The important role that PAT (Process Analytical Technology) plays in Technology Developments

that Enhance Process Optimization while Achieving Lower Costs.

Mel Koch, CPAC University of Washington NEXTLAB 2014 April 4, 2014

Enhancing process optimization using new analytical tools and approaches

PROCESS ANALYTICAL TECHNOLOGY (PAT)

• WHAT IS IT ? – Real Time Measurement

• WHY IS IT IMPORTANT ?

• WHAT WILL IT HELP?

Real-time Data Acquisition • . . . has provided researchers with

a “vision” into a process.

• What was accomplished? – Composition – Reaction Pathways & Kinetics – Emission Monitoring – Hazard Evaluation Issues – On-line Feasibility Studies

Courtesy Dow Chemical

PAT Tools • PAT tools should be categorized as:

– Process analyzers – Process control tools – Multivariate tools for design, data acquisition

and analysis – Continuous improvement and knowledge

management tools

• PAT is more than just an analyzer!

Quality by Design - QbD

A Systematic approach to development Begins with predefined objectives Identifies Critical Process Parameters Emphasizes product and process

understanding and process control Based on sound science and quality risk

management PAT impacts all of these points From ICH Q8

M. Nasr, FDA October 2008

Consortia are an effective approach to develop new measurement capabilities - as resources within an individual organization are normally limited.

• Globalization of Businesses • Consolidation of Industries • Constricted Resources

• Within an Organization • Across Industry • Industry-University • Industry-Government-

University

Recent Directions in Industry

Partnering is Needed

Industry Academic Consortium

• 30 years of bringing industry and academia together

• Solving multidisciplinary challenges in process analysis through fundamental and applied academic research

• CPAC is focused on developing tools that enable process optimization, control and quality improvements for our industrial partners

Center for Process Analysis and Control

UNIVERSITY OF WASHINGTON, SEATTLE

• Biannual Sponsor Meetings • Graduate Education • Industry Driven Initiatives • Technology Webinars • Rome Workshop (March) • Summer Institute (July) • IFPAC and IFPAC Europa • FACSS, AIChE, ISA-AD • FDA (PAT, QbD)

CPAC Activities

Product and Process Characterization leading to Process Optimization (Resulting in Improved Process Control)

Co-Sponsors FDA, EMA, CPAC

IFPAC ® - Europa 2014

28 September - 1 October 2014 Centro Convegni Sant’Agostino

Cortona, Italy

Advances in Pharmaceutical Innovation & Manufacturing Control

International meeting on Process Optimization, Continuous Processing, and Quality by Design.

Achieving Regulatory Harmonization within the Pharmaceutical and Biotechnology Industries.

EUROPA

• Chemometrics (Multivariate Data Analysis) • Sensors (Chemical, Physical, Biological) • Spectroscopy / Imaging • Chromatography / Separation Science • Continuous Flow Chemistry and Analysis • Process Control

CPAC Core Research Areas

Examples of CPAC Technology For Process Optimization and Product Improvement

Developments and Applications

• Pharmaceuticals/chemicals

• Food quality and safety

• Polymers/coatings

• Fermentation/biotech

• Cellular/tissue

• Oil/fuels/petrochemicals

• Oceanography/environment 12

Applied Optical Sensor Applications

Marquardt Lab

Raman Spectroscopy Raman probes Standard and Mini (1/8” o.d.): • Effective in liquid, solids, and vapor applications

Monitoring Bioprocesses • Raman used to monitor and control

cellulosic hydrolysis and fermentation processes

Investigating the use of Laser Induced Breakdown Spectroscopy (LIBS) as an

effective process analysis tool • Remote elemental analysis

with no sample preparation • Fiber-optic delivery or long

range delivery of laser by telescope for remote analysis

• Laser-induced plasma ablates and super heats samples to provide elemental spectral emission data

Brian Marquardt, Sergey Mozharov, Tom Dearing, Applied Physics Lab University of Washington

Environmental Analysis

Material Sorting Toxic Substance

Detection Chemical and

Pharmaceutical

Biological Fermentation

media Biofuel feedstock

Production Control Anthropology Geology Solid State Analysis

Applications of LIBS

LIBS/Raman Setup Pulsed Laser

1064 nm Raman Instrument

532 nm

Echelle Spectrometer

retractable mirror

Raman probe

beam expander

dichroic mirror

collection lens

collection fiber

Delay generator

EMCCD

16

17

Rapid spectroscopic techniques: (NIR, Raman, FT-IR) Effective tools for food process control • Enables efficient monitoring and control of complex products

and processes • Main challenge: large variability in raw materials! • Often need to characterize every single sample in the

production line

Raw

materials

Sorting

Processing

Optimised value/quality

Measurem

ents Jens-Petter Wold, CPAC Rome workshop March 2014

Developing robust, sensitive, and stable optical sensors • Based on vapochromic technology • Extremely optically and chemically stable • Very sensitive and selective to a variety of chemicals • Fast response times in liquid, gas and vapor phases • Sol-gels are being developed as protective coatings for

optical components due to their high optical transmission and chemical robustness.

• Process ready Real-time Monitoring of

Dissolved Oxygen Concentrations During a Fermentation

Optical Chemical Sensors

18

ure es i (in development)d nitrate (future deve

Oxygen Moisture Ammonia Hydrogen Common Solvents (Alcohols, Esters Amines Chlorinated Organics

Organic Hydrocarbons (BTEX)

Carbon Dioxide Hydrogen Sulfide Phosphate and

nitrate (future)

Pharmaceutical coating

Fringing Electric Field Sensing

Alex Mamishev Electrical Engineering UW

Sensing MoistureSensing Texture

Sensing Density

Sensing Distance

Fringing electric fields can detect various characteristics of a sample.

Paper machine moisture

Flow of Biomass Undergoing Enzymatic Hydrolysis

• Rheological measurements • Liquefaction characterization

• Kinetic modeling

NMR for Process Analysis and Control

1Department of Food Science & Technology, UC Davis 2Department of Chemistry 3Aspect Imaging 4 Department of Biological and Agricultural Engineering

Terahertz Spectroscopy

• Oil and gas industry: chemical signatures of alkanes varies by carbon chain length

• Biomolecules: Spectral signatures of Amino Acids in food supplements

• THz signatures of specialty chemicals • Pharmaceutical industries: (uniformity of tablet coatings)

D. Winebrenner UW Applied Physics Lab

Fitzgerald et al. J. Pharm. Sci., 94, 177-183 (2005).

Fundamental Advances for High Speed Process Gas Chromatography

Modeling and Instrumentation

Robert E. Synovec, Department of Chemistry

Optimize 1D-GC and GC x GC peak capacity production, while providing sensitive detection

with a robust instrumental platform and Chemometric data interpretation

Complex mixtures – crude oil, Metabolomics, food, etc.

Other monitoring and improved unit operations technology resources in CPAC include:

• NIR monitoring • FTIR monitoring • Mass Spectroscopy • Surface Plasmon Resonance (bio-sensors) • Micro-scale Chromatography • Modular Sensing Architecture for Low-Cost

Wireless Monitoring

CPAC LEGACY • CREATES FORUMS FOR PROMOTING ADVANCES IN

PROCESS OPTIMIZATION AND IN GLOBAL APPROACHES TO TECHNICAL COOPERATION IN PAT – RESPONDING TO INDUSTRY NEEDS

Recent CPAC Research Initiatives

• Bio-Processing Improvements • Measurement Tools for Food Quality and Safety • Micro-Instrumentation for High Throughput Experimentation and Process Optimization •Chemometrics On-Line Initiative (COPA) • New Sampling and Sensor Initiative (NeSSI)

What is NeSSI™? • Industry-driven effort to define

and promote a new standardized alternative to sample conditioning systems for analyzers and sensors GEN I - Standard fluidic interface

for modular surface-mount components ISA SP76

GEN II - Standard wiring and

communications interfaces

GEN III - Standard platform for many types of analytics

NeSSI allows a move to on the pipeline

Transition from large analyser Shelters to on pipeline analysis

How can this be achieved?

Courtesy of EIF - Astute

Flange mounted system with C2V Micro GC and H2Scan hydrogen analyzer

Pipeline mounted sample system integrated with MicroSam

Courtesy of Dow Chemical

CPAC has Demonstrated Lab Level Process Analytical for Chemical Reactions and for Fermentation Monitoring

27

A microreactor is a fluidic system which allows continous flow reactions

• Main advantages:

• Control of Chemical Reactions - good mixing - effective heat exchange - improved safety

• Rapid Optinization of Reactions - continuous and batch

Including: Volker Hessel Claude De Bellefon Paul Watts Kurt vandenBussche Brian Marquardt Ray Chrisman Frank Gupton Etc.

– Funded by the FDA to demonstrate the benefits of improved reactor design, effective sampling and online analytics to increase process understanding and control

– Demonstration of Quality by Design for continuous processing – QbD

• Partners: FDA, CPAC, Parker, Corning, Kaiser Optical

US Food and Drug Administration (FDA) Sponsored Continuous Flow Reactor Project

at CPAC

29 Brian J. Marquardt CPAC APL UW

Reactor System

Development of a continuous flow reactor system with integrated monitoring and control NeSSI sampling

system with all digital analytics and spectroscopy on reagent and product streams

Develop and optimize complex chemistry Pharmaceutically relevant chemistry Control-driven reaction – multiple steps Resource intensive batch chemistry (cryogenic)

Swern Oxidation meets the following requirements Cryogenic temperatures in CF vs. batch

Offer distinct advantage over batch Compatible with sampling system, reactor, seals Spectroscopically active

Continuous Flow Reactor Project Scope:

Experimental Batch - Development

Reactants were cooled before addition using reactor plate to -20°

Maintained -70°C bath Vessel included three

analytical probes plus port for addition of chemicals

Reaction profile developed during the reaction

32

Configuration 1 was constructed to replicate batch in continuous flow Previous batch experiments indicated that product

formation only occurs after TEA quench addition

Configuration 2 combines batch knowledge with CFR capabilities

Reactor Configurations Evolved

DMSO(1) TFAA(2) Alcohol(4) TEA(6)

DMSO(1) TFAA(2) Alcohol(4) TEA(6)

Acetophenone

Acetophenone

Configuration Effects on % Yield

Batch regime requires significantly lower temperatures, results in lower yield Configuration 1 brings higher yields at higher temperatures – as high as -10°C Configuration 2 has significantly improved CF yield across temperature range

based upon understanding gained from batch

Temp (°C) % Yield

Batch -70 70

-30 2

Configuration 1

-20 81

-10 73

0 37

10 14

20 5

Configuration 2

-20 79.5

-10 79.5

0 77

10 71

20 67

Bio-Processing Improvement Initiative

Measurements for process or system analysis Search for underlying functional relationships In depth analysis of the interaction of the organisms with

their environment

Provide capabilities for process control Setting up and maintaining the optimum environmental

conditions for growth and/or formation of product

Process and Product Monitoring – Chemical, Biological, and Physical

NeSSI with Analytics on Bio-Reactor. Fast-loop Design

• Custom designed NeSSI interfaces for all process analyzers in Marquardt lab • Plug and play analytics for any flowing system (liquid, slurry or gas) 36

Automated NeSSI Sampling System

Backwash Reservoir, pneumatically actuated valves and digital sensors (pressure, temperature, flow rate) Marquardt Lab

No one analytical technique can fully describe a complex feed

• While multivariate techniques such as spectroscopy or chromatography cover significant portions of the variable space,

other variables can still be present and impact the results • For example, some components are below detection limits

and others are non-detectable in the technique (such as metal ions or pH in NIR measurements)

Examples of where more characterization information could be used to reduce

process variability

Qualifying raw materials Organism growth media Excipients Water soluble polymers Surfactants Glues, adhesives, and coatings Flocculants Food extracts Polymer monomers and additives

Polymerization reactions including pre-polymer formation R. Chrisman, Atochemis

Data Fusion for complex feeds

Raman IR GC

HPLC NMR

Mass Spec LIBS

UV-Vis

Chemometric Model

PROCESS OPTIMIZATION

Concept Take multiple sources of information and fuse them together. The sum has greater predictive power than the individual parts

B. Marquardt, T. Dearing UW APL

Fused model Better prediction means better control

01234567

API Weight % H2

RSE

P /%

Raman IR NMR FusedQuantity Raman IR NMR Fused

°API 1.96% 1.85% 0.477% 0.237%

Weight % 2.50% 6.36% 0.844% 0.451% H2 Content 0.708% 0.463% 0.063% 0.03%

Comparison of Individual Models to Fused Model using relative standard error of prediction (lower is better)

Multiple Analytics for Improved Understanding of Bio-Reactors

- improved data analysis needed to quickly capture the information

42

1000 2000 3000 4000 5000 60000

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Variables

Sig

nal I

nten

sity

Fused IR, Raman and LIBS Spectra

Fused Raw Spectra in Media Characterization

IR

LIBS Raman

43

0

24

6

-2

-1

0

1

2

-1.5

-1

-0.5

0

0.5

1

1.5

Scores on PC 1 (77.77%)

Scores on PC 2 (9.63%)

Sco

res

on P

C 3

(4.0

1%)

ModG1xMediaSupp

NutrientBroth1x

XYT2

Liu1xSupp

LeightDoiSupp and NutrientBroth2x

Fused Data Classification of Media Legend Innoculated Noninnoculated

44

More data can be very valuable for better process control but the question becomes how to cost effectively gather more data that contain usable information

R. Chrisman, Atochemis

The use of “big data” concepts with chemometric analysis for raw materials and nutrient characterization, as well as for process control, will have a significant impact

9ARD112236-010 A

© ABB Group April 29, 2014 | Slide 46

FERMENTATION WHAREHOUSE SEPARATION

Ferm. 100l

Ferm. 500l

Purification, UF NF, Cromatogr.

PURIFICATION

Filtration, Separation, Centrifuge

Stock Raw /Finshed Math

Plant Utilities, CIP/SIP, Refrigerators, Boilers, Cogeneration, PW, WFI, Biological Controls, Power Integration, Fire Systems, Access Controls, TVCC, Remote alarming notification

PREPARATION

PLC

BARCODE

PLC

Weigh/Disp.Dispensing

Operational excellence: Primary production / API An integrated solution for Continuous Manufacturing Using Multiple Instruments

PLC BARCODE

PAT, Chemomectric, Multivariate and Method Execution OPC UA ADI Server

Integrated Batch Control Monitoring and Operations 800xA

Workflow, Material Genealogy, RTRT, EBR, Reporting MES CPM

NIR NIR FBRM

Ferm. 25l

(Disposable Fermentor)

M. Banti CPAC Rome workshop March 2014

• Multidisciplinary • Showcase Emerging

technologies • Provide practical focus • Compete well for scarce

resources

Industrial Centers Enhance Academic Programs UNIVERSITY OF WASHINGTON, SEATTLE

CPAC Website

www.cpac.washington.edu

Thank you and questions? Contact info: Mel Koch CPAC – Principal Scientist Phone: 206-616-4869 mel@cpac.washington.edu Brian J. Marquardt Director - Center for Process Analysis and Control Phone: 1.206.685.0112 Email: marquardt@apl.uw.edu www.cpac.washington.edu