Process Analytical Technology (PAT) Capabilities and Implementations under QbD Principles QbD and PAT Department

Process Analytical Technology (PAT)

Capabilities and Implementations under QbD Principles

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Overview and Concepts

Fixed Process and

low knowledge

Pharmaceutical

manufacturing Process

Input

Quality Control (QC)

of the final product

Product waste

Output

Quality check

of raw materials



Actual situation:

Variable

raw material properties +

Fixed

manufacturing process =

Variable

product quality (variable output)

Time delay

RCPE – QbD and PAT 2 Jan 2013

Overview and Concepts

Variable Process

and Mechanistic

Understanding

Pharmaceutical

manufacturing Process

Input

Quality Control (QC)

of the final product

(Prediction of Quality)

Product waste

Output

Quality check

of raw materials



Desired situation:

Variable

raw material parameters +

Variable

manufacturing process =

Fixed

output

Real Time

Release

(RTR)

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Quality by Design Approach

Pharmaceutical Quality System

Pharmaceutical Quality System (ICH Q10)

Criticality Assessment Risk Analysis Product Understanding Quality Target Product Profile (QTPP) critical Quality Attributes (cQAs) Risk Analysis Process Understanding Process Modelling and Simulation Process Analysis Inputs → Outputs Process Analytical Technologies

Pr

ior Kno

w

ledg

e

Control Strategy for cPPs

Real Time Release

Design of Experiment

Risk Analysis

Process Control

Feedback Control Loops

Control Strategy for cPPs

Real Time Release Process Analytical Technologies Regulator y Impleme ntatio n

Quality Manual (ICH Q10)

Quality Risk Management (ICH Q9)

QbD documentation Product & Process Continuous Improvement

Kno

w

ledg

e

Managemen

t

(Q

10)

RCPE – QbD and PAT 4 Jan 2013

Process Analytical Technology



Analytical

in the context of PAT includes much more than measuring, it

is all about an overall process understanding!

Process Control

Knowledge based process understanding – developement of a

Design Space (DS)

Data Analysis and

Management

Design of Experiment (DoE) and Multivariate Data Analysis (MVDA)

Measurement of Critical

Attributes/Parameters

Process analysers for in-line non-invasive quality monitoring

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CFD-Simulation under QbD principles

Fermentation Process



Problem

: No reliable simulation-based tools for bioreactor design exist



Goal

: Prediction of fermentation process performance depending on reactor design and

operational parameters



Concept

: Use of CFD-simulation under QbD principles and validation of the simulation by

means of literature and experimental data

CFD bioreactor characterisation

1) oxygen saturation after air injection

2) bubble injection

3) velocity field



Simulation-based design of a fermentation process and

simulation validation

6 Jan 2013

Application of Statistical Science



Creation of Design Spaces



Multivariate analyses of data



Computation of parameter relations

-6 -4 -2 0 2 4 6 8 10 ASA TA B M C C A S A *A S A T A B *T A B M C C *M C C A S A *T A B A S A *M C C T A B *M C C ° N=19 R2=0,774 RSD=0,8343 DF=13 Q2=0,374 Conf. lev.=0,95

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

Investigation of knowledge management application areas in pharma



Development of an overall knowledge management platform and

ensure essential functionalities

Jan 2013

RCPE – QbD and PAT 8



Closing gap of information management

PAT for Process Monitoring

Multi-Probe-NIR-Spectrometer Prototype



Testing and implementing a spectrometer prototype by EVK GmbH, Austria.

Compact spectrometer with

wavelength dispersion system

25 standardized ports for monitoring 25

fiber optic probes at once

Simultaneous online monitoring of



multiple process spots



process steps



multiple processes



without differences between spectrometers



no time delays

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

Closed-Loop Control: Feedback connection via SIPAT



Integration of Simca, Matlab, Camo into SIPAT system

Input parameters:



Barrel temperatures



Adapter temperature



Screw speed



Feed rate

Output parameters

:



Barrel temperatures



Adapter temperature



Screw speed



Feed rate



Material pressure



Material temperature



Torque



Spectrum

PAT at Pharmaceutical Extrusion

Monitoring and Supervisory Control

RCPE – QbD and PAT Jan 2013

Monitoring of Continuous Processing

Pharmaceutical Extrusion



Monitoring of API content variations and

residence time distribution with PLS model



Investigation of the influence of kneading

elements on API content fluctuations

kneading screw

conveying screw

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PAT at Tablet Press

Monitoring of Powder Homogeneity

RCPE – QbD and PAT 12 Jan 2013

Sentro probe

Filling shoe

API

main

excipient

wavelength [nm]

abs

orpt

ion

unit

s

[

a.

u

.]

visible

fluctuations

minor deviation

2

princ

ipal

c

om

ponent

1

principal component

possible major deviation

(last 30 sec of process)



Principle Component Analysis (PCA) shows

clear differences over time



Definition of limits (regions in PCA plot)

to differentiate

in spec

and

out of spec

PAT at Tablet Coating in a Fluid Bed

Monitoring of Coating Thickness

0 0.25 0.5 0.75 1 -0.2 0 0.2 0.4 0.6 0.8 1 1.2 Time (h) m e a s u re d c o a ti n g / d e s ir e d c o a ti n g l e v e l window fouling () crystal coating () 0 0.25 0.5 0.75 1 -0.2 0 0.2 0.4 0.6 0.8 1 1.2 Time (h) 0 0.25 0.5 0.75 1 -0.2 0 0.2 0.4 0.6 0.8 1.0 1.2 Time (h) 0 % 100 %



Monitoring with NIR and Spatial Filter Velocimetry

0 % 100 %

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New PAT-Tool for Tablet Coating

Optical Coherence Tomography

RCPE – QbD and PAT 14

Co

atin

gp

roce

ss

In cooperation with

Development of



Pharma conform sensor



Algorithm for coating thickness out of

moving tablet bed

Project Goal:



In-line monitoring of coating process

Excerpt of Scientific Publications

• Adam, S., Suzzi, D., Radeke, C., Khinast, J. G., An integrated Quality by Design (QbD) approach towards design space definition of a blending unit operation by Discrete Element Method (DEM) simulation, Eur. J. Pharm. Sci. 42 (2011), 1-2, 106-115

• Koller D. M., Hannesschläger, G., Leitner, M., Khinast, J. G, Non-Destructive Analysis of Tablet Coatings with Optical Coherence Tomography, Eur. J. Pharm. Sci. 44 (2011), 142–148

• Hodzic, A., Llusa, M., Fraser, S. D., Scheibelhofer, O., Koller, D., Reiter, F., Laggner, P., D. M., Khinast, J. G., Small- and Wide-Angle X-Ray Scattering (SWAXS) for Quantification of Aspirin Content in a Binary Powder Mixture, Int. J. Pharm. 428 (2012), 1–2, 91–95

• Heigl, N., Hodzic, A., Llusa, M., Tritthart, W., Reiter, F., Fraser, S., Laggner, P., Khinast, J. G., Potential of Raman Spectroscopy for Evaluating Crushing Strength of Tablets, J. Pharm. Innov. 7 (2012), 76-86

• Hodzic, A., Llusa, M., Heigl, N., Tritthart, W., Fraser, S. D., Laggner, P., Khinast, J. G., Effect of process variables on the Small and Wide Angle X-Ray Scattering (SWAXS) patterns of powders, granules and pharmaceutical tablets, Powd. Tech. 221 (2012), 447–452

• Scheibelhofer, O., Hohl, R., Salar-Behzadi, S., Haack, D., Koch, K., Kerschhaggl, P., Sacher, S., Menezes, J., Khinast, J. G., Fluid bed in a Flash, AIChE Annual Meeting 2012, Pittsburgh

• Wahl, P., Markl, D., Treffer, D., Menezes, J., Koscher, G., Roblegg, E., Khinast, J. G., PAT for Pharmaceutical Extrusion Monitoring and Supervisory Control, AIChE Annual Meeting 2012, Pittsburgh

• Scheibelhofer, O., Balak, N., Wahl, P., Koller, D., Glasser, B. J., Khinast, J. G., Monitoring Blending of Pharmaceutical Powders with Multipoint NIR Spectroscopy, AAPS Pharm. Sci. Tech. (2012), in press

• Scheibelhofer, O., Balak, N., Koller, D., Khinast, J. G., Spatially Resolved Monitoring of Powder Mixing Processes via Multiple NIR-Probes, Powd. Tech., accepted for publication

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Concluding Remarks



RCPE: the one stop point for

QbD & PAT pre-industrial research projects



Pharmaceutical Engineering



Matching specific PAT tools with user requirements



Interaction of PAT-tools, models and control software



Risk Analysis with state-of-art tools



Design of Experiments, Design-space development



Multivariate Data Analysis



QbD implementations and training



Qualification of equipment and analytical methods

RCPE – QbD and PAT 16 Jan 2013

Contacts

Dr. Simon Fraser, ppa.

Deputy Director

Massimo Bresciani

Director Scientific Operations

Contacts: e-mail: [email protected] phone: +43/316/873/30915

Dr. Thomas K. Klein

Director – Business

Prof. Dr. Johannes G. Khinast

Director – Science

Dr. Stephan Sacher

Team Leader QbD/PAT

Contacts:

e-mail: [email protected] phone: +43/316/873/30959