1. Recognition of the 'high quality’ forgeries among medicines
Oxana Rodionova
Semenov Institute of Chemical Physics, RAS
Moscow
Russian Chemometric Society
Kazan WSC-6
August 23, 2019

2. Kazan WSC-6
August 23, 2019

3. Forgery types Low concentration/quality of active substance Placebo
Wrong active substance
Another excipient
Forgery types
Produced with violation of technological regulations
Contain no declared substances
Kazan WSC-6
August 23, 2019

4. Why NIR - based approach ?
Near- infrared (NIR) spectroscopy
Multivariate data analysis (chemometrics) +
Advantages
Routine test time min
Sample preparation No
Personal training level Low
Trade-off
Disadvantages
NIR is not a stand-alone technology. Mathematical calibration for each type of medicine is required
Kazan WSC-6
August 23, 2019

5. Methods
Measurements
NIR (800 – 2 500nm) reflectance spectra with integrating sphere
Data pre-processing
SNV/MSC + column-wise data centering
Variable reduction
PCA
Supervised pattern recognition
SIMCA+special critical limits
Kazan WSC-6
August 23, 2019

6. Data Set Overview N Description Genuine batches Forgery batches Total1
Complex antibacterial drug (2 active substances)
5 (5) 50 2
Antispasmodic drug
1 (10)
1 (9) 19 3
Antibiotic drug
17 (5-10)
2 (5)
109 4
Digestive enzyme (Manufacture 1)
4 (5) 30 5
Digestive enzyme
(Manufacture 2)
11 (5) 75
Kazan WSC-6
August 23, 2019

7. Forgeries of different 'quality'
1. Easily detected without instruments
Dietary supplements
2. Easily detected by a regular pharmacopeia test as well as by the NIR-based approach
3. Easily detected by NIR-based approach but are not detected by the pharmacopeia tests
4. Various intricate cases for NIR approach and are not detected by the pharmacopeia tests
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August 23, 2019

8. Complex antibacterial drug (2 active substances)
25 original tablets from 5 batches
25 counterfeit tablets from 5 batches
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August 23, 2019

9. Antispasmodic drug 10 original pills 9 counterfeit pills Kazan WSC-6
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10. Antibiotic drug 89 original tablets from 17 batches
20 counterfeit tablets from 2 batches
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August 23, 2019

11. Main steps SIMCA classification with class limits for genuine samples
PCA model for genuine samples
SIMCA classification with class limits for genuine samples
Representative calibration set
Pertinent external validation
Proper variable selection
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August 23, 2019

12. Variability of genuine drugs A digestive enzyme (Data sets 4 &5)
Manufacture N1
Manufacture N2
20 original tablets from 4 batches
10 counterfeit tablets from 1 batch
55 original tablets from 11 batches
Kazan WSC-6
August 23, 2019

13. Influence of spectral region. Data set 5. (A digestive enzyme)
Counterfeit
4 batches (5 pills)
Genuine Sample
45 pills from 9 batches
Genuine
11 batches (5 pills)
75 Samples
Calibration
Test
10 pills from 2 batches
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August 23, 2019

14. Calibration & Classification (previous lecture)
outlier
outliers
extreme
A=2
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August 23, 2019

15. Unscrambler overview
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August 23, 2019

16. NIR spectra
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17. Classification on short spectral region
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August 23, 2019

18. Step-by-step classification . Data set 3
Synthetic Antiprotozoal and Antibacterial Agent, 1-(β-hydroxy-ethyl)-2-methyl-5-nitroimidazole,
Genuine
17 batches (5-10 pills)
Counterfeit
2 batches (5 pills)
Test
109 Samples
Calibration
Counterfeit
2 batches (5 pills)
Genuine Sample
68 pills from 12 batches
Genuine Sample
31 pills from 6 batches
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August 23, 2019

19. Initial PCA model G25 G25 4 3 5 DoF_h 1.99 5.68 4 DoF_v 5.87 5.78 5 MM
IQR 4 3 5
N=68, A=4
g=0.01
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August 23, 2019

20. Classification .
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21. Classification without batch G25
Calibration
Test
N=64, A=3
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22. Peculiarity of G25
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23. NIR spectra for G25
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August 23, 2019

24. Conclusions
Each medical product should be carefully tested for batch-to-batch variability
The selection of a spectral region should be done for each type of medicine individually. The choice of the spectral region may essentially influence the final classification results.
It is crucial not only to recognize forgeries but also to avoid misclassification of genuine samples. The application of reliable acceptance limits is of great importance
Kazan WSC-6
August 23, 2019

25. Thanks! Be Healthy! Do not apply any remedy!
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August 23, 2019