Design through start up of a multi product mAb Launch ... · PDF fileBuffer make-up Media make-up Production cell culture ... • Separate rooms also for, ... o ISPE Baseline Pharmaceutical

1Company ConfidentialCopyright © 2010 Eli Lilly and Company

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Design through start up of a multi product mAb Launch facility IE42CASSS CMC Strategy Forum

Aug 1st 2011


Agenda

Environment in Lilly, 2006ConstructionFacility design/ platformCommissioning & Qualification to Process ValidationOrganisation build/ trainingBusiness systemsLearnings


BIOTECH MANUFACTURING STRATEGY

Lilly Biotech 2006R&D strategy maturing and pipeline evolution% of Pipeline Monoclonal antibodies growingManufacturing requirements analysisPipeline marketing forecastsDesire for Incremental approach Strategy to keep drug substance manufacturing in housePlatform approachEffectively linking between designed processes and facilities critical for successful tech transfer and future process validation

Kinsale 2006Potential small molecule reductions in 10 yr horizonReputation for delivery +Reputation as a source of talent Capacity available in site infrastructureRecent capability enhancements / investments

Ireland 2006Focus on biotechnologyInvestment in educationPro technology business Wyeth, Centocor, Pfizer, Amgen decisions


Decision

• Build commercialisation and supply centre on existing Kinsale site

• Leverage existing site infrastructure• Leverage existing site management and presence in

Ireland• First increment – focus on capability• Timing driven by first molecule• Same scale / platform as Multiproduct Pilot Plant in

Indianapolis - meeting Lilly pipeline needs


KINSALE BIOTECH APPROACH, 2006

• BUILD TECHNICAL DEPTH/COMPETENCE/BRAND/CREDIBILITY in the core biotech disciplines of Upstream, Downstream, analytical, unit operations, regulatory, micro/viral.o Seed the technical organisation of the future with top talent graduates – leverage

International assignment programmeo Maximise level of conversion frMaximise use of contractors for future flexibilityo om small molecule

• DELIVER on short term commitments and thus build a reputation with external customers/ regulatory bodies for reliability and technical competence

• BUILD AND FOSTER EXTERNAL RELATIONSHIPS o Initial focus on partnership with BR&D and Irish / UK academic institutionso Focus on Lilly Global Facilities Delivery partnership to maintain project scheduleo Significant benchmarking inside / outside Ireland

• BUILD A KINSALE BIOTECH IDENTITY, TEAM AND MANAGEMENT PROCESS

• DEMONSTRATE VALUE (Quality, speed, cost) For potential supply and development work


So how did we get from this in January 2008…..

….to this in early 2010?


Project Constraints

• IE42 to be a “replication” of Lilly’s multiproduct biotech development facility in Indianapolis, completed in 2006.

• Ready to run first non-GMP batches in 2010• Minimal variation from designs of bioreactors

and downstream unit operations.• IE42’s design, then, began with a built-in “scope-

control” mechanism.


Things in Our Favour• New facility within an existing and well-established site with a utility

infrastructure.• Existing and proven process technologies.• Constrained scope.• Opportunities for replication of previous designs.• Experienced project team and established professional relationships.• Reasonable cost and schedule targets.• Experiences and learnings from previous modular projects.

Key Decisions

•Choice to use facility modules from beginning.•Assembled team from earlier projects, as best means of applying lessons learned and leveraging opportunities for replication.


So Why Modules?• Some pros:

– Quality; predictable and reliable.– Reduced hours on site, less mess - Safety.– Opportunities for schedule reduction.– Demands front-end loading; scope control.– Predictable costs since design/fabrication is fixed cost.– Addresses absence of skilled labour.

• Some areas of concern:– Be prepared to make decisions….and stick with them.– Must be able to assemble owner’s team early.– Reduced capability for making changes.– Certainly a perception of higher capital costs.– Likely duplication of some design/construction roles and functions.– Flexibility for future facility changes.


Creation of Open Spaces


Buffer make-up Media make-up Production cell culture

Seed cell culture Inoc Lab

MediaColdRoom

Primary RecoveryInitial PurificationBuffer HoldFinal PurificationAPI dispensing (bulk fill)

Equipment Wash

Weigh/dispense

ColumnPacking

IE42 main processing floor layout



Design strategy to support multiproduct

• Design facility to produce a low bioburden drug substance - frozen liquid bulk.

• Multiproduct facilityo Campaigned production runso Rolling changeoverso 1 expansion cell culture train, 3 X 5k’s production bioreactors & 1

downstream train• Consulted with Irish Medicines Board on design• Benchmarked with other Biotech companies on ‘best’ design features

• Ambient temperature purification processing

• Orthogonal viral clearance strategy

• Use of disposable technology (mainly downstream)

• Use of aqueous based buffers only – no solvents, urea etc.



• Facility design provides for central supply corridor for people flow and outer return corridor for flow of equipment and waste

• Separate rooms for principal operating steps: o Media & Buffer make-up

Platform basis for all media and buffers

o Inoculation/flask expansion labRemoved 2nd lab during VE process, option of building a 2nd lab if required

o Cell cultureSplit into expansion suite and production suite

o Primary recovery o Initial Purificationo Final Purificationo Drug substance dispensing

• Separate rooms also for, equipment wash/prep, raw materials dispensing, cleaning agent make-up, filter testing etc.



• Principal room classification is ISO 8*• Inoculation lab classification is ISO 7*, with open flask operations in

ISO 5 biosafety cabinet.• Drug substance dispensing classification is ISO 8 *. Liquid drug

substance will be dispensed in a biosafety cabinet.• Separate Air handling units per suite – allowed for phased

Environmental Monitoring PQ approach• Mobile equipment is not molecule specific• Facility Design Guidance

o ISPE Baseline Pharmaceutical Engineering Guide: Biopharmaceutical Manufacturing Facilities (June ‘04)

o EN/ISO 14644-1

* with viable monitoring levels


Project Timeline

Design

Construction

Commissioning & Qualification (up to OQ)

Performance Qualification

Practise Lots

Process Validation2013 Submission

2011

2009

2008

2010

We Are Here

2007

2006

Transfer of Care, Custody & Control to Operations


WetSystemCommissioning

Key Activities

Water Checks

Water Runs(IntegratedCommissioning)

Key Activities

Integrated SystemsSeed Train5K ReactorsPrimary RecoveryMedia Make-upBuffer Make-upWater RunsNo CellsNo Solids/LiqsRecipes

OQ(System OQ)

Key Activities

OQ of Eachsystem

PQActivities

Key Activities

Media Make-upMedia HoldReactor KLA’sPacking StudiesBuffer Make-upsBuffer TransfersWater RunsPurificationTraining

Eng &Demo Runs

Key ActivitiesCell Culture &PurificationCleaning Studies/Cleaning Validation‘Go clean’Env MonitoringEng & Demo RunsAPI comparabilityTraining

PV Lots

Key Activities

5 PV Lots

C &Q Team / IE42 Start-up Team IE42 Start-up Team

C&Q to PV


Operations Organisation Build

• Majority of Operator and Technical Support roles sourced from within original Kinsale Small Molecule site.o 63% of operators from small moleculeo Supplemented “converts” with Biotech experienced personnel to build capability

• Operator training approach consisted of 4 parts;o 5 week Biotech Training Course developed in conjunction with NIBRTo Operators time spent in Biotech Development plant in Indianapoliso Early Involvement in C&Q and PQ activities in the facility

• Technical staff training consisted of;o Time (18 months) at Biotech Development plant in Indianapolis o In-house Lilly Training o External Courses– e.g. MSc in Biopharmaceutical Science


Business System Design

Volume Difference vs Small Molecule adds to Complexity

Large Molecule1Large Molecule 2


Business System Design

• Significant effort focused on business system design with the use of Lean six sigma tools i.e.o Work instructionso Batch recordso Consumables designo Batch numberingo Sample managemento Alarm managemento Raw material samplingo Data management/ trendingo E-logs

Biotech Six Sigma – Lean Design


LEARNINGS FROM THE JOURNEY• Strategy

o Focus on capability build. o Investment in partnership by both Bioprocess R&D and Kinsaleo Significant changes to Business Plan assumptions during the journey – this should be

viewed as the norm

• Organisation / management systemo Allowing core management group to focus on Biotech / Operating as plant within plant for

project duration

• People o Importance of core group of technical leaders / advocates / zealots!o Graduate quality & International assignment paybacko Ability to convert / train genuinely interested people o Leveraging Irish university and training infrastructureo Degree of effort required with new sciences – recruiting strategy adjustments

• Generalo Quality standards of Drug Substance v’s APIo Criticality of material management systems to operations

• Facilityo Modular build vs stick - premiumo Continuity / replication of people, design and processo EU regulations vs FDA


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Questions ?

Documents

Design through start up of a multi product mAb Launch ... · PDF fileBuffer make-up Media make-up Production cell culture ... • Separate rooms also for, ... o ISPE Baseline Pharmaceutical