GAMP Overview Presentation 04-03-2012 FINAL

Risk-Based Validation – The Benefits of the GAMP®  Approach Kevin C. Martin Chair, GAMP ®  Americas Sr. Vice President Azzur Group LLC

Agenda • 20 Years of the GAMP® Organization • GAMP Benefits • GAMP Contribution • Validation Productivity • Lean Validation • Current Technology Trends • Current Regulatory Activity

Agenda • 20 Years of the GAMP® Organization • GAMP Benefits • GAMP Contribution • Validation Productivity • Lean Validation • Current Technology Trends • Current Regulatory Activity

20 years of GAMP Development Validation Productivity!

plus …

GAMP ®  Americas Leadership • Officers • •

Chairman:

•

Kevin Martin, Azzur Group

•

Co-Chairman: Michael Rutherford, Eli Lilly

•

Secretary: Lorrie Schuessler, GSK

• ISPE Staff PM •

• Steering Committee

Scott Ludlum

Blue indicates GAMP® Council *Denotes GAMP Council Chair

• • • •

• • • • •

Winnie Cappucci* , Retired- Bayer

Waunetka Clark, Abbott Jim John, ProPharma Group Paige Kane, Pfizer Klaus Krause, Allergan Eugene Longo , GAMP® Puerto Rico Randy Perez, Novartis Judy Samardelis, Medimmune Eric Staib, Covance Robert Tollefsen, FDA Bob Wherry, Sunovion

Active GAMP ®  SIGs GAMP ®  Americas

GAMP ®  Europe

•

Laboratory Systems

•

Process Control Systems

•

Manufacturing Execution Systems (co-chaired with Europe)

•

Testing (with USA)

•

Supplier Relationships

•

Risk Management

•

Outsourcing and Offshoring (with USA)

•

Joint Equipment Transition Team (JETT)

• •

Calibration

Outsourcing and Offshoring (with Europe)

•

Development Models and Methods

IT Infrastructure Control & Compliance (with Europe)

•

•

GxP Controls Framework (proposed)

R&D / Clinical Systems (coordinated GAMP ®  D-A-CH with Europe) • Supplier Cooperation •  Automated Testing (sub-set of • Open Source Software Testing SIG)

• • •

Metrics

GAMP ®  Italia

Equipment Qualification Workgroup

GAMP ®  Nordic

•

Virtualization

Active GAMP ®  SIGs - Brazil • • •

GTG "Validation of IT Infrastructure and Processes”

•

GTG “Understanding e-records and e-signatures (ANVISA / EMA Annex 11 / 21CFR Part 11 / GAMP)”

• • • • •

GTG “Validation Master Plan and Validation Plan for CSV”

GTG " Validation of PLCs, Automated Systems, Shop-floor Systems, MES and BMS” GTG "Change Management for Computerized Systems and Maintenance of Validated Status”:

GTG “Legacy Systems” GTG " Qualification and Suppliers Assessment” GTG "Testing GxP Systems (base GPG GAMP)“ GTG "Organizational Structure for CSV”

GAMP Good Practice Guides 1.

Validation of Process Controls Systems (Second Edition Feb 2011)

2.

Calibration Management (Second Edition Nov 2010)

3.

Manufacturing Execution Systems  – A Strategic and Program Management Approach (Feb 2010)

4.

A Risk-Based Approach to Operation of GxP Computerized Systems - A Companion Volume to GAMP® 5 (Jan 2010)

5.

Electronic Data Archiving (Jul 2007)

6.

Testing of GxP Systems (Dec 2005)* (2nd Edition 3Q2012)

7.

Global Information Systems Control and Compliance (Nov 2005)

8.

IT Infrastructure Control and Compliance (Sep 2005)

9.

Validation of Laboratory Computerized Systems 2Q2012)

(Apr 2005) (2nd Edition

10. Risk-Based Approach to Electronic Records and Signatures (Feb 2005)

11. Legacy Systems (Nov/ Dec 2003)* * Available as a download at no cost to ISPE Members Only

G A M P ®    5 

GAMP® 5 Overview Published: Feb 2008

G A M P ®    5 Continues to Address… • Current regulatory initiatives 





FDA’s cGMPs for the 21st Century

PIC/S Guidance Risk-based Part 11 Guidance

• Global Standards 

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ICH Q8, Q9, Q10  ASTM E2500

• Escalating cost pressures mandate efficiency 





Facilitate a single company QMS Need to take full advantage of supplier capability Better compliance with less cost!

 Simplified V-model G A M P ®    5  Verifies Validationmodel better illustrates scalability Validation This options for phases Plan

Report

Validation Activities • Blended specifications (e.g. URS/FS, FS/DS, even URS/FS/DS) • Design review as opposed to formal DQ • Blending User of “classical” qualification  Acceptance of Verifies(e.g. IOQ, OQ/PQ, melding Requirements computer validation with equipment C&Q) (URS)

Plan Functional Specification (FS)

Development  Activities

Design Specify Specification (DS)

GAMP ®  5  stresses that this model does not  imply

Verifies Risk Management throughout the Verifies process

testing (PQ)

Report Functional testing (OQ) Installation Verify

Verification  Activities

(IQ)

This can be applied to nonlinear approaches like spiral or or Build Developer testsiterative methodologies, agile aSystem waterfallBuild development SystemBuild (Structural, unit, & (including Configure integration) software development, etc. methodology developer tests)  Activities

 Life Cycle Concept G A M P ®    5  Features: • Simplified V-

Repetitive “V” Activities Within the Life Cycle

migration

Model 



URS

Release

Changes







GxP Assessment



Concept

Project

Operation

Retirement

Supplier Involvement*

* • This could be a complex supply chain • Supplier may provide knowledge, experience, documentation & services throughout lifecycle

Plan Specify Build Verify Report Risk mgmt throughout process

• Repetition of Vactivities for changes • Incorporates end-of-life activities

Risk Management Goals • Systematic process for identifying, assessing, mitigating, controlling, and communicating risk, based on 



Good science Process and product understanding

• Recognize that zero risk is impractical and unattainable 

 Aim is for a c c e p t a b l e r is k

• Consistent with risk-based approach based on ISO 14971 (and ERES GPG) as well as other contemporary risk based tools

5-Step Quality Risk Management Process Step 1

Perform initial risk assessment & determine system impact Step 2

Identify functions impacting patient safety, quality, and data integrity Step 3

Perform functional risk assessments & identify controls Step 4

Implement & verify appropriate controls Step 5

Review Risks and monitor controls

The Desired State… Historical State

Desired State

1990’s Validation Approach    t   r   o    f    f    E   n   o    i    t   a    d    i    l   a    V   s   u   c   o    F

High

Medium

Low

Risk Based Approach    t   r   o    f    f    E   n   o    i    t   a    d    i    l   a    V   s   u   c   o    F

High Medium Low

Stakeholders – the GAMP ®  Benefits •  All stakeholders depend on reliable systems 

Performing as expected …



from the beginning …



…continuously …



with minimal attention

•  A proven roadmap when going from ‘manual’ to automated systems We have a great responsibility!

GAMP ®  5 – Enables Increased Validation Productivity • Focussed on efficient and effective validation • Making validation ‘productive’ • OED: ‘producing abundantly’ • Webster's: ‘Yielding results, benefit or profit’ Eliminate the Waste!!!

Universal Approach • GAMP methodology applies to all types of systems • Large database systems • Process control systems • Spreadsheets etc. • Needs tailoring to each project for maximum efficiency 

Consider all the elements of the validation process

Uniform Approach • The ‘V’ model is almost universally applicable • It is capable of considerable flexibility • Many ‘dialects’ exist • Fundamentals remain Design Review

Document Handover

Plan >Check > Do > Record Planning Specifications

Protocols Change management

QMS* for Systems Validation The Validation Process is well-documented • Based on QMS principles • Widely understood •  Adopts standard elements of QMS 

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Planning Specifications Risk-based approach Verification Documentation Change management Continuous improvement

*QMS = Quality Management System

Knowledge of Systems • To validate effectively we need to know our systems; 

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





Why we want them What they do How they do it Where the risks lie How the risks are controlled

• Follow a System Life Cycle - Use GAMP5 ® as a tool • Payback is immediate – increased efficiency of operation

Benchmarking for Continuous Improvement

12 Good Validation Practices • • • • • •

Policies and Procedures Good Project Management Practices Validation Planning Validation Strategy Specifications and Design Review Protocols

 Acknowledgment: David Selby, NSF-DBA

• • • • • •

Documentation Change Management Practices Training Handover Maintaining Control in Operation Post-project reviews

Benchmark Assessment • Highest scores highlighted Green • Next lowest highlighted Yellow • Lowest Scores highlighted Red •  Absolute numbers not meaningful •  Averages are more reliable • Look at the concentration of colour

 Acknowledgment: David Selby, NSF-DBA

Benchmarking Results - Typical •8

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Protocols, •6 •8 •6 Documentation •6 •8 •8 Change •8 •7 •8 Management

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Policies and •4 Procedures•7

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•4 •6 Specifications and •5 •6 •5 Design Review •9

Project •2 •4 Management •5 •4 Planning •5 •7 Strategy •7 •4

Handover •4 •4 •3 Control in Operation •3 •6 •5 Post-project Reviews

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•145

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•79

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Example 1: Ampoule Filling Line • Mid ’90s • Comparison of validation of two liquid injection filling lines Pre-GAMP

Post-GAMP2

Specification Development

5 days

Specification Development

5 weeks

Protocol Development

1 week

Protocol Development

4 weeks

FAT Testing

3 days

FAT Testing

2 weeks

Initial efficiency

35%

Initial efficiency

75%

Final Efficiency

65%

Final Efficiency

95%

Cost Effective Approach How much does Validation Cost?

• Some figures (% of total project cost):



Current industry average 20 – 25% Major pharma company (top 10) 16% GSK ≤ 4%*



Pfizer ≤ 4%*



Best in class ~ 1.2%





* Figures published in 2008

Example 2: SAP Financials • GAMP methodology applied to global implementation of SAP Financials 

Scenario:  – Lead site  – Decision to use “validation rigor” (GAMP Methodology) for

all modules  – Lead by QA validation expert  – Tough to get Finance to understand what that meant  – IT Project manager: “This guy has no idea how to implement a finance system.”  – Testing went like a dream!

 – Project on time and on budget  – “We’ve never had a test phase that went so smoothly with so few problems”  Acknowledgment: Randy Perez, Novartis

Example 3: Re-engineering the Verification Process

Validation Waste Waiting

Motion Slow project initiation

Inactive players

Physical document circulation

Sequential activities

Priority conflicts

Long lead times for meetings High training requirement

Defects

Staff turnover

Wrong skills mix

Implementation of optional features

Unclear purpose

 Acknowledgment: Guy Wingate, GSK

Effort to re-work

WASTE Multiple planners

Too many documents

Multiple forms Too many signatures

Over-production Transportation

Late detection

Extra Processing

Too many people

Inventory

Example 3: Re-engineering the Verification Process

Savings identified:  Adopting good practices

~5%

 Adopting standardized practices Focussing of GMP activities

~30+% ~20%

Scaled approach ~10% Leverage supplier expertise Rigorously applied risk-based approach

 Average Cost of Validation  Acknowledgment: Guy Wingate, GSK

Example 3: Re-engineering the Validation Process

Upgrade Projects

Cost Savings*

1

50%

2

58%

3

72%

Total Savings

>$1.5m

Cost savings comparing V model alone (GAMP 4) vs. V model + E 2500 (GAMP 5)

 Acknowledgment: Lily Mo, Pfizer Global Quality Operations

Example 4: Application of Risk Management (Scaleability) High

Medium

Low

Definition

Severe potential harm to patients, (e.g. death, hospitalization, long term effects).

Risk has potential for nonserious impact on patient safety and/or product quality.

Risk has little or no potential impact on patient safety and/or product quality.

Criteria

•Product is unusable or

•Impacts product quality but with

•Regulatory requirement with

ineffective such that harm is likely. •Loss or corruption of records has potential for severe harm to patients.

no or negligible impact on patient safety (e.g. cosmetic defect). •Loss or corruption of records would have non-serious impact on patient safety or product quality. •..... and so on for your

little or no impact on product quality and/or patient safety. •Loss or corruption of records would violate regulatory requirements but have no impact on patient safety or product quality • ...and so on for your

organisation.

organisation.

•....and so on for your organisation.

...Thin k c arefu lly h ere... Possible Examples

•Training management for staff

•Incomplete break line on OTC

•Training management for non-

operating in aseptic area. •Dispensing of active ingredients for production, sterilization hold times.

tablet. •Checkweigher detection of incompletely filled blister packs.

production staff. •Corrupt electronic signature on audit report.

 Acknowledgment: Ellis Daw, GSK

Example 4: Application of Risk Management (Scaleability) Probability of Failure (Development Classification)

1 (Customised)

2 (Configurable)

3 (Non-Configurable)

High (H)

Intensive

Standard

Minimal

Medium (M)

Intensive

Standard

Minimal

Low (L)

Standard

Minimal

Minimal

Severity

Rigor of Verification Intensive

Standard

Minimal

Positive and negative testing (as appropriate) -evidence required (e.g., critical screen shots, report(s), witness signatures - QA and 2nd person review required Positive testing, including multiple/alternative path testing -standard evidence required (outcome, tester initials, date) - 2nd person review required (QA review not required) Minimal testing -Vendor or leveraged documentation - verification may be required to test requirement - 2nd person review required (QA review not required)

High: functions impacting product release, process control, batch records, complaints, recall,

regulatory filings, adverse event recording etc. Medium: functions impacting support processes driven by GMP regulations, critical business processes Low: functions impacting supporting processes NOT driven by regulation  Acknowledgment: Lily Mo, Pfizer Global Quality Operations

Example 5: Leveraging Supplier Testing

• System  – Business Workflow Mapping Tool  – Limited configuration required to implement at customer’s site

•  Approach  – Extended audit to verify Supplier

Functional Risk Assessment and Testing  –  Additional effort, 4 days to conduct the review of Functional Risk Assessment and Supplier Testing

• Outcome  – Regulated company testing more spot

checks of high impact functions (3 days)  – Original regulated company test plan allowed for 6 man weeks testing  Acknowledgment: Chris Reid, Integrity Solutions Ltd.

Example 6: Business Benefits •

Pre GAMP 







Business processes not defined Requirements unclear/incomplete Projects over-ran User expectations not met

 Acknowledgment: Winnie Cappucci (formerly Bayer)

•

Post GAMP •

Adoption of lifecycle approach

•

Brought discipline (painfully!)

•

Users understood business processes

•

Users understood business needs

•

Requirements and quality attributes traceable to business process

•

Requirements prioritised

•

Compliance to timelines and costs (mostly)

•

System understood by users

•

Systems accepted by users

•

Traceability made maintenance easy

What is Lean Validation? • Lean Validation is defined as the delivery of validation services with as little “waste” as possible.

History of the Problem

Problem Statement • COST OF VALIDATION 

~ 25% of the total capital

• TIME 





Inadequate cycle times Effort takes too long Inability to support timelines based on business needs

What have we typically seen? • • • • • • • •

No uniform practice Unclear expectations Unclear roles and responsibilities Duplication of effort and rework Significant resource commitment Inconsistencies Functionally siloed activities Re-interpretation of requirements leading to re-drafting of protocols • Multiple reviews / approvals for each protocol

What is the impact? • Major cause of contract breaks 

schedule



cost

• Work environment 

stress



anxiety



morale

Current Qualification Practice rework IQ

“churn”

OQ PQ rework

Let’s Re-design the Process • Integration and alignment of Qualification & Capital execution

• Application of Front-End Loading (FEL) principles 

Early cross-functional involvement, understanding, consensus and commitment

• Conformance to regulatory and cGMP expectations from the start

Re-design Tools • Defined, integrated work flow process Identification of key milestones identified interdependencies between construction & qualification activities • Responsibilities Matrix Defined roles and responsibilities • Standard Qualification templates Process & Packaging Equipment Laboratory Systems  Any Automation!!! 





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



Cost Savings • Reduced cost to less than 20% of capital expenses •  Achieved a cost profile of 10% or less of capital expenses • Eliminating or reducing non-value added work

Some Other Cost Savings Measures…

Document Approvers • Typical approval cycle is five validation documents approvers • Lean Approach: Should be two document approvers 



System Owner Quality

Benefits (of reduced approvers) • Reduced cycle times • Faster turnaround of verification documents • Cost efficient • Reduced numbers of EDM users 

Lower license cost for reduced number of document approvers

Verification Forms Implementation of verification forms instead of protocols • • • •

Driven by SOP Individual Forms are pre-approved Installation & Functional Verification forms Forms can be created by leveraging existing protocols

Verification Forms (cont.) • Forms can be created from requirements and design documents • Forms can be used for the validation of changes to existing systems • Examples of verification forms 

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Security verification Recipe verification  Audit trail verification Parameter verification P&ID verification Loop check verification

Benefits of implementing verification forms • • • •

Cycle time reduction Faster turnaround time Only one approval cycle Cost reduction: ~ $ 750 per form vs $ 5,000 per protocol

Productive Validation – its Very Important! • Companies need systems for: 

operations to make much-needed products for patients

•  And to promote: 



increased assurance of product quality sustainability

• Systems need validation • Validation needs to be efficient and effective by: 







having an efficient validation process applying effective governance good in-depth training and expertise continuous improvement

So what is left to do? • Improve our validation processes 

they’re capable of much further

refinement

• Standardize the approach • Judiciously apply risk management and E 2500 • Spend project time on the front end of the system life cycle process • Look at the final steps around handover • Get into the continuous improvement mind-set

Validation Productivity Priorities • Upgrade the validation system •  Focus on the 



•6.6

the front end (validation planning, strategy and specification development) the back end (handover and maintaining control in operation)

•6.2

•6.0

•5.7

•5.5

•7.0

•7.5

•7.4

•5.5

•4.4

•4.6

•3.6

Validation Productivity Priorities

• Standardize the approach across the organization •  Focus on 









Defining the deliverables Scalability Integration of E 2500 into the process Involvement of SMEs and QA  Applying Globally

Validation Productivity Priorities

• Focus on 





Integrating risk management into the entire process  Apply it ruthlessly Spread it throughout the organization … … once it’s right

High

Medium

Low

Validation Productivity Priorities

• Spend project time 







on planning using risk management using the expertise of SMEs on design review

Validation Productivity Priorities

• … and don’t forget 

Handover  – data accessibility for users  – knowledge transfer  – measured performance criteria

Validation Productivity Priorities

• Continuous Improvement 







Embrace new approaches Learn from each project Build the learning back into the validation process Spread the word

Validation Productivity – The target? • Continuous improvement 

cost effective validation projects  –  a few % of project cost



from



 be part of the solution