Calibration Transfer: A Pharmaceutical Case Study
James K. Drennen, III DCPT
Duquesne University Center for Pharmaceutical Technology (DCPT)
http:// http://www.pharmacy.duq.edu/DCPT/home.html www.pharmacy.duq.edu/DCPT/home.html
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DCPT Activities • • • • •
PAT Method Development PAT Validation Pharm. Formulation and Development Biotech. Dosage Form Development Sensor Technology – NIR, Chemical Imaging, Acoustic Spectroscopy
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Outline • Introduction and Methodology – – – – –
Calibration transfer vs. calibration update Instrumental or product drift Failure detection Investigation/Remediation activities Appropriate transfer standards
• Pharmaceutical Analysis Case Study – Failure Detection – Application of calibration transfer method – Results
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Calibration Transfer • In general, calibration transfer refers to the derivation of a model to relate two sets of measurements – Calibration transfer from lab. to line – Calibration transfer after instrument maintenance/repair
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Introduction • Definition of “calibration transfer”? – Calibration transfer is an understatement of the process. In many situations, instrument matching or instrument update is sufficient, while in others, calibration transfer entails complicated models relating one measurement paradigm to another (different sampling geometry, instrument make/model, even transfer between methods)…
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Continuum of Calibration Transfer Types Preprocessing Methods (scatter correction, derivatives, etc.)
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Instrument Matching (univariate linear, etc.)
Orthogonal Projection Methods
Complex, black-box Method-Method: PDS, ANN
Calibration Update • Definition: The enhancement of an existing calibration model through the inclusion of additional calibration samples – Calibration update samples are more representative of the current test samples than the original calibration samples
• Calibration update performed following change in product (eg: new supplier) 8
Possible Outcomes of NIR Prediction of Assay Results
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Valid NIR Result
Not-Valid NIR Result
In Spec
1
2
Out of Spec
NIR Test Result for Tablet:
Evaluation of NIR Test:
4
3
1. Accepted result - pass 2. Investigation required (NIR result not acceptable) 3. Investigation required (NIR result not acceptable) 4. Accepted result – fail or During initial period – Investigation recommended
Failure Detection NIR Instrument
Sample
Potential errors ( B) due to: -Raw material change -Process change
Potential errors ( A) due to: -New instrument -Changed instrument response
NIR Data
Pre treatment
Instrument Matching
Model
Instrument Standardization
Result (Prediction)
Calibration Transfer Processes
NIR Prediction
Historical data and action threshold
Is prediction valid? (Q res and T 2 )
Result requires investigation
Result is valid
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Final Result
Prediction Validity
Instrument Evaluation and corrective action
Calibration Transfer Data from tablet test
Instrument Evaluation and corrective action
Review internal Performance test results External Instrument Performance test Rescan Tablet
Faulty Initial Scan?
No
Has instrument performance changed significantly
No
Type B problem
Collect data from appropriate samples
Perform calibration update procedure
Yes Yes
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Verify sample positioning system operation
Type A problem
Resume NIR testing
Recall PDS samples
Validate changes
Collect PDS data
Perform PDS instrument update protocol
Validate changes
Resume NIR testing
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Potential investigation actions 1. Review daily internal performance test and internal performance test history 2. Run an internal performance test 3. Rescan tablet 4. Review SPC of method assessment 5. Review SPC of tablet test results 6. Perform a parallel laboratory test on tablet
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•
Potential remediation actions A. Instrument repair, standardization, and external performance test B. Calibration update C. Address as an out-of-specification (OOS) investigation
Instrument evaluation and corrective action (legend)
Instrument evaluation and corrective action
Normal performance test results
Close to limit
Instrument performing correctly
1
Tablet positioning error
A
Normal performance test results Original spectrum not representative of sample
QC NIR measurement indicates in-spec tablet
4-6
QC NIR prediction
OOS tablet
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6
OOS tablet
In-spec tablet
In-spec tablet
B
• Investigation tests/actions: 1-6 • Remediation actions: A-C • See Exhibit 5 for legend
QC NIR measurement indicates OOS tablet
3 In-spec tablet
Spectrum representative of sample
2
Fail
C
Document and continue
C
A
B Instrument evaluation and corrective action (continued)
Type A problem
Type B problem
Recall standardization samples Collect data from appropriate samples Collect standardization data Perform calibration update procedure Perform instrument standardization protocol
Validate changes
Validate changes
Resume NIR testing 14
Pharmaceutical Case Study: Online Tablet Analysis • Why are transfer/update protocols necessary? – Need for a calibrated backup instrument – Eventual expansion to further lines – Transfer-in-time of knowledge from earlier experiments
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Example: Master and slave instruments 1.4 1.3
Reflectance Ratio
1.2 1.1 1 0.9 0.8 0.7 0.6 1300
1400
1500
1600
1700
Wavelength ( nm )
16
1800
1900
2000
Comparison of new and reference instruments Reference Inst. Absorbance @ 1440 nm
1.05 1 0.95 0.9 0.85 0.8 0.75 0.7 0.65
0.6
0.65
0.7
0.75
0.8
0.85
0.9
0.95
New Instrument Absorbance @ 1440 nm
17
1
1.05
Calibration transfer model 0.6
0.5
Multiplicative Constant
Arbitrary Units
0.4
0.3
0.2
Additive Coefficients 0.1
0
-0.1 1300
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1400
1500
1600 1700 Wavelength ( nm )
1800
1900
2000
Prediction Following InstrumentInstrument Transfer Predicted Content ( mg, bias corrected)
70 65
N = 78 RMSEP = 2.25 %RSD = 23.2 % r = 0.973
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r2 = 0.946
55 50 45 40 35 30 30
35
40
45
50
55
Measured Content ( mg )
19
60
65
70
Example: Lamp change 1.4
1.3
Reflectance Ratio
1.2
1.1
1
0.9
0.8
0.7 1300
1400
1500
1600
1700
Wavelength ( nm )
20
1800
1900
2000
Calibration transfer model for correcting lamp change 0.05 0.04 0.03
Reflectance Ratio
0.02 0.01
Additive Calibration Transfer Coefficients
0 -0.01 -0.02 -0.03 -0.04 -0.05 1300
1400
1500
1600
1700
Wavelength ( nm )
21
1800
1900
2000
Justification for baseline subtraction method Following Lamp Change, Uncorrected ( mg )
50 49.5 49 48.5 48 47.5 47 46.5 46 46
22
46.5
47
47.5 48 48.5 Prior to Lamp Change, ( mg )
49
49.5
50
Following Lamp Change, Transfer Corrected ( mg )
Prediction quality with calibration transfer 50 49.5 49 48.5 48 47.5 47 46.5 46 46
46.5
47
47.5
48
48.5
Prior to Lamp Change, ( mg )
23
49
49.5
50
Relative Error (multiple)
How Many Transfer Samples?
1
5
10
15
20
Number of Transfer Samples ( n )
24
25
30
Stability of transfer standards 4 3.8
Transfer SEP ( mg )
3.6 3.4 3.2 3 2.8 2.6 2.4 2.2 2
0
5
10
15
20
Time ( days )
25
25
30
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Summary • Definition of calibration transfer/calibration update procedure is critical component of method development efforts • Calibration transfer standards may include samples of product
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Acknowledgements • Carl Anderson • Robert Cogdill • David Molseed
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• AstraZeneca • Brimrose Corp.
Duquesne University Center for Pharmaceutical Technology (DCPT)
http:// http://www.pharmacy.duq.edu/DCPT/home.html www.pharmacy.duq.edu/DCPT/home.html
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