Post on 03-Feb-2018
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
slide 2
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
slide 3
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 Science Ingredients
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
Life Science Ingredients
Bioscience
Life Science Ingredients
Life Sciences
Portfolio
(over 90%)
40%
52%
8%
Custom Manufacturing
slide 4
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
slide 5
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
Process R&D Services
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
Process R&D Services
Cell Therapy Autologous & Allogeneic Cell
Bioassays & Reagents
Process R&D Services
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
Process R&D Services
Media Custom Media & Buffers
Bioprocess Containers
Verviers, BE
Slough (UK) Mammalian Cell Culture 200L to 2,000L cGMP
Process R&D Services
Applied Protein Services
Kouřim, CZ
Kouřim (Czech Republic) Microbial Fermentation 75L to 75,000L cGMP
Process R&D Services
Houston, TX (USA) Viral-based Therapeutics Phase 1-3
Process R&D Services
Houston
slide 6
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
slide 7
Increasing Molecular Weight (MW)
Chemical
Molecule
Peptide
Antibody
Protein
Complexity by molecular weight
Virus
Cell /
Tissue
slide 8
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
slide 9
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
slide 10
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
slide 11
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
slide 12
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
slide 13
Commercial manufacturing
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
slide 14
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
slide 15
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
slide 16
Singapore facility construction and start-up
Build to buy
Commercial manufacturing
Clinical manufacturing & IND support
Process Development
Cell Line creation
slide 17
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
slide 18
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
slide 19
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
slide 20
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
slide 21
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
slide 22
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
slide 23
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
slide 24
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
slide 25
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
slide 26
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
slide 27
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
slide 29
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
slide 30
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
slide 31
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
slide 32
Start-up challenges & strategies:
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
slide 33
Start-up challenges & strategies:
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
slide 34
Start-up challenges & strategies:
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
slide 35
Start-up challenges & strategies:
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
slide 36
Start-up challenges & strategies:
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
slide 37
Start-up challenges & strategies:
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
slide 38
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
slide 39
Start-up challenges & strategies:
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
slide 40
Start-up challenges & strategies:
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
slide 41
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
slide 42
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
slide 43
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