Facility construction and start up for commercial scale manufacturing of monoclonal antibodies - A case study

Transcription

1 24 th Interphex, Japan, Technical Conference June 29 th, 2011 Michael Brown Facility construction and start up for commercial scale manufacturing of monoclonal antibodies - A case study

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 Microbial Control Agriculture Materials Science Global leader in custom manufacturing Chemical and biological APIs, cell therapy Lead optimization through market supply slide 2

3 slide 3 Lonza Custom Manufacturing 52% Life Sciences Portfolio (over 90%) 8% Exclusive Custom Synthesis Manufacturing & Biopharmaceuticals Custom manufacturing and development services for active ingredients Bioscience Life Science Ingredients Biology-based products for customers in R&D, production and quality control Nutrition Ingredients Life Science Ingredients Life Science Ingredients 40% Nutritional supplements, food ingredients, Microbial cosmetics, disinfectants Control and agrochemicals Exclusive Custom Synthesis Manufacturing & Biopharmaceuticals Custom manufacturing and development services for active ingredients Performance Intermediates Custom Manufacturing Development Services Biological Manufacturing Chemical Manufacturing Bioscience Therapeutic Cell Solutions Testing Solutions Research Solutions Bioscience 8% Biology-based products for customers in R&D, production and quality control Life Science Ingredients Nutritional supplements, food ingredients, cosmetics, disinfectants and agrochemicals

4 slide 4 Our broad offering enables us to meet the diverse needs of our customers Technologies Locations Products & Experience Advanced Chemical Synthesis Peptide Synthesis Microbial Fermentation Microbial Biopharma Mammalian Cell Culture Cell Therapy & Custom Media Visp, Switzerland Nansha, China Braine l Alleud, Belgium Visp, Switzerland Kouřim, Czech Republic Nansha, China Kouřim, Czech Republic Visp, Switzerland Visp, Switzerland Hopkinton, MA (USA) Kouřim, Czech Republic Slough & Cambridge, UK Portsmouth, NH (USA) Porriño, Spain Singapore Walkersville, MD (USA) Verviers, Belgium Singapore Synthetic therapeutic small molecules (GMP/ISO) Highly Potent APIs / Antibody drug conjugates (ADCs) Small molecules (biotransformation) Continuous Flow / MicroReactor technology Synthetic peptides (liquid + solid phase) Recombinant DNA peptides Therapeutic proteins (oral & topical) Metabolites (fermentation) Non-parenteral fermented ingredients Industrial enzymes Therapeutic proteins (injectable & oral) Antibody fragments Vaccines (protein antigen & bacterial vector) Plasmid DNA Monoclonal antibodies Therapeutic proteins 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

5 slide 5 Our biologics facilities, products and services are global and leading-edge Houston Hopkinton, MA (USA) Microbial Biopharma 40L to 2,800L cgmp Process R&D Services Walkersville Houston, TX (USA) Viral-based Therapeutics Phase 1-3 Process R&D Services Portsmouth, NH (USA) Mammalian Cell Culture 1,500L to 20,000L cgmp Portsmouth Hopkinton Verviers, BE Slough, UK Porriño, SP Walkersville, MD (USA) Cell Therapy Autologous & Allogeneic Cell Bioassays & Reagents Process R&D Services Media Custom Media & Buffers Bioprocess Containers Slough (UK) Mammalian Cell Culture 200L to 2,000L cgmp Process R&D Services Applied Protein Services Porriño (Spain) Mammalian Cell Culture 4 x 10,000L cgmp Kouřim, CZ Visp, CH Visp (Switzerland) Microbial Biopharma 20L to 15,000L cgmp Process R&D services Microbial Fermentation Process R&D Services Verviers (Belgium) Cell Therapy Autologous & Allogeneic Cell Bioassays, Reagents Process R&D Services Media Custom Media & Buffers Bioprocess Containers Kouřim (Czech Republic) Microbial Fermentation 75L to 75,000L cgmp Process R&D Services Singapore 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

6 slide 6 We offer a full range of development and cgmp manufacturing services Discovery Development Manufacture Distribution basic research disease discovery drug discovery drug development clinical trials production packaging marketing sales distribution pre-development screening cell line construction cgmp cell banking lab supply clinical supply process development scale up launch supply in- market supply cgmp manufacturing support for regulatory submissions

7 slide 7 Complexity by molecular weight Chemical Molecule Peptide Protein Antibody Virus Cell / Tissue Increasing Molecular Weight (MW)

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 8

9 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

10 Cell Line creation Supported from UK and now Singapore Latest GS TM 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 ed DNA sequence for the product Transfection, clone selection and MCB creation in 30 weeks slide 10

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 11

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 12

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 13

14 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

15 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 Process Transfers to Mammalian Manufacturing - February 2011 Each site has dedicated MSAT (Manufacturing Science and technology) teams in place for these activities UK Forecast US Forecast Porriño Forecast Singapore Forecast UK Complete US Complete Porriño Complete Singapore Complete 10 There is a documented and proven TT protocol

16 slide 16 Singapore facility construction and start-up Build to buy Commercial manufacturing Clinical manufacturing & IND support Process Development Cell Line creation

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 17

18 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

19 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

20 Facility design and build approach 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) slide 20

21 Progress checks / Quality Assurance 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 slide 21

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 22

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 23

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 24

25 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

26 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 Q Cell Therapy staff to 60 when at full capacity, R&D staff to 30+ at full capacity Space available for further expansion as required

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 27

28 slide 29 Large scale cell culture production successfully completed on time & within budget 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 Approximately 3 years from Go decision point to full GMP operations

29 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 Q Small Scale cgmp Manufacturing for Clinical/Commercial Supply at 200-1,000L scale Q cgmp Cell Therapy Operations Q slide 30

30 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 31

31 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 32

32 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 33

33 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 34

34 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 35

35 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 36

36 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 37

37 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 38

38 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

39 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 40

40 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 41

41 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 42

42 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 slide 43