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. 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. 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.  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. WHO WILL BE THE FIRST ONE
TO CORNER THE MARKET USING CONTINUOUS?
BATCH CONTINUOUS
Gold Panning Sluice

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. 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. Process Methodology Definitions
 Continuous Processing – raw materials progress
through a unit operation/unit operations in a
contiguous manner to produce an end product

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. 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. “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.  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.  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. 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. 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.  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.  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. 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. 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. 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. 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.  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.  TFF
 Centrifugation
 Chromatography
 Viral reduction
 Crystallization
 Precipitation
 Membrane adsorption
 Others
BATCH VS CONTINUOUS PROCESSING
Downstream Processing

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.  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. In-line
On-line
At Line
Offline
PAT APPLICATIONS

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. 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. SOME RESOURCES FOR PAT
TECHNOLOGIES
 Nalas Engineering Services (In-house
services)
 Mettler- Toledo
 Applied Instrument Technologies
 Endress & Hauser

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.  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.  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.  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. 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.  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.  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.  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.  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.  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.  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. 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.  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.  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.  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.  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.  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.  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.  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.  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. 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. ATF Case Study
Manufacturer 2
Manufacturer 3
Manufacturer 4
Idea
Innovator
Startup
Manufacturer
Process
Development
Vendor
Manufacturer
PRODUCTION
Engineering
Firm(s)
Other
Vendors

52.  Dave Marks, DME Alliance Engineering Consultants
 Abby Johnson, DME Alliance Engineering Consultants
 Robert Snow, CPIP- Sanofi Biologics Development
 ANY QUESTIONS?
ACKOWLEDGEMENTS

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.  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.  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.  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. 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.  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