure: 0.9 and 1.2 atm • The worst cases, when it operates at • 20 oC and 0.9 atm • 35 oC and 1.2 atm • 20 oC 0.9 and 1.2 atm • 35 oC and 0.9 atm

  18. Performance Qualification PQ • Similar to the Operational Qualification, but the real manufacture is running • Permit accepted fluctuations up to their limits (incl. worse conditions, if occur)

  19. Qualification

  20. Type of process New Existing Sterile products  Non-sterile Requirement Every new process before approval for routine All processes affecting the sterility, and manufacturing environment including sterilization stage Low dose tablets and capsules: mixing and granulation, content uniformity (possible other parameters) Other tablets and capsules: uniformity of mass(possible other parameters) ValidationPriorities for Process Validation

  21. Validation Types of Documentation • Validation Master Plan (VMP) • Validation protocols (VP) • Validation reports (VR) • Standard Operating Procedures (SOPs)

  22. Validation TheValidation Master Plan could consist of: • Approval page and table of contents • Introduction and objectives • Facility and process description • Personnel, planning and scheduling • Responsibilities of committee members • Process control aspects • Equipment, apparatus, processes and systems to be validated • Acceptance criteria • Documentation e.g.validation protocols and reports • SOPs • Training requirements

  23. Validation Protocol • Objectives of the validation and qualification study • Site of the study • Responsible personnel • Description of the equipment • SOPs • Standards • Criteria for the relevant products and processes

  24. Validation Report • Title • Objective of the study • Refer to the protocol • Details of material • Equipment • Programmes and cycles use • Details of procedure and test methods

  25. Let us spend some time on the Validation Master Plan now

  26. Validation • The Validation Master Plan • (VMP) • Philosophy • Content • Strategy

  27. Validation Validation Master Plan • Recommendation only • Cover manufacturer’s validation policy and needs • Provides information on validation organization • It should describe: • why? • what? • where? • by whom? • how? • when?

  28. Validation Validation Master Plan • Prospective validation • Concurrent validation • Retrospective validation • Revalidation • Change control

  29. Validation The VMP • Identifies validation items (products, processes, systems) • Definesnature and extent of testing expected • Outlines test procedures and protocols • Summary document • Management agreement

  30. Validation The VMP helps: • Management • Validation team members • Project leaders • GMP inspectors

  31. Validation Validation Activities in VMP • Every validation activity included • Revalidation • Validation of new process cycles • Large validation projects have separate VMPs • Include reasonableunexpected events

  32. Validation The VMP: • Enables overview of entire validation project • Lists items to be validated with the planning schedule as its heart • Is like a map

  33. Validation The “Introduction” to the VMP • Validation policy • Project scope • Location and timing (including priorities) • Validation procedures • Standards

  34. Validation VMP should state who is responsible for: • Preparing the VMP • The protocols and SOPs • Validation work • Report and document preparation and control • Approval/authorisation of validation protocols and reports in all stages of validation process • Tracking system • Training needs in support of validation

  35. Validation VMP should contain: • Cross references to documents • Specific process considerations • Specific characteristicsbriefly outlined • Validation list (What to validate) • premises, systems and equipment • processes • products

  36. Validation VMP should contain, 2: • Descriptions of • plant (where to validate) • processes • products • Personnel attributes • expertise and training • Key acceptance criteria

  37. Validation VMP should contain, 3: • Format for protocols and other documentation • List of relevant SOPs (How) • Planning and scheduling (When) • Location (Where) • Estimate of staffing requirements (Who) • A time plan of the project (When) • Annexes

  38. Validation VMP should contain change control • Policy and procedure • Risk assessment • Authorization • Failure to properly document changes to the system means invalidation of the process

  39. Validation Changes that require revalidation • Software changes;Controllers • Site changes; Operational changes • Change of source of material • Change in the process • Significant equipment change • Production area changes • Support system changes

  40. Validation In summary, a VMP should contain at least: • Validation policy • Organizational structure • Summary of facilities, systems, equipment, processes to be validated • Documentation format for protocols and reports • Planning and scheduling • Change control • Training requirements

  41. Finishing Validation Master Plan, something about the Validation Protocol and Report

  42. Validation WHO Model for Validation Protocol and Report, 1 • Part 1 – Purpose and prerequisites • Part 2 – Presentation of the process • Part 3 – Validation protocol

  43. Validation WHO Model for Validation Protocol and Report, 2 • Part 4 – Installation qualification • Part 5 – Qualification protocol/report • Part 6 – Product characteristics

  44. Validation WHO Model for Validation Protocol and Report, 3 • Part 7 – Evaluation • Part 8 – Certification • Part 9 – Summary

  45. Special validation types • Validation of • cleaning • manuf. process • QC relatedprocesses

  46. Cleaning validation

  47. Cleaning validation Objectives To review: • General requirements • Validation protocol requirements • How to check limits • Analytical requirements • Sampling methods

  48. Cleaning validation Why cleaning validation is so important (1) • Pharmaceuticals can be contaminated by potentially dangerous substances • Essential to establish adequate cleaning procedures

  49. Cleaning validation Why cleaning validation is so important (2) • “Particular attention should be accorded to the validation of … cleaning procedures” (WHO) • “Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure” (PIC/S) • “The data should support a conclusion that residues have been reduced to an ‘acceptable’ level” (FDA)

  50. Cleaning validation Possible contaminants • Product residues • Cleaning agent residues and breakdown • Airborne matter • Lubricants, ancillary material • Decomposition residues • Bacteria, mould and pyrogens