PAT and UPLC Round Table Introducing PATROL Systems Biopharma_UPLC fo… · PAT and UPLC Round Table Introducing PATROL Systems David Lascoux ... ©2012 Waters Corporation 13

©2012 Waters Corporation 1

PAT and UPLC Round Table

Introducing PATROL Systems

David Lascoux

Jean-Michel Plankeele

Biopharma LC Meeting

Eschborn, October 17th


What Is PAT? What Are the PATROL Systems For?

PAT, PATROL: Process Analytical Technology

– ICH Guideline Q8(R2) and ICH Q9 & Q10 :

o A system for designing, analyzing, and controlling

manufacturing through timely measurements (i.e., during

processing) of critical quality and performance attributes of raw

and in-process materials and processes with the goal of ensuring

final product quality

All tools (techniques) for measuring/controlling the quality of

any (chemical/production) process

What is the Purpose of PAT?

– Improve knowledge (about a process) & reduce variability

– Improve the process

– Implementation of a QbD approach with real time data


Sensor Technology Utilized for PAT Applications Today

Probes (Temp, pH)

Dissolved Gas (02, CO2)

Total Organic Carbon (TOC)

Near-Infrared (NIR)

Infrared (IR)

Raman

UV-visible

Fourier Transform Infrared (FTIR)

X-Ray Powder Diffraction (XRPD)

…

Real time, simple, non destructive, fast response

But not quantitative, not specific, lack of resolution


Liquid Chromatography Lab Analysis Reference Standard

HPLC is a major analytical technique in every QC lab

– Too slow to get a “real-time” answer

– But it is not a major tool for Online/At-line analysis

UPLC overcomes limitations of HPLC

– Performance improvements

– Richer information

– Increased speed times of 10x or faster

End of Process

0 3 6 9 12 15 18 21 24 27 30 33 36 39

UPLC

HPLC

Minutes


Waters’ answer and solutions PATROL System

UPLC power

– « UPLC Inside » systems

– Speed, resolution, sensitive

Specially designed autosampler : PSM

– At-line and On-line sampling

– Automated dilutions

Rugged configurations for unattended use

Three configurations meeting lab/pilot and production scales

– Patrol UPLC Laboratory Analyzer

– Patrol UPLC Pilot system

– Patrol UPLC Process Analyzer (in the manufacturing area)

Connections with lab/plant environment

– Fluidics (eg sterile sampling)

– Informatics : DCS and Data management


PATROL UPLC Process Analyzer Three Configurations

Stainless steel cabinet Solvent & containers

Corporate network

UPLC BSM

UPLC Process Sample Manager

UPLC CM

PATROL Flex cart ELSD or SQD or TQD

PATROL Lab PC

Empower PATmanager

Laboratory/Pilot System Process System

PDA / TUV


Biopharmaceutical Process LC Dependant Large Molecule Applications

DOWNSTREAM UPSTREAM


On-Line Reaction Monitoring As the reaction progresses you

map the formation of the API and

the consumption of the starting

material

Additionally because of the high

linear range of the detector, you

can also monitor the formation of

any low level impurities

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Minutes

0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00

Injection #1

Injection #14

Injection #37

Injection #60

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60

Pe

ak A

rea

%

Injection #

API Starting Material Process Impurity 1 Process Impurity 2 Process Impurity 3 Process Impurity 4


Downstream Processing off-line, HPLC control of fractions

0 12 hours

Main Peak widths are measured in Hours

40 minute analysis

A minimum of 160L

requires reprocessing

Initial process

recovery yield 40%

Final recovery yield

after reprocessing

58%

COLLECT WASTE REPROCESS


Downstream Processing on-line, UPLC control of fractions

0 12 hours

Main Peak widths are measured in Hours

3.5 minute analysis

No fractions need

to be reworked

Total initial process

recovery yield

of 87% (40%/58%)

6 month ROI (1 of 4

steps)

COLLECT WASTE


UPLC Analysis

3.5 minute chromatography

Total initial process recovery:

87%

No reprocessing required

6 month ROI

Downstream Process Biopharmaceutical Purity Analysis

HPLC Analysis

40 minute chromatography

Initial process recovery - 40%

160L reprocessed at minimum

Final recovery after reprocessing:

58%


Biopharmaceutical Process LC Based Application Opportunities

Cleaning validation Additional process steps

Waste water testing

Waste Stream


Opening Questions

Would direct transfer method & process be beneficial?

– Improve handshake between development and production?

– Minimize scale up risk?

– Enable broader use of scientific information?

How does “real time” monitoring & control benefit your process?

– Enable improved yields & cycle times while reducing offline testing?

– Create fewer operator, dilution or equipment variability errors?

– What is the commercial value of this impact?

Can technology effectively extend the life of your product?

Time to Market (12-14 yrs)

Patent Protection (20 yrs)

Sales/Profits (10-12 yrs)


Technical Overview


Waters’ answer and solutions

UPLC power






Two configurations meeting lab/pilot and production scales


– Patrol UPLC Process Analyzer





Online Process Sample Manager Fluidic Components

Process Pump

Process Valve

Sample Pump Inject Valve

Diluent Pump

Priming Valve

Sampling Valve

Courtesy of Bob Tacconi


Atline Dilution Capabilities Linearity (n = 6)

R2 = 0.99994 1/x Weighting Excellent linearity across the entire

dilution range Aqueous rProtein sample diluted with 6M urea

Undiluted 2x Dilution 4x Dilution 10x Dilution 20x Dilution 100x Dilution

Dilution %RSD

Undiluted 0.11

2x 0.48

4x 0.70

10x 0.49

20x 0.59

100x 0.66


Online Injections

R2 = 0.99977


Technical Overview


Waters’ answer and solutions

UPLC power






Two configurations meeting lab/pilot and production scales


– Patrol UPLC Process Analyzer





Online Process Sample Manager Fluidic Components

Process Pump

Process Valve

Sample Pump Inject Valve

Diluent Pump

Priming Valve

Sampling Valve

Courtesy of Bob Tacconi


Sample Work Flow Comparison ACQUITY & PATROL Atline

LOAD

VIAL

VERIFY

VIAL

READ

BARCODE

VALIDATE

SAMPLE

ASPIRATE

SAMPLE

DILUTE

SAMPLE

INJECT

SAMPLE

ACQUITY

SAMPLE

MANAGER

LOAD

VIAL

ASPIRATE

SAMPLE

INJECT

SAMPLE

PATROL

PROCESS

SAMPLE

MANAGER


Process Sample Manager

Sample Introduction Access Door (open position)

Sample/Standard Insertion Slide (open with vial partially inserted)


The Process Sample Manager

can be included in UPLC (BSM)

and H-Class (H-Class Bio)

systems

This is another sample

manager for UPLC (SM-FL, SM-

FTN, 2777, OSM and PSM)

Empower control

On-line and At-line

32 sample position

Bar code reader

Sample dilution

PATROL Laboratory System


Patrol UPLC Laboratory Analyzer

Designed for Lab & Pilot use

Easy connection with small size reactors

Flexibility of detection around PSM

– TUV

– PDA

– FLR

– DEDL


PATROL Process System PATROL Laboratory System

UPLC based analyzer for the online /atline analysis of inprocess samples

Online UPLC analyzes reaction progress

– Measures concentration of starting material, intermediate, impurities, and final product

– Reaction stopped when residual starting material target achieved or impurities reach a threshold value

Two configurations:

– Patrol Process System (explosion proof cabinet)

– Patrol Laboratory System (benchtop or flex cart)

Automatic or manual transfer

On line dilution of samples


UPLC Module Access and Maintenance


Documents

PAT and UPLC Round Table Introducing PATROL Systems Biopharma_UPLC fo… · PAT and UPLC Round Table Introducing PATROL Systems David Lascoux ... ©2012 Waters Corporation 13