Incorporate CPV and ContinualImprovement into Your Validation Plan   Presented by: Karen S Ginsbury   PCI Pharmaceutical C...
To be considered…•   Regulatory requirements for Process Validation•   21 CFR part 820 QSR•   21 CFR part 211•   ICH Q10: ...
To be considered…• II. Policy and Practice• Adopt the lifecycle concept (Validation Policy)• Policy:   – Post launch for n...
To be considered…III. Continual Improvement through managing   variation  – Studying variables and variation    using DOE ...
Validation = Intensive Testing"My Bread is Fresh and Tasty”Can’t test quality into a productMust design quality into a pro...
21 CFR 820 Subpart C:       820.30(f) Design verification• Each manufacturer shall establish and maintain  procedures for ...
21 CFR 820 Subpart C:         820.30(g) Design validation• Each manufacturer shall establish and maintain procedures  for ...
GMP Regulations - cfr 21 cfr 211.68  Automatic/mechanical/electronic equipment..routinely  calibrated /inspected/checked ...
ICH Q10 Pharmaceutical Quality System
Annex 15 -EUDQ, VMP, PQ / PV, Cleaning
Annex 15 -EU
Validation   Action of proving, in accordance with   principles of GMP, that any procedure,   process, equipment, material...
Qualification   Action of proving that any equipment   works correctly and actually leads to the   expected results.   The...
Annex 15 – “In-Use” Facilities  Qualification of established (in-use) facilities,  systems and equipment• Evidence should ...
FDA PV Guidance              15
Process validation definition• …the collection and evaluation of data, from  the process design stage throughout  producti...
Life Cycle Approach                                   Identification         Process                                     o...
Stage               FDA Process Validation 2011                 Purpose                                  ActivitiesProcess...
Worst Case• A condition or set of conditions encompassing  upper and lower processing limits and  circumstances, within st...
GHTF Guidance 2004
GHTF: PV within the QMS• Process validation is part of the integrated  requirements of a Quality Management System• It is ...
PV Decision Tree
Warning Letter
Water System Warning
And the Big One….• Failure to establish a written procedure to calibrate, inspect,  and check automated, mechanical, or el...
EMA Draft Guideline (March 2012)     Any problems you can see here?
EMA Draft Guideline (March 2012)
EMA Draft Guideline (March 2012)
EMA Draft Guideline (March 2012)
And now to policy and practice:      implementation
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Incorporate CPV and Continual Improvement into your Validation Plan

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This workshop examines the approach to Continued Process Verification and demonstrating that your product and process are operating in a state of control and continue to do so over the life of the product. Without any prior coordination, the theme was elaborated by the afternoon speakers once the conference itself was underway. The concept of “step up step down” for adjusting the level of product scrutiny both for process parameters monitoring and for sampling and testing quality attributes was explored and developed.

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Incorporate CPV and Continual Improvement into your Validation Plan

  1. 1. Incorporate CPV and ContinualImprovement into Your Validation Plan Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd IVT’s 4th Annual Validation Week Copenhagen, Denmark March 2013 Stage 1: Stage 2: Process Qualification Stage 3: Continued Process Stage 2a: Equipment & Stage 2b: Process Process Verification Design Facility Qualification Performance Qualification
  2. 2. To be considered…• Regulatory requirements for Process Validation• 21 CFR part 820 QSR• 21 CFR part 211• ICH Q10: PQS and Lifecycle• EU Annex 15 and EU PV Guideline March 2012• FDA process validation guide January 2011• GHTF Guidance, 2004• Inspectional observations and expectations
  3. 3. To be considered…• II. Policy and Practice• Adopt the lifecycle concept (Validation Policy)• Policy: – Post launch for new products – Legacy products• CPV templates• Data collection plan: product / process and CAPA sources• Data analysis and feedback
  4. 4. To be considered…III. Continual Improvement through managing variation – Studying variables and variation using DOE in design – Post Launch Scrutiny and Ongoing verification – An ongoing exercise to increase efficiency (the real “lean”)
  5. 5. Validation = Intensive Testing"My Bread is Fresh and Tasty”Can’t test quality into a productMust design quality into a product
  6. 6. 21 CFR 820 Subpart C: 820.30(f) Design verification• Each manufacturer shall establish and maintain procedures for verifying the device design• Design verification shall confirm that the design output meets the design input requirements• The results of the design verification, including identification of the design, method(s), the date, and the individual(s) performing the verification, shall be documented in the DHF
  7. 7. 21 CFR 820 Subpart C: 820.30(g) Design validation• Each manufacturer shall establish and maintain procedures for validating the device design• Design validation shall be performed under defined operating conditions on initial production units, lots, or batches, or their equivalents• Design validation shall ensure that devices conform to defined user needs and intended uses and shall include testing of production units under actual or simulated use conditions• Design validation shall include software validation and risk analysis, where appropriate• The results of the design validation, including identification of the design, method(s), the date, and the individual(s) performing the validation, shall be documented in the DHF
  8. 8. GMP Regulations - cfr 21 cfr 211.68 Automatic/mechanical/electronic equipment..routinely calibrated /inspected/checked to assure proper performance 21 cfr 211.110 Establish control procedures to assure batch uniformity. Monitor output, validate performance or manufacturing processes that may be causing product variability
  9. 9. ICH Q10 Pharmaceutical Quality System
  10. 10. Annex 15 -EUDQ, VMP, PQ / PV, Cleaning
  11. 11. Annex 15 -EU
  12. 12. Validation Action of proving, in accordance with principles of GMP, that any procedure, process, equipment, material, activity or system actually leads to the expected results (see also Qualification)EU Rules & Guidance for Pharmaceutical ManufacturersAnnex 15
  13. 13. Qualification Action of proving that any equipment works correctly and actually leads to the expected results. The word “validation” is sometimes widened to incorporate the concept of qualificationEU Rules & Guidance for Pharmaceutical Manufacturers
  14. 14. Annex 15 – “In-Use” Facilities Qualification of established (in-use) facilities, systems and equipment• Evidence should be available to support and verify the operating parameters and limits for the critical variables of the operating equipment• Additionally, the calibration, cleaning, preventative maintenance, operating procedures and operator training procedures and records should be documented
  15. 15. FDA PV Guidance 15
  16. 16. Process validation definition• …the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering (product meeting its CQAs and intended use KSG) quality product• …involves a series of activities taking place over the lifecycle of the product and process 2011 FDA Guidance
  17. 17. Life Cycle Approach Identification Process of process design variables PROCESS Process VALIDATION monitoring Control and strategyimprovement Process qualification
  18. 18. Stage FDA Process Validation 2011 Purpose ActivitiesProcess Design Define commercial process based on  Integrated product and process design knowledge gained through  Product development activities development and scale up activities  DOE combined with Risk Assessment Outcome: design a process for routine to explore process parameters, manufacture that will consistently variability, effect on quality attributes deliver product meeting its (critical) and process controls quality attributesProcess Confirm process design as capable of  Facility design reproducible commercial manufacturing  Equipment & utilities qualificationQualification  Process Performance qualification  Emphasis on use of statistically based sampling plans, statistically valid acceptance criteria and statistical analysis of process data to understand process consistency and performanceContinued Provide ongoing assurance that the  Organized data collection every batchProcess process remains in a state of control  Data trending and statistical analysisVerification during routine production through  Product review quality procedures and continuous  Equipment and facility maintenance improvement initiatives  Calibration  Management review and production  Employee feedback
  19. 19. Worst Case• A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, which pose the greatest chance of product or process failure when compared to ideal conditions• Such conditions do not necessarily induce product or process failure - Annex 15 glossary
  20. 20. GHTF Guidance 2004
  21. 21. GHTF: PV within the QMS• Process validation is part of the integrated requirements of a Quality Management System• It is conducted in the context of a system including design and development: – Control – Qualiity assurance – Process control – CAPA
  22. 22. PV Decision Tree
  23. 23. Warning Letter
  24. 24. Water System Warning
  25. 25. And the Big One….• Failure to establish a written procedure to calibrate, inspect, and check automated, mechanical, or electronic equipment used to manufacture drug products to assure proper performance. [21 CFR 211.68 (a)]• Specifically, there is no data to demonstrate that production equipment (two mixers, one filler, a water system) has been properly validated (installation qualification, operational qualification, and performance qualification) as acceptable for its intended uses
  26. 26. EMA Draft Guideline (March 2012) Any problems you can see here?
  27. 27. EMA Draft Guideline (March 2012)
  28. 28. EMA Draft Guideline (March 2012)
  29. 29. EMA Draft Guideline (March 2012)
  30. 30. And now to policy and practice: implementation

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