facility construction and start up for commercial scale

24th Interphex, Japan, Technical Conference

June 29th, 2011

Michael Brown

Facility construction and start up for

commercial scale manufacturing of

monoclonal antibodies - A case study

Lonza AG

Financially stable / global footprint

CHF 2.7 billion (2010 sales)

27 facilities; 8,300 employees

Markets Served

Bioresearch

Pharma & Biotech

Nutrition

Personal Care

Global leader in custom manufacturing

Chemical and biological APIs, cell therapy

Lead optimization through market supply

Microbial Control

Agriculture

Materials Science

Lonza Custom Manufacturing

Therapeutic

Cell Solutions

Testing

Solutions

Research

Solutions

BioscienceCustom Manufacturing

Development Services

Biological Manufacturing

Chemical Manufacturing

Nutrition

Ingredients

Microbial

Control

Performance

Intermediates

Life Science

Ingredients

Therapeutic

Cell Solutions

Testing

Solutions

Research

Solutions

BioscienceCustom Manufacturing

Development Services

Biological Manufacturing

Chemical Manufacturing

Nutrition

Ingredients

Microbial

Control

Performance

Intermediates

Life Science

Ingredients

Custom manufacturing and development

services for active ingredients

Biology-based products for customers in

R&D, production and quality control

Nutritional supplements, food ingredients,

cosmetics, disinfectants and agrochemicals

Exclusive Synthesis & Biopharmaceuticals

Bioscience

Life Science Ingredients

Bioscience


Life Sciences

Portfolio

(over 90%)

40%

52%

8%

Custom Manufacturing

Custom manufacturing and development

services for active ingredients

Biology-based products for customers in

R&D, production and quality control

Nutritional supplements, food ingredients,

cosmetics, disinfectants and agrochemicals

Exclusive Synthesis & Biopharmaceuticals

Bioscience


Bioscience


Life Sciences

Portfolio

(over 90%)

40%

52%

8%

Custom Manufacturing

Our broad offering enables us to meet

the diverse needs of our customers

Technologies Locations Products & Experience

Advanced Chemical Synthesis Visp, Switzerland

Nansha, China

Synthetic therapeutic small molecules (GMP/ISO)

Highly Potent APIs / Antibody drug conjugates (ADCs)

Small molecules (biotransformation)

Continuous Flow / MicroReactor technology

Peptide Synthesis

Braine l’Alleud, Belgium

Visp, Switzerland

Kouřim, Czech Republic

Nansha, China

Synthetic peptides (liquid + solid phase)

Recombinant DNA peptides

Microbial Fermentation Kouřim, Czech Republic

Visp, Switzerland

Therapeutic proteins (oral & topical)

Metabolites (fermentation)

Non-parenteral fermented ingredients

Industrial enzymes

Microbial Biopharma Visp, Switzerland

Hopkinton, MA (USA)

Kouřim, Czech Republic

Therapeutic proteins (injectable & oral)

Antibody fragments

Vaccines (protein antigen & bacterial vector)

Plasmid DNA

Mammalian Cell Culture

Slough & Cambridge, UK

Portsmouth, NH (USA)

Porriño, Spain

Singapore

Monoclonal antibodies

Therapeutic proteins

Cell Therapy & Custom Media Walkersville, MD (USA)

Verviers, Belgium

Singapore

Cell-based therapeutics

Custom liquid and powdered media & buffers

UltraPAK™ bioprocess containers

CELL-Tainer™ single use bioreactor

Viral-Based Therapeutics Houston, TX (USA) Viral vaccines / vectors

Our biologics facilities, products and

services are global and leading-edge

Portsmouth

Hopkinton

Singapore

Visp, CH

Slough, UK

Porriño, SP

Hopkinton, MA (USA) Microbial Biopharma 40L to 2,800L cGMP

Process R&D Services

Portsmouth, NH (USA) Mammalian Cell Culture 1,500L to 20,000L cGMP

Verviers (Belgium) Cell Therapy Autologous & Allogeneic Cell

Bioassays, Reagents


Media Custom Media & Buffers

Bioprocess Containers

Porriño (Spain) Mammalian Cell Culture 4 x 10,000L cGMP

Tuas (Singapore) Mammalian Cell Culture 4 x 20,000L cGMP


Cell Therapy Autologous & Allogeneic Cell

Bioassays & Reagents


Visp (Switzerland) Microbial Biopharma 20L to 15,000L cGMP

Process R&D services

Microbial Fermentation Process R&D Services

Walkersville

Walkersville, MD (USA) Cell Therapy Autologous & Allogeneic Cell

Bioassays & Reagents


Media Custom Media & Buffers

Bioprocess Containers

Verviers, BE

Slough (UK) Mammalian Cell Culture 200L to 2,000L cGMP


Applied Protein Services

Kouřim, CZ

Kouřim (Czech Republic) Microbial Fermentation 75L to 75,000L cGMP


Houston, TX (USA) Viral-based Therapeutics Phase 1-3


Houston

basic

research

disease

discovery

drug

discovery

drug

development

clinical

trials production packaging

marketing

sales

distribution

Discovery Development Manufacture Distribution

process

development

pre-development screening

cGMP

manufacturing

support for regulatory submissions

cell line construction

cGMP cell banking

scale up

We offer a full range of development

and cGMP manufacturing services

clinical

supply

lab supply

launch

supply

in- market supply

Increasing Molecular Weight (MW)

Chemical

Molecule

Peptide

Antibody

Protein

Complexity by molecular weight

Virus

Cell /

Tissue

Mammalian Biologics:

Client base and operations

From Small Biotech to Large Pharma

US, EU, Japan, Australia

100+ projects on-going in process development and

manufacturing

20+ years of experience in mammalian cell technology

MAbs, Recombinant Proteins

Mammalian Biologics:

Portfolio of Services

Build to buy

Commercial manufacturing

Clinical manufacturing & IND support

Process Development

Cell Line creation Multiple potential points of

entry and exit for clients

Cell Line creation

Supported from UK and now Singapore

Latest GSTM expression systems and cell lines

available

CHO K1, NS0 cell types typically used

Productivity for MAb’s up to 5g/L is typical

In-house cell line and expression system

development will increase productivity in the future

– targeting 10g/L in 14 days

Process can start with just an e-mailed DNA

sequence for the product

Transfection, clone selection and MCB creation in

30 weeks

Process Development

Upstream

Chemically defined cell culture media, animal component

free

Laboratory scale bioreactor development proven to scale

from 200L through to 20,000L

Productivity increased through fed-batch culture and

precisely controlled operating conditions

Downstream

Experience of huge range of chromatography

techniques, matrices and filtration technologies

Scale up experience to 2.0m columns

In-house platform technology development will

increase process productivity in the future

Clinical manufacturing

Experience from 200L through to 5,000L for

early phase clinical supply

UK, US, Spain and Singapore sites

Stirred tank technology, disposable systems,

air-lift

Experience from 200L through to 20,000L

for late phase clinical supply

Appropriate CMC packages supplied to

support submissions


Commercially licensed products are made in

UK, US, ES and once completed, Singapore

Successful inspection history for US FDA, EU

EMEA, Japanese PMDA plus many more

Variety of scales offered – 500L through to

20,000L

CMC support provided for BLA, EMEA

submission

Documentation, process validation packages,

process support

Build to buy

Lonza organises the construction, start up, validation, operation and

licensing of a new facility

Lonza to design facility. Emphasis on leveraging Lonza’s existing processes, equipment, design and operation (both technical and quality) for speed and cost benefit

Customer platform process can be part of design basis

Facility purchase price is fixed

Lonza “profit” based on milestone achievement through to Regulatory Approval

Technology Transfer experience

Between the mid ’90’s and the end of 2010, Slough has had experience of transferring over a hundred and twenty processes into and out of it’s facilities in the UK

In the same period, Portsmouth US has had experience of transferring 35 processes into and out of it’s facilities

Since 2008 Porrino had 6 transfers and Singapore has had one in each plant

Each site has dedicated MSAT (Manufacturing Science and technology) teams in place for these activities

There is a documented and proven TT protocol

Process Transfers to Mammalian Manufacturing - February 2011

0

5

10

15

20

25

1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

UK Forecast UK Complete

US Forecast US Complete

Porriño Forecast Porriño Complete

Singapore Forecast Singapore Complete

Singapore facility construction and start-up

Build to buy


Clinical manufacturing & IND support

Process Development

Cell Line creation

Lonza Singapore operations

Facility 1 – Build to buy for Genentech/Roche

Mammalian cell culture

Manufacturing for commercial operations

only

Facility 2 – Typical Lonza CMO model

Mammalian cell culture

Process Development

Manufacturing for clinical development

Manufacturing for commercial operations

Cell Therapy

Lonza facility 1 - Build to buy model

Large Scale cell culture production facility dedicated for the production of Avastin® for Genentech / Roche

Genentech held an option to purchase the facility

GMP operations in mid 2009 Staff of 300+

Roche exercised purchase option in Aug 2009

Key principles – design and build

Lonza to design facility. Emphasis on leveraging Lonza’s existing processes, equipment, design and operation for speed and costs

Customer platform process can be part of design basis

Facility purchase price is fixed. Customer gets visibility to challenge but Lonza assumes benefit / risk for actual facility cost

Lonza to procure equipment / services, build and directly fund facility

Customer to fund the capital based on agreed milestone achievements e.g. shell completion, mechanical completion successful pilot batch, successful PV series etc

Lonza “profit” based on milestone achievement through to regulatory approval

Specification of equipment and systems per Lonza

standard

Use of previously qualified Lonza vendors for

equipment fabrication, automation and building works

Example – considerable advantage in using Lonza

automation platform (Emerson Delta V) which may

not be customer standard

Customer would have every opportunity to review the

quality and implementation of these in real life model

(Lonza US, Singapore Facility 2)

Facility design and build approach

Lonza believes that customer should have every

opportunity to review facility progress and adherence to

agreed standard

Progressive engineering design reviews at agreed

milestones

Review of selected vendors

Mechanical completion inspections

Regular engineering reviews to give customer

assurance that Lonza is building to agreed

specification

Typically takes place progressively as

construction nears completion

Thorough due diligence at facility purchase

Progress checks / Quality Assurance

Key principle – operational enablement

Lonza recruits and trains employees

Validation, commissioning and facility start-up led by

Lonza using Lonza quality systems

All operating costs and net working capital costs (raw

materials for runs etc) are reimbursed at cost on a

recurring basis

Lonza can provide additional support and services if

required (e.g. tech transfer, pilot, engineering,

PV batches) under supplemental agreements

at agreed rates

Migrate from Lonza quality systems after PAI, if desired

Typical milestone structure

Milestones to be agreed based on Lonza’s ability to

construct, startup and deliver an approved facility

Time based with an agreed window for completion

e.g. FDA approval between June and

December 2018 is 100% achievement,

with sliding scale beyond this date

Milestones to be split into capital and operational

milestones

Key principle – facility purchase

Full commitment to facility purchase required, or

In lieu of purchase, Lonza may consider entering into a

long term take or pay supply agreement

100% capacity of facility for 10 years at an agreed

batch price

Lonza facility 2 – typical CMO model

Cell culture production facility - multi product, campaign based,

contract manufacturing,

Multiple scales of operation – 200L to 20,000L

Multiple technology transfer programs in progress

Currently 249 staff and rising to 300 when at full capacity

Cell Therapy and Process Development

Cell culture facility for Cell Therapy operations on Level 2

Process Development and analytical services operations on Level 1

Construction ongoing – completion for operations in Q1 2012

Cell Therapy staff to 60 when at full capacity, R&D staff to 30+ at full capacity

Space available for further expansion as required

Facility concept

Cell culture production facility essentially copy the Lonza plant in Portsmouth, USA

Commercially successful

High success rate campaigns

Multiple successful global, FDA and EMEA regulatory inspections

Cell therapy production essentially copy the Lonza plant in Walkersville, USA

Both plants leverage existing designs, know-how and documentation into the new facility design

Incorporate all lessons learned from multiple years of GMP operation

Flexible operations at a variety of scales

Re-use proven process technology and quality systems, localize infrastructure

Lonza Biologics Confidential

Large scale cell culture production successfully

completed on time & within budget

Approximately 3 years from “Go” decision point to full GMP operations

2007 2008 2009 2010 2011 2012

Civil Design, Permitting

Construction of Shell

Engineering Design

Order Long Lead Equipment

“GO” Decision

Construction Fit Out

Start Up/Validation

Employee Training Group 1

Employee Training Group 2

Pilot & Engineering Runs

GMP Production

Submission & Inspection

Approval

Singapore operations status

Operational

Process Development

Small Scale non-cGMP Pilot Operations

Large Scale cGMP Manufacturing for Clinical/Commercial Supply

at 5,000 - 20,000L scale

In progress through Q1 2012

Small Scale cGMP Manufacturing for

Clinical/Commercial Supply at 200 - 1,000L scale

Q3 2011

cGMP Cell Therapy Operations Q1 2012

Start-up challenges & strategies:

General

First of its kind plant in Singapore Everything was being done for the first time at this scale

Learning curve was steep for everyone involved – employees,

contractors, agencies

Strategy Site Leadership was an equal mix of Lonza expats & local employees

Entire Lonza Site Leadership Team migrated from Facility 1 to Facility 2

after divestment

Vast majority of staff were local but some key technical positions from

other Lonza sites - Manufacturing, MSAT, Engineering, QC

Short term assignees from the Lonza network bridged any gaps

Lessons learnt – meticulously recorded and followed up between

facilities


Design & engineering

Design & engineering Significant amounts of new / large scale equipment for the region

Multiple locations for engineering and skid construction

Time difference

Strategy Designed to minimize learning curve – the design around process

equipment was kept intact – compared to “design as you go”

Identical naming convention, similar equipment design, flow paths etc

Sequences were successful from the word “Go”

Short Term assignees from other sites were very familiar with the

Singapore setup – ease of commissioning, training

Time difference – was converted to an advantage. US operations

provided support during Singapore nights – Ensured 24 x 7 coverage +

leveraged on experience


Change management

Changes impact schedule & cost Later and more frequent the changes, the more the impact

Strategy Clear definition of Scope and buy-in from all stakeholders

Changes thereafter had to be defended by the Change agent

Changes proposed were critically evaluated for benefit vs. impact

Common focus on deliverables and milestones

Schedule and status was communicated regularly to the entire site

via town hall meetings, C&V updates

Rigorous oversight


Resources

Manpower for operations (Biotechnologist levels) Non-availability of local workforce trained in biologics manufacturing

Knowledge of cGMP for biologics from existing Pharma industry

Fresh graduates with engineering / biochemical backgrounds

Strategy Utilized Singapore EDB’s TAP and STRAT schemes to train local

graduate employees

Multiple waves sent to other Lonza sites (UK, US, Spain) for training

in biologics for up to 18 months – both for Facility 1 & 2

Manufacturing, QA, QC, MSAT and Engineering

Hired back in Singapore once successfully completed the

program(s)

Continued training and personal development


Resources

Supervisory & middle management resources Limited supply of candidates capable of manning supervisory

positions

No previous opportunities to gain experience in biologics

manufacturing

Strategy Rigorous selection process focused on internal candidates

Internal leadership training program established to “facilitate the

jump”

Targeted at Manufacturing initially and expanded to other technical

areas

Intense training schedule + training stints in multiple Lonza

mammalian sites + mentorship


Resources

Manpower for Start-up activities Need personnel familiar with systems to minimize snags /

troubleshoot

Training on equipment operation

Strategy 100+ trained personnel were involved in walking systems down

C & Q protocols were executed mostly in-house.

Progressively increasing familiarity with systems – walk-down,

commissioning, executing protocols etc.

Experienced short term assignees from other Lonza sites to lead

and train – significantly higher in Facility 1 - much lesser in Facility 2

– the core team had progressed much further in terms of

experience and confidence


Systems training

Policies / SOPs / Training / Quality Systems Quality Systems, Policies and SOPs need to be developed and

made effective for training to be completed

Critical to start-up and GMP Commissioning

Strategy Facility 1 and Facility 2 Quality Systems, Policies and SOPs were

harmonized with Lonza US

Most of the process systems were identical

Key advantage of the Facility Concept

Training by short term assignees from Lonza US

Lonza US for critical operations in Facility 1

Expertise of other sites such as Spain and UK utilized for training in

Facility 2 critical operations

Start-up challenges & strategies –

Go clean

Setting up an EM Program - Disinfection Ineffective disinfection cycle or disinfectants could cause delays to

the ability to maintain classification in clean rooms and

consequently HVAC qualification and GMP commissioning

Strategy Disinfection program modeled after Lonza US

Disinfectant efficacy studies were conducted earlier on in Facility 1.

Knowledge gained in Facility 1 was useful in Facility 2

Right choice of disinfectants and cycles – No delays to GMP

Commissioning


Go clean

Cleaning of GMP areas Steep learning curve for GMP cleaners

Literacy needs vs. fit / willingness to work

High turnover of cleaning crew

Strategy Many training sessions + frequent refresher sessions

Handholding of cleaning contractor to set up a sustainable program

Contractor selection + training was initiated 2 months ahead of the first go-clean in Facility 2. GMP Cleaning commenced more than a month before “go-clean”

Float cleaners identified and trained from the general custodial cleaning crew.

Incentive program to promote retention – made to feel valued part of the overall team


Raw materials

Raw material sourcing Challenge to establish Supply Chain, identify and qualify local sources

Vendor qualification, generation of Raw Material Specifications are

typically time critical

Long lead times for basic raw materials

Strategy Supply Chain was established early on with assistance from Lonza US

Material Review Board met weekly to prioritize and review progress

Entire flow of raw materials from BOM creation to release of raw

material were clearly visible to all stakeholders for each item – status

was known and bottlenecks identified quickly

Assistance from other Lonza sites alleviated schedule constraints for

some materials

Overall lessons learnt

Getting Goals and Expectations Clear and Agreed

Making sure everyone is on the same page and each team understands

its role and how it connects to site

Ensuring transparency of the validation program – planning and

execution

Connecting capital project team and the operational team to align

expectations and standards

Maintaining continuity and harmonisation with the rest of the

Lonza network

Quality procedures and site audit follow-ups need to be

monitored carefully

Operational practices can change / be upgraded

Regular site to site updates – all departments

Short term assignees help

Overall lessons learnt

Raw materials

Start procurement early for the operational start-up

Leverage the network to minimise lead times

Leveraging the Lonza network

Successful internal collaboration across the network was critical

for success in all areas

All the various groups within Lonza contributed the overall

success of the projects in Singapore

Conclusion

Lonza is able to support clients

for mammalian biologics using a

number of flexible business

models

Two facilities constructed and

operational in Singapore

Key was / is to leverage the

global manufacturing network

Standardise on as much as

possible / only change what you

must

facility construction and start up for commercial scale

Documents