PDA: A Global Association

Technical Excellence in Parenteral Manufacturing

Mauro Giusti giusti_mauro@lilly.com Eli Lilly Italia

2014 PDA Meeting Nov 4-5, Munich, Germany

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•Lilly Italia •Introduction to Technical Excellence •Develop a Technical Excellence Program

•Technical/Scientific Education •Issues Prevention/Prediction •Technical/Scientific Innovation

• Strategic Evolution • Success Factors

Lilly Italia

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2000

• Eli Lilly Italia was established in 1959 and the plant built in 1961

• Eli Lilly Italia became a global Manufacturing Site for dry and parenteral products in the mid ’90s.

• In 2003 a decision was made to change the plant mission to Insulin products.

Lilly Italia Mfg Plant - Today

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•Insulin Cartridges manufacturing in Isolators and packaging/combi products (Line 1 and Blister packaging line operational since Oct 2009, Line 2 and Insulin Pen assembly line operational since Nov 2012)

•Insulin Cartridges manufacturing in RABS (Line 3 start up planned in Q 4 2014)

•Chemical and Biological Lab, Utilities, Waste Waters Treatment Plant, full automated chillroom

•State of the art parenteral mfg technology :

• Rigid piping, use of CIP and SIP

• High speed filling in both Isolators/RABS and in electronic inspection

•Advanced level of process automation, system integration and paperless instructions

•Operations run 24hrs/6 days for F&F , 24hrs/5 days for Pen assembly/packaging, 16hrs/5 days Blister and Sorting.

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Technical Excellence or nothing

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A new high complexity mfg reality to face:

• Parenteral Production • Large Molecules/Complex Formulations • Computer Integr. Mfg (Systems/Wkcenters) • High volume batches (2500 lt) • High speed filling line (600/min) • High speed electronic inspection • Minimal Tolerances of finished product • High precision dosing device • Automated assembly process

“It is possible to fly without motors, but not without knowledge and skill”

Wilbur Wright

Only way to manage successfully

all these aspects in an integrated fashion

is to aim to Technical/Scientific Excellence.

Strategy for the Site in 2007

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LILLY ITALIA MFG BRAND – What will differentiate us in terms of excellence

1. Technical Excellence (State of the art technical solutions and competences)

2. Efficiency – Product cost, Productivity, Lead Times 3. Flexibility – Reaction times 4. Quality and Health/Safety/Environment – Not Negotiables!

THE ORGANIZATION – How we will make it happen • Focused on the production process – The production process as a priority • Functional alignment – Superb Functional competence • Cross-functional integration – integration through specific teams • Lilly Network Integration – from local to global site • Flat (# Levels) - Management “close” to the process and to the people • Lean (Dir/Indir ratio) – Minimum organizational complexity

Technical Excellence

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Initial focus (2009) on 4 areas: 1 area of excellence to leverage, 3 weak areas to strenghten

Differentiation Factor To design and develop an excellence area System Integration and Workcenter Integration

Insulin Manufacturing Sterility Assurance Equipment Computer Integrated

Manufacturing (CIM)

Material Science Vision System

Pen Assembly

3 additional areas to strenghten added at later date (2012):

Technical excellence

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The three pillars of Technical Excellence: Technical Education and Capabilities development

Issues Prevention/Prediction

Continuous/Breakthrough Technological Innovation

Capabilities Development 2007-2009

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Training @ Network Sites (1-2 years on-the-job, about 20 people)

Training @ Vendors

Insulin Academy (43 days per person, 384 employees)

Involvement of people in validation activity

Direct involvement and contribution from other Network sites and Central functions

Transformation competencies from the production of antibiotics to

Insulin

400 classrooms/more than 3000 hours of training

Technical Education 2009 - today

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The process to acquire/transfer knowledge and competences to make more effective the contribution of all employees to the manufacturing operations. It provides an overview of principles of why we do thing the way we do and, where required, a deep dive on given technical aspects. Education has two very different, but connected, purposes:

Differentiated Dissemination for large Mfg population

Specialization/Expertise development for Subject Matter Experts (SMEs)

Provide the right level of knowledge to the right attendees, considering the starting level and the learning agility. Ensure that the BIG PICTURE and the WHYs are well understood. E.g. Different training material for Operators/Technicians/Professionals

Design a specialization paths for SMEs of the various areas. Invest in their education and personal growth in promoting partecipation to forum, seminar, external training, etc

Technical Education: Dissemination

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Courses are very detailed and thorough, Sterility Assurance courses also have multiple case studies, built on real like examples.

• Formulation process for insulin solution products • Formulation process for insulin suspension prods • Formulation process for insulin mixtures • pH adjustment in formulation • Solutions - Transfer + Filling • Suspensions - Transfer + Filling • Optical Density – Logic and Process Monitoring • Advanc. course for Component Processor System

Insulin Mfg Courses • Cleaning & Sanitization • Dry Heat Sterilization/Depyrogenation • Environ. Monitor, Viable and non viable • Steam 1 (Theory + Autoclaves) • Steam 2 (SIP + CPS) • Filtration, gas and liquid • Isolators • Media Fill • Leaks Management

Sterility Assurance Courses

Here below some training corses developed for two of the focus areas

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Develop internal training course

Arrange Technical Seminar with Global Steward

Attend Mfg operations at a Lilly Site

Sterility Assurance shadowing with Central Function

Stay/Visit at Suppliers shop on specific topics

Participation to Lilly Aseptic Engin. Focus

Group

Participation to Lilly Molecule stewards forum

Attend PDA/ISPE forums And Equipment shows

Technical Benchmarking Internal + External

Technical debate with Suppliers on improvements,

Validation approach, etc.

Lilly Site Lilly Network Lilly Suppliers Pharma Industry/Universities

Technical Excellence: Specialisation

R&D projects with Universities

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Issues Prevention/Prediction - iMCS

ICH Q9/ISO14971

ICH Q9/ISO14971

Application of ICH Q8, Q9, & Q10

Pharmaceutical Quality System

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• Life Cycle Approach • Enablers Knowledge & Risk management •Control Strategy Execution and Verification • Continuous Improvement

Pharmaceutical Development

•Life Cycle Approach •Product knowledge •Design space •Manufacturing process development •Control Strategy development

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•Risk to the patient safety and product quality •Manufacturing link CQA’s to controls, monitoring •Enabler of Pharmaceutical Quality System

Quality Risk Management

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iMCS

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Step 4 FTA to id

causes that impact CQA’s

per unit op per CQA

Partnership w/ Development and Medical

Patient Safety Efficacy Requirements

Control Strategy

Step 5 FMEA

Identify controls of causes rank occ and det

Evaluate Risk

Step 1 Identify

CQA’s and CPPs& OPPs Level 1 & 2

Step 2 ID Harm and Rank Severity to Patient (PHA)

Step 3 Identify Process Unit operations

Determine Leading Indicators and Lagging Indicators

CT Manufacturing/Development/Tech Transfer/Registration Stability lots

Stage 1 Pharm Dev.

Stage 2 PPQ (PV)

Stage 3 Continued Verification

Validate Control Strategy

Continued Monitoring Of Leading and

Lagging Indicators

Leading Indicators

Lagging Indicators

Issues Prevention/Prediction - iMCS

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Product: CQAs For patient safety,

efficacy and quality (as ICH Q8/Q6a)

Product: CQAs For patient safety,

efficacy and quality (as ICH Q8/Q6a)

Other Product Attributes & Business Requirements

e.g. cost, safety, environmental,

manufacturability

Other Product Attributes & Business Requirements e.g. Safety, environmental,

Manufacturability, cost

Controls to Enable Product CQAs to be met

e.g. CPPs , material attributes & components,

equipment and facility operation s that must be

monitored or controlled to achieve product CQAs

Controls to Enable Product CQAs to be met

e.g. CPPs , material attributes & components,

equipment and facility operation s that must be

monitored or controlled to achieve product CQAs

Other Controls Other parameters and material attributes &

components, equipment & facility operations that must be monitored or controlled to achieve

other product attributes & business requirements

Other Controls Other parameters and material attributes &

components, equipment & facility operations that must be monitored or controlled to achieve

other product attributes & business requirements

Analytical, Engineering & Other Control Methods Analytical methods (off line, at - line, in - line, or on - line)

Equipment and facility engineering controls PAT (including process models and control models)

Automation and manual controls Procedures

Analytical, Engineering & Other Control Methods Analytical methods (off line, at - line, in - line, or on - line)

Equipment and facility engineering controls PAT (including process models and control models)

Automation and manual controls Procedures

Control Strategy Level 2

Control Strategy Level 3

PATIENT BUSINESS

Control Strategy Level 1

Systems to

facilitate other

business controls

ISPE - PQLI Control Strategy Model

PQS (ICH Q10) and

GMPs

Issues Prevention/Prediction - iMCS

Issues Prevention/Prediction - iMCS

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Critical Quality Attributes

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.

Preliminary Hazards Analysis

Hazards are the

failures on the CQA that may cause harm to the patient. Each

Hz is evaluated through a Risk

Assessment approach considering related

severity and Probability of Harm

Process Map Development

Identify Process Unit operations

Fault Tree Analysis

Each process step is reviewed by a proper

team of SMEs to identify each possible failure that may occur

in the production process

Failure Modes and Effects

Analysis

Each identified Failure mode of the FTA is

evaluated through a Risk Assessment

approach identifying tha probability of

occurrence /detection and each available

Preventive and Detection control in

place

FTA FMEA CQA PHA Process Map

“The planned set of controls, derived from current product and process understanding, that assures process performance and product quality.”

ICH Q 10

Technological Innovation - examples

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Design of new Primary Packaging Components

To address issues

Rapid Micro Methods development/implementation

To shorten response time

Particoloscope to Determine nature

Of particle

FT-IR/SEM to characterise particles

Equipment Monitoring thru micro cameras

to improve troubleshooting

Fully Automated Chillroom to minimise

headcount/people exposure to cold

temperature

Tertiary Loop Concept (Group of Experts,

see next slide)

RFiD to track Material handling

and Time Out of fridge

Continuous Improvement Cycle LONG RANGE

PLAN BREAKTHROUGH

TECHNICAL TEAM

IMPROVEMENT

PROCESS TEAM

CAPABLE COMPLIANT

IN CONTROL

CHECKING ACTIVITY

DATA PROCESS

•ANALYSIS OF PROBLEM THROUGH BUSINESS AND PROCESS MEASURES •ANALYSIS OF ROOT CAUSES

TEST PROPOSED SOLUTION

NO

NO

NO

YES YES

NO

•PROCESS MEASURES •BUSINESS MEASURES (MEETS SPECS)

(COMPLIANCE) (PREDICTABLE)

PRIMARY LOOP

SECONDARY LOOP

TERTIARY LOOP

Technological Innovation is typically a Breakthru one

and is originated primarily by Tertiary Loop people.

However it needs to be grounded in the shop floor and ensure improvement of shop floor activities.

Technical Governance – Tertiary loop

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Tertiary

Secondary

Primary

• Fix daily production issues • Provide feedback from floor shop

Process Team

• Propose and implement changes • Provide expertise to support process teams

Technical Team

Expert Team

• Site Technical Education • Breakthrough improvements and innovations

• Company Internal Networking • External Organizations/Regulators interaction

Tertiary Loop people are not strictly linked to routine ops

and have therefore time and opportunities to focus on Breakthru Innovation and

to other activities bringing value in the long run.

Loop

Loop

Loop

Lilly Italia Strategic Evolution

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• From “Flexible Site” to Biotech Products launch Site

• From being the ones that learn to become those who teach, still continuing learning

Operational Excellence Efficiency Technical Excellence Flexibility

Enhance focus on people development and make it even more explicit

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Success Factors for Technical Excellence

Site Head and Mfg Lead Team to drive and support Technical Excellence initiatives

One Mfg Lead Team member as Technical Excellence Champion, to provide oversight and coordination of activities

Focus on successful recruitment, then induction and accelerated development of new employees.

Leverage strengths of more senior employees to develop them as SMEs and become tutors/mentors of the less senior ones

Ensure appropriate reward and career development for employees on technical roles. Example set-up a TECHNICAL LADDER

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Technical Ladder – skills required

Scientific Excellence

Business Results

Leadership

If you think education is expensive, try ignorance!

Derek Bok, Past President, Harvard University

However beautiful the strategy, you should occasionally look at the results.

Sir Winston Churchill, Prime Minister of the Uk Nobel Prize Winner for Literature

In matters of style, flow with the current. In matters of principle, stand like a rock.

Thomas Jefferson, 3rd President of the United States

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Thank You for the Attention