compliance by design and compliance master plan
DESCRIPTION
In this presentation from IVT's GMP Week, Journal of Validation Technology Editor-in-Chief, Paul Pluta, Ph.D., asks "can compliance be improved by using quality by design [QbD] concepts?" Pluta discussed the QbD application, development of validation master plans, and the lifecycle approach to process validation. Furthermore, he discusses how to incorporate these essential parts of the validation process to implement effective, and efficient, compliance by design into the quality system.TRANSCRIPT
QbD/Valida*on Applica*on -‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐-‐
COMPLIANCE BY DESIGN (CbD) QUALITY SYSTEMS BY DESIGN (QSbD)
and COMPLIANCE MASTER PLAN (CMP)
QUALITY SYSTEMS MASTER PLAN (QSMP)
A LIFECYCLE Approach
Paul L. Pluta, PhD
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OUTLINE / OBJECTIVES
1. Why? 2. Quality by Design (QbD)
– Compliance by Design (CbD) comparison 3. Valida@on Master Plan (VMP)
– Compliance Master Plan (CMP) comparison 4. Lifecycle Approach
– Compliance Lifecycle comparison 5. Implementa@on 6. Benefits and Problems 7. Discussion
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WHY CbD / CMP / LIFECYCLE APPROACH?
Development has been revolu@onized by QbD -‐-‐ an organized approach with defined objec@ves and steps. Industry and regulatory have strongly embraced and supported QbD.
Valida@on Master Plans (VMP) are successful and widely accepted documents useful to industry and regulatory.
The FDA Process Valida@on Guidance has introduced the lifecycle approach to process valida@on.
Coincident with growth and success of QbD have been serious GMP compliance incidents (heparin, glycerin, Viracept, J&J, Genzyme).
Can QbD, VMP, and lifecycle approaches be applied to improve compliance?
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CbD / CMP / LIFECYCLE OVERVIEW QUALITY SYSTEMS
Development of system – Objec@ve and aYributes of quality systems – Parameters to achieve objec@ves and aYributes – Varia@on affec@ng parameters – Control of varia@on Performance of system – Quality system performance process Maintaining system – Maintain and monitor quality system – Improvement projects Documenta@on
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QUALITY BY DESIGN • Target product profile (TPP) and cri@cal quality aYributes (CQA)
• Drug substance and excipient proper@es • Formula@on design and development • Manufacturing process design and development • Iden@fica@on of cri@cal process parameters (CPP) and cri@cal material aYributes (CMA)
• Risk assessment and design space • Scale up, iden@fica@on of variables, and control strategy
Red = Original QbD
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COMPLIANCE by DESIGN CbD is an organized approach to compliance with quality systems. CbD has a defined structure with objec@ves and associated content. CbD con@nues throughout the lifecycle of the quality systems.
CbD approaches quality systems as a development project in the manner of QbD.
Can compliance be improved by using QbD concepts?
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COMPARISON – COMPLIANCE BY DESIGN and QUALITY BY DESIGN
Objec@ves and cri@cal compliance aYributes (CCA) – What are the goals of each quality system? – What makes a quality system successful?
Cri@cal compliance parameters (CCP) – What factors may significantly influence the success of the quality system?
Input varia@on and control – What varia@on in quality system opera@on is expected and how is it
controlled? Ongoing maintenance and management
– How is performance monitored and maintained?
Con@nuous improvement projects – How can the quality system be improved?
CbD approach equivalent to QbD = Stage 1 process valida*on Ongoing maintenance and management = Stage 3 process valida*on Con*nuous improvements expected from ongoing monitoring.
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VALDIATION MASTER PLAN
Sec@ons discuss site valida@on categories – Valida@on policy – Equipment – Facili@es (HVAC) – U@li@es – Process – Cleaning
Tables with document references (IQ, OQ, PQ) Valida@on commitments and @melines Regular updates (quarterly?) related to needs frequency
Note “chapters” of VMP
VMP is rou*nely requested by regulatory auditors.
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COMPLIANCE MASTER PLAN
CMP is an organized approach to documen@ng the CbD methodology. CMP has a defined approach, structure, and content. CMP is a working document that is con@nually maintained throughout the quality systems lifecycle.
Can compliance documenta*on be improved by use of VMP concepts?
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COMPLIANCE MASTER PLAN • Quality System • Facili@es and Equipment System • Materials System • Produc@on System • Packaging and Labeling System • Laboratory Control System • Training System • Valida@on System • Product Review System • Stability System • Product Complaint System • Others
Red = FDA Quality Systems Note “chapters” of CMP
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COMPLIANCE MASTER PLAN
SYSTEM TITLE • System and subsystem descrip@ons
– Objec@ve and cri@cal aYributes – Cri@cal parameters affec@ng objec@ve – Input variables and control strategy – Ongoing maintenance and management
• Con@nuous improvement project status • References (includes project reports)
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LIFECYCLE APPROACH FDA Process Valida*on Guidance (January 2011)
Lifecycle Approach to Process Valida*on • Stage 1. Process Design
– Includes QbD, PAT, risk management
• Stage 2. Process Qualifica@on • Stage 3. Con@nued Process Verifica@on
Process valida@on always ongoing Con@nuous improvements expected
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LIFECYCLE APPROACH 1. Understanding and planning 2. Performance 3. Maintenance and monitoring
• System performance
4. Con@nuous improvement
Applica*on to equipment, computer systems, etc.
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LIFECYCLE APPROACH
Valida*on Evolu*on
1978 -‐-‐ CGMP includes Valida@on
1987 -‐-‐ Development -‐-‐ VALIDATION -‐-‐ Control
2008 à 2011 Lifecycle approach Con@nuum of understanding – valida@on – maintenance
UNDERSTANDING à VALIDATION à MAINTENANCE à IMPROVEMENT
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LIFECYCLE APPROACH
Recent speakers on various aspects of valida@on and qualifica@on have adopted the lifecycle approach to their fields. – Equipment – Facili@es – U@li@es – Cleaning – Computer systems
Can compliance be improved by use of lifecycle concepts of process valida*on?
Are quality systems designed, maintained, and monitored to yield con*nuous system improvements?
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LIFECYCLE APPROACH
ICH Q10. Pharmaceu*cal Quality Systems • Pharmaceu@cal Development • Technology Transfer • Manufacturing • Product Discon@nua@on
ICH Q10 primary focus -‐-‐ product performance throughout product lifecycle.
CbD focus -‐-‐ quality systems performance throughout quality system lifecycle.
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IMPLEMENTATION AND EXAMPLES
Overview and approach
Material System • Mul@ple subsystems in process series • Equivalent to manufacturing processes
Training System • One system serves all site areas • Different competency requirements, i.e., different risk levels
Valida*on System • One system serves all site areas • Different valida@on requirements, i.e., manufacturing process , cleaning process,
equipment, facili@es, u@li@es, etc.
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CbD / CMP / LIFECYCLE IMPLEMENTATION
1. Iden@fy systems in the organiza@on – FDA systems (6) are major systems – Addi@on “subsystems” are iden@fied in FDA Quality System – Other systems support mul@ple major systems
2. For an individual system: – Iden@fy complete business process – Iden@fy subsec@ons – Iden@fy objec@ves , CCA, CCP, varia@on, controls for all subsec@ons – Gap analysis of subsec@ons – Risk analysis of subsec@ons
3. Con@nuous improvement projects based on gap analysis, risk analysis, and ongoing monitoring
4. Documenta@on in CMP 5. Repeat for all systems based on risk.
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CbD / CMP LIFECYCLE IMPLEMENTATION – Iden@fy complete business process – Iden@fy system subsec@ons – Iden@fy objec@ves and CCA, CCP, varia@on, and controls for all
subsec@ons – Gap analysis of subsec@ons – Risk analysis of subsec@ons – Ini@ate improvement projects – Documenta@on
Above analysis and evalua*on conducted by management, each sec*on staff, and QA -‐-‐ with cross func*onal input – Staff par*cipa*on cri*cal – Cross-‐func*onal input cri*cal
Ex: Process experience, incoming test data, vendor audits Ex: Process experience, devia@ons, CAPA, training
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EXAMPLE: MATERIAL SYSTEM BUSINESS PROCESS
1. Iden@fy approved vendors to source incoming materials – Vendors approved by Vendor QA
2. Receive incoming materials 3. Store incoming materials – quaran*ne status 4. Submit samples for tes*ng 5. Receive and evaluate test results 6. Transfer tested materials to materials to status areas
– Approved or Rejected. Materials on test remain in quaran*ne
7. Dispense approved materials to manufacturing and packaging loca*ons 8. WFI, gas, and compressed air distribu*on 9. Received and store manufactured / finished products – quaran*ne
status 10. Transfer tested materials to status areas
– Approved or Rejected. Materials on test remain in quaran@ne
11. Transfer approved materials to distribu*on center 12. Ship approved materials from distribu*on center to customer
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COMPLIANCE BY DESIGN MATERIAL SYSTEM SUBSECTIONS
Incoming Materials -‐-‐ Sourcing Incoming Materials – Storage/tes*ng/disposi*on Drug dispensing Water/gas/air tes*ng/distribu*on Finished Products – Storage/tes*ng/disposi*on Finished Products – Distribu*on Finished products – Offsite distribu*on
Above customized to site organiza*on
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COMPLIANCE BY DESIGN -‐-‐ MATERIAL SYSTEM INCOMING MATERIALS -‐-‐ SOURCING
System objec*ve and cri*cal akributes • Obtain high quality materials (API, excipients, commodi@es) from QA-‐approved vendors for eventual
dispensing to product manufacturing Cri*cal parameters affec*ng objec*ve • QA audit, inves@gate, and approve material suppliers • Vendor procedure, process, and management changes Input variables and control strategy • Material varia@on • Vendor outsource commodity items Ongoing maintenance and management • Approved supplier list • Material specifica@ons • Material test data monitoring • Non-‐conforming materials received Con*nuous improvement project status 1. Risk analysis of incoming materials. See Appendix for project descrip@on. 2. Supplier risk evalua@on. See Appendix for project descrip@on. Reference documenta*on • Risk analysis of incoming materials. J. Doe, 1-‐1-‐10. • Supplier risk evalua@on. J. Smith 1-‐4-‐10 Appendix 1. Project Descrip@on: Risk analysis of Incoming Materials. 2. Project Descrip@on: Supplier Risk Evalua@on.
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COMPLIANCE BY DESIGN -‐-‐ MATERIAL SYSTEM INCOMING MATERIALS – STORAGE / TESTING / DISPOSITION
System objec*ve and cri*cal akributes • Storage of high quality materials (API, excipients, commodi@es) prior to dispensing to
product manufacturing. Materials stored according to recommended temperature. Materials stored according to QA disposi@on (Approved, Quaran@ne, Rejected)
Cri*cal parameters affec*ng objec*ve • Vendor storage recommenda@ons • Vendor expira@on date recommenda@ons • Power supply to storage areas Input variables and control strategy • Storage recommenda@ons per vendor checklist. • Expira@on date recommenda@ons per vendor checklist. • Alarm system for temperature limits Ongoing maintenance and management • Material inventory list ongoing • Facility monitoring system Con*nuous improvement project status • Refrigera@on backup generator Reference documenta*on • Material requirements
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EXAMPLE: TRAINING SYSTEM BUSINESS PROCESS Func*ons, work centers, procedures (training modules), and personnel
Training system uses validated tracking sokware Training system defines training categories Func@on defines work centers Func@on assigns procedures to work centers -‐ Procedures include training category and retraining frequency (risk based) -‐ Training modules wriYen -‐ Training modules approved Func@on assigns personnel to work centers Func@ons, work centers, procedures, and personnel entered into tracking sokware QA approval
1. Personnel trained according to category and frequency 2. Personnel training comple@on in tracking system 3. Training status reported by sokware 4. Training modules evaluated by trainees
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TRAINING CATEGORIES
Company informa@on (general news, holidays) Awareness of common procedures (ethics, analy@cal methods, tablet machine parameters) – read and sign
Policies and procedures – (GMP) -‐-‐ classroom Performance (OtJ) training (HPLC, tablet machine opera@on) qualifica@on
SME qualifica@on (expert designa@on) External con@nuing educa@on (scien@fic mee@ngs)
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COMPLIANCE BY DESIGN – TRAINING SYSTEM System objec*ve and cri*cal akributes • Provide effec@ve training to site personnel Cri*cal parameters affec*ng objec*ve • Development of high quality training modules • Selec@on of appropriate training category and retraining frequency • Competency of training instructors Input variables and control strategy • Employee experience and learning mo@va@on • Work center recommenda@ons on training category and retraining frequency Ongoing maintenance and management • Training module comple@on records • Trainee evalua@ons • Correla@on of training modules and excep@on events Con*nuous improvement project status 1. Risk analysis of site posi@ons. See Appendix 2. Training Module X development
Reference documenta*on • Risk analysis of site posi@ons. J. Jones, 1-‐1-‐10. Appendix Project Descrip@on: Risk Analysis of Site Posi@ons
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EXAMPLE: VALIDATION SYSTEM BUSINESS PROCESS 1. Site functions design / develop new systems or changes 2. Site functions initiate new validations and qualifications or changes to validated
systems. • New product / processes • New equipment, facilities, utilities • Other Sources of validation / qualification activities • R&D, Technical Support • Operations • Quality Assurance / Quality Control • Maintenance 3. Validation process /documentation written/monitored by validation group • Different requirements for different validation / qualification • Risk analysis 4. Appropriate post-validation tracking responsibility of QA • Product process data (APR) • Non-conformances and deviations; complaints, changes, others • Management review
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VALIDATION CATEGORIES
Process valida@ons • Manufacturing • Cleaning • Packaging • Analy@cal • Others Qualifica@ons – IQ, OQ, PQ; ASTM E2500 • Equipment • Facili@es • U@li@es • Computer systems • Others
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COMPLIANCE BY DESIGN – VALIDATION SYSTEM System objec*ve and cri*cal akributes • Provide effec@ve lifecycle valida@on services to site
Cri*cal parameters affec*ng objec*ve • Development of high quality products/processes, equipment, other systems. • Documenta@on of development process and ac@vi@es and retrieval of documents • High quality valida@on documenta@on • Post-‐valida@on monitoring program with periodic management review
Input variables and control strategy • Technical exper@se • Knowledge or valida@on requirements and expecta@ons • Employee training, experience, and mo@va@on
Ongoing maintenance and management • Iden@fica@on of appropriate post-‐valida@on monitoring • Management review program • Change control awareness; Change control program within related areas
Con*nuous improvement project status • Iden@fica@on of improvement projects, e.g., valida@on training
Reference documenta*on • Valida@on documenta@on
Appendix • Project reports
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COMPLIANCE MASTER PLAN • Introduc@on and policy • Quality System • Facili@es and Equipment System • Materials System • Produc@on System • Packaging and Labeling System • Laboratory Control System • Training System • Valida@on System • Product Review System • Stability System • Product Complaint System • Others
Each system with subsec*ons has descrip*on, objec*ves, CQA, CCP, varia*on, control of varia*on, projects completed (improvements), commitments, etc.
CMP available to auditors 30
CbD / CMP / LIFECYCLE POSITIVES • Organized and comprehensive focus on compliance based on risk to
the pa@ent and the organiza@on – Based on successful concepts • System design -‐-‐ Gap analysis • Risk analysis • Cross-‐func@onal systems thinking • Consistent priori@zed mi@ga@on ac@vi@es across func@ons – based
on risk • Varia@on iden@fica@on and control strategy • Centralized tracking of commitments • Con@nuous improvements based on systems monitoring • Standardized audit expecta@ons and documenta@on • Organiza@on commitment, transparency, and credibility • Track organiza@on accomplishments completed • Strong message to employees • Strong message to auditors • Poten@al “credit” in audits for projects completed and new
commitments iden@fied 31
CPD / CMP / LIFECYCLE NEGATIVES Difficult • Gepng organized is extremely difficult! • Risk analysis is difficult • Gap analysis is difficult • Changes are difficult Transparency • Being open about gaps and deficiencies may have regulatory and poli@cal risks
Organiza*onal commitments • Headcount needed to correct deficiencies
Do the benefits outweigh the nega*ves?
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OTHER THOUGHTS ASTM E2500 • Addresses valida@on cri@cism by risk priori@za@on • Pfizer using
FDA Comments • Prosecu@on of responsible execu@ves / management • Transparency • Generally posi@ve comments on QbD -‐-‐ Concerns about implementa@on • Site organiza@on according to systems
ICH Q10 Pharmaceu*cal Quality System Elements • Process performance and product quality monitoring system • CAPA system • Change management system • Management review of process performance and product quality
Medical Devices • Management controls • Design controls • CAPA • Produc@on and process controls • Steriliza@on process controls • Sampling plans instruc@ons
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REGULATORY COMMENTS
US and Interna@onal Regulatory • Generally very posi@ve • No nega@ve comments • “I’d be blown away if a company did this!” • “Wow” • Other comments awaited
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GETTING STARTED 1. Iden@fy high risk areas
– Example: Sourcing of incoming materials – Example: Asep@c core area training
2. Senior management discussion – risks to opera@on 3. Func@on management discussion – risks to opera@on 4. Iden@fy recep@ve individuals in high risk area 5. Training of appropriate individuals 6. Start slowly 7. Communica@on. Modify strategy as needed to insure
success 8. Expand effort based on success 9. Expect resistance
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COMPLIANCE BY DESIGN AND COMPLIANCE MASTER PLAN LIFECYCLE APPROACH -‐-‐ SUMMARY
• CbD based on QbD, CMP based on VMP • Lifecycle approach based on lifecycle approach to process valida@on
– Design, Perform, Monitor • Iden@fy quality systems: FDA, Quality Systems, support systems • Iden@fy business process of systems à system subsec@ons • Iden@fy objec@ves and CCA, CCP, varia@on, controls, gaps, and risks • Con@nuous improvement projects based on gap, risks, monitoring • Documenta@on in CMP • Posi@ves: Organized and comprehensive focus based on risk to the pa@ent and
the organiza@on, strong message to employees and to auditors, “credit” in audits • Nega@ves: Difficult, transparent, deficiencies iden@fied • Consistent with FDA direc@on (Process Valida@on, risk), ASTM E2500, and ICH Q8,
Q9, Q10 • Cost effec@ve -‐-‐ High risk ac@vi@es emphasized and priori@zed • Implementa@on approach
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INTERACTIVE DISCUSSION
Comments on CbD Comments on CMP Comments on Lifecycle
Terminology: Compliance by Design (CbD) and Compliance Master Plan (CMP)
or Quality Systems by Design (QSbD) and Quality Systems Master Plan
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REFERENCES Pluta, Paul L. and Richard Poska. “Compliance by Deisgn (CbD)
and Compliance Master Plan (CMP). An Organized Approach to Compliance.” J. GXP Compliance, V 14, #2, Spring 2010.
Pluta, Paul L., Richard Poska, and Timothy J. Fields. “Compliance by Design and Compliance Master Plan” Pharmaceu4cal Technology, V35, #3, March 2011.
Nash, Robert A. “The Concept of Establishing a Compliance Master Plan (CMP).” J. Valida4on Technology, V 12, #2, February 2006.
Borkar, M.M., A.A. Shirwaikar, and P.G. Shilotri. “Step by Step Approach to Quality System Implementa@on and Regulatory Compliance.” J. GXP Compliance, V 9, #2, January 2005.
Yu, Lawrence X., et. al., “Quality by Design for Generic Drugs.” PharmTech.com, October 2, 2009.
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COMMERCIAL
Book chapter authors
Pilot program • System or subsec@on using CbD approach
Writers for JVT and JGXP • Sample journals • Brochure with example papers • New features and ongoing features
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PAUL L. PLUTA, PhD Editor-‐in-‐Chief • Journal of Valida4on Technology • Journal of GXP Compliance
Adjunct Associate Professor • University of Illinois at Chicago (UIC) College of Pharmacy, Chicago, IL, USA
Editor and Chapter Author • Cleaning and Cleaning Valida4on, Volume 1. Basics, Expecta4ons, and
Principles. PDA and Davis Healthcare Interna@onal (DHI) Publishing, 2009 • Cleaning and Cleaning Valida4on, Volume 2 . Applica4ons of Basics and
Principles. PDA and Davis Healthcare Interna@onal (DHI) Publishing, 2012 (expected)
Contact: [email protected]
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