Steven Galvin Presentation Gap Analysis

29/03/2012
IVT’s 3rd Annual Validation Week EU

28-30th March 2012, Dublin
Effectively Conduct a Gap Analysis of Your Validation

Program
Stephen Galvin B.Sc (Hons), MSc

Eli Lilly S.A – Irish Branch
29/03/2012 Copyright © 2011 Eli Lilly and Company
Agenda
I. Plan a Validation Gap Analysis
II. Case Study:

Introduction of Biologics Drug Substance
Manufacturing into a Small Molecule API
manufacturing site.
III. Interactive Exercise
29/03/2012 Copyright © 2011 Eli Lilly and Company 2
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29/03/2012
Agenda
Understand the audience – what standards are we
being assessed against?
Determine roles, responsibilities and scope of the
gap assessment.
Tools to use when performing a typical gap
assessment.
Implement a remediation plan.
Life cycle of a gap analysis.
What is a Validation Gap Analysis

A validation gap analysis is a documented review/challenge
of a validation program against :
Regulatory standards and guidance

Corporate procedures
Site Procedures
Industry Guidance Documents
Benchmarking
to identify potential gaps and process improvements and

implement a plan to address them.
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Standards
• Understand the audience – what standards /
guidelines are we being assessed against?
•FDA Guidance for Industry Process Validation: General Principles and Practices
•ICH, Q7A, Guidance on Good Manufacturing Practice for Active Pharmaceutical
Ingredients.
•ICH Q5D Derivation and Characterization of Cell Substrates used for production of
Biotechnological / Biological Products.
•EU Annex 13, Manufacture of investigational medicinal products.
•Annex 2 to EU GMP Guide, Manufacture of Biological Medicinal Product for
Human Use.
•Annex 15 to EU GMP Guideline, January 2001.
•Revised Draft Qualification and Validation, Annex 15 to the European GMPs,
Effective June 2001.
•FDA, CDER – Guideline on General Principles of Validation, May 1987.
•FDA Draft Guidance to Industry: Manufacturing, Processing, or Holding Active
Pharmaceutical Ingredients, April 1998.
Standards
•FDA, Guideline on General Principles of Process Validation, May 1987.
•Pharmaceutical Inspection Convention, PIC/S, April 2000.
•Canadian Therapeutic Products Program, Cleaning Validation Guidelines, May
2000.
•Good Manufacturing Practices, 1998 Edition Canada: Therapeutic Products
Program, Health Canada.
•European Medicines Evaluation Agency, Committee for Proprietary Medicinal
Products.
•Note for Guidance on Process Validation (CPMP/848/96), European Medicines
Evaluation Agency, Committee for Proprietary Medicinal Products.
•Principles and Guidelines to Good Manufacturing Practice (91/356/EEC,
91/412/EEC). European Medicines Evaluation Agency, Committee for Proprietary
Medicinal Products.
•PDA Technical Report No.42, Process Validation of Protein manufacturing.
•ICH Q8 Pharmaceutical Development
•ICH Q9 Quality Risk Management
•ICH Q10 Pharmaceutical Quality Systems
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FDA Guidance
Process Validation - Three Stages
Defines the • Confirms the • Ongoing

commercial process design assurance
process capable, in process remains
commercial in a state of
production. control
Control strategy
adequacy
ICH Q 8, Q9, Q 10 Synergistic Triad
Life Cycle Approach

Control Strategy & Robustness
Statistical Control
Scope & Extent

Design 9
8
Sampling 10
Monitoring & Revalidation
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ICH Q 8, Q9, Q 10 Synergistic Triad
Life Cycle Approach

Stage 1 Process
Control Strategy
Design & Robustness
Statistical Control
Stage 3 Continued Process
Verification
Scope & Extent

Design
Stage 2 Process
9
8
Sampling
Qualification 10
Monitoring & Revalidation FDA PV Guidance Stages
9 Added
Overlap of FDA PV Guidance Stages

and ICH Documents
Stage Title Description (FDA guidance) Goal Activities
Process Design
Design a process suitable for Risk analysis

PV Stage 1
routine commercial Lab Studies

Building and Capturing Design of Experiment (DOE)
manufacturing that can
Process Knowledge and Control Strategy
consistently deliver a product
Understanding Development History Report
that meets its critical quality
attributes.
Process design is confirmed Commissioning & Qualification

Process Performance
as being capable of Process Performance Qualification

Demonstrate the equipment
Qualification
reproducible commercial PV batches

PV Stage 2
and process is capable of

manufacture.
routinely manufacturing
Two elements:
product that consistently
(1) facility, utility, &
meets the critical quality
equipment qualification
attributes.
(2) Process performance
qualification
Continued Process
Complaints
Continually assure that the Adverse events
Verification
PV Stage 3
An ongoing program that Deviations – Root cause analysis

process remains in a state of
collects and analyzes product Batch Rejection
control (the validated state)
and process data that relate to Defect trend analysis
during commercial
product quality. Annual Product Review
manufacture.
Change management
Q8 Pharmaceutical Development Q9 Quality Risk Management Q10 Quality Management
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Roles and Responsibilities

Importance to have clear roles and responsibilities for a gap assessment (best to
have individuals named NOT Departments):
RACI Chart
Responsible
Person primarily responsible for doing the work. May be the leader of a group of
people, or may be more than one person.
Accountable
Person who is accountable for the status of the activity (at a high level). This
person must be a member of the subgroup/function that is identified as the owner
and for used for escalation purposes.
Consulted
Should include persons or functions that MUST be consulted on/be involved in the
activity.
Informed
Should include persons or functions that MUST be informed once the activity is
completed.
Scope
The Scope of the Gap Assessment needs to be
defined up front – will help the prevent ‘scope creep’.
Project / Gap Assessment Charter is useful in

defining the scope and ensuring key stakeholders
‘buy-in’
Scope needs to be realistic and the Gap

assessment resources appropriately.
e.g. Gap analysis of our Stage 3 (Continued
Process Verification) procedures / systems.
(Stage 1/2 NOT in scope)
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Gap Assessment Tools

Tools to use when performing a typical gap
assessment:
 RACI
Frances R A C I
Sexton Responsible Accountable Consulted Informed
Schedule Activities to be owned
ENGINEERING
PV Studies
ENG Mixing Studies XX XX XX
ENG KLA Studies XX XX XX
ENG Bioreactor Media Challenge XX XX XX
ENG PQ DS Mixing Studies Assesment / Execution XX XX XX
ENG Water Trail - Downstream - Decision XX XX XX

 Project Charter
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29/03/2012

 Process Flows / Process Mapping
Current State V’s Future State
Brainstorming / Brown Paper Exercise
Risk Assessment Tools (e.g. FMEA)
Remediation plan
Remediation plan is required once the gaps have been identified i.e. how they are
going to be addressed, who is responsible and the time-frame.
Evaluate Possible Action plan and Implement

Interim Actions
Solutions
Verify the
Standardise &
Results
Implement
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Risk based Remediation plan

Once the Gap analysis is complete draft a risk remediation plan:
•Business or compliance risks?

•Put an action plan in place, with associated timelines in relation to each gap will be
addressed starting with the compliance gaps.
•Ensure your Quality System (e.g. CAPA system) compliance
•Implement controls to mitigate against the risk associated with compliance gaps if
immediate changes or testing cannot be performed.
Examples include:
•Elimination by design
•Perform additional testing
•Broaden the scope of requalification programs
•Manage the gaps to an acceptable levels e.g. manual procedures
•Increased QC testing
•Enhanced training programs
Life cycle of a gap analysis.

Once a Gap Analysis is completed and actions
implemented it should be reviewed periodically to
incorporate:
•New/ Updates to Regulatory Standards /

Guidelines
•New / Updates to Site Systems / Processes.
Best Practice is to proceduralise the Gap assessment

process.
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Agenda
II. Case Study:

manufacturing site.
III. Interactive Exercise
Agenda
II. Case Study:
Eli Lilly Introduction
Chemical versus Biologically derived
pharmaceuticals
Identify differences between small and large
molecule validation.
Example of real life gaps identified.
Process Support Qualification.
Risk management tools in action.
Maintenance of the validated and qualified state.
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29/03/2012
Eli Lilly…..A Global Company
• Major R&D facilities in 8 countries

HEADQUARTERED IN
INDIANAPOLIS, IN • Major Manufacturing facilities in 13
countries
• Net Sales of $23 Billion

38,000 EMPLOYEES
WORLDWIDE • R&D driven company R&D as a percentage
of sales: 21%
• Conduct clinical trials in more than 50

PRODUCTS SOLD
countries
IN 125 COUNTRIES
• Participates in more than 140 R&D
collaborations
Eli Lilly S.A – Irish Branch (Kinsale)

Site History
Site of 112 acres purchased in 1976
First batch of product manufactured in 1981
Independent site with historically strong links with community

W:\Plant Staff\Lead
Team\2009\Visitors &
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Eli Lilly S.A – Irish Branch (Kinsale)

Commercial Product Portfolio
Lilly Commercial
Protein Products
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From this in January 2008…..
Strategic decision to base new Biomolecule Drug

Substance facility in Kinsale
….to this in early 2010
Completion of
mAb
Validation
Campaign in
Q4 2011
Lilly’s Biotech Production

Platform Strategy
Centrifuge
Capture
Polish
Filter
API
Freeze
Purification
Cell culture: Primary Goal:
Full synthesis recovery: Simplified and more efficient common

downstream processing
and secretion Remove cells
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2012 – PART OF A mAb NETWORK
Biopharm Industry Internal Partners

Pfizer, Janssen, GFD
Biogen, Genentech, Tech Centres Academia
Abbot Regulatory NIBRT
ISPE Irish Universities
PDA, PCI UCL
ESACT
Process
Development Customers
Patients
DISCOVERY Kinsale Drug
Biotech Business Units
Product
Diabetes
ImClone CareOncology
Systems Inc. Biomedicines
Building a mAb network
External Service
Providers Regulators
IMB
External Business Partners FDA
Chemical versus Biologically derived

pharmaceuticals
Traditional pharmaceuticals
are chemically synthesized
Biomolecules or “Biologics”
are synthesized from living
systems
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29/03/2012
Small Molecules and Large Molecules

are very different
Aspirin
Size - 180 Daltons
Insulin
Size - 5,800 Daltons
Monoclonal
Antibody
Size - 150,000 Daltons
Manufacturing Differences Between Large

& Small Molecule….some highlights
Consumables
Small Molecule: 20 / batch
Large Molecule: ~200 / batch
Disposables widely used in large molecule manufacturing
Raw Materials
Small Molecule: 5 / batch
Large Molecule: 30-40 / batch
Batch Records
Small Molecule: ~5 / batch
Large Molecule: ~100 / batch
API Shipment
Small Molecule: Ambient
Large Molecule: >65deg C
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Biotech Validation Documentation Hierarchy

Biotech Validation Master Plan
Cleaning
Strategy Product Protection
Control Strategy
Sub Master Plans / Strategies

Automation
Steaming /
Sanitization
Commissioning
and Qualification
Shipping
Strategy
Extractables &
Leachables
Process
Strategy
Validation
Master Plan
Analytical
Master Plan
Biotechnology Validation Master Plan

•Describes the site approach to qualification and validation.
–Overall validation philosophy and strategy
•Describes high-level qualification and validation requirements for facilities,

equipment, systems, analytical methods ad processes impacting product
quality
•Describes the approach and controls to maintain a validated state
•Describes the schedule of activities, prioritization and rationale for risk

based approach.
•VMP must be written before approval of protocols for qualification and

validation activities
•The VMP must be reviewed and approved annually.

•The BVMP is not Product Specific
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29/03/2012
Biotech Validation Documentation Hierarchy
Process Validation Master

Plan Strategies :
•Mixing
Schedule / Execution •Cleaning
Plan •Filtration
•Extractables / Leachables
•Hold Studies (In Process, Buffer, Media)
•Reprocessing
•Column Lifetime
PV Protocols
Misc Protocols :
•Cleaning
•Hold Studies (In Process, Buffer, Media)
•Reprocessing
•Column Lifetime (concurrent)
PV Reports
Biotechnology VMP V’s Process VMP
Site Validation Master Plan Process Validation Master Plan

• Site / Capability Specific • Project / Process Specific
• Overall Validation • Validation Strategy for
Strategy / philosophy process
• High Level qualification • Stability requirements for
and validation project
requirements for • Plan to assess supporting
systems: systems (Process Specific):
– Facilities, Equipment, – Facilities, equipment,
computer systems, computer systems, analytical
analytical methods, methods, Cleaning, etc
Processes, cleaning etc
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29/03/2012
Process Validation Master Plan
The Anymolecule Process VMP is an umbrella document, which covers the

general validation strategy.
The purpose of the process VMP is to define the process validation studies
required to support licensure of Drug Substance manufacturing .The Process
Validation Master Plan provides a general description of the process, outlines
the process validation strategy and defines the validation studies that have
been, or will be conducted to support the full validation of the commercial scale
drug substance manufacturing process.
Drug Substance process validation is intended to demonstrate that the

manufacturing process is reproducible, consistent & in control.
Process Support Qualification

Process Support Qualification is a program of post Installation and Operational
Qualification (IQ / OQ), pre manufacturing activities, designed to qualify specific
manufacturing operations prior to Process Validation (PV)
The documentation hierarchy is as follows:
•Strategy Document (or assessment)
•Development Study (if required)
•Qualification Documents (Protocol / Report)
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Process Support Qualification Examples

Process Support Qualification
Hold Strategy Mixing Strategy
Buffers Buffers
Process Additions Process Additions
Cell Culture media and feed preparations Cell Culture media and feed preparations
Process intermediates Process intermediates
Filtration Assessment Extractable / Leachables

Upstream Upstream
Downstream Downstream
Buffers / Cell Culture media and feed Buffers / Cell Culture media and feed
preparations. preparations.
Process Validation Documentation Gap Assessment

Small Molecule Large Molecule
Small Molecule Biotechnology Validation
Validation Master Plan Master Plan
Cleaning PPCS Process VMP

Strategy NPI Manual
Analytical VMP PSQ Studies
Change C&Q Plan CSV

Control C&Q Plan NPI VMP
Cleaning Change
Strategy Control
PV SOP
PSQ Studies Steaming PV SOP
Strategy Control
Process
CSV Description Extractables / Strategy
Leachables
Validation
Protocols Validation Process
Readiness to Validation Protocols Description
Validate Campaign
Readiness to Validation
Validate Campaign
Validation Reports Validation Reports
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29/03/2012
Slide Courtesy of Dr. Marie Murphy
Resin lifetime Validation Protocols

(Concurrent Validation)
Regulatory Typically studies at small
expectation. scale provide a prospective
estimate of resin lifetime
“Resin lifetime studies (assurance prior to
demonstrate that the production scale
resin is capable of manufacturing).
maintaining
acceptable Execute long term
performance confirmatory studies at
characteristics manufacturing scale under
throughout its (concurrent PV) protocol.
intended use period”
PDA Tech Report No. 14: Validation Resin lifetime studies are
of Column-Based Chromatography Process for the
Purification of Proteins 2008 Vol 62 No. S3 required per molecule.
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Disposables in Biologics = E&L

Assessments
2Ds 3D in Bag Holders
Media
USP Buffer
DSP
3D in Totes
Extractables and Leachables

Extractable: Chemical compounds that migrate from any product contact
material when exposed to an appropriate solvent under exaggerated conditions
of time and temperature – Potential to affect a drug product
Leachable: Chemical compounds' typically a subset of extractables, that migrate

into drug product formulations from any product contact material as a result of
direct contact under normal process conditions or accelerated storage conditions
(likely to be found in the final product) – Actual effect exerted on drug product.
Performing a risk assessment of materials contacting products offers the

following benefits:
• Assignment of numerical scores reduces subjectivity.
• Quantifies risk and guides selection of appropriate product contact materials.
• Allows appropriate design and prioritization of qualification studies.
• Promotes quality by design and continuous improvement.
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Extractables and Leachables Risk

Assessment
Maintenance of the Validated State

Composite of ongoing control systems and procedures which are designed
to assure that the product specifications and acceptance criteria are met
and that the critical process parameters are maintained within specified
ranges.
Process Validation Schedule

Revalidation of the process may be conducted as a result of the following
circumstances:
•Change to the process
•Trends or data observed during processing or the Annual Product

Review
•Planned periodic revalidation.
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Maintenance of the Validated State

Preventative Maintenance and Calibration
A preventative maintenance program operates to ensure equipment and systems are maintained in
a qualified state.
Annual Product Review

The Annual Process Review (APR) is a process intended to monitor, measure and analyse
manufacturing processes and products, using statistical techniques, on a routine basis to evaluate
trends over time.
Change Control
All changes proposed for a manufacturing system, equipment, method or process must be
evaluated under Change Control as per local procedure to assess the impact on validation/
qualification and the requirement for additional validation / qualification,
Periodic Review of Facilities, Utilities, Equipment and Computer Systems

Utilities, facilities, equipment and computer systems that are used in the manufacture of drug
substance are periodically evaluated. The purpose of the Periodic Quality Evaluation (PQE) is to
evaluate trends, compare data with historical information to determine shifts and assess the state of
control of the facility, utility, equipment and computer system.
Agenda
II. Case Study:

manufacturing site.
III. Interactive Exercise: Review and discuss a typical

gap analysis of a validation program and perform an
interactive exercise using risk management tools.
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Interactive Exercise:
Background Information
Extractables / Leachables Risk Assessment
Scenario Background
•Large Molecule Drug Substance Manufacturer
•Cell Culture (Upstream)
•Purification (Downstream)
•Using a primarily disposable manufacturing process

•Disposable seed and production Bioreactors
•Disposable Chromatography Media
•Disposable containers for Process Intermediates
The risk assessment process comprised the following steps:

1. Prepare an inventory of all consumables,
2. Determine the quantities of consumable used in each process step,
3. For each component assign a risk score against each risk factor,
4. Sum the risk scores,
5. Determine the overall risk category.
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Risk Factor Risk Level Comment Risk Score
Proximity to the High Formulation and API/DS 10
DS Filling.
Medium Downstream operations up 6
to and including final
diafiltration
Polysorbate 80 preparation
Low Upstream operations up to 2

and including primary
recovery
Buffer & Media
Preparation
Surface Area High > 6000 cm2 10
Medium > 500 and < 6000 cm2 6
Low < 500 cm2 2
Risk Factor Risk Level Comment Risk Score
Extraction High Organic solvents /Strong 10
Capability of the Bases
Solvent Medium Water/ organic mixed solvents Ratio of organic
fraction
Low Water and salt buffers 4
Contact Time High > 30 days 10
Medium > 24 hrs and < 30 days 6
Low < 24 hours 2
Temperature High > 70 deg C 10
Medium > 37 and < 70 deg C 6
Low < 37 deg C 2
Inherent resistance High Elastomers and plasticized 10
of material to polymers
extraction Medium Rigid plastics 4
Low Metals and glass 1
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Risk Category Risk Score
High 40 – 60
Medium 30 - 39
Low 13 – 29
Interactive Exercise
Component Description Function
•Used Upstream
•28 day cycle time
•Surface area: > 6000 cm2
200L Single Use Bioreactor Bag •Aqueous solution
•37deg C Bioreactor Temperature
•Multilayer plastic irradiated flexible container
•Used Downstream
•28 day cycle time
•Surface area: > 6000 cm2
Single Use Ion Exchanger,
•Aqueous process stream
(10" capsule; 180 mL) •Ambient Operating Temperature
• Multiple materials of construction including
Elastomers and plasticized polymers
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29/03/2012
Interactive Exercise
Component Description Function
•Used Downstream (pre diafiltration)
•>1 min contact time
•Surface area:< 500 cm2
60 mL sterile syringe •Aqueous solution
•Ambient Temperature
•Rigid plastic with polymeric asket
10 L Drug Substance Bottles •Used Downstream (post Diafltration)
•Long Term Storage of Drug Substance
•Surface area:>6000cm2
•Aqueous solution
•Stored NMT -65degC
•Rigid Plastic Container
Interactive Exercise: Output
Inherent
Extraction
Component Surface Contact Proximity Contact Resistance Total Risk Risk
Capability of
Description Area Time to DS Temperature to Score Rating
the Solvent
Extraction
200L Disposable
Bioreactor Bag
Ion Exchanger,
(10" capsule; 180 mL)
60 mL sterile syringe
10 L Drug Substance
Bottles
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Interactive Exercise: Output
Inherent
Extraction
Component Surface Contact Proximity Contact Resistance Total Risk Risk
Capability of
Description Area Time to DS Temperature to Score Rating
the Solvent
Extraction
200L Disposable
10 10 2 4 6 10 42 High
Bioreactor Bag
Ion Exchanger,
(10" capsule; 180 mL)
10 2 6 4 2 10 34 Med
60 mL sterile syringe 2 2 2 4 6 10 26 Low
10 L Drug Substance 10 10 10 4 2 4 40 High

Bottles
Bonus Material
Example of a Large Molecule

Validation Master Plan
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Conclusions
? Thanks for your
attention………….any questions?
Acknowledgements
Eli Lilly, SA – Irish Branch

• Graham McCartney
• Marie Murphy
• Matthew Deacon
• Damien Power
• Brian Mullan
• Manufacturing Science and Technology
Bioprocess Research and Development, Indianapolis

• Graham Tulloch
• Christopher Breen
Global Validation Support

• Joanne Barrick
Copyright © 2011 Eli Lilly and Company 58
29/03/2012
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29/03/2012

IVT’s 3rd Annual Validation Week EU

Effectively Conduct a Gap Analysis of Your Validation

Stephen Galvin B.Sc (Hons), MSc

29/03/2012 Copyright © 2011 Eli Lilly and Company

II. Case Study:

III. Interactive Exercise

29/03/2012 Copyright © 2011 Eli Lilly and Company 2

29/03/2012 Copyright © 2011 Eli Lilly and Company 3

What is a Validation Gap Analysis

Regulatory standards and guidance

to identify potential gaps and process improvements and

29/03/2012 Copyright © 2011 Eli Lilly and Company 4

29/03/2012 Copyright © 2011 Eli Lilly and Company 5

29/03/2012 Copyright © 2011 Eli Lilly and Company 6

Defines the • Confirms the • Ongoing

29/03/2012 Copyright © 2011 Eli Lilly and Company 7

ICH Q 8, Q9, Q 10 Synergistic Triad

Life Cycle Approach

Scope & Extent

ICH Q 8, Q9, Q 10 Synergistic Triad

Life Cycle Approach

Scope & Extent

29/03/2012 Copyright © 2011 Eli Lilly and Company 9

Overlap of FDA PV Guidance Stages

Design a process suitable for Risk analysis

routine commercial Lab Studies

Process design is confirmed Commissioning & Qualification

as being capable of Process Performance Qualification

reproducible commercial PV batches

and process is capable of

An ongoing program that Deviations – Root cause analysis

Q8 Pharmaceutical Development Q9 Quality Risk Management Q10 Quality Management

29/03/2012 Copyright © 2011 Eli Lilly and Company 10

Roles and Responsibilities

Project / Gap Assessment Charter is useful in

Scope needs to be realistic and the Gap

Gap Assessment Tools

Schedule Activities to be owned

29/03/2012 Copyright © 2011 Eli Lilly and Company 13

Gap Assessment Tools

29/03/2012 Copyright © 2011 Eli Lilly and Company 14

Gap Assessment Tools

Brainstorming / Brown Paper Exercise

Risk Assessment Tools (e.g. FMEA)

29/03/2012 Copyright © 2011 Eli Lilly and Company 15

Evaluate Possible Action plan and Implement

Risk based Remediation plan

•Business or compliance risks?

29/03/2012 Copyright © 2011 Eli Lilly and Company 17

Life cycle of a gap analysis.

•New/ Updates to Regulatory Standards /

Best Practice is to proceduralise the Gap assessment

29/03/2012 Copyright © 2011 Eli Lilly and Company 18

II. Case Study:

III. Interactive Exercise

29/03/2012 Copyright © 2011 Eli Lilly and Company 19

29/03/2012 Copyright © 2011 Eli Lilly and Company 20

Eli Lilly…..A Global Company

• Major R&D facilities in 8 countries

• Net Sales of $23 Billion

• Conduct clinical trials in more than 50

29/03/2012 Copyright © 2011 Eli Lilly and Company 21