IVT Presentation Batch vs Continuous - 45min_REV3

BATCH vs CONTINUOUS PROCESSING

CAN CONTINUOUS PROCESSING WORK FOR YOUR GMP FACILITY/PROCESS OPERATION?

Eric Sipe, Senior Process EngineerTim J. Hancock, Ph.D, Senior Process Engineer

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

From: Perry’s Chemical Engineerings’ HandbookPerry’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?

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

WHO WILL BE THE FIRST ONETO 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

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)

Process Methodology Definitions Continuous Processing – raw materials progress

through a unit operation/unit operations in a contiguous manner to produce an end product

INDUSTRY EXAMPLESNon-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

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

“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

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

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

Process and Business Driving Forces for Going Continuous

Smaller equipment Smaller facility

Better facility/equipment utilizationEasier/more robust scale-up

Better control and product qualityContinuous product quality assurance

Improved yield Reduced waste

Reduced in process materials such as buffers

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

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

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

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

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

Process MethodologiesBatch 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.

BATCHFERMENTATION Concentrated

Feed

FED BATCHFeed

SpentMedium &Product

CellRetention

Device

CONTINUOUS(PERFUSION)

CULTURE

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)

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 TechnologiesHarvest

Single Pass TFF

Retentate

BatchTFF

TFF Centrifugation Chromatography Viral reduction Crystallization Precipitation Membrane adsorption Others

BATCH VS CONTINUOUS PROCESSINGDownstream 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 & CONTINUOUS PROCESSING

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)

In-line On-line At Line Offline

PAT APPLICATIONS

Focused Beam Reflectance Measurement (FBRM)

Infrared Technologies Raman Spectroscopy UV-visible Particle Imaging Acoustics Fluorescence

SOME PAT TECHNOLOGIES Beyond Traditional In-line Measurements

Tim Hancock

Eric, should we clarify this to say PAT Technologies beyond existing measurement instrumentation

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, CrystallizationUV visible Reaction monitoringParticle imaging Wet GranulationAcoustics Wet GranulationFluorescence Hot Melt Extrusion

APPLICATIONS FOR PAT TECHNOLOGIES

SOME RESOURCES FOR PAT TECHNOLOGIES

Nalas Engineering Services (In-house services)

Mettler- ToledoApplied Instrument Technologies

Endress & Hauser

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

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

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

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

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

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: 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.


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?

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)


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

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

Risk Assessment Topics – Different from Traditional Batch

Definition of a batchWhat is a valid residency time distribution What are the CPPs and CQAsQuality 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


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)


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

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

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

SPTFF (Single Pass TFF) Cadence SPTFF PALL

Corporation Pellicon SPTFF EMD Millipore

Current and Emerging TechnologiesHarvest

ATF (Alternating Tangential Flow Filtration) Refine Technology

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 TechnologiesChromatography

Product Load

Equilibration buffer

Wash Buffer

Elution Buffer

Regeneration buffer

Continuous Product Capture

Waste

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 Technologiesfor Continuous Synthesis of Small Molecule

Organic Compounds

SPINIDChemtrixUniqsis

Access 2 FlowProteaf

Micronit MicrofluidicsCofloreCorningFluitecLonza

Resources For Current and Emerging Technologies - Continuous Synthesis of Small Molecule Organic

Compounds

ATF Case Study

Manufacturer 2

Manufacturer 3

Manufacturer 4

Idea Innovato

r

Startup

ManufacturerProcess Development

Vendor

ManufacturerPRODUCTION

Engineering Firm(s)Other Vendors

Dave Marks, DME Alliance Engineering Consultants

Abby Johnson, DME Alliance Engineering Consultants

Robert Snow, CPIP- Sanofi Biologics Development

ANY QUESTIONS?

ACKOWLEDGEMENTS

http://www.dmealliance.com/DME Alliance, Inc. Engineering Consultants

7540 Windsor Drive, Suite 311Allentown, PA 18195 Phone: 610-366-1744

Eric Sipe, Senior Process [email protected]

Tim J. Hancock, Ph.D, Senior Process [email protected]

ANY QUESTIONS?

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

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 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


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

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

Documents

IVT Presentation Batch vs Continuous - 45min_REV3