GAMP Overview Presentation 04-03-2012 FINAL

April 10, 2012 ISPE CASA Technology Show

Risk-Based Validation – The

Benefits of the GAMP® Approach

Kevin C. Martin

Chair, GAMP® Americas

Sr. Vice President

Azzur Group LLC

2

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

20 years of GAMP Development

Validation Productivity!

plus …

3 April 10, 2012 ISPE CASA Technology Show

http://www.fda.gov/default.htm


GAMP® Americas Leadership

• Officers • Chairman:

Kevin Martin, Azzur Group

• Co-Chairman:

Michael Rutherford, Eli Lilly

• Secretary:

Lorrie Schuessler, GSK

• ISPE Staff PM • Scott Ludlum

• Steering Committee • 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

• 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

• Virtualization


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”


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


GAMP® 5

GAMP® 5 Overview

Published: Feb 2008


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!


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

GAMP® 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

Validation Activities


GAMP® 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

Changes

Repetitive “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*

Concept Project Operation Retirement


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


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


High Medium Low

Low

Risk Based Approach 1990’s Validation Approach

Focus V

alid

ation E

ffort

Focus V

alid

ation E

ffort

Historical State Desired State

The Desired State…

High

Medium


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

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

*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

• 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 •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 •3.6

Protocols,

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%

* 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 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

Acknowledgment: Guy Wingate, GSK


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

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 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).


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.


would violate regulatory

requirements but have no impact

on patient safety or product

quality

• ...and so on for your

organisation.

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 non-

production staff.

•Corrupt electronic signature on

audit report.

...Think carefully here...

Acknowledgment: Ellis Daw, GSK


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 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


• 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 have we typically seen?


• Major cause of contract breaks

schedule

cost

• Work environment

stress

anxiety

morale

What is the impact?


IQ

OQ

PQ

rework

“churn”

rework

Current Qualification Practice


• 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

Let’s Re-design the Process


• 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!!!

Re-design Tools


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

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

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



• 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



• Focus on

Integrating risk management into the

entire process

Apply it ruthlessly

Spread it throughout the organization …

… once it’s right

Low Medium High



• Spend project time

on planning

using risk management

using the expertise of SMEs

on design review



• … and don’t forget

Handover

– data accessibility for users

– knowledge transfer

– measured performance criteria



• 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


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

Thank You!


mailto:[email protected]

mailto:[email protected]

Documents

GAMP Overview Presentation 04-03-2012 FINAL