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
 Topics
∗ Process Methodologies
∗ Batch and Fed-Batch to Semi-Continuous and Continuous
∗ Implementing Continuous vs. Batch
∗ Process Driving Forces
∗ Selecting a Test Method
∗ Continuous Testing and Process Analytical Testing (PAT)
∗ Regulatory Requirements
∗ Current and Emerging Technologies for Biologic Manufacturing
∗ Perfusion
∗ Harvesting
∗ Purification
∗ Analytics
 Overview

∗ Batch processing has dominated the API industry due to available

technologies, risk aversion and regulatory expectations.

∗ However continuous processing can often be more efficient and

lucrative and is an acceptable processing method per the FDA.

∗ 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.
 Why Use Batch?
From: 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.”
BATCH vs CONTINUOUS PROCESSING
PARADIGMS
∗ 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 operations are less risky because small discrete lots can be
made and held at points throughout the process
∗ Continuous process are used only to produce a large amount of
product and are monitored and controlled throughout the process
∗ 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
 WHO WILL BE THE FIRST ONE
TO CORNER THE MARKET USING CONTINUOUS?
BATCH CONTINUOUS
Gold Panning Sluice
 Process Methodology Definitions

∗ Batch Processing - raw materials progress through a

unit operation/unit operations in a step wise fashion
to produce an end product
∗ Semi-batch Processing – batchwise process with
aspects of continuous processing (introduction or
removal of material; i.e. concentration of a tank of
aqueous waste)
∗ Continuous Processing – raw materials progress
through a unit operation/unit operations in a
contiguous manner to produce an end product
 INDUSTRY EXAMPLES
NON-GMP BATCH PROCESSING PHARMA INDUSTRY EXAMPLES OF BATCH PROCESSING
∗ Formulation of plastic mixtures ∗ Centrifugation of API chemical entity
∗ Crystallization of API chemical entity
∗ Sedimentation of solids in waste water ∗ Extraction of product from reaction mixture
treatment plant
∗ Milling of a lot of material
∗ Electroplating of parts ∗ Isolation of a biopharm product via adsorption column
∗ Manufacture of sodium aluminate ∗ Tablet coating
∗ Autoclaving of stoppers
∗ Washing of filler change parts

NON-GMP INDUSTRY EXAMPLES OF SEMI-BATCH PHARMA INDUSTRY EXAMPLES OF SEMI-BATCH

PROCESSING PROCESSING
∗ Fed-batch solvent recovery from a contaminated ∗ Fed-batch cell culture/fermentation
solvent waste stream ∗ Diafiltration
∗ Solvent exchange
∗ Hydrogenation reactions
∗ Exothermic reaction of API material
∗ Metered quenching reactions

NO-GMP CONTINUOUS PROCESSING PHARMA INDUSTRY EXAMPLES OF CONTINUOUS

∗ Refining of crude oil PROCESSING
∗ Manufacture of granular aluminum sulfate ∗ Production of WFI/Clean Steam
∗ Vial Filling Operations
∗ Manufacture of bleach in pipeline reactor
∗ Biowaste Inactivation Operations
∗ Manufacture of water treatment polymers ∗ Perfusion Fermentation
∗ Stripping of solvents from aqueous waste
stream
 KEY TERMS & DEFINITIONS

∗ 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 Under this strategy,
market release of products can be based upon meeting the defined critical
quality parameters and not on performing approved quality control tests.
∗ 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
 KEY TERMS & DEFINITIONS

∗ 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 of starting
materials, in-process materials and processes with the aim
of ensuring the quality of the finished product. “ from
GMP-News, September 8, 2003
∗ Quality By Design – quality is designed into the product
not achieved by final QC testing of the product.
 KEY TERMS & DEFINITIONS

∗ 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”.
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

∗ 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.
∗ Islands of Continuous Processing – segments of a manufacturing process
where continuous processing can be executed; needed on way to
completely continuous manufacturing processes
 Biopharmaceutical Product
Processes Historically
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.
 REASONS FOR BATCH PROCESSING OF
SMALL MOLECULE PHARMA PRODUCTS

∗ Multi-step synthesis processes with additional unit

operations to isolate desired chemical entity
∗ Laboratory development of chemical entities has
historically been done via discrete batch operation.
∗ Historically continuous flow options were not
available for chemical synthesis operations
REASONS FOR BATCH PROCESSING OF
BIOLOGICS PRODUCTS

∗ Historically continuous flow options were not

commercially available for both upstream and
downstream processes
∗ Chromatography is a batch reaction
∗ TFF has been developed as a batch operation
∗ Laboratory development of biologics has historically
been done via discrete batch operation.
 Implementing Continuous vs. Batch Manufacture
Process Driving Forces
Guidance for Industry PAT - A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality
Assurance

Conventional pharmaceutical manufacturing is generally accomplished using batch processing with

laboratory testing conducted on collected samples to evaluate quality. This conventional approach has been
successful in providing quality pharmaceuticals to the public. 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.

Unfortunately, the pharmaceutical industry generally has been hesitant to introduce innovative systems into
the manufacturing sector for a number of reasons. One reason often cited is regulatory uncertainty, which
may result from the perception that our existing regulatory system is rigid and unfavorable to the
introduction of innovative systems. For example, many manufacturing procedures are treated as being
frozen and many process changes are managed through regulatory submissions. In addition, other scientific
and technical issues have been raised as possible reasons for this hesitancy. Nonetheless, industry's
hesitancy to broadly embrace innovation in pharmaceutical manufacturing is undesirable from a public
health perspective. Efficient pharmaceutical manufacturing is a critical part of an effective U.S. health care
system. The health of our citizens (and animals in their care) depends on the availability of safe, effective, and
affordable medicines.
Pharmaceuticals continue to have an increasingly prominent role in health care. 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 (e.g., individualized therapy, genetically tailored
treatment). Regulatory policies must also rise to the challenge.
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
 IMPLEMENTING CONTINUOUS VS. BATCH
MANUFACTURING
Process and Business Driving Forces

Process and Business Driving Forces

Smaller equipment
Smaller facility
Better facility/equipment utilization
Easier scale-up
Better control and product quality
Continuous product quality assurance
Improved yield
Reduced waste
Reduced in process materials such as buffers
 IMPLEMENTING CONTINUOUS VS. BATCH
MANUFACTURING
Process and Business Driving Forces
Decrease development risks, costs and time to market
∗ When introducing new products scale-up may be eliminated if you can manufacture development,
clinical, and commercial product on the same equipment by running longer.
∗ Continuous development is significantly faster due to the ability to change steady state with
perturbations versus classical batch DOE development work.
∗ Much smaller amounts of material are needed to develop continuous processes than for batch
process development, which can significantly reduce costs.

Manufacturability
∗ Batch production of complex, less‐stable proteins is often impossible, for instance decreases in
MAb product quality over the course of fed‐batch culture is known to occur preventing batch
production.
∗ One of the big benefits to continuous manufacturing is eliminating a fixed batch size, allowing one
to make as little or as much as needed.
∗ Continuous manufacturing product lead times (Raw materials procurement to distribution of
finished product) are typically significantly less than for batch which can substantially reduce
inventory carrying costs.
∗ Improved safety based on processing smaller quantities of hazardous materials and operating at a
safe steady state point rather than cycling through changes of state in batch processing.
Some Physiochemical Factors that Influence
Change from Batch to Continuous: Small
Molecule
∗ 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: Biologics
∗ Cell Culture
∗ Cell stability and robustness,
∗ Excretion of product from cell
∗ 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
 Unit Operations – Batch Processes
OPERATION HOW ACCOMPLISHED MONITORING

MIXING AGITATED VESSEL, Agitator speed, agitator

RECIRCULATION OF power
VESSEL
FILTRATION/SEPARATION PLATE FILTER, Camera system

QUENCHING LIQUID ADDITION TO pH, Conductivity

REACTOR
COOLING/HEATING JACKETED VESSEL, Temperature, heat transfer
INTERNAL COIL, calculation
EXTERNAL LOOP, REFLUX
OF BOILED VAPOR
REACTION METERED ADDITION OF TEMPERATURE, pH,
REACTANT
 Unit Operations – Batch Processes

OPERATION HOW ACCOMPLISHED MONITORING

DISTILLATION AGITATED VESSEL WITH TEMPERATURE,

CONDENSER PRESSURE, REFRACTIVE
INDEX
TRANSFERS VACUUM, LOAD CELLS, FLOW
OVERPRESSURE, METERS
PUMPING
EXTRACTION/DUAL SEPARATION IN VESSEL CONDUCTIVITY, VISUAL
LIQUID PHASE AFTER AGITATION
SEPARATION
 Unit Operations – Continuous Processes

OPERATION HOW ACCOMPLISHED MONITORING

MIXING STATIC MIXERS, INLINE Density

MIXERS
FILTRATION/SEPARATION CARTRIDGE FILTERS, RO Conductivity, turbidity

QUENCHING LIQUID INJECTION INTO pH

PIPELINE AND STATIC
MIXER
COOLING/HEATING INLINE HEAT EXCHANGERS, Temperature, heat transfer
FLASHING CHAMBERS calculation

REACTION PIPELINE REACTORS, Density, conductivity, FTIR

CSTRs, PLATE REACTORS
 Unit Operations – Continuous Process
OPERATION HOW ACCOMPLISHED MONITORING

DISTILLATION DISTILLATION COLUMN TEMPERATURES,

REFRACTIVE INDEX,
PRESSURES
TRANSFERS PIPELINE Flow

EXTRACTION/DUAL EXTRACTION COLUMN CONDUCTIVITY, DENSITY

LIQUID PHASE
SEPARATION
 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. CONTINUOUS
(PERFUSION)
CULTURE
BATCH FED BATCH Spent
FERMENTATION Concentrated Medium &
Feed Feed
Product

Cell
Retention
Device
 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
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
BATCH VS CONTINUOUS PROCESSING
Downstream Processing
∗ Crystallization
∗ Precipitation
∗ Centrifugation
∗ Membrane adsorption
∗ TFF
∗ Chromatography
∗ Viral reduction
∗ Others
 BENEFITS OF SIMULATED MOVING
BED/CONTINUOUS VERSUS BATCH
CHROMATOGRAPHY

∗ 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
 Current and Emerging Technologies
Harvest

∗ Single-pass TFF eliminate the recirculation loop.

∗ It allows continuous operation at high conversion.
∗ Separation takes place in the module, and the concentrated
product (retentate) exits the retentate port.
 PAT & CONTINUOUS PROCESSING

∗ 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 APPLICATIONS

∗ In-line ( Testing instrument in process)

∗ On-line (Sample drawn from process directly into the
test instrument)
∗ At Line (Sample withdrawn from process and tested
near the process)
∗ Offline (Sample withdrawn from process and tested
in a remote lab)
 PAT TECHNOLOGIES

∗ Focused Beam Reflectance Measurement (FBRM)

∗ Fourier Transform Infrared (FTIR)
∗ Near Infrared (NIR) Spectroscopy
∗ Raman Spectroscopy
∗ Particle Size
∗ Mid-IR
∗ UV-visible
 PAT TECHNOLOGIES

∗ Particle Imaging
∗ Particle Vision Measurement (PVM)
∗ Acoustics
∗ Fluorescence
APPLICATIONS FOR PAT TECHNOLOGIES
PAT TECHNOLOGY
Focused Beam Reflectance
Measurement (FBRM)
Fourier Transform Infrared (FTIR)
Near Infrared (NIR) Spectroscopy
Raman Spectroscopy
Particle Size
Examples of where Technology can
be used
Crystallization, Wet Granulation,
Compounding
Dispensing, Reaction Monitoring,
API Drying
Crystallization, Compounding,
Blending, Freeze Drying
Dispensing, Roller Compaction
APPLICATIONS FOR PAT TECHNOLOGIES

PAT TECHNOLOGY Examples of where Technology can

be used
Mid-IR Fermentation, Crystallization,
UV visible Reaction monitoring,
Particle imaging Wet Granulation
Particle Vision Measurement (PVM) Crystallization, Wet Granulation
Acoustics Wet Granulation
Fluorescence Hot Melt Extrusion
 VENDORS FOR PAT TECHNOLOGIES

PAT TECHNOLOGY
FBRM Nalas Engineering Services,

PVM Nalas Engineering Services

Raman Nalas Engineering Services, Applied
Instrument Technologies
FTIR Applied Instrument Technologies
NIR Applied Instrument Technologies
 RAPID MICROBIAL TESTING AND
CONTINUOUS PROCESSING

∗ Rapid Microbial Testing (RMT) leads to expedited

bioburden detection - needed for continuous processing
to be possible for sterile and biorpharm products
∗ Rapid Microbial Testing (RMT) leads to expedited sterility
assurance - needed for continuous processing to be
possible for sterile and biorpharm products
∗ Rapid Microbial Testing (RMT) leads to quicker release of
raw materials, in-process materials and final product -
needed for continuous processing to be possible for sterile
and biorpharm products
 RAPID MICROBIAL TESTING
TECHNOLOGIES

∗ ATP BIOLUMINESCENCE - detection of microbial

contamination based on ATP (component of all
microbes) measurement
∗ CYTOMETRY – fluorescent cell labeling and laser
scanning
∗ POLYMERISE CHAIN REACTION – microbiology based
microbe detection method based on amplification of
specific sections of microbial nucleic acids
RAPID MICROBIAL TESTING VENDORS

∗ 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)
Current Regulatory Environment
∗ No FDA or EU regulations prohibit continuous processing in
pharmaceuticals or biologics
∗ However, methods of how to meet all requirements with a continuous
process are still in development

∗ 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)
∗ 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)
∗ 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
Must produce a batch but what is a batch?
When not processing batchwise?
∗ 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.
∗ 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.
∗ 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)
Why Does Defining a Batch Matter?
∗ Laboratory determination of final specifications for release
21 CFR 211.165(a): For each batch of drug product, there shall be appropriate laboratory
determination of satisfactory conformance to final specifications for the drug product
[…] prior to release

∗ Documentation of manufacturing
21 CFR 211.188 Batch product and control records shall be prepared for each batch of
drug product produced and shall include complete information relating to the
production and control of each batch

∗ Extended investigations of unexplained discrepancies

21 CFR 211.192: The investigation shall extend to other batches […] that may have been
associated with the specific failure of discrepancy.

∗ Recall situation
21 CFR 211.150(b): Distribution procedures shall include […] a system by which the
distribution of each lot of drug product can be readily determined to facilitate its recall
if necessary
From C. Moore, FDA, 13SEP2011

Safety - Identity - Strength - Quality - Purity

Regulatory Approach to Continuous
Processing
∗ Validation master plan required prior to implementation
∗ Risk assessment required
∗ Assement topics
∗ Batch definition (Part of the development of the batch definition should include an idea of how
long the batch remains in each unit operation)
∗ Residency time distribution
∗ Startup and shut down to steady state
∗ Plant shutdowns: planned or unplanned
∗ Equipment, resin and membrane lifespans
∗ Continuous process qualification
∗ Release Testing
∗ Offline and online testing
∗ Offline in process sampling
∗ Batch/lot testing
∗ Paramteric release / Real Time Release Testing (RTRT)
∗ Initial process qualification and validation
∗ Continuous/ongoing process qualification
∗ Statistical process control
∗ Paramteric release (RTRT,) must be supported by process and equipment qualification and
process validation
∗ Suggested to develop for whole process prior to qualification.
 Control Strategy and Process
Qualification and Validation
∗ 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
∗ 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
∗ Traceability of input lots (based on flow, RTD)
∗ Steady State turn down ratios
∗ Ability to run at different rates over run time
∗ System run time
∗ Raw material and batch stability over run time (Define space definition)
∗ Microbial 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
∗ Intermediates and final product
∗ Instrument delay and testing time vs. RTD
∗ Cleaning strategy and validation
∗ Batch documentation strategy / MES
Disposables and Continuous Processing

∗ Chromatography single-use columns

∗ Disposable TFF cassettes for SPTFF
∗ Perfusion bioreactors at 2000L and less easily utilize
existing single use bag based bioreactors
Current and Emerging Technologies
Harvest

∗ SPTFF (Single Pass TFF) - Cadence SPTFF PALL Corporation

∗ SPTFF (Single Pass TFF) – Pellicon SPTFF EMD Millipore
Current and Emerging Technologies
Chromatography

∗ Novasep – Sequential Multi-Column Chromatography (SMCC)

∗ GE Healthcare – 3-Column Periodic Counter Current (3C-PCC)
∗ Tarpon Biosystems – Bio SMB (Simulated Moving Bed)
Resources for Continuous Synthesis of
Small Molecule Organic Compounds

∗ SPINID
∗ Chemtrix
∗ Uniqsis
∗ Access Flow
∗ Proteaf
∗ Micronit Microfluidics
∗ ConsiGma™
∗ Fluitec
∗ Lonza
 ATF Case Study
Idea

Innovator Manufacturer 2
Vendor

Startup
Engineering Manufacturer 3
Firm(s)
Other
Vendors
Manufacturer
Manufacturer
Process Manufacturer 4
Development PRODUCTION
 ACKOWLEDGEMENTS

∗ Dave Marks, DME Alliance Engineering Consultants

∗ Abby Johnson, DME Alliance Engineering Consultants
∗ Robert Snow, CPIP- Sanofi Biologics Development