Andrey Bogomolov

J&M GmbH, Germany

PAT-enabling Hard- and Software

OutlineOutline

• Good news• in 2007 one more person started to earn his leaving from doing

chemometrics

• J&M: the company

• Process monitoring• J&M special equipment for PAT• two industrial cases

• PAT philosophy• PAT chemometrics software concept • components making up a PAT solution

J&M: IntroductionJ&M: Introduction

• About J&M GmbH• since 1987• spectroscopic equipment and components

specifically, UV-Vis/NIR, DAD, fiber optics, microspectroscopy

• positioned as “fast and precise”• recent years trend: spectroscopic equipment for PAT

• What kind of company?• strongly PAT-oriented• pro-chemometrics • active, growing• innovative • open-minded and collaboration-friendly

J&M ProductsJ&M Products

Integrated in-situ Dissolution Test System

8-channel parallel Chromatography SystemTIDAS II NIR (1100 – 2100 nm)

NOVA fully-integrated Process Analyser

TIDAS fully-integrated spectrometer for pharmaceutical applications

Labo

rato

ryIn

dust

ry

PAT and beyond…PAT and beyond…

• Process Analytical Technology (PAT)• is an initiative of FDA to create a regulatory framework for innovative

pharmaceutical development and quality assurance

• innovative methods [of data analysis=chemometrics] are allowed not only for research, but to provide the legal evidence (e.g. of product quality) for FDA

• the impact goes beyond the regulated environment, since any production is more or less bound with quality requirements

• The basic idea behind PAT is on-line process monitoring• product quality assurance

• process control

• process understanding

• process optimisation

• PAT and Chemometrics• chemometrics and spectroscopy are important components of PAT

• multivarite statistical process control (MSPC) replaces classical [univariate] statistics in the industry

PAT players and driving forcesPAT players and driving forces

quality& safety

quality& safety

consumer

producer profit,

image

regulative organisatio

n

price

LightHouse ProbeLightHouse ProbeTMTM (LHP) (LHP)

• Joint patent with GEA Pharma Systems

• Features and applications:• for on-line measurement of diffuse

reflectance NIR-spectra • e.g. granulation, drying, blending,

coating processes • through 7 sapphire windows• self-cleaning technology • multiple applications

moisture content, composition, homogeneity

particle size monitiring process end-point detection etc.

• Advantages (compared to surface-mounted probes):• reduced window fouling (cleaning) • enhanced contributing sample weight• better sampling: 3D-effect • => better performance

Case 1. Moisture monitoring Case 1. Moisture monitoring

• Granulation and drying• granulation is routinely carried

out in the pharmaceutical production

• fluid-bed granulator• drying is the last step• proceeds to a sertain residual

moisture content (e.g. 2%)

• Moisture monitoring• process end-point detection• Loss on Drying (LOD) the direct

off-(at-) line technique

• PAT Classics• NIR monitoring of H2O is well-

established in-line technique 1200 1400 1600 1800 2000-0.1

0

0.1

0.2

0.3

0.4

Wavelength (nm)

Abs

orba

nce

Case 1. Moisture monitoring (2)Case 1. Moisture monitoring (2)

r = 0.993RMSECV = 0.58a = 2

0 10 20 30 40 50 60 70 80 900

5

10

15

20

25

time (min)%

H2O

40 50 60 70 800

2

4

6

8

r = 0.996RMSECV = 0.17

a = 1 (!)

heating was interrupted

Case 2. Pellet CoatingCase 2. Pellet Coating

• Polymer coating of pellets for capsule filling

• PrecesionCoaterTM • patented in 1998• well-controlled particle flow due to the Swirl

Accelerator

• Process conditions • constant heating; product temperature is

controlled• coating is followed by drying stage

• Materials• pellet size up to 1100 µm• layer thickness up to 30-40 µm

• Critical parameters• layer thickness • moisture content

• Is it possible to predict the dissolution profile?!

Case 2. Pellet Coating (2)Case 2. Pellet Coating (2)

1200 1400 1600 1800 2000-2

-1

0

1

2

3

Wavelength (nm)

Abs

orba

nce

SNV-corrected spectra

0 50 100 150 200 250 3001100

1120

1140

1160

1180

1200

1220

time (min)

Par

ticle

dia

met

er (

m

)

0 50 100 150 200 250 3000

0.5

1

1.5

2

2.5

3

3.5

%H

2O

RMSEP = 0.12

a = 2

RMSECV = 4.05a = 3

moisture

predicted

deviation

calibration sample

particle size

ProDicht ProjectProDicht Project

Probe window

Wash tubes

Movable Tip

Additional wash tube

Mirror

• On-going J&M project funded till 2010• Reutlingen University (Prof. R. Kessler)• University of Applied Sciences,

Offenburg (Prof. B. Spangenberg)• Light-Technical Institute, Karlsruhe• Laser technique by Optimags

• Spectroscopic probe for liquids• transmission and reflection modes• tunable pathlength• supports UV-Vis, NIR, IR, Raman,

Imaging, …• ability to combine multiple techniques

• Analysis in condense/ dispersive media• milk, creams, grease• fat content

Technically, PAT is…Technically, PAT is…

• PAT = Hardware + Softwarere

• PAT hardware• sensors• analytical [spectroscopic] instrumentation• computers

• PAT software• instrument control software (data acquisition)• data processing and modelling (chemometric packages)• operating software (process visualisation, alarms, end-point

detection)• information/knowledge management software (LIMS)• PAT software !?

connect all hardware and aquire the data synchronise the data acquisition build and connect models predict, observe and operate process document the process

Data handling software Data handling software

• Levels of data handling• data acquisition

instrument control, visualisation FFT, averaging

• data [pre-]processing baseline correction, smoothing,

derivation, subtraction, normalisation, peak picking, integration, transforms etc.

• [advanced] data analysis modelling decision making (chemometrics)

• information management LIMS, ERP, …

. .. …..

… .

acquire

process

analyse

manage

IMS

PA

T

Inst

rum

enta

l

Exp

ert

x=!

Towards the PAT SoftwareTowards the PAT Software

• Concept elements• process as the main object• PAT solution as an output

“universal process modelling language”?• modular [open] toolkit

PAT platform• expert (model building) and operating (routine

application) level should be clearly separated• new principles of data handling

delivering the document on-line• “web-compatible”

remote information sources web-based solutions

• Software becomes a dominating part of the data analytical system

PAT SolutionPAT Solution

• PAT company• software

development• linked to

hardware vendors

• scientific expetise

• independent

hardware

soft

war

e

serv

ice

science

Technical companies

Consulting companies

Software companies Academia

Welcome to CollaborationWelcome to Collaboration

• Scientific expertise• experimental design• sampling• image analysis• new algorithms• uncertainty estimation

• Practical applications• industrial process control• environmental monitoring• quality control• …

• Joint development• PAT hardware• PAT software• integrated systems

The endThe end

Thank you for attention!