Technology update: SmartFactory solutions for continuous processing. Barbara A. Paldus June 12, 2017

Transcription

1 Technology update: SmartFactory solutions for continuous processing Barbara A. Paldus June 12, 2017

2 What is Perfusion? Definition: Continuously adding nutrient solutions to a bioreactor while removing waste or product from it. The cell culture media is passed through a separation device and the cells are returned to the bioreactor and the cell free media is removed. This removed media is either waste (in some processes) or contains the product. There are several types of separation devices/systems: - Acoustic Separator - Centrifugal Separator - Cell Cube Separator - Hollow Fiber Cell Separator

3 Cell Retention Methods Sample Sample Tangential flow filtration For any bioreactor SU Filter Flexible, many different sizes and porosity Alternating tangential filtration For any bioreactor Not single-use Improves flux over filter membrane SU Bioreactor Floating filter filtration For rocking bioreactor formats Single-use format Quick and easy setup Limited scale

4 Acoustic Separator System Acoustic Separator (BioSep) uses high frequency sound waves which cause the cells to be suspended inside the sound chamber. Periodically the sound wave is turned off and the cells either fall back into the vessel or are flushed back. The BioSep controller can be electrically connected to the Finesse system by a dry contact relay to coordinate the turning off of the sound and the reversing of the Harvest pump. Vessel size range: 1L to 200L Finesse Examples: 15L Glass for Insight Israel. Integration requires custom software

5 Centrifuge Separator System Cell culture is removed from the bioreactor via separation pump and delivered to centrifuge inlet; pinch valves are closed. Centrifuge ( Centritech Lab III) concentrates the cells over a set time period. Upon completion, the separation pump is turned off, and the pinch valves adjusted so that the concentrated cells are returned to the bioreactor. Pump adds new media based on the system weight when needed

6 Centrifuge Separator System Integrated native DeltaV custom control tower Centritech centrifuge with custom control of pinch valves Integration with SUB/glass bioreactors with custom Finesse code used Vessel size range: Labscale to 1000L SUB Finesse Examples: Shire, Lexington Finesse RDPD with centrifuge

7 CellCube System CellCube (Corning) has a modular cube that contains a series of parallel plates that are joined to create thin laminar flow spaces. Each culture plate has been treated to ensure dense, uniform cell growth. Media is circulated via the oxygenator back into the CellCube. Media is harvested from the oxygenator also. Vessel size range: Labscale Finesse Examples: Merck USA, Boehringher-Ingelheim VetMedica

8 Cell Cube System Single-use centrifuge scalable to 1000L single-use bioreactor Separation mechanism: cell cube vs oxygenator 1. Cells adhere to cell cube walls; cell cube surface area is scalable Oxygenator provides measurement and control of process parameters Recirculation Pump continuously flushes cells with new media

9 Cell Cube System -Example Seeded 100-layer CellCube module 384.9x10 6 cells total 11 L of 4.32x10 5 cells/ml cell suspension harvested 4.75x10 9 cells total collected Average viability of 95.8%

10 Hollow Fiber Cell Separator (ATF) System ATF Alternating Tangential Flow (Refine Tech/Repligen) has a plastic diaphragm that is inflated / deflated acting as a pump to move the cell culture back and forth through a Hollow Fiber Cell Filter. Cells are retained by the filter and return back into the vessel. Media passes through the filter and to the collection vessel. The ATF controller is not part of Finesse control system. Pumps & Pressure monitoring are controlled by Finesse. Vessel size range: 1L to 2000L Finesse Examples: LG, Crucell, Transgene, Boehringer-Ingelheim, Wuxi-Apptec, etc.

11 Hollow Fiber Cell Separator Tangential Flow (Spectrum Labs) uses a disposable magnetic levitating pump to move the cell culture through a Hollow Fiber Cell Filter. Cells are retained by the filter and circulate back into the vessel. Media passes through the filter and to the collection vessel. The Spectrum Labs controller can be integrated to the Finesse control system. Vessel size range: 1L to 2000L Finesse Examples: Use Spectrum Labs TFF Filter with Finesse controller not using Spectrum Labs controller.

12 Fixed Feed Rate Control Control can be based on a Fixed Feed rate into the vessel Feed SIC-1 SIC-3 Bleed Waste Harvest SIC-2 Media FIC Bioreactor WIC Waste or Product ATF ATF Controller

13 Fixed Harvest Rate Control Control can be based on a Fixed Harvest rate from the vessel Feed SIC-1 SIC-3 Bleed Waste Waste or Product WIC Harvest SIC-2 Media Bioreactor FIC ATF ATF Controller

14 Summary of Perfusion at Finesse Finesse is a market leader in perfusion automation and is driving fully integrated upstream-downstream skids Traditional - ATF Centrifuge Custom

15 SmartCart: Universal Filtration STANDARD CONFIG. 2x shelves 6x filter brackets 3x Pendotech pressure xmit 2x Redlion Freq. xmit for flow 3 channel pressure 2 channel flow 1x Temperature (omega Tx) 2x mixer connections via Remote VAB panels 1x VFI 1x Load cell interface 6x pneumatic pinch-type valves EXTENDED CONFIG. 2x shelves 6x filter brackets 3x Pendotech pressure xmit 2x Redlion Freq. xmit for flow 3 channel pressure 2 channel flow 1x Temperature (omega Tx) 2x mixer connections via Remote VAB panels 1x VFI 1x Load cell interface 6x pneumatic pinch-type valves 4x Aux Loops (0-10 VDC) for external pumps 4x Aux Loops (0-10 VDC) for external pumps 2x 4-20mA AI's 2x 4-20mA AI's 2x VAC Recepticles (non-estop) 2x VAC Recepticles (non-estop) 2x VAC Recepticles (STOP) 2x VAC Recepticles (STOP) Pumps 2x WM520 pumps for ph control 1 x ph/conductivity 1x rosemount 1056 analyzer ph/cond OPTIONS quattroflow 1200 pump Max qty = 4 Max pressure = 4 bar Watson Marlow 720 Pump Max qty = 4 Max pressure = 2 bar VAB panels Max qty = 2 Pressure Transmitters For single use sensors Max qty = 4 (for system total of 7) Local HMI TruViu Control Panel (1 required per area) OPTIONS quattroflow 1200 pump Max qty = 4 Max pressure = 4 bar Watson Marlow 720 Pump Max qty = 4 Max pressure = 2 bar VAB panels Max qty = 2 Pressure Transmitters For single use sensors Max qty = 4 (for system total of 7) Local HMI TruViu Control Panel (1 required per area)

16 The Aim of Modular Automation Modular approach to production gaining popularity in the Process Industry Improving Efficiency more capable, intuitive skids Increasing Flexibility build-as-you-go and plug-and-play modules Reducing Time to Market COTS solutions with greatly reduced validation cost Synergies between Modular Automation and Single Use Technologies Modular Production will help to master the challenges of the Process Industry

17 Traditional to Modular Automation Modular design = new approach Merging PLC & DCS paradigms: * Local control of skids (PLC) * Internet-based flexibility (DCS) HMI < 2010 Today Controller MES Batch I/O I/O I/O > 2020 Controller I/O HMI Internet of Things Batch / MES SMART1.0 Module A SMART1.0 Module B HMI Batch/MES SMART2.0 Module A SMART2.0 Module B SMART2.0 Module C

18 PLC/SCADA vs DCS PLC Smaller Applications Discrete Control Sequencing Logic Inexpensive Local unit control DCS Larger Applications Batch Recipes Continuous Control Expensive Plant wide control DCS has additional benefits of: Controller-based alarming Natural redundancy Dedicated consoles and direct communications

19 Extra Source Code Change Control NO Extra Source Code PLC PLC/SCADA vs DeltaV DeltaV Historian Historian Change Control Mapping Interface Batch Management Mapping Interface Alarming Mapping Interface Operator Interface Batch Management Alarming Operator Interface Mapping Interface Basic control Logic Basic control Logic Changes require source code engineering and validation External Change Control Multiple Suppliers Complex Documentation No Source Code Engineering No Source Code Validation Integrated Change Control Approved and Audited Supplier Simple Documentation

20 Change Control NO Extra Source Code Change Control NO Extra Source Code Traditional DeltaV vs SmartDCS Traditional DeltaV SmartDCS Historian Historian Batch Management Batch Management Alarming Alarming Operator Interface Operator Interface Basic control Logic Basic control Logic SmartParts: Faster control loops Auto-recognition Higher precision Custom engineering and validation effort Expensive licensing Peripheral integration and scale-up challenging Configure-to-order products and modular validation Efficient use of licensing Plug-and-play peripherals Based on DeltaV (benefits)

21 Financial Benefit of SmartDCS Highly Flexible Systems SmartParts enable rapid configure-to-order delivery of equipment (later decision with lower risk) SmartParts are cost-effective components applicable to both upstream and downstream skid implementation Affordable Factory Automation Finesse architecture minimizes licensing cost: Bioreactor and filtration skid licensing is small compared to an equivalent stainless steel vessel/skid (>500 DST) Chromatography is more cost-effective with a 5X reduction in licensing SmartParts can be daisy chained to further minimize licensing points Total SmartFactory Automation Cost: $1-$3M DeltaV HW + licensing = US$ 1.1M SmartFactory MESLite system: US$ M Upstream DST AO AI DO/DI Batch Mixer Optional Bioreactor Optional Not including digital weigh or feeding scales (3DST = 2 AO + 1 AI) Filtration DST AO AI DI/DO Batch Harvest Optional VF Yes UF/DF Yes Final licensing will depend on system complexity typical shown Chrom DST AO AI DI/DO Batch GE DeltaV Prot A IEX Finesse /200 90/200 31/16 Yes Yes Yes Licensing depends on system complexity typical shown SmartSystems minimize DeltaV licensing costs

22 Technology and Product Overview SmartParts Intelligent components for modular bioprocess measurement and control SmartSystems Combines universal hardware with flexible software to enable all scales of upstream and downstream processes SmartMES / SmartFactory Turn-key single use facility integrating unit operations into a seamless network that optimizes resource utilization and generates electronic batch reports Sensors Upstream Controllers Manufacturing Execution System 1 Actuators Downstream Controllers SmartFactory Bioreactors Software Modular systems, featuring plug-and-play integration, ease of use Fully integrated components reduce costs and enable higher performance Configure-to-order allows shorter lead times Allows upstream and downstream processes to be combined with universal controls and flexible software Universal controllers enable customer flexibility across a variety of production platforms and suppliers Alvotech SmartFactory Inoculation to drug substance automation of the entire process Complete solution including data collection, validation and commissioning Quality lot release by exception 1) A manufacturing execution system (MES) is a computerized system for managing and monitoring work-in-process on a factory floor

23 BPD Workflow Upstream Downstream Cell line development and media optimization Mixing, cell culture and fermentation Harvest and collection Purification Bulk storage and final fill Freedom CHO cell lines Process development and media optimization services Gibco cell culture media, feeds, and enhancers Single-use fermentors, bioreactors and mixers POROS harvest and separation products QC and analysis Storage and transport POROS chromatography resins CaptureSelect affinity ligands and resins Storage and transport BPCs, manifolds and containers Shaker flasks and rigid containment BioProcess containers Mycoplasma and viral detection Transfer assemblies Acclimate single-use frozen handling system Production chemicals Sensors insite Integrity Testing System Cell factories GMP warehousing, sampling and lot control Host cell DNA, protein and protein A quantitation Large volume liquids Pump Tower Skids Sensors Software Lab-scale Bioreactors Lab-scale Controllers Software (TruBio) Large volume liquids Sensors Controllers US Controllers/Skids Software (TruPur) DS Controllers/Skids Software (TruChrom) Software (TruBio) SmartFactory Legend Grey text: Legacy BPD capabilities Red text: Finesse expanded capabilities

24 From SmartParts to SmartFactories SmartMES Flexible, powerful MES Vision: Facility harmonization SmartSystems Universal or SmartSwitch Controllers SmartParts Intelligent Components

25 SmartFactory: Future Generations Now SmartFactory SmartFactory II MyCellFactory Current Processes; improved automation Traditional batch and fed-batch with predominantly single-use equipment Automation enables significant reduction in the operator skill set, not an increase SmartFactory I will Automate major phases of process Make equipment easier to use Cost reduce a full factory < $20M MAb drugs including chemotherapy Orphan Drugs and BRIC markets Evolution to Continuous Processing Perfusion (Smartvessel, SmartFiltration, continuous chromatography, etc) Automation enables unskilled operators to operate a complex process SmartFactory II will Minimize volumes required Further reduce personnel required Cost reduce a full factory < $15M MAb drugs including chemotherapy Combining diagnostics with treatments to optimize therapy MyCellFactory: individualized treatments & production Personalized drugs based on genetics Stem Cell therapies (e.g. baldness, diabetes, cancer, organs) Will require stations, not factories for production of cures Full factory cost: <$1M TARGET: Medical device 510K classification for deployment in hospitals/clinics 16

26 Paradigm Change: Continuous Processing Current biopharma business models can be improved using continuous processing (CP) Paradigm is shifting from titer to process optimization and analytics (manage complexity) SMART technologies exist today which can increase flexibility, decrease cost, and improve production Process intensification has been proven successful; SmartSystems will enable ease of use and wider deployment Modular Automation (4.0) will further enhance CP