the role of a center of excellence in developing pat ...€¦ · pittcon 2005 orlando fl, march 2nd...

AstraZeneca PAT Center of Excellence1

The Role of a Center of Excellence in The Role of a Center of Excellence in The Role of a Center of Excellence in The Role of a Center of Excellence in The Role of a Center of Excellence in The Role of a Center of Excellence in The Role of a Center of Excellence in The Role of a Center of Excellence in Developing PAT ApplicationsDeveloping PAT ApplicationsDeveloping PAT ApplicationsDeveloping PAT ApplicationsDeveloping PAT ApplicationsDeveloping PAT ApplicationsDeveloping PAT ApplicationsDeveloping PAT Applications

! Pittcon 2005 Orlando FL, March 2nd 2005

! Nils-Erik AnderssonAstraZeneca R&D, Mölndal Sweden


OutlineOutlineOutlineOutlineOutlineOutlineOutlineOutline

! Business needs and New ways of working

! PAT tools and Process understanding

! Conclusions


! Stocks

! Cycle time

! Waste Reduction

! Variability

! Quality by Design

Business needs Business needs Business needs Business needs Business needs Business needs Business needs Business needs –––––––– PAT benefitsPAT benefitsPAT benefitsPAT benefitsPAT benefitsPAT benefitsPAT benefitsPAT benefits


R&D R&D R&D R&D R&D R&D R&D R&D –––––––– Operations Operations Operations Operations Operations Operations Operations Operations Joint Joint Joint Joint Joint Joint Joint Joint (Ad)(Ad)(Ad)(Ad)(Ad)(Ad)(Ad)(Ad)Venture!Venture!Venture!Venture!Venture!Venture!Venture!Venture!

FormulationFormulationDevelopmentDevelopment

Analytical Analytical DevelopmentDevelopment

ManufacturingManufacturing

Process Process EngineeringEngineering

Quality Quality AssuranceAssurance

RegulatoryRegulatoryAffairsAffairs

Real Time Release?Real Time Release?Robust Process!Robust Process!

Process MeasurementsProcess MeasurementsMultivariate AnalysisMultivariate Analysis

Raw Material CharacterisationRaw Material Characterisation

Quality Risk AssessmentQuality Risk AssessmentCritical Control PointsCritical Control Points

Control LoopsControl LoopsDesign SpaceDesign Space

PAT Tools EvaluationPAT Tools EvaluationPAT Tools DevelopmentPAT Tools Development

PAT Tools ImplementationPAT Tools Implementation


PAT DefinitionPAT DefinitionPAT DefinitionPAT DefinitionPAT DefinitionPAT DefinitionPAT DefinitionPAT DefinitionFDA Guidance for Industry, Sept 2004FDA Guidance for Industry, Sept 2004

PAT is a system

for designing, analyzing and controlling manufacturing

through timely measurements of critical quality and performance attributes

with the goal of ensuring final product quality


PAT RealityPAT RealityPAT RealityPAT RealityPAT RealityPAT RealityPAT RealityPAT Reality

! Many technologies available

! However, few tools available off the shelf

! Use of technology is evolving

! Applications are product and unit specific

! Focus is on enhancing process understanding

! Scientifically based nomenclature needed

We need scientifically justified tools!


How can a PAT Center of How can a PAT Center of How can a PAT Center of How can a PAT Center of How can a PAT Center of How can a PAT Center of How can a PAT Center of How can a PAT Center of Excellence contribute?Excellence contribute?Excellence contribute?Excellence contribute?Excellence contribute?Excellence contribute?Excellence contribute?Excellence contribute?

! Hub for corporate scientific and technical competence" Evaluate and advice on selection of PAT technology,

including IT systems" Congregate critical mass to develop cutting edge PAT

technology" Coordinate external scientific cooperation and internal work

! Increase speed of PAT implementation in all parts of the company" Provide the glue between formulation development and

analytical development, between R&D and Operations and between science and corporate experience


“When you can measure what you are speaking about, “When you can measure what you are speaking about, and express it in numbers, you know something about it; and express it in numbers, you know something about it;

but when you cannot measure it,but when you cannot measure it,when you cannot express it in numbers,when you cannot express it in numbers,

your knowledge is of a meager and unsatisfactory kind”your knowledge is of a meager and unsatisfactory kind”

Lord KelvinLord Kelvin

Old Truth...Old Truth...Old Truth...Old Truth...Old Truth...Old Truth...Old Truth...Old Truth...


! Vibrational Spectroscopy (NIR, Raman, midIR etc.)

! UV-Vis! Fluorescence! Acoustics (e.g. ultrasound)! NMR! MS! Imaging (e.g. Vision, Process Tomography)! Spectroscopic Imaging (e.g. NIR Imaging,

Raman microscopy, IR microscopy)! Accelerated Dissolution! Chemometrics

" Design of Experiments" Multivariate Analysis (PCA, PLS, NN etc.)" Multivariate SPC

PAT PAT PAT PAT PAT PAT PAT PAT ToolsToolsToolsToolsToolsToolsToolsTools........................


PATScheme

PATInvestigations

Advanced Process Control

Characterization ofProcess Chemistry/Dynamics

Real-Time Quality Control

Process optimizationProcess scale-up Process validation

Trouble shooting

PAT PAT PAT PAT PAT PAT PAT PAT Tools in use…Tools in use…Tools in use…Tools in use…Tools in use…Tools in use…Tools in use…Tools in use…

Process control loops Assessment of material properties

AstraZeneca PAT Center of Excellence

-0.30

-0.20

-0.10

0.00

0.10

0.20

0.30

-2 -1 0 1 2

t[2]

t[1]

Hpc_lf.M1 (PLS), Untitled, Work setScores: t[1]/t[2]

Ellipse: Hotelling T2 (0.05)

1

2

3

4

5

67

89

10

11

12

13

1415

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33 34

3536

37

38

39

40

41

42

43

44

4546

47

4849

50

515253

5455

56

57

58

59

60

6162

636465

66

67

68

69

70

71 72

7374

75

76

7778

7980

81

82

83

8485

86

8788

89

90

91

92

9394

95

9697

98

99 100

101

102

103

104

105

106

107

108

109

110

111112113

116

117

118119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134 135

136

137

138139

140141

142143

144

145

146147

148

149

150

151

152

153

154155

156

157158

159

160 161

162

163

164

165166167

168

169

170

171

172

173

174175176

177

178

179

180

181

182

183

184

185

186

187

188

189

190191

192

193

194

195

Simca-P 7.01 by Umetri AB 1998-11-10 17:21

Principal Component Analysis(PCA) of NIR datafor different batches of the same “quality” of raw material supplied fromtwo different vendors. Note that all batches comply withpharmaco-peialstandards!

Vendor 1

Vendor 2

• J. Vessman, Pharm. Anal., Overview, in Encyclopedia of Anal. Sciences, Academic Press Limited, 1995, p. 3807.• O. Svensson, M. Josefson, F.W. Langkilde, Applied Spectroscopy, 51 (1997) 1826-1835.

Raw material quality

Process UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingNatural VariabilityNatural Variability


NIR Spectroscopy NIR Spectroscopy NIR Spectroscopy NIR Spectroscopy NIR Spectroscopy NIR Spectroscopy NIR Spectroscopy NIR Spectroscopy –––––––– a PAT toola PAT toola PAT toola PAT toola PAT toola PAT toola PAT toola PAT tool

! Chemical information!

! Physical information!

! Selective? Sensitive?

! Sampling?

! Robust towards process or material changes?

! Instrument variations?

! Calibration transfer and maintenance?


Measurement number

Spec

tral r

esid

uals

SS

Q /

10-4

0 50 100 150 200 250 300 350

B

0

0.5

1

1.5

2

2.5

3

3.50 m/s 0.09 m/s 0.19 m/s 0.38 m/s 0.73 m/s

Measurement number

Spec

tral r

esid

uals

SS

Q /

10-4

0 50 100 150 200 250 300 350

B

0

0.5

1

1.5

2

2.5

3

3.50 m/s 0.09 m/s 0.19 m/s 0.38 m/s 0.73 m/s

Scanning grating NIR

M. Andersson, O. Svensson, S. Folestad, M. Josefson, K.-G. Wahlund, “NIR Spectroscopy on Moving Solids Using a Scanning Grating Spectrometer – Impact on Multivariate Analysis”, Chemometrics and Intelligent Laboratory Systems, 75 (2005), 1-11.

! ”Sampling” on moving solids by scanning grating NIR exhibit spectral artefacts

! Artefacts interfere in qualitative and quantitative analysis

! Emanate from varying sample scattering properties

! Can not be mathematically deconvoluted!

Process Measurements: InProcess Measurements: InProcess Measurements: InProcess Measurements: InProcess Measurements: InProcess Measurements: InProcess Measurements: InProcess Measurements: In--------Situ NIRSitu NIRSitu NIRSitu NIRSitu NIRSitu NIRSitu NIRSitu NIR


! ”Sampling” on moving solids by FT NIR exhibit spectral artefacts in interferograms

! Transformation to frequency domain → artefacts well outside NIR spectral region

! FT NIR is a suitable technique for qualitative and quantitative analytical process applications

FT-NIR

O. Berntsson, L.-G. Danielsson, S. Folestad, “Characterization of Diffuse Reflectance Fiber Probe Sampling on Moving Solids using a Fourier Transform NIR Spectrometer, Analytica Chimica Acta , 431 (2001) 125-131

Process Measurements: InProcess Measurements: InProcess Measurements: InProcess Measurements: InProcess Measurements: InProcess Measurements: InProcess Measurements: InProcess Measurements: In--------Situ NIRSitu NIRSitu NIRSitu NIRSitu NIRSitu NIRSitu NIRSitu NIR


• O Berntsson, L-G Danielsson, M O Johansson, S Folestad. Analytica Chimica Acta 419 (2000) 45-54• O Berntsson, L-G Danielsson, B Lagerholm, S Folestad. Powder Technology 123 (2002) 187-195

Mixer

Raw data

Calibration

Statistical process control (SPC)

Process UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingInIn--situ blend monitoringsitu blend monitoring


O Berntsson, S Folestad,L-G Danielsson, B Lagerholm, PowderTechnology, 123 (2002) 187-195

In-situblendmonitoring:Scale-up

PAT PAT PAT PAT PAT PAT PAT PAT -------- Process UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess Understanding


ConclusionsConclusionsConclusionsConclusionsConclusionsConclusionsConclusionsConclusions

! PAT tools are not available off the shelf

! A PAT scheme is built upon a high level of process understanding

! PAT implementation requires extensive cross functional working

! PAT is not only techniques, it is a mind set!

! A Center of Excellence can make the difference between failure and success when implementing meaningful PAT!

the role of a center of excellence in developing pat ...€¦ · pittcon 2005 orlando fl, march 2nd...

Documents