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
April 10, 2012
ISPE CASA Technology Show
Agenda
20 Years of the GAMP Organization
GAMP Benefits
GAMP Contribution
Validation Productivity
Lean Validation
Current Technology Trends

Current Regulatory Activity
April 10, 2012 ISPE CASA Technology Show 2
20 years of GAMP Development Validation Productivity!
plus
April 10, 2012 3
April 10, 2012
GAMP Americas Leadership

Officers
Chairman: Kevin Martin, Azzur Group Co-Chairman: Michael Rutherford, Eli Lilly Secretary: Lorrie Schuessler, GSK
Steering Committee
ISPE Staff PM
Scott Ludlum
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
Blue indicates GAMP Council *Denotes GAMP Council Chair

Active GAMP SIGs

GAMP Americas GAMP Europe
Laboratory Systems
Manufacturing Execution Systems (co-chaired with Europe)

Risk Management Joint Equipment Transition Team (JETT)
R&D / Clinical Systems (coordinated D-A-CH GAMP with Europe) Supplier Cooperation Automated Testing (sub-set of Testing SIG)
Process Control Systems
Testing (with USA)

Supplier Relationships Outsourcing and Offshoring (with USA) Calibration
GxP Controls Framework (proposed)
Outsourcing and Offshoring (with Europe)

IT Infrastructure Control & Compliance (with Europe)
Open Source Software
Development Models and Methods

Equipment Qualification Workgroup
GAMP Italia GAMP Nordic
Metrics
Virtualization
6
April 10, 2012
Active GAMP SIGs - Brazil

GTG "Validation of IT Infrastructure and Processes GTG " Validation of PLCs, Automated Systems, Shop-floor Systems, MES and BMS GTG "Change Management for Computerized Systems and Maintenance of Validated Status: 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 Legacy Systems GTG " Qualification and Suppliers Assessment GTG "Testing GxP Systems (base GPG GAMP) GTG "Organizational Structure for CSV
April 10, 2012
GAMP Good Practice Guides

1.
2. 3. 4. 5. 6. 7. 8. 9.
Validation of Process Controls Systems (Second Edition Feb 2011)
Calibration Management (Second Edition Nov 2010) Manufacturing Execution Systems A Strategic and Program Management Approach (Feb 2010) A Risk-Based Approach to Operation of GxP Computerized Systems - A Companion Volume to GAMP 5 (Jan 2010) Electronic Data Archiving (Jul 2007) Testing of GxP Systems (Dec 2005)* (2nd Edition 3Q2012) Global Information Systems Control and Compliance (Nov 2005) IT Infrastructure Control and Compliance (Sep 2005) Validation of Laboratory Computerized Systems (Apr 2005) (2nd Edition 2Q2012)
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
GAMP 5
GAMP 5 Overview
Published: Feb 2008
April 10, 2012
GAMP 5 Continues to Address

Current regulatory initiatives
FDAs cGMPs for the 21st Century PIC/S Guidance Risk-based Part 11 Guidance
Global Standards
ICH Q8, Q9, Q10 ASTM E2500 Facilitate a single company QMS Need to take full advantage of supplier capability Better compliance with less cost!
ISPE CASA Technology Show 10
Escalating cost pressures mandate efficiency
April 10, 2012
GAMP 5 Simplified V-model

Verifies Validation Validation This model better illustrates scalability options for phases
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 testing computer validation with equipment C&Q) (URS) (PQ) Plan Functional
Specification (FS)
Plan
Report
Development Activities
Design Specify Specification (DS)
Risk Management throughout the Verifies process
Verifies
Functional testing (OQ)
Report Verification Activities
Installation Verify (IQ)
GAMP 5 stresses that this model does not imply a waterfall development System Build methodology Activities
April 10, 2012
This can be applied to nonlinear approaches like spiral or Build or System Build Developer tests iterative methodologies, agile (Structural, unit, & (including Configure integration) software development, etc. developer tests)
11
GAMP 5 Life Cycle Concept

Repetitive V Activities Within the Life Cycle
Features: Simplified Vmigration
Model

URS
Release
Changes
GxP Assessment
Plan Specify Build Verify Report Risk mgmt throughout process
Concept
Project
Operation
Retirement
Repetition of Vactivities for changes Incorporates end-of-life activities
Supplier Involvement*
* This could be a complex supply chain

Supplier may provide knowledge, experience, documentation & services throughout lifecycle
April 10, 2012
12
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 acceptable risk
Consistent with risk-based approach based on ISO

14971 (and ERES GPG) as well as other contemporary risk based tools
April 10, 2012
13
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
April 10, 2012
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The Desired State

Historical State
1990s Validation Approach
Desired State
Risk Based Approach
Focus Validation Effort
Focus Validation Effort
High Medium Low
High
Medium
Low
April 10, 2012
15
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
We have a great responsibility!

manual to automated systems
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

April 10, 2012
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
April 10, 2012
Protocols Change management

QMS* for Systems Validation

The Validation Process is well-documented Based on QMS principles Widely understood Adopts standard elements of QMS

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;

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
April 10, 2012
Documentation Change Management Practices Training Handover Maintaining Control in Operation Post-project reviews
Acknowledgment: David Selby, NSF-DBA

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

Benchmarking Results - Typical

8 7 6 8 7 6 7 4 7 7 6 9 9 7 8 8 6 8 5 8 5 7 4 6 4 4 6 7 9 7 10 9 5 9 6 8 5 6 8 4 7 6 5 5 7 5
Protocols, 6 8 6 Documentation 6 8 8 Change 8 7 8 Management

7 7 7 6 6 8 8 8 7 7 8 7 6 8 7 7 8 6 154 9 7 6 7 8 8 9 7 7 7 6 7 8 9 8 8 8 6 165 8 8 8 7 9 9 8 6 7 7 8 6 7 6 6 9 8 7 162
5 3 8 10 6 8 6 4 7 3 6 4 5 4 4 3 2 6 Training 6 8 7 6 121
4 5 4 8 4 4 5
5 7 5 5 5 3 2
1 6 6 3 7 2 5
4 6 Specifications and 5 6 5 Design Review 5 7 6 6 5 3 5 8 4 6 5 7 5 8 5 7 5 5 7 6 6 3 126 6 7 3 6 5 6 6 5 3 5 6 6 6 4 120
Handover 4 4 3 Control in Operation 3 6 5 Post-project Reviews

4 3 2 4 4 5 5 3 4 5 7 5 5 97 3 6 2 4 3 3 5 4 5 6 8 6 4 101 1 4 0 1 1 5 3 3 3 6 5 5 4 79
Policies and 4 Procedures 7

8 7 6 3 7 7 8 8 7 145
Project 2 4 Management 5 4 Planning 5 7 Strategy 7 4

7 7 137 5 3 133
6.6
6.2
6.0
5.7
5.5
7.0
7.5
7.4
5.5
4.4
4.6
3.6
Example 1: Ampoule Filling Line

Mid 90s Comparison of validation of
two liquid injection filling lines
Pre-GAMP
Specification Development
Protocol Development FAT Testing Initial efficiency Final Efficiency
Post-GAMP2
5 days
1 week 3 days 35% 65%
Specification Development Protocol Development FAT Testing Initial efficiency Final Efficiency
5 weeks 4 weeks 2 weeks 75% 95%
April 10, 2012
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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 Weve never had a test phase that went so smoothly with so few problems
Acknowledgment: Randy Perez, Novartis April 10, 2012 ISPE CASA Technology Show 27
Example 3: Re-engineering the Verification Process
Validation Waste
Waiting
Inactive players Long lead times for meetings High training requirement Physical document circulation
Motion
Slow project initiation Priority conflicts Wrong skills mix
Defects
Sequential activities Late detection Effort to re-work
Staff turnover
WASTE
Implementation of optional features Multiple planners Multiple forms Too many signatures Too many people Too many documents
Unclear purpose
Over-production
Transportation
Acknowledgment: Guy Wingate, GSK April 10, 2012 ISPE CASA Technology Show
Inventory
Extra Processing
28
Example 3: Re-engineering the Verification Process
Savings identified:
Adopting good practices
Adopting standardized practices Focussing of GMP activities
~5%
~30+% ~20%
Scaled approach ~10% Leverage supplier expertise Rigorously applied risk-based approach
Average Cost of Validation

Acknowledgment: Guy Wingate, GSK April 10, 2012 ISPE CASA Technology Show 29
Example 3: Re-engineering the Validation Process
Upgrade Projects 1 2 3
Cost Savings* 50% 58% 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 April 10, 2012 ISPE CASA Technology Show 30
Example 4: Application of Risk Management (Scaleability)

High Definition Medium Low
Severe potential harm to patients, (e.g. death, hospitalization, long term effects). Product is unusable or ineffective such that harm is likely. Loss or corruption of records has potential for severe harm to patients. ....and so on for your organisation.
Risk has potential for nonserious impact on patient safety and/or product quality. Impacts product quality but with 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 organisation.
Risk has little or no potential impact on patient safety and/or product quality. Regulatory requirement with 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.
Criteria
...Think carefully here...

Possible Examples
Training management for staff operating in aseptic area. Dispensing of active ingredients for production, sterilization hold times.
Incomplete break line on OTC tablet. Checkweigher detection of incompletely filled blister packs.
Training management for nonproduction staff. Corrupt electronic signature on audit report.
Acknowledgment: Ellis Daw, GSK April 10, 2012 ISPE CASA Technology Show 31
Example 4: Application of Risk Management (Scaleability)

Probability of Failure (Development Classification)
Severity High (H) Medium (M) Low (L) 1 (Customised) Intensive Intensive Standard 2 (Configurable) Standard Standard Minimal 3 (Non-Configurable) Minimal Minimal Minimal
Rigor of Verification
Intensive
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)
Standard
Minimal
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 April 10, 2012 ISPE CASA Technology Show 32
Example 5: Leveraging Supplier Testing
System
Business Workflow Mapping Tool Limited configuration required to implement at customers 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. April 10, 2012 ISPE CASA Technology Show 33
Example 6: Business Benefits
Pre GAMP Business processes not defined Requirements unclear/incomplete Projects over-ran User expectations not met
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
Acknowledgment: Winnie Cappucci (formerly Bayer) April 10, 2012 ISPE CASA Technology Show 34
What is Lean Validation?

Lean Validation is defined as the
delivery of validation services with as little waste as possible.
April 10, 2012
35
History of the Problem
April 10, 2012
36
Problem Statement
COST OF VALIDATION
~ 25% of the total capital

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

April 10, 2012
37
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 stress anxiety morale

39
Work environment

April 10, 2012
Current Qualification Practice

rework IQ
churn
OQ PQ rework
April 10, 2012
40
Lets 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
April 10, 2012
41
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!!!
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
April 10, 2012
43
Some Other Cost Savings Measures
April 10, 2012
44
Document Approvers
Typical approval cycle is five
validation documents approvers Lean Approach: Should be two document approvers

System Owner Quality
April 10, 2012
45
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
April 10, 2012
46
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
April 10, 2012
47
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
Security verification Recipe verification Audit trail verification Parameter verification P&ID verification Loop check verification
April 10, 2012
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
April 10, 2012
49
Productive Validation its Very Important!

Companies need systems for:
operations to make much-needed products for patients increased assurance of product quality sustainability
And to promote:

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
April 10, 2012
50
So what is left to do?

Improve our validation processes
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
theyre capable of much further refinement
April 10, 2012
51
Validation Productivity Priorities

Upgrade the validation system Focus on the
the front end (validation planning, strategy and specification development) the back end (handover and maintaining control in operation)
6.6
6.2
6.0
5.7
5.5
7.0
7.5
7.4
5.5
4.4
4.6
3.6
April 10, 2012
52

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
April 10, 2012

Focus on
Integrating risk management into the entire process Apply it ruthlessly Spread it throughout the organization once its right
High
April 10, 2012
Medium
Low

Spend project time

on planning using risk management using the expertise of SMEs on design review
April 10, 2012
55

and dont forget
Handover
data accessibility for users knowledge transfer measured performance criteria
April 10, 2012
56

Continuous Improvement

Embrace new approaches Learn from each project Build the learning back into the validation process Spread the word
April 10, 2012
57
Validation Productivity The target?

Continuous improvement
cost effective validation projects

a few % of project cost
from
be part of the solution

April 10, 2012
Thank You!
Resources / More Information
Kevin C. Martin GAMP Americas Chair Azzur Group LLC Sr. Vice President +1.215.260.6327 kevin.martin@azzurgroup.com Michael L. Rutherford GAMP Americas Vice Chair Consultant Business Systems Support Development Center of Excellence Eli Lilly and Company 317-276-1473 ml.rutherford@lilly.com
ISPE GAMP Community of Practice (COP) Website http://www.ispe.org/gampcop
April 10, 2012
59

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Risk-Based Validation The Benefits of the GAMP Approach

April 10, 2012

ISPE CASA Technology Show

Current Technology Trends

20 years of GAMP Development Validation Productivity!

ISPE CASA Technology Show

April 10, 2012

ISPE CASA Technology Show

GAMP Americas Leadership

Blue indicates GAMP Council *Denotes GAMP Council Chair

Active GAMP SIGs

Manufacturing Execution Systems (co-chaired with Europe)

Process Control Systems

Testing (with USA)

GxP Controls Framework (proposed)

Outsourcing and Offshoring (with Europe)

Open Source Software

Development Models and Methods

GAMP Italia GAMP Nordic

April 10, 2012

ISPE CASA Technology Show

Active GAMP SIGs - Brazil

April 10, 2012

ISPE CASA Technology Show

GAMP Good Practice Guides

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

11. Legacy Systems (Nov/ Dec 2003)*

April 10, 2012

ISPE CASA Technology Show

GAMP 5 Continues to Address

Escalating cost pressures mandate efficiency

April 10, 2012

GAMP 5 Simplified V-model

Design Specify Specification (DS)

Risk Management throughout the Verifies process

Functional testing (OQ)

Report Verification Activities

Installation Verify (IQ)

ISPE CASA Technology Show

GAMP 5 Life Cycle Concept

Features: Simplified Vmigration

Plan Specify Build Verify Report Risk mgmt throughout process

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

* This could be a complex supply chain

April 10, 2012

ISPE CASA Technology Show

Risk Management Goals

Recognize that zero risk is impractical and unattainable

Aim is for acceptable risk

Consistent with risk-based approach based on ISO

April 10, 2012

ISPE CASA Technology Show

5-Step Quality Risk Management Process

April 10, 2012

ISPE CASA Technology Show

The Desired State

Focus Validation Effort

Focus Validation Effort

High Medium Low

April 10, 2012

ISPE CASA Technology Show

Stakeholders the GAMP Benefits

Performing as expected from the beginning continuously with minimal attention