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Quality Risk Management

According to ASTM E2500:

Standard Guide for Specification, Design and Verification for
Pharmaceutical and Biopharmaceutical Manufacturing Systems and
Brian Evald Andreasen, May 2009
Direct telephone: +4530751381

Fra indbydelsen:
• På mødet vil Brian Andreasen fra NNE Pharmaplan
fortælle om hans erfaringer med at implementere
standarden hos Pfizer globalt.

• Han vil give et overblik over indholdet i standarden

sammenholdt med traditionel kvalificering,

• og der vil blive givet konkrete eksempler på Risk

Management og Verifikation.

Slide 2
NNE Pharmaplan, my workplace
• Over 80 years of experience in the pharma and biotech industries

• Spanned over 3 continents across Europe, North America and Asia

• Workforce 2008: More than 1500

• Turnover 2007: DKK 1.444M, €194M, $249M

• ISO 9001 certified since 1995; certified worldwide in 2008

• ISO 14001 certified since 2003

Slide 3
Global reach - local knowledge

Slide 4
Where is the best Quality?

David Dolgin, Abbott

2008 Washington ASTM C&Q

Traditional New Risk Based

C&Q Verification
Approach Slide 5
The benefits from E2500 are

Moves away from ‘paper quality’ and rigid

documentation practices -
to product quality and patient safety.

u e
Faster project execution
Focus on patient safety
l y
Significantly reduces documentation
Enhanced process understanding

o b
Saves time and resources

Higher production yield (OEE)
Improved quality at less costs - better use of expertise

n d
Compliance with Health Authorities expectations

to risk based approach

Thus, improved quality, major cost reduction (above 40%), faster to market and
longer time to take the right decisions for investments.

Slide 6
The Pfizer case

Pfizer is the largest pharmaceutical company in the world

They had with support from NP implemented a risk based verification

system globally in the company according to the new ASTM E2500
(Before Pfizer had a traditional C&Q approach according to ISPE C&Q
guide Vol 5 similar to NN)

•By adapting the new risk based approach…Pfizer expect to:

• save 40% of all expenses to Commissioning and Qualification

• Eliminate between 2 and 6 month of project execution time.
• Get improved quality level

Slide 7
What is that….?
• Large voluntary standards development

• Not-for-profit organization

• Established in 1898

• Purpose is to develop standards in response to

market needs

• Technical standards for materials, products,

systems, and services

• HQ in Philadelphia,
• Sub-offices in London, Mexico City &

Slide 8
ASTM Committee E55

• Established Spring 2003

• Development of standardized nomenclature and

definitions of terms recommended practices, guides,
test methods, specifications, and performance
standards for the manufacture of pharmaceutical

Slide 9
Issued Standards (Pharma) :
• E2363-06a Standard Terminology Relating to Process Analytical
Technology in the Pharmaceutical Industry

• E2474-06 Standard Practice for Pharmaceutical Process Design Utilizing

Process Analytical Technology

• E2500-07 Standard Guide for Specification, Design, and Verification of

Pharmaceutical and Biopharmaceutical Manufacturing Systems and

• E2503-07 Standard Practice for Qualification of Basket and Paddle

Dissolution Apparatus

• E2537-08 Standard Guide for Application of Continuous Quality

Verification to Pharmaceutical and Biopharmaceutical Manufacturing

Slide 10
Work Items in Progress (E55.01)
• WK5930 Standard Practice for Risk Assessment and Risk Control as it Impacts the
Design, Development, and Operation of PAT Processes for Pharmaceutical
Manufacture (Gawayne Mahboubian Jones)

• WK5935 Standard Guide to Process Understanding (Jean Marie Geoffroy)

• WK9192 Standard Practice/Guide for the Application of Continuous processing in the

Pharmaceutical Industry (Trevor Page)

• WK15151 Standard Guide on Sampling (Joep Timmermans)

• WK9182 Standard Guide for Verification of Process Analytical Technology (PAT)

Control Systems (Bruce Davis)

• WK9191 Standard Guide for Multivariate Data Analysis Related to Process Analytical
Technology (Chun Cai)

• WK13538 Standard Practice for Identification of Critical Attributes of Raw Materials in

Pharmaceutical Industry (Marino Nebuloni) WK11898 Standard Practice for Real-time
Release of Pharmaceutical Water for the Total Organic Carbon Attribute (Rich Godec)

• WK15778 Guide for Science-based and Risk-based Cleaning Process Development and
Validation (Andrew Walsh)

• WK16888 Guide for Validation of PAT Methods (Jim Rydzak)

Slide 11
Essence of the E2500

The scope and extent of quality risk

management for
specification, design, and verification
activities and documentation should be
based on the risk to product quality
and patient safety.

The level of effort, formality and

documentation of the quality risk
management process should be
commensurate with the
level of risk.

Slide 12
Important Terms
Critical Quality Attributes (CQA)
A Critical Quality Attribute is defined as a
physical, chemical, biological, or
microbiological property or characteristic that
should be within an appropriate limit, range or
distribution to ensure the desired product
quality (ICH Q8)

Content Slide 13
Important Terms
Critical Process Parameters

A Critical Process Parameter is defined as a

process parameter whose variability has an
impact on a CQA and therefore should be
dP Time
monitored or controlled to ensure the process
Speed parameters produces the desired quality (ICH
Pressure Pressure



Dissolution Time
Content Slide 14
Important Terms
Critical Aspects Critical Aspects are defined as
functions, features, abilities, and
performance or characteristics
necessary for the manufacturing
process and systems to ensure
consistent product quality and patient
Sanitary safety (ASTM E-2500-07)

Parameter alarms Non turbulent

agitor Filter integrity

Vision system for

Batch documentation
Content Calibration Slide 15
Slide 15
Important Terms
Subject Matter Experts (SME)

SME is defined by ASTM as:

• Individuals with specific expertise and
responsibility in a particular area or field (for
example, quality unit, engineering, automation,
development, operations, and so forth).

Slide 16
The SME role & responsibilities

From E2500

• Subject matter experts should take the lead role in the

verification of manufacturing systems as appropriate within
their area of expertise and responsibility.

• Subject matter expert responsibilities include planning and

defining verification strategies, defining acceptance criteria,
selection of appropriate test methods, execution of
verification tests, and reviewing results.

Slide 17
Risk Based Approach
The old way

Impact Assessment – (systems & Components)

• Evaluating design for impacting the product quality, but no

evaluation of the level of potential risk for product and
• No Risk Mitigation
• System and component level focused
• Component ImpactC Assessment is conducted after design
Direct Impact

Indirect Impact

Slide 18
Risk Based Approach
The new way
Quality Risk Management – Risk 1 ..

Ongoing and iterative Risk Management


From CQA and CPP are defined to

………handover for operation.

Slide 19
Risk Based Approach
The new way
Quality Risk Management – Risk 1 ..

• Definition of CQA, CPP & Critical aspects

• Risk ranking
• Risk mitigation:
¾ Design solutions
¾ Control strategy
¾Design Review
¾ Suppliers selection
¾ SME allocation
¾ Test
¾ Documentation
¾ etc

Slide 20
Quality Risk Management
Determination of Critical Aspects

Risk 1 ..

Critical Aspects must be identified during the risk
Management process.
Critical Aspects are derived directly from CQA and the
general GMP compliance issues.
Critical Aspects are subject to risk assessment and
risk mitigation; if possible and Verification testing.

Slide 21
Quality Risk Management
Identifying potential Risk

New New Customized

Vendor technology
Well known
Well known technology
Customized Simple Copy
Complex process Equipment Equipment
many interfaces Critical Process
Unstable process

Equipment Slide 22
Quality Risk Management
Risk Mitigation – Safe design solutions & Control strategy

Sanitary issue:
Removal of pumps,
by using gravity

Monitoring Monitoring

Risk 1 ..
Equipment …

Monitoring Manual

Slide 23
Quality Risk Management
Risk Mitigation - Vendor Assessment Risk 1 ..

to other disciplines
Custom made
or vendors ?
or bulk?

New Technology?

employee? Slide 24
Quality Risk Management
Risk Mitigation -Design Review (DR)
The DR is an important part of the risk management
process, and DR must be focused on the risk

• Design meets the mitigated unacceptable risk Risk 1

√ ..

derived from the risk assessment process. … √

• Planned Verification testing and acceptance criteria √
are sufficient and commensurate to level of √
quality risk.

• Design Meets relevant Critical aspects and
ensure that Critical Process Parameters can be
controlled to the desired level

• The Critical Quality Attributes (CQA) can be

ensured by the proposed design

Slide 25
Quality Risk Management
Use of Vendors test results etc

Vendors test documentation may be used as part of the verification

documentation, if the vendor is assessed, and there is evidence of:

• An acceptable vendor quality system,

• Vendor technical capability

• Vendor application of GEP such that information obtained from

the vendor will be accurate and suitable to meet the purpose of

If inadequacies are found then we have to mitigate potential risks

by applying specific, targeted, additional verification checks or
other controls rather than repeating vendor activities and
replicating vendor documentation.

Slide 26
Quality Risk Management
Test- planning

Critical Aspects
Risk Assessment



Commensurate Intensive test

with the Vendor test Vendor test SME participation
level of risk SME Approval SME surveillance & SME approval
Slide 27
Graphic Model
Issued by ASTM

Slide 28
Quality Risk Management Process

Mitigation Design
CQA Critical Risk + Vendor SME
+ Verification
CPP aspects Ranking DER issues Involve-
ranking issues ment

Link to

Slide 29
Risk Mitigation

Slide 30
Quality activities commensurate with the
level of risk.

Slide 31
Pfizer ASTM E2500 Transformation
Pfizer Case
ASTM E2500 Transformation
• Transformation from C&Q to
Verification based on ASTM

• Part of a Lean project to

streamline current practices
and enable more production
capacity for the same
investment capital
Pfizer C&Q
• Transformation project done
by global Engineering &
Quality team together with
NNE Pharmplan

• 2 project phases:
• Gap mapping & Scope
• Document writing, review
and approval
• Pilot implementation ongoing Pfizer Verification

Slide 33
Pfizer Case
ASTM E2500 Transformation - 2
• Combines E2500 with Quality by
Design principles and Lean

• Integrates
• Engineering
• Automation
• Quality
• Maintenance etc.

• Based on Quality by Design

Quality Risk Management
principles (ICH Q8, Q9, Q10)

• Applies to new and legacy

manufacturing systems

• Global Engineering Rollout on all

sites is ongoing
Pfizer Verification

Slide 34
Quality by Design in NNE Pharmaplan:
Transform C&Q to ASTM Verification
• Pfizer Client Case 2008
• Global Engineering - for global use on all
manufacturing sites

• Transformation of Pfizer C&Q program to
the ASTM E2500 standard for
Verification, for use globally
• Combined with a Pfizer Lean Program to
streamline current practices and get
more value of investments – both on
money and time
• 3 months delivery time Dissolution
• 5 consultants in NP Consulting Denmark Apperance
and USA plus global roll-out assistance Hardness
Content uniformity

• Full update of existing procedures to
ensure the harvesting of benefits of the Customer Quote:
Verification approach instead of the ”We selected NNE Pharmaplan for the work
traditional validation approach of
Commissioning and Qualification because these guys really understands
the QbD principles in practice.
What’s in it You guys really got it!”
• Faster and more cost-effective
verification compared to traditional ASTM E2500 Standard Guide
’validation’ for Specification, Design, and
Verification of Pharmaceutical
and Biopharmaceutical
Manufacturing Systems and
Slide 35
C&Q vs Verification Opportunities

100% #1 Fewer systems in Quality Unit scope

#2 Leverage GEP & Subject Matter Experts (Less details)
#3 Leverage Supplier Documentation
#4 Avoid repetition of tests etc.
#5 Reduce Periodic Review Scope
#6 Reduce number of docs retained etc.
#7 Flexibility and Scalability
#8 Other
C&Q Cost

Verification Cost

Slide 36
1st Generation – and the next:
Face the Learning Curve
• Every new paradigm has its learning curve
• 1st Generation is not always right
• Example: From the Horse Cap to the 1st Generation Taxi

1st Generation Taxi 2nd Generation Taxi

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Direct telephone: +4530751381
Slide 38
Back up slides

Slide 39
A Brief Validation History
First FDA Validation Guideline
• “Process validation is
evidence which provides
a high degree of assurance
that a specific process will
consistently produce a
product meeting its pre-
specifications and

Slide 41
ISPE C&Q Baseline Guide 2001

• “The application of this C&Q

process helps to ensure that
the appropriate resources are
applied to those systems and
components within a facility
that have the potential
to affect product
quality; and secondly,
provides the rationale to reduce
the scope of work for the
qualification of the plant, while
still ensuring compliance for the

• Commissioning (i.e. GEP)

• Qualification (i.e. QA)
ISPE Baseline Engineering Guide
Commissioning & Qualification
(Baseline Guide 5) 2001 Slide 42
New FDA Process Validation Guide
DRAFT Nov. 2008
• “Effective process validation contributes
significantly to assuring drug quality.
• The basic principle of quality assurance is
that a drug should be produced that is
fit for its intended use

• This principle incorporates the

understanding that the following
conditions exist:
• Quality, safety, and efficacy are
designed or built into the product.
• Quality cannot be adequately assured AFT
merely by in-process and finished- D R
product inspection or testing.
• Each step of a manufacturing process
is controlled to assure that the
finished product meets all design
characteristics and quality attributes
including specifications. “
Stage 1 – Process Design
Stage 2 – Process Qualification
Stage 3 – Continued Process
Verification Slide 43
C&Q vs. ASTM E2500
Engineering Change Management

QA Change Control

Old C&Q Design

Enhanced Commissioning PQ Process
Design Review Validation


Engineering Change Management QA Change


New Verification
Risk Based Approach Development
ASTM E2500
Design Review Commissioning PT Process

Slide 44
Verification overview
From ISPE’s draft of coming new Verification guideline

Slide 45
Planning Verification

From E-2500:

• The acceptance criteria and verification strategy should be documented in

appropriate verification plans.

• The verification plan should define what constitutes acceptable documentation

of subsequent verification activities.

• The verification plan should be developed and approved by subject

matter experts.

• Verification plans for systems containing critical aspects should be approved

by the quality unit.

Slide 46
Graphic model
NNE Pharmaplans model

Slide 47
NNE Pharmaplan is involved in the
new Pharma Standard Settings
• NNE Pharmaplan is closely involved in the
setting of the new standards of the
pharmaceutical industry
• ASTM Committee E55 on Manufacture of
Pharmaceutical Products
• We have participated in setting the new
standards of the pharmaceutical industry
in ISA, GAMP, ISPE, PDA and ASTM for 20

• We call it ”More than Engineering…”

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