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

∗ 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

Topics

∗ 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.

Overview

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.”

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

∗ 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 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

∗ 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

NON-GMP BATCH PROCESSING ∗ Formulation of plastic mixtures∗ Sedimentation of solids in waste water

treatment plant∗ Electroplating of parts∗ Manufacture of sodium aluminate

INDUSTRY EXAMPLESPHARMA INDUSTRY EXAMPLES OF BATCH PROCESSING ∗ 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

PHARMA INDUSTRY EXAMPLES OF CONTINUOUS PROCESSING∗ Production of WFI/Clean Steam∗ Vial Filling Operations∗ Biowaste Inactivation Operations∗ Perfusion Fermentation

NON-GMP INDUSTRY EXAMPLES OF SEMI-BATCH PROCESSING ∗ Fed-batch solvent recovery from a contaminated

solvent waste stream∗ Hydrogenation reactions∗ Metered quenching reactions

NO-GMP CONTINUOUS PROCESSING∗ 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 INDUSTRY EXAMPLES OF SEMI-BATCH PROCESSING ∗ Fed-batch cell culture/fermentation∗ Diafiltration∗ Solvent exchange∗ Exothermic reaction of API material

∗ 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”.

∗ 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

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

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

∗ 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 SMALL MOLECULE PHARMA 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.

REASONS FOR BATCH PROCESSING OF BIOLOGICS PRODUCTS

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.

Implementing Continuous vs. Batch Manufacture

Process Driving Forces

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 assuranceImproved 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 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.

IMPLEMENTING CONTINUOUS VS. BATCH MANUFACTURING

Process and Business Driving Forces

∗ 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∗ 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

Unit Operations – Batch Processes

OPERATION HOW ACCOMPLISHED MONITORING

MIXING AGITATED VESSEL, RECIRCULATION OF VESSEL

Agitator speed, agitator power

FILTRATION/SEPARATION PLATE FILTER, Camera system

QUENCHING LIQUID ADDITION TO REACTOR

pH, Conductivity

COOLING/HEATING JACKETED VESSEL,INTERNAL COIL, EXTERNAL LOOP, REFLUX OF BOILED VAPOR

Temperature, heat transfer calculation

REACTION METERED ADDITION OF REACTANT

TEMPERATURE, pH,

Unit Operations – Batch Processes

OPERATION HOW ACCOMPLISHED MONITORING

DISTILLATION AGITATED VESSEL WITH CONDENSER

TEMPERATURE, PRESSURE, REFRACTIVE INDEX

TRANSFERS VACUUM, OVERPRESSURE, PUMPING

LOAD CELLS, FLOW METERS

EXTRACTION/DUAL LIQUID PHASESEPARATION

SEPARATION IN VESSEL AFTER AGITATION

CONDUCTIVITY, VISUAL

Unit Operations – Continuous Processes

OPERATION HOW ACCOMPLISHED MONITORING

MIXING STATIC MIXERS, INLINE MIXERS

Density

FILTRATION/SEPARATION CARTRIDGE FILTERS, RO Conductivity, turbidity

QUENCHING LIQUID INJECTION INTO PIPELINE AND STATIC MIXER

pH

COOLING/HEATING INLINE HEAT EXCHANGERS, FLASHING CHAMBERS

Temperature, heat transfer calculation

REACTION PIPELINE REACTORS, CSTRs, PLATE REACTORS

Density, conductivity, FTIR

Unit Operations – Continuous Process

OPERATION HOW ACCOMPLISHED MONITORING

DISTILLATION DISTILLATION COLUMN TEMPERATURES,REFRACTIVE INDEX, PRESSURES

TRANSFERS PIPELINE Flow

EXTRACTION/DUAL LIQUID PHASESEPARATION

EXTRACTION COLUMN CONDUCTIVITY, DENSITY

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

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

∗ Crystallization∗ Precipitation∗ Centrifugation∗ Membrane adsorption∗ TFF∗ Chromatography∗ Viral reduction∗ Others

BATCH VS CONTINUOUS PROCESSINGDownstream Processing

∗ 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

∗ 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.

Current and Emerging TechnologiesHarvest

∗ 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

∗ 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 APPLICATIONS

∗ 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

PAT TECHNOLOGIES

PAT TECHNOLOGY Examples of where Technology can be used

Focused Beam Reflectance Measurement (FBRM)

Crystallization, Wet Granulation, Compounding

Fourier Transform Infrared (FTIR)

Near Infrared (NIR) Spectroscopy Dispensing, Reaction Monitoring, API Drying

Raman Spectroscopy Crystallization, Compounding, Blending, Freeze Drying

Particle Size 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)Acoustics

Crystallization, Wet GranulationWet Granulation

Fluorescence Hot Melt Extrusion

APPLICATIONS 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

VENDORS FOR PAT 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

∗ 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 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

∗ 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

Current Regulatory Environment

∗ 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)

Must produce a batch but what is a batch?When not processing batchwise?

∗ Laboratory determination of final specifications for release21 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 manufacturing21 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 discrepancies21 CFR 211.192: The investigation shall extend to other batches […] that may have been associated with the specific failure of discrepancy.

∗ Recall situation21 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

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

∗ 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.

Regulatory Approach to Continuous Processing

∗ 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

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

Disposables and Continuous Processing

∗ SPTFF (Single Pass TFF) - Cadence SPTFF PALL Corporation∗ SPTFF (Single Pass TFF) – Pellicon SPTFF EMD Millipore

Current and Emerging TechnologiesHarvest

∗ Novasep – Sequential Multi-Column Chromatography (SMCC)∗ GE Healthcare – 3-Column Periodic Counter Current (3C-PCC)∗ Tarpon Biosystems – Bio SMB (Simulated Moving Bed)

Current and Emerging TechnologiesChromatography

∗ SPINID∗ Chemtrix∗ Uniqsis∗ Access Flow∗ Proteaf∗ Micronit Microfluidics∗ ConsiGma™∗ Fluitec∗ Lonza

Resources for Continuous Synthesis of Small Molecule Organic Compounds

ManufacturerProcess

Development

Startup

Idea

Engineering Firm(s)Other

Vendors

Innovator

ManufacturerPRODUCTION

Vendor

ATF Case Study

Manufacturer 2

Manufacturer 3

Manufacturer 4

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

ACKOWLEDGEMENTS