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IVT Presentation Batch vs Continuous - 45min_REV3

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IVT Presentation Batch vs Continuous - 45min_REV3

  1. 1. BATCH vs CONTINUOUS PROCESSING CAN CONTINUOUS PROCESSING WORK FOR YOUR GMP FACILITY/PROCESS OPERATION? Eric Sipe, Senior Process Engineer Tim J. Hancock, Ph.D, Senior Process Engineer
  2. 2. Batch processing has dominated the Pharmaceutical industry due to available technologies, risk aversion and expectations of regulatory hurdles. However continuous processing can often be more efficient and lucrative and is an acceptable processing method per the FDA and EU Regulatory Authorities. Emerging technology has opened up a lot of options in this area to make continuous more feasible in drug manufacturing. Process methodologies, implementation, current and emerging technologies, and expectations will be discussed. Overview
  3. 3. From: Perry’s Chemical Engineerings’ Handbook Perry’s 23-4 CHEMICAL REACTORS - MODELING CHEMICAL REACTORS “The general characteristics of the main types of reactors—batch and continuous—are clear. Batch processes are suited to small production rates, to long reaction times, or to reactions where they may have superior selectivity, as in some polymerizations. They are conducted in tanks with stirring of the contents by internal impellers, gas bubbles, or pumparound. Temperature control is with internal surfaces or jackets, reflux condensers, or pumparound through an exchanger.” Why Use Batch?
  4. 4.  Batch processing is used for smaller quantity higher value products – APIs, perfumes, specialty chocolates  Continuous processing is used for high throughput lower margin products – gasoline, milk, Chef Boyardee BATCH vs CONTINUOUS PROCESSING PARADIGMS  However a new paradigm is being realized: There is no reason that continuous processing can not be used to produce a small or large amount of product efficiently whether low margin or high value
  5. 5. WHO WILL BE THE FIRST ONE TO CORNER THE MARKET USING CONTINUOUS? BATCH CONTINUOUS Gold Panning Sluice
  6. 6. Process Methodology Definitions  Batch Processing - raw materials progress through a unit operation/unit operations in a step wise fashion to produce an end product
  7. 7. Process Methodology Definitions  Semi-batch Processing – batchwise process with aspects of continuous processing (introduction or removal of material; i.e. solvent strip from a batch reactor)
  8. 8. Process Methodology Definitions  Continuous Processing – raw materials progress through a unit operation/unit operations in a contiguous manner to produce an end product
  9. 9. INDUSTRY EXAMPLES Non-GMP: • Formulation of plastic mixtures • Sedimentation of solids in waste water treatment plant • Electroplating of parts • Manufacture of sodium aluminate Pharma: • Centrifugation of API chemical entity • Crystallization of API chemical entity • Extraction of product from reaction mixture • Milling of a lot of material • Isolation of a biopharm product via adsorption column • Tablet coating • Autoclaving of stoppers • Washing of filler change parts Non-GMP: • Fed-batch solvent recovery from a contaminated solvent waste stream • Hydrogenation reactions • Metered quenching reactions Pharma: • Fed-batch cell culture/fermentation • Diafiltration • Solvent exchange • Exothermic reaction of API material Non-GMP: • Refining of crude oil • Manufacture of granular aluminum sulfate • Manufacture of bleach in pipeline reactor • Manufacture of water treatment polymers • Stripping of solvents from aqueous waste stream Pharma: • Production of WFI/Clean Steam • Vial Filling Operations • Biowaste Inactivation Operations • Perfusion Fermentation BATCH SEMI-BATCH CONTINUOUS
  10. 10. The Biopharmacuetical industry typically has relied on Product Discovery and Product Innovation for entering and sustaining product market for profitability This has always been followed by a continued reliance on existing batch technology that provided a risk averse, safe and reliable process. Process Innovation has not been a significant feature in biopharmaceutical development and manufacturing Many new product processes have and are being fit into existing facilities and their available batch equipment leading to processing inefficiencies and increased costs, especially as product titers improve. Biopharmaceutical Product Processes Historically
  11. 11. “However, today significant opportunities exist for improving pharmaceutical development, manufacturing, and quality assurance through innovation in product and process development, process analysis, and process control……. ….One reason often cited [for lack of change] is regulatory uncertainty……. ….. Efficient pharmaceutical manufacturing is a critical part of an effective U.S. health care system……. …..Therefore pharmaceutical manufacturing will need to employ innovation, cutting edge scientific and engineering knowledge, along with the best principles of quality management to respond to the challenges of new discoveries (e.g., novel drugs and nanotechnology) and ways of doing business…” Implementing Continuous vs. Batch Manufacture Guidance for Industry PAT - A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance ; U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Veterinary Medicine (CVM) Office of Regulatory Affairs (ORA) Pharmaceutical CGMPs September 2004
  12. 12.  Multi-step synthesis processes with additional unit operations to isolate desired chemical entity  A + B C + D E  Laboratory development of chemical entities has historically been done via discrete batch operation.  Historically continuous flow options were not available for chemical synthesis operations SOME REASONS FOR BATCH PROCESSING OF SMALL MOLECULE PHARMA PRODUCTS
  13. 13.  Historically continuous flow options were not commercially available for both upstream and downstream processes  Bind and Elute Chromatography is a batch process  TFF has been developed as a batch operation  Laboratory development of biologics has historically been done via discrete batch operation. SOME REASONS FOR BATCH PROCESSING OF BIOLOGICS PRODUCTS
  14. 14. Process and Business Driving Forces for Going Continuous Smaller equipment Smaller facility Better facility/equipment utilization Easier/more robust scale-up Better control and product quality Continuous product quality assurance Improved yield Reduced waste Reduced in process materials such as buffers
  15. 15. Decrease development risks, costs and time to market  When introducing new products scale-up may be eliminated  Continuous development is significantly faster  Much smaller amounts of material are needed. Manufacturability  Batch production of complex, less‐stable proteins is often impossible  Continuous manufacturing can eliminate a fixed batch size, allowing one to make as little or as much as needed.  Continuous manufacturing product lead times are typically significantly less than for batch which can substantially reduce inventory carrying costs.  Improved safety Process and Business Driving Forces for Going Continuous
  16. 16.  Unit Operation Cycle Times  Reaction Kinetics  Drying Rates  Separability of Constituents  Ease of aqueous/organic layer seperation  Robustness of Intermediate and Product  Effect of Temperature  Effect of agitation Some Physiochemical Factors that Influence Change from Batch to Continuous: Small Molecule
  17. 17.  Cell Culture  Cell stability and robustness,  Excretion of product from cell (cell culture vs fermentation)  Production/removal of toxins during cell growth  Product stability  Ability to grow at a steady state  Cell cycles  Chromatography  Bind and Elute (IEX and affinity chromatography) is inherently a batch process  Robustness of Intermediate and Product  Effect of temperature, pH and agitation Some Physiochemical Factors that Influence Change from Batch to Continuous: Biologics
  18. 18. DISTILLATION BATCH VS CONTINUOUS HOW ACCOMPLISHED BATCH HOW MONITORED BATCH HOW ACCOMPLISHED CONTINUOUS HOW MONITORED CONTINUOUS AGITATED AND JACKETED VESSEL WITH CONDENSER TEMPERATURE, PRESSURE, REFRACTIVE INDEX DISTILLATION COLUMN TEMPERATURE, PRESSURE, REFRACTIVE INDEX
  19. 19. REACTIONS BATCH VS CONTINUOUS HOW ACCOMPLISHED BATCH HOW MONITORED BATCH HOW ACCOMPLISHED CONTINUOUS HOW MONITORED CONTINUOUS METERED ADDITION OF REACTANT TO REACTION VESSEL TEMPERATURE, pH, TIME PIPELINE REACTOR, CSTRs IN SERIES, PLATE REACTORS TEMPERATURE, PRESSURE, pH, REFRACTIVE INDEX, FLOW
  20. 20. Process Methodologies Batch and Continuous Cell Culture  Batch  Add materials at the beginning, production yield is nominally 1x  Fed-Batch (Semi-Batch)  Media addition to increase production yield up to 2x to 3x.  Continuous  Perfusion culture to increase production yield up to 10x. BATCH FERMENTATION Concentrated Feed FED BATCH Feed Spent Medium & Product Cell Retention Device CONTINUOUS (PERFUSION) CULTURE
  21. 21. Overview of Perfusion Culture  Continuous addition of fresh media (nutrient feed)  Continuous removal of waste products (harvest)  Animal cells retained at high concentration  Separation by Size Exclusion (TFF, ATF, spin- filtration)  Separation by Particle Mass (sedimentation, hydrocyclones, centrifugation, acoustic resonance)  Types of Perfusion  Heterogeneous perfusion (microcarriers)  Homogeneous perfusion (Cells in suspension)
  22. 22.  Single-pass TFF eliminate the recirculation loop.  It allows continuous operation at high conversion.  The retentate exits the retentate port and does not return to a hold tank. Concentrated product or waste either exits at the retentate or permeate ports. Current and Emerging Technologies Harvest Single Pass TFF Retentate BatchTFF
  23. 23.  TFF  Centrifugation  Chromatography  Viral reduction  Crystallization  Precipitation  Membrane adsorption  Others BATCH VS CONTINUOUS PROCESSING Downstream Processing
  24. 24.  PAT promotes continuous monitoring of processes  PAT promotes better process understanding  PAT fosters parametric release (continuous assurance that a process is working correctly and the product is of the right quality) throughout the process PAT & CONTINUOUS PROCESSING
  25. 25.  Process Analytical Technology (PAT) – “a system for the design, analysis and monitoring of pharmaceutical manufacturing by means of real time measurements of critical quality and performance attributes …..with the aim of ensuring the quality of the finished product. “ from GMP-News, September 8, 2003  Parametric Release (Real Time Release) –a quality assurance release program where demonstrated control of the process enables a firm to use defined critical process controls, in lieu of final quality control testing, to fulfill the intent of 21 CFR 211.165(a), and 211.167(a).5 Process Analytical Technology (PAT)
  26. 26. In-line On-line At Line Offline PAT APPLICATIONS
  27. 27.  Focused Beam Reflectance Measurement (FBRM)  Infrared Technologies  Raman Spectroscopy  UV-visible  Particle Imaging  Acoustics  Fluorescence SOME PAT TECHNOLOGIES Beyond Traditional In-line Measurements
  28. 28. PAT TECHNOLOGY Examples of where Technology can be used Focused Beam Reflectance Measurement (FBRM) Crystallization, Wet Granulation, Compounding Near Infrared (NIR) Spectroscopy Dispensing, Reaction Monitoring, API Drying Raman Spectroscopy Crystallization, Compounding, Blending, Freeze Drying Mid-IR Fermentation, Crystallization UV visible Reaction monitoring Particle imaging Wet Granulation Acoustics Wet Granulation Fluorescence Hot Melt Extrusion APPLICATIONS FOR PAT TECHNOLOGIES
  29. 29. SOME RESOURCES FOR PAT TECHNOLOGIES  Nalas Engineering Services (In-house services)  Mettler- Toledo  Applied Instrument Technologies  Endress & Hauser
  30. 30. RAPID MICROBIAL TESTING AND CONTINUOUS PROCESSING Leads to expedited bioburden detection Leads to expedited sterility assurance Leads to quicker release of raw materials, in-process materials and final product
  31. 31.  ATP BIOLUMINESCENCE - based on ATP (component of all microbes) measurement  CYTOMETRY – fluorescent cell labeling and laser scanning  POLYMERASE CHAIN REACTION (PCR) – microbiology based microbe detection method based on amplification of specific sections of microbial nucleic acids RAPID MICROBIAL TESTING TECHNOLOGIES
  32. 32.  PALL – ATP BIOLUMINESCENCE (PALLCHECK)  PALL – POLYMERISE CHAIN REACTION (GENE DISC)  RAPID MICRO BIOSYSTEMS - ATP BIOLUMINESCENCE (GROWTH DIRECT)  MILLIPORE - ATP BIOLUMINESCENCE (MILLIFLEX)  AES CHEMUNEX – CYTOMETRY (SCAN RDI)  CELSIS - ATP BIOLUMINESCENCE (RAPISCREEN) RAPID MICROBIAL TESTING VENDORS
  33. 33.  Islands of Continuous Processing – segments of a manufacturing process where continuous processing can be executed; needed on way to completely continuous manufacturing processes.  Process Intensification “Process intensification consists of the development of novel apparatuses and techniques that, compared to those commonly used today, are expected to bring dramatic improvements in manufacturing and processing, substantially decreasing equipment-size/production-capacity ratio, energy consumption, or waste production, and ultimately resulting in cheaper, sustainable technologies. Or, to put this in a shorter form: any chemical engineering development that leads to a substantially smaller, cleaner, and more energy efficient technology is process intensification!” - Chemical Engineering Progress January 2000 PATHS FORWARD
  34. 34. No FDA or EU regulations prohibit continuous processing in small molecule or biologic pharmaceuticals manufacturing However, methods for meeting all regulatory requirements for continuous processing are still evolving Current Regulatory Environment
  35. 35.  FDA encouraging continuous manufacturing (presentations C. Moore, 2011, and S. Chatterjee, 2012) – why?  Regulatory interests moving to a “Quality by Design” (QbD) model, with scientifically-based process design and proactive risk assessment (ICH Q8-11). Current Regulatory Environment
  36. 36.  FDA has recently redefined how process validation is performed – instead of 3-lots-and-done, now the process is qualified and all lots must be demonstrably in control (Continuous Process Verification, CPV: ICH Q10; Guidance for Industry Process Validation: General Principles and Practices, FDA January 2011 Revision 1).  Continuous processing with PAT and RTRT allows for real-time data collection throughout the process, with statistical process control on monitored variables.  Process is demonstrated to be IN CONTROL at all times. Current Regulatory Environment
  37. 37.  FDA 21 CFR 210.3  Batch - a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture  Lot - a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within specified limits. Must produce a batch but what is a batch? When not processing batchwise?
  38. 38.  ICH Q7  A batch or lot is defined as a specific quantity of material produced in a process or series of processes so that it is expected to be homogeneous within specified limits. In the case of continuous production, a batch may correspond to a defined fraction of the production. The batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval. Must produce a batch but what is a batch? When not processing batchwise?
  39. 39.  So... as long as it is uniform, can define batch based on:  Production time period (ICH, FDA)  Quantity manufactured (ICH, FDA)  Production variation (input lots, etc.) (FDA)  Dependent on equipment cycling capability (FDA)  Other (FDA) Must produce a batch but what is a batch? When not processing batchwise?
  40. 40.  To facilitate a laboratory determination of product compliance with specifications for release  To facilitate assembly of a documentation package for manufacturing operations  To define the boundaries for extended investigations of unexplained discrepancies  To define the extent of material in question in a recall situation Why Does Defining a Batch Matter? From C. Moore, FDA, 13SEP2011 Safety - Identity - Strength - Quality - Purity
  41. 41. Validation master plan required prior to implementation Risk assessment required Initial process qualification and validation Continuous/ongoing process verification required Regulatory Approach to Continuous Processing
  42. 42.  Risk Assessment Topics – Different from Traditional Batch Definition of a batch What is a valid residency time distribution What are the CPPs and CQAs Quality of the product during non-steady state situations such as startup and shutdown What needs to be done to return from Atypical processing situations i.e. planned or unplanned process outages Regulatory Approach to Continuous Processing
  43. 43.  Risk Assessment Topics – Different from Traditional Batch Component lifespans - Equipment, resin and membranes What monitoring is needed for continuous process verification What type of Release Testing is sufficient in addition to continuous monitoring  Offline and online testing  Offline in process sampling  Batch/lot testing  Parametric release / Real Time Release Testing (RTRT) Regulatory Approach to Continuous Processing
  44. 44.  Control Strategy should be defined prior to manufacturing and demonstrated in process qualification  Control Strategy should include:  Traceability of input lots (based on flow, Residency Time Distribution)  Acceptable steady state turn down ratios  Ability to run at different rates over run time  Duration of time the continuous process can run without required stoppage  Raw material and batch stability over run time (Define space definition) Control Strategy and Process Qualification & Validation
  45. 45.  Control Strategy Should include (continued):  Provisions for microbial monitoring and control  Is material growth-inhibiting, growth-neutral or growth-promoting?  How can bioburden be controlled, and if a contamination occurs, how can it be detected?  Sampling & monitoring plan in addition to continuous monitoring  Intermediates and final product  Instrument delay and testing time vs. Residency Time Distribution  Strategy for how and when to clean process system and how the cleaning operations will be validated  Strategy for documentation of batch and batch package assembly: MES? Control Strategy and Process Qualification and Validation
  46. 46.  Chromatography single-use columns  Disposable TFF cassettes for SPTFF  Perfusion bioreactors at 2000L and less easily utilize existing single use bag based bioreactors  Better utilization of high cost single use Single Use and Continuous Processing
  47. 47.  SPTFF (Single Pass TFF)  Cadence SPTFF PALL Corporation  Pellicon SPTFF EMD Millipore Current and Emerging Technologies Harvest  ATF (Alternating Tangential Flow Filtration)  Refine Technology
  48. 48.  Novasep – Sequential Multi-Column Chromatography (SMCC)  Prochrom® Varicol technology  GE Healthcare – 3-Column Periodic Counter Current (3C-PCC)  Tarpon Biosystems – Bio SMB (Simulated Moving Bed) Current and Emerging Technologies Chromatography Product Load Equilibration buffer Wash Buffer Elution Buffer Regeneration buffer Continuous Product Capture Waste
  49. 49.  Spinning disc reactor  Microreactors, modular flow reactors, inline mixers  Flow reaction testing equipment/reactor development  Lab-to-manufacturing scale continuous process intensification services  Agitated cell reactor Current and Emerging Technologies for Continuous Synthesis of Small Molecule Organic Compounds
  50. 50. SPINID Chemtrix Uniqsis Access 2 Flow Proteaf Micronit Microfluidics Coflore Corning Fluitec Lonza Resources For Current and Emerging Technologies - Continuous Synthesis of Small Molecule Organic Compounds
  51. 51. ATF Case Study Manufacturer 2 Manufacturer 3 Manufacturer 4 Idea Innovator Startup Manufacturer Process Development Vendor Manufacturer PRODUCTION Engineering Firm(s) Other Vendors
  52. 52.  Dave Marks, DME Alliance Engineering Consultants  Abby Johnson, DME Alliance Engineering Consultants  Robert Snow, CPIP- Sanofi Biologics Development  ANY QUESTIONS? ACKOWLEDGEMENTS
  53. 53. http://www.dmealliance.com/ DME Alliance, Inc. Engineering Consultants 7540 Windsor Drive, Suite 311 Allentown, PA 18195 Phone: 610-366-1744 Eric Sipe, Senior Process Engineer esipe@dmealliance.com Tim J. Hancock, Ph.D, Senior Process Engineer thancock@dmealliance.com ANY QUESTIONS?
  54. 54.  Process Understanding – “A process is generally considered to be well understood when (1) all critical sources of variability are identified and explained, (2) variability is managed by the process, and (3) product quality attributes can be accurately and reliably predicted over the design space established for the materials used, process parameters, manufacturing, environmental and other conditions”.  Quality By Design – quality is designed into the product not achieved by final QC testing of the product.  Design of Experiments – structured approach to assessing process responses to changes in inputs or control changes; important for determining acceptable values/ranges for process critical parameters. KEY TERMS & DEFINITIONS Guidance For Industry PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance; U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Veterinary Medicine (CVM) Office of Regulatory Affairs (ORA) Pharmaceutical CGMPs September 2004
  55. 55.  Control Strategy defined prior to manufacturing and demonstrated in process qualification  Should include:  Define criteria to determine when process is “in control” / steady- state  CPPs and CQAs – definitions, specifications; may include models and distributions  Assess start-up/shut-down periods and timing; periods may not align for all unit operations connected continuously  Consider planned transient or changed states (ex: new lot of RM, refill of hopper)  Flow properties of continuous process must be well-defined compared to a batch process Control Strategy and Process Qualification and Validation
  56. 56.  Control Strategy defined prior to manufacturing and demonstrated in process qualification  Should include:  How to handle atypical processing situations  What material is retained or discarded  How material is segregated and how process disturbances are contained  Acceptable carryover material Control Strategy and Process Qualification and Validation
  57. 57. Perfusion Engineering Challenges  Long term aseptic performance  Cell damage – shear, cavitation  Cell residence time / environment in separation device  Protein retention  Ability to selectively retain viable cells  Biomass removal requirements  Mass balance in bioreactor  CIP/SIP  Process Validation
  58. 58.  Reduced purification suite footprint  Eliminates harvest and clarification tanks  Buffer and resin usage is significantly reduced  Increase productivity (g/L resin-day)  Significantly smaller columns (up to 100X)  Fully automatic operation (ΔUV PAT)  Utilization of small single use columns BENEFITS OF SIMULATED MOVING BED/CONTINUOUS VERSUS BATCH CHROMATOGRAPHY

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