Best Practices Commissioning & Validation

Best Practices Commissioning & Validation
Presented by Gearoid Cronin, Commissioning, Qualification & Field Sales Manager,

PM Group Asia
2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D
September 2009 1
Best Practices Commissioning & Validation
Facilitating Quicker Pharmaceutical Project Delivery

2
Agenda
This presentation will discuss the current trends in Commissioning

and Qualification (C&Q), it will cover
– Review of current (FDA and EU) regulatory environment and

trends
– Master Planning Commissioning and Qualification
– Best Practice Commissioning and Start-up
– Risk Assessment to Reduce Qualification Load
– Leveraging and Utilising Vendor Testing to maximum impact
– Change control strategy across the project lifecycle

3
Establishing the Regulatory Basis

4
Regulatory Drivers
21st Century cGMP Initiative

PIC/S Guidance
EU Volume 4

5
Other Drivers
ISPE Product Quality Lifecycle Implementation (PQLI) Initiative

Practical Implementation of ICH Guidance and Quality by Design
ASTM E2500 Standard Guide for Specification, Design, and Verification of
Pharmaceutical and Biopharmaceutical Manufacturing Systems and
Equipment
GAMP 5 Guidance
ISPE GEP best practise guide
FDA draft PV guidance 2008
ISPE Baseline Guide 12 Draft Verification guide
FDA: Quality Systems Approach to Pharmaceutical cGMP Regulations –
2006
EU Annex 20, Quality Risk Management – March 2008
ICH Q8 Pharmaceutical Development - Nov 2005
ICH Q10 – Quality Systems – June 2008

6
Beginning with the End in Mind
Traditional ‘V’ Model or Risk Based

Verification
User
Performance
Requirements related to
Qualification
Specification
Functional related to
Operational
Specification Qualification
Design Installation
related to
Specification Qualification
System
Build
Lean Thinking is equally relevant

7
Back to the Basics – Why Qualify?
FDA regulatory perspective
Process validation is required in both general and specific terms, by the

Current Good Manufacturing Practice Regulation for Finished
Pharmaceuticals, 21 CFR Parts 210 and 211.
§ 211.210 Sampling and testing of in-process materials and drug products.

(a) To assure batch uniformity and integrity of drug products, written
procedures shall be established and followed that describe the in-process
controls, and tests, or examinations to be conducted on appropriate samples
of in-process materials of each batch.
Such control procedures shall be established to monitor the output and to
validate the performance of those manufacturing processes that may be
responsible for causing variability in the characteristics of in-process material
and the drug product.

8
Qualification – The “old way”
“Process validation is
Validation
establishing Protocol
documented evidence
Product
which provides a high Installation
Performance
Qualification
degree of assurance Qualification
that a specific process

Process
will consistently produce Validation
a product meeting its
pre-determined Process
Revalidation
Performance
Documentation
specifications and Qualification
quality attributes”.
Retrospective
Process
U.S. Food and Drug Administration. Guideline on
General Principles of Process Validation, p 3: May Validation
1987.

9
Back to the Basics – Why Qualify?
EU Regulatory Perspective
“It is a requirement of GMP that manufacturers identify what
validation work is needed to prove control of critical aspects
of their particular operations. Significant changes to
facilities, the equipment and the processes, which may affect
the quality of the product, should be validated. A risk
assessment approach should be used to determine scope
and extent of validation.”
EU Guide to GMP Vol 4, annex 15 – Qualification and Validation- Issue Sept 2001
Activities are designated as:

DQ ( “First element …could be DQ”)
IQ
OQ
PQ

10
Overarching Philosophy
The overarching philosophy articulated in both the

CGMP regulations and in robust modern quality
systems is:
– Quality should be built into the product, and testing alone cannot be
relied on to ensure product quality
FDA Guidance for Industry Sept 2004

‘Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations’

11
What Next C&Q ---------- Verification ?

12
Qualification Results
The old way: Efficiency:

– Documentation focused
– Poor Scope Definition
– Late Involvement of QA
– Poor Commissioning
Programmes
– Commissioning running on
into Qualification effort

13
The New Way
The old way:

– Regulatory environment and
industry is ready for change
– Verification focus based on
science and risk through Process
User Requirements
• CQA, CPP’s
– Risk Assessment confirms
appropriate risk mitigation
measures identified, used through
the lifecycle
– Project is RFT and C&Q is
streamlined under the ASTM
guidance

14
Old Vs New

15
How ?
Use of the 8 ASTM principles coupled with:
– Integrated Lifecycle
– Integrated Team
– Integrated Design
– Integrated Procurement
– Integrated Scheduling
– Integrated Construction/ Fabrication
– Integrated Field Engineering
– Integrated Change Management
– Integrated Handover

16
ASTM E2500-07
Good Engineering Practice

Product
Knowledge
Process Requirements Specification Verification Acceptance

Knowledge and Design and Operation &
Release Continuous
Improvement
Regulatory
Requirements.
Company
Quality Reqs.
Risk Management
Design Review
Change Management
Figure 1 – The Specification, Design, and Verification Process

17
4 x 4 Step Process
1. Requirements Definition 1. Good Engineering Practice

2. Specification and Design 2. Risk Management
3. Design Reviews
3. Verification
4. Change Management
4. Acceptance and Release
applied throughout the process.

18
Verification Process Flow Chart
interdiscipl.
R&D Subject Matter Expert (SME)
expert team
Process approved list Verification

Verifi-
Know- Risk of Critical (Design to Operation) Completion of
cation verification
ledge Assessm. Aspects
Plan
to confirm Critical Aspects
(CPP, CQA) meet Acceptance Criteria activities is
documented
appropriate in a Summary
GEP, Project Quality Plan
tool
List approved appr. Summary

Review by second,
by Quality by Q approved by
independent SME
Unit Unit Quality Unit
CPP: critical process parameter

CQA: critical quality attribute

19
What has to Change ?
Adoption of the ASTM E2500-07 Standard Approved in

July 2007
Implement ICH Q8, Q9, Q10
GEP best practise guide to be implemented
In the meantime, we outline the applications of guidance
and practices currently in use in an effort to demonstrate
the most effective and successful implementation
models
Approval of the draft PV guide

20
Where to Next….ASTM ?
Construction
Construction
Commissioning
Commissioning
IQOQ
IQOQ
Construction
Construction
Commissioning
Commissioning
IQOQ
IQOQ
Construction
Construction
Verification
Verification

21
Steps to a successful Commissioning and Qualification
Phase
1. Master Planning Commissioning and Qualification
2. Best Practice Commissioning and Start-up
3. Risk Assessment to Reduce Qualification Load.
4. Leveraging and Utilising Vendor Testing to maximum
impact.
5. Change control strategy across the project lifecycle.

22
Should be done regardless of the model (New/ Old)

Define:
– What testing is being performed in each PHASE
– What testing is being done by each GROUP
Tools:
– Overall C&Q logic chart
– Test Matrix
– Integrated Project Schedule
– Roles and Responsibility Matrix

23
Have an Integrated Handover

Approach ETOP
Design Lifecycle
Field
Team
Engineering
Integrated
C&Q
Change Schedule/
Management Program
Procurement Construction

24
Planning Step 1: Start-Up Master Plan
ELECTRICAL SUPPLY / AUTOMATED SYSTEMS
GAS BOILERS / STEAM GENERATION
BRINE
POTABLE WATER COOLING WATER CHILLERS PQ DISTRIBUTION
WFI STILL/CLEAN STEAM

PRE TREATMENT PW GENERATORS WFI DISTRIBUTION
GENERATION
CLEAN STEAM
DISTRIBUTION
AIR COMPRESSED COMPRESSED AIR
DRAINS / CIVIL WORKS

25
Planning Step 2: C&Q logic

26
Planning Step 3: Test Master Plan
Test FAT Mechanical Commissioning IQ OQ CQ/PQ/PV
Completion / SAT
Drawing Check
Component Checks
Documentation Checks
Calibration
Motor Rotation Check
Handwired Interlock Checks
Service / Leak Test
Flushing and Blowdown An interactive planning
Passivation / Cleaning
Loop Checks
session identify which test
Alarm Testing
is done where and by whom
Back-Up and Restore
Trending
Security and Access Control
Power Failure
Functional Testing
Alarm Testing
Operational Testing Utilities Also could add
Operational Testing Process Receipt Verification
Operational Testing Packaging etc

27
Planning Step 4: Fully Integrated schedule

– Start with a level 1 schedule from Design to regulatory approval
– Construction Dates as Input date
– Handover as Output date
– Integrated Planning session essential
– Feedback
Planning Step 5: Roles and Responsibilities Matrix

– For example LACTI Matrix
• L = Leads
• A = Approves
• T = Tasked
• C = Consults
• I = Informed

28
During project execution:

– Monitor Schedule Progress
– Carefully manage Commissioning and Qualification:
• Track Progress
– Upstream systems
– Test Documents
– Construction dates
– Completion dates
• Handover meetings to ensure smooth Handover:
– From Construction
– To User
• Daily/ Weekly Toolbox talks
– Have a clear reporting tool

29
Progress Percentage
Forecast
0%
20%
40%
60%
80%
100%
120%
Plan Progress
Variance ( + ‐ )
1.
Actual Progress
Remaining No. of
1
Actual No. of Docs.
Complete per Week
No. of Docs. Plan to
Completed per Week
Documents to Complete
2
Week Ending
Cut‐off Date:
Week No.
3
0.00% 0.00% 0.00% 14/03/08
0
0
1
4
0.00% 2.97% 2.97% 21/03/08
9
9
2
5
0.00% 3.74% 3.74% 28/03/08
1
1
3
6
27‐Jun‐08
0.00% 3.74% 3.74% 04/04/08
0
0
7
4
0.77% 20.77% 20.00% 11/04/08
41
40
5
9
0.31% 27.67% 27.36% 18/04/08
21
21
6
221 212 211 211 170 149

7.30% 37.78% 30.48% 25/04/08
22
10
7
11.58% 42.84% 31.25% 02/05/08
8
17.71% 55.67% 37.96% 09/05/08
1 15
9
23.65% 62.90% 39.25% 16/05/08
10 23 13
10
No. of Docs. Plan to Complete per Week
12.86% 64.75% 51.89% 23/05/08
6
4 21
11
16.70% 68.90% 52.20% 30/05/08
9
12
7.01% 70.44% 63.43% 06/06/08
2
1 17
13
8.90% 75.52% 66.62% 13/06/08
9
‐1.10% 76.44% 77.54% 20/06/08 14
3
7 22
15
81.82% 4.29% 81.82% 77.54% 27/06/08
7
16
87.85% 83.85% 04/07/08
0
0 16
17
89.23% 85.23% 11/07/08
127 117 94 81 75 66 64 55 52 45 45 45
0
18
91.08% 91.08% 18/07/08
0
3 13
19
91.08% 91.08% 25/07/08
0
0
20
Week No.
92.77% 92.77% 01/08/08
0
4
21
Actual No. of Docs. Completed per Week
93.08% 93.08% 08/08/08
0
1
22
94.31% 94.31% 15/08/08
0
4
23
95.08% 95.08% 22/08/08
0
1
24
95.38% 95.38% 29/08/08
0
1
25
95.38% 95.38% 05/09/08
0
0
26
Plan Progress
0 96.15% 96.15% 12/09/08

1
27
96.46% 96.46% 19/09/08

0
1
28
96.46% 96.46% 26/09/08

0
0
29
97.23% 97.23% 03/10/08

0
1
30
Black Utilities Pre-execution Documents Progress Graph
Forecast
97.54% 97.54% 10/10/08

0
1
31
97.54% 97.54% 17/10/08

30 45 45 45 45 45 45 45 45 45 45 45 45 45 45
0
0
32
98.31% 98.31% 24/10/08

0
1
33
98.62% 98.62% 31/10/08

0
1
34
99.38% 99.38% 07/11/08

0
1
35
Actual Progress
99.38% 99.38% 14/11/08

0
0
36
99.69% 99.69% 21/11/08

0
1
37
99.69% 99.69% 28/11/08

0
0
38
100.00% 100.00% 05/12/08

0
1
39
Master Planning Commissioning and Qualification
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43
100.00% 100.00% 12/12/08

0
0
40
0
5
100.00% 100.00% 19/12/08

0
0
10
15
20
25
30
35
40
45
41
100.00% 100.00% 26/12/08 No. of Documents

0
0
42
100.00% 100.00% 02/01/09

0
0
45 45 45 45 45 45 45 45 45 45 45
43
2. Best Practice Commissioning and Start-Up
The key to effective Commissioning and start-up is GEP
Definition of GEP:
– “Established engineering methods and standards that are applied throughout
the project lifecycle to deliver appropriate cost-effective solutions.”
– ISPE Baseline Guide, Volume 5
The application of well understood, easy to use GEP’s enables the

delivery of effective integrated C&Q projects.
New Good Practice Guide from ISPE is approved on GEP outlining core
concepts and core practices- available from www.ispe.org

31
2. Best Practice Commissioning and Start-Up
Good Practice Guide – GEP, 2008 Key Concepts

32
2. Best Practice Commissioning and Start-Up -
Ongoing Focus on GEP’s
“The concept of a focused qualification effort is based on the

assumption that these good engineering practices, and in
particular a robust commissioning process, have been used to
ensure the equipment, systems and associated automation and
controls are acceptable from an engineering perspective and
are fit for the purpose of meeting user requirements.”

33
3. Risk Assessment to Focus Qualification on CPP’s and QCA’s
ICH Q9 Risk Assessment Mode
RISK COMMUNICATION

34
3. Risk Assessment to Reduce Qualification Load
Reducing the Load – All design criteria
All Elements GEP
Science and
Risk- Based
Approach
Process Critical Qualification/

Elements Validation

35
3. Risk Assessment to Reduce Qualification Load
Some Tools Relevant to C&Q
Item Note
System and Component Identify and qualify direct impact systems.

Assessment Identify critical components to reduce qualification requirements.
Family Approach/ Equivalence Group identical vessels to reduce OQ and PQ testing.
Functional Risk Assessments Identify Critical Functions
FMEA Failure Modes and Effects Analysis
Process Risk Assessments Identifying Process Risks

Functional Component Criticality Identify Critical Functions
Assessments
Quality Risk Assessments (QRA’s) Based on the outcomes of the risk assessments the critical aspects for each
direct impact system shall be identified.
Many more tools available, but should always be based on science

and knowledge, and performed by a subject matter expert with
support from the complete multidiscipline team

36
4. Leveraging and Utilising Vendor Testing to Maximum
Impact
Leveraging
– Leveraging can be defined as the process by which testing or

verification from one phase of the project is used to substitute or
enhance testing or verification of another phase of the project. (Either
Vendor Dossier/Construction to Commissioning or Commissioning to
Qualification).
– Should be identified up front in the testing matrix
– For Information or tests to be leveraged :
• The test must have been successfully completed, and pass its
acceptance criteria,
• Reviewed by a competent project team member,
• Good Documentation Practice (GDP) must be adhered to,
• Change control must be in effect.

37
4. Leveraging and Utilising Vendor Testing to
Maximum Impact
Vendor Testing
– Can be a Major Leveraging source

– This must be planned at the procurement phase and built into the
commercial contract
– Advantages
• Vendor is an expert- so should be less cost
• Makes handover clear “only when it works”
• Encourages “turnkey” thinking
– Some Pitfalls
• Bad Document Quality/ practices
• Poor Change Control
• Less control by Customer
• Training opportunity lost

38
5. Change control strategy across the project
lifecycle.

39
5. Change control strategy across the project
lifecycle.
Change Control Notes
– Robust Change control required at all stages of design and

construction.
– Keep it Simple……….
• Competent Peer Review
• Regular Review thorough audits
• Detailed analysis of the impact of changes
– Expectation should be that at handover from construction /

Mechanical completion all drawings, dossiers and specifications are
red lined and as-installed
– Leveraging often confuses start of QA change control agree the
ground rules at project initiation

40
References and Acknowledgments
ISPE Baseline guide 5

Draft ISPE baseline guide 12 ‘Verification’
GEP best practise Guide
ICH Q9
Lean C&Q Webinar ISPE Mar 2009

41
Question and Answer Session

42

Best Practices Commissioning & Validation

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Best Practices Commissioning & Validation

Presented by Gearoid Cronin, Commissioning, Qualification & Field Sales Manager,

Facilitating Quicker Pharmaceutical Project Delivery

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

This presentation will discuss the current trends in Commissioning

– Review of current (FDA and EU) regulatory environment and

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

Facilitating Quicker Pharmaceutical Project Delivery

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

 21st Century cGMP Initiative

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

 ISPE Product Quality Lifecycle Implementation (PQLI) Initiative

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

Traditional ‘V’ Model or Risk Based

Lean Thinking is equally relevant

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

 Process validation is required in both general and specific terms, by the

 § 211.210 Sampling and testing of in-process materials and drug products.

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

that a specific process

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

Activities are designated as:

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

 The overarching philosophy articulated in both the

FDA Guidance for Industry Sept 2004

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

Facilitating Quicker Pharmaceutical Project Delivery

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

 The old way: Efficiency:

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

 The old way:

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

 Use of the 8 ASTM principles coupled with:

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

Good Engineering Practice

Process Requirements Specification Verification Acceptance

Figure 1 – The Specification, Design, and Verification Process

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

1. Requirements Definition 1. Good Engineering Practice

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

Process approved list Verification

List approved appr. Summary

CPP: critical process parameter

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

 Adoption of the ASTM E2500-07 Standard Approved in

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

 Should be done regardless of the model (New/ Old)

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

 Have an Integrated Handover

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

ELECTRICAL SUPPLY / AUTOMATED SYSTEMS

GAS BOILERS / STEAM GENERATION

POTABLE WATER COOLING WATER CHILLERS PQ DISTRIBUTION

WFI STILL/CLEAN STEAM

AIR COMPRESSED COMPRESSED AIR

DRAINS / CIVIL WORKS

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

2009 International Forum on Pharmaceutical Engineering and Generic Drug R&D

 Planning Step 4: Fully Integrated schedule

21st Century cGMP Initiative

ISPE Product Quality Lifecycle Implementation (PQLI) Initiative

Process validation is required in both general and specific terms, by the

§ 211.210 Sampling and testing of in-process materials and drug products.

The overarching philosophy articulated in both the

The old way: Efficiency:

The old way:

Use of the 8 ASTM principles coupled with:

Adoption of the ASTM E2500-07 Standard Approved in

Should be done regardless of the model (New/ Old)

Have an Integrated Handover

Planning Step 4: Fully Integrated schedule

Planning Step 5: Roles and Responsibilities Matrix

During project execution:

The application of well understood, easy to use GEP’s enables the

ISPE Baseline guide 5