Compliance by Design and Compliance Master Plan

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

1

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

2

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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Health & Medicine

Compliance by Design and Compliance Master Plan