Risk-Based Validation
Risk-Based Validation
–
–
The
The
Benefits of the GAMP
Benefits of the GAMP
®
®
Approach
Approach
Kevin C. Martin
Kevin C. Martin
Chair, GAMP
Chair, GAMP
® ®Americas
Americas
Sr. Vice President
Sr. Vice President
Azzur Group LLC
Azzur Group LLC
Agenda
Agenda
•
•
20 Years of the GAMP
20 Years of the GAMP
®
®
Organization
Organization
•
•
GAMP Benefits
GAMP Benefits
•
•
GAMP Contribution
GAMP Contribution
•
•
Validation Productivity
Validation Productivity
•
•
Lean Validation
Lean Validation
•
•
Current Technology Trends
Current Technology Trends
•
Agenda
Agenda
•
•
20 Years of the GAMP
20 Years of the GAMP
®
®
Organization
Organization
•
•
GAMP Benefits
GAMP Benefits
•
•
GAMP Contribution
GAMP Contribution
•
•
Validation Productivity
Validation Productivity
•
•
Lean Validation
Lean Validation
•
•
Current Technology Trends
Current Technology Trends
•
20 years of GAMP
20 years of GAMP Development
Development
Validation
Validation Productivity!
Productivity!
plus …
plus …
GAMP
GAMP
®
®
Americas
Americas
Leadership
Leadership
••
Officers
Officers
••
Chairman:
Chairman:
Kevin Martin
Kevin Martin
, Azzur Group
, Azzur Group
••
Co-Chairman:
Co-Chairman:
Michael Rutherford
Michael Rutherford
, Eli Lilly
, Eli Lilly
••
Secretary:
Secretary:
Lorrie Schuessler, GSK
Lorrie Schuessler, GSK
••
ISPE Staff PM
ISPE Staff PM
•
•
Scott Ludlum
Scott Ludlum
••
Steering Committee
Steering Committee
•
•
Winnie Cappucci
Winnie Cappucci
*
*
, Retired- Bayer
, Retired- Bayer
•
•
Waunetka Clark, Abbott
Waunetka Clark, Abbott
••
Jim John, ProPharma Group
Jim John, ProPharma Group
•
•
Paige Kane
Paige Kane
, Pfizer
, Pfizer
••
Klaus Krause, Allergan
Klaus Krause, Allergan
•
•
Eugene Longo , GAMP
Eugene Longo , GAMP
®®Puerto Rico
Puerto Rico
•
•
Randy Perez
Randy Perez
, Novartis
, Novartis
••
Judy Samardelis, Medimmune
Judy Samardelis, Medimmune
••
Eric Staib, Covance
Eric Staib, Covance
••
Robert Tollefsen, FDA
Robert Tollefsen, FDA
••
Bob Wherry, Sunovion
Bob Wherry, Sunovion
Blue indicates GAMP
Blue indicates GAMP
®®Council
Council
*Denotes GAMP Council Chair
Active GAMP
®
SIGs
GAMP
®Americas
•
Laboratory Systems
•
Manufacturing Execution Systems
(co-chaired with Europe)
•
Risk Management
•
Joint Equipment Transition Team
(JETT)
•
R&D / Clinical Systems (coordinated
with Europe)
•
Automated Testing (sub-set of
Testing SIG)
•
Outsourcing and Offshoring (with
Europe)
•
IT Infrastructure Control &
Compliance (with Europe)
•
Metrics
GAMP
®Europe
•
Process Control Systems
•
Testing (with USA)
•
Supplier Relationships
•
Outsourcing and Offshoring (with USA)
•
Calibration
•
GxP Controls Framework (proposed)
GAMP
®D-A-CH
•
Supplier Cooperation
•
Open Source Software
•
Development Models and Methods
GAMP
®Italia
•
Equipment Qualification Workgroup
GAMP
®Nordic
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)“
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)* (2
ndEdition 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) (2
ndEdition
2Q2012)
10.
Risk-Based Approach to Electronic Records and Signatures (Feb 2005)
11.
Legacy Systems (Nov/ Dec 2003)*
G A M P
®
5
GAMP
®
5 Overview
G A M P
®
5 Continues to Address…
•
Current regulatory initiatives
FDA’s
cGMPs for the 21
st
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!
Risk
Management
throughout the
process
Specify
Build or
Configure
Verify
Report
Plan
GAMP
®5
stresses that
this model
does not
imply
a waterfall development
methodology
G A M P
®
5
Simplified V-model
This can be applied to
non-linear approaches like spiral or
iterative methodologies, agile
software development, etc.
This model better illustrates scalability options for phases
•
Blended specifications (e.g. URS/FS, FS/DS, even URS/FS/DS)
•
Design review as opposed to formal DQ
• Blending of “classical” qualification (e.g. IOQ, OQ/PQ, melding of
computer validation with equipment C&Q)
User Requirements (URS) Validation Plan Functional Specification (FS) Design Specification (DS) System Build (including developer tests) Developer tests
(Structural, unit, & integration) Functional testing (OQ) Acceptance testing (PQ) Validation Report Installation (IQ) Verifies Verifies Verifies Verifies
Development
Activities
Verification
Activities
System Build
Activities
G A M P
®
5
Life Cycle Concept
Features:
•
Simplified
V-Model
Plan
Specify
Build
Verify
Report
Risk mgmt
throughout
process
•
Repetition of
V-activities for
changes
•
Incorporates
end-of-life
activities
ChangesRepetitive “V” Activities Within the Life Cycle
URS
migration
Release
GxP Assessment
*
• This could be a complex supply chain• Supplier may provide knowledge, experience, documentation & services throughout lifecycle Supplier
Involvement*
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 bl 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
High Medium Low
Low
Risk Based Approach
1990’s Validation Approach
F o c u s V a l i d a t i o n E f f o r t F o c u s V a l i d a t i o n E f f o r tHistorical State
Desired State
The Desired State…
High
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
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’
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
Plan >Check > Do > Record
Planning
Specifications
Design Review
Protocols
Change management
Document
Handover
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
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
•
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
Benchmarking Results - Typical
•8 •9 •7 •6 •7 •6 •7 •6 •5 •4 •5 •1 •7 •9 •9 •8 •6 •6 •8 •6 •3 •5 •7 •6 •6 •7 •7 •5 •5 •6 •8 •8 •8 •4 •5 •6 •8 •8 •10 •6 •5 •8 •7 •8 •10 •8 •5 •3 •7 •8 •9 •8 •7 •7 •9 •8 •6 •4 •5 •7 •6 •6 •5 •4 •5 •7 •7 •8 •8 •4 •3 •2 •7 •8 •9 •4 •6 •7 •6 •8 •6 •5 •2 •5 •4 •5 •5 •6 •5 •6 •7 •7 •4 •4 •4 •3 •7 •8 •5 •4 •6 •6 •8 •9 •7 •3 •6 •5 •7 •5 •7 •6 •7 •8 •8 •9 •3 •4 •3 •1 •6 •7 •6 •5 •3 •8 •9 •8 •6 •3 •6 •4 •4 •4 •6 •7 •6 •8 •7 •6 •4 •2 •2 •0 •7 •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 •3 •2 •4 •5 •3 •6 •8 •7 •2 •3 •4 •3 •7 •5 •4 •5 •5 •8 •9 •6 •6 •4 •5 •3 •7 •5 •7 •7 •6 •7 •8 •6 •6 •5 •6 •6 •8 •7 •4 •6 •6 •7 •8 •9 •8 •7 •8 •5 •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 •3.6Protocols,
Documentation
Change
Management
Handover
Control in Operation
Post-project Reviews
Project
Management
Planning
Strategy
Training
Policies and
Procedures
Specifications and
Design Review
Example 1: Ampoule Filling Line
Pre-GAMP
Specification
Development
5 days
Protocol Development
1 week
FAT Testing
3 days
Initial efficiency
35%
Final Efficiency
65%
Post-GAMP2
Specification
Development
5 weeks
Protocol Development
4 weeks
FAT Testing
2 weeks
Initial efficiency
75%
Final Efficiency
95%
•
Mid ’90s
•
Comparison of validation of
two liquid injection filling lines
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%
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”
Example 3: Re-engineering the Verification Process
Validation Waste
Waiting
Motion
Defects
Transportation
Over-production
Extra Processing
Inventory
WASTE
Inactive
players
Long lead
times for
meetings
Slow project
initiation
Priority
conflicts
Sequential
activities
Staff
turnover
Late
detection
Effort to
re-work
High training
requirement
Physical
document
circulation
Implementation of
optional features
Unclear
purpose
Multiple
planners
Multiple
forms
Too many
signatures
Too many
people
Too many
documents
Wrong
skills mix
Example 3: Re-engineering the Verification Process
Savings identified:
Adopting good practices
~5%
Adopting standardized practices
~30+%
Focussing of GMP activities
~20%
Scaled approach
~10%
Leverage supplier expertise
Rigorously applied risk-based approach
Average Cost of Validation
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)
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 non-serious 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.
Possible
Examples •operating in aseptic area.Training management for staff
•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 non-production staff.
•Corrupt electronic signature on audit report.
...Thin k c arefu lly h ere...
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
Positive and negative testing (as appropriate)
-evidence required (e.g., critical screen shots, report(s), witness signatures - QA and 2nd person review required
Standard
Positive testing, including multiple/alternative path testing -standard evidence required (outcome, tester initials, date) - 2nd person review required (QA review not required)
Minimal
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
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
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
What is Lean Validation?
•
Lean Validation is defined as the
delivery of validation services with as
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
•
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
•
Major cause of contract breaks
schedule
cost
•
Work environment
stress
anxiety
morale
IQ
OQ
PQ
rework
“churn”
rework
•
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
•
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
Some Other Cost Savings
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
Security verification
Recipe verification
Audit trail verification
Parameter verification
P&ID verification
Benefits of implementing verification
forms
•
Cycle time reduction
•
Faster turnaround time
•
Only one approval cycle
•
Cost reduction: ~ $ 750 per form vs
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
the front end (validation planning,
strategy and specification development)
the back end (handover and maintaining
control in operation)
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
Validation Productivity Priorities
•
Focus on
Integrating risk management into the
entire process
Apply it ruthlessly
Spread it throughout the organization …
… once it’s right
Low
Medium
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
Validation Productivity Priorities
•
Continuous Improvement
Embrace new approaches
Learn from each project
Build the learning back into the
validation process
Validation Productivity
–
The target?
•
Continuous improvement
cost effective validation projects
–
a few % of project cost
