1. technology and computing

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
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20 years of GAMP Development
Validation Productivity!
plus …
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GAMP® Americas Leadership
• Officers
•
•
•
• Steering Committee
Chairman:
Kevin Martin, Azzur Group
Co-Chairman:
Michael Rutherford, Eli Lilly
Secretary:
Lorrie Schuessler, GSK
•
•
•
•
•
•
•
•
•
•
• 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
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Active GAMP® SIGs
GAMP® Americas
GAMP® Europe
•
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•
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Process Control Systems
•
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Open Source Software
•
•
•
•
Laboratory Systems
Manufacturing Execution Systems
(co-chaired with Europe)
Risk Management
Joint Equipment Transition Team
(JETT)
•
•
Supplier Relationships
Outsourcing and Offshoring (with USA)
Calibration
GxP Controls Framework (proposed)
R&D / Clinical Systems (coordinated
® D-A-CH
GAMP
with Europe)
• Supplier Cooperation
Automated Testing (sub-set of
Testing SIG)
•
Testing (with USA)
Outsourcing and Offshoring (with
Europe)
GAMP® Italia
IT Infrastructure Control &
Compliance (with Europe)
•
Metrics
•
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Development Models and Methods
Equipment Qualification Workgroup
GAMP® Nordic
Virtualization
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Active GAMP® SIGs - Brazil
•
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•
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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”
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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 (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
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GAMP® 5
GAMP® 5 Overview
Published: Feb 2008
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GAMP® 5 Continues to Address…
• Current regulatory initiatives



FDA’s cGMPs for the 21st Century
PIC/S Guidance
Risk-based Part 11 Guidance
• Global Standards


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!
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GAMP® 5 Simplified V-model
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
testing
computer
validation
with
equipment
C&Q)
(URS)
(PQ)
Plan
Functional
Specification
(FS)
Development
Activities
Design
Specify
Specification
Risk
Management
throughout the
Verifies
process
(DS)
GAMP® 5 stresses that
this model does not imply
aSystem
waterfallBuild
development
methodology
Activities
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Report
Functional
testing
(OQ)
Verifies
Installation
Verify
Verification
Activities
(IQ)
This can be applied to nonlinear approaches like spiral or
or
SystemBuild
Build Developer
testsiterative methodologies, agile
(Structural, unit, &
(including
Configure
integration) software development, etc.
developer tests)
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GAMP® 5 Life Cycle Concept
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
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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 acceptable risk
• Consistent with risk-based approach based on ISO
14971 (and ERES GPG) as well as other contemporary
risk based tools
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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
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The Desired State…
Historical State
Desired State
High
Medium
Low
Risk Based Approach
Focus Validation Effort
Focus Validation Effort
1990’s Validation Approach
High
Medium
Low
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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!
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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!!!
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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

April 10, 2012
Consider all the elements of the
validation process
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Uniform Approach
• The ‘V’ model is almost universally
applicable
• It is capable of considerable flexibility
• Many ‘dialects’ exist
• Fundamentals remain
Document
Handover
Design Review
Plan >Check > Do > Record
Planning
Specifications
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Protocols
Change management
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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
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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
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Benchmarking for Continuous
Improvement
12 Good Validation Practices
•
•
•
•
•
•
Policies and
Procedures
Good Project
Management Practices
Validation Planning
Validation Strategy
Specifications and
Design Review
Protocols
•
•
•
•
•
•
Documentation
Change Management
Practices
Training
Handover
Maintaining Control in
Operation
Post-project reviews
Acknowledgment: David Selby, NSF-DBA
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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
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Benchmarking Results - Typical
•8
•9
•7
•6
•7
•7
•9
•9
•8
•6
•6
•7
•7
•5
•5
•8
•8
•10
•6
•5
•7
•8
•9
•8
•7
•6
•6
•5
•4
•5
•7
•8
•4
•5
•7
•8
•5
•4
•7
•5
•7
•6
•7
•6
•7
•6
Protocols,
•6
•8
•6
Documentation
•6
•8
•8
Change
•8
•7
•8
Management
•5
•4
•5
•1
•3
•5
•7
•6
•8
•4
•5
•6
•10
•8
•5
•3
•7
•9
•8
•6
•4
•5
•7
•7
•7
•8
•8
•4
•3
•2
•7
•6
•8
•6
•5
•2
•5
•6
•7
•7
•4
•6
•6
•8
•9
•7
•6
•7
•8
•8
•9
•3
•4
•3
•1
•6
•5
•3
•8
•9
•8
•6
•3
•6
•4
•4
•6
•7
•6
•8
•7
•6
•4
•2
•2
•0
•6
•5
•5
•5
•7
•7
•7
•5
•4
•4
•1
•8
•4
•3
•8
•6
•7
•7
•7
•4
•4
•3
•1
•7
•4
•5
•5
•6
•8
•6
•8
•4
•5
•3
•5
•6
•6
•8
•7
•5
•7
•7
•6
•3
•5
•5
•3
•5
•3
•6
•8
•7
•2
•3
•4
•3
•5
•5
•8
•9
•6
•6
Training
•4
•5
•3
•7
•6
•7
•8
•6
•6
•5
•6
•6
•6
•6
•7
•8
•9
•8
•7
•8
•5
Policies and
•4
Procedures•7
•3
•7
•7
•8
•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
•8
•7
•5
•6
•6
•8
•8
•8
•7
•5
•6
•5
•7
•7
•3
•3
•4
•6
•6
•7
•6
•5
•4
•4
•145
•137
•133
•126
•120
•154
•165
•162
•121
•97
•101
•79
•6.6
•6.2
•6.0
•5.7
•5.5
•7.0
•7.5
•7.4
•5.5
•4.4
•4.6
•3.6
Acknowledgment: David Selby, NSF-DBA
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%
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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
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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
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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
Late
detection
Staff
turnover
Wrong
skills mix
Effort to
re-work
WASTE
Implementation of
optional features
Unclear
purpose
Multiple
planners
Multiple
forms
Too many
signatures
Over-production
Transportation
Too many
documents
Too many
people
Inventory
Extra Processing
Acknowledgment: Guy Wingate, GSK
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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
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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
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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
ineffective such that harm is
likely.
•Loss or corruption of records
has potential for severe harm to
patients.
•....and so on for your
organisation.
•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.
•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.
...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.
Acknowledgment: Ellis Daw, GSK
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•Training management for nonproduction staff.
•Corrupt electronic signature on
audit report.
Example 4: Application of Risk Management (Scaleability)
Probability of Failure (Development Classification)
Severity
1 (Customised)
2 (Configurable)
3 (Non-Configurable)
High (H)
Intensive
Standard
Minimal
Medium (M)
Intensive
Standard
Minimal
Low (L)
Standard
Minimal
Minimal
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
April 10, 2012
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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.
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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)
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What is Lean Validation?
• Lean Validation is defined as the
delivery of validation services with as
little “waste” as possible.
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History of the Problem
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Problem Statement
• COST OF VALIDATION

~ 25% of the total capital
• TIME



April 10, 2012
Inadequate cycle times
Effort takes too long
Inability to support timelines based on
business needs
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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
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What is the impact?
• Major cause of contract breaks

schedule

cost
• Work environment
April 10, 2012

stress

anxiety

morale
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Current Qualification Practice
rework
IQ
“churn”
OQ
PQ
rework
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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
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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
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Some Other Cost Savings
Measures…
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Document Approvers
• Typical approval cycle is five
validation documents approvers
• Lean Approach: Should be two
document approvers


April 10, 2012
System Owner
Quality
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Benefits (of reduced approvers)
• Reduced cycle times
• Faster turnaround of verification
documents
• Cost efficient
• Reduced numbers of EDM users

April 10, 2012
Lower license cost for reduced number
of document approvers
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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
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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
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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
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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:




April 10, 2012
having an efficient validation process
applying effective governance
good in-depth training and expertise
continuous improvement
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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
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Validation Productivity Priorities
• Upgrade the validation system
• Focus on the


•6.6
April 10, 2012
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
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•7.4
•5.5
•4.4
52
•4.6
•3.6
Validation Productivity Priorities
• Standardize the approach across the
organization
• Focus on





April 10, 2012
Defining the deliverables
Scalability
Integration of E 2500 into the process
Involvement of SMEs and QA
Applying Globally
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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
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Medium
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Low
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Validation Productivity Priorities
• Spend project time




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on planning
using risk management
using the expertise of SMEs
on design review
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Validation Productivity Priorities
• … and don’t forget

Handover
– data accessibility for users
– knowledge transfer
– measured performance criteria
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Validation Productivity Priorities
• Continuous Improvement




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Embrace new approaches
Learn from each project
Build the learning back into the
validation process
Spread the word
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Validation Productivity – The target?
• Continuous improvement

cost effective validation projects
– a few % of project cost

from

be part of the solution
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Thank You!
Resources / More Information
Kevin C. Martin
GAMP Americas Chair
Azzur Group LLC
Sr. Vice President
+1.215.260.6327
[email protected]
Michael L. Rutherford
GAMP Americas Vice Chair
Consultant – Business Systems Support
Development Center of Excellence
Eli Lilly and Company
317-276-1473
[email protected]
ISPE GAMP Community of Practice (COP) Website
http://www.ispe.org/gampcop
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