investigation on packaging material of counterfeit...
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INVESTIGATION ON PACKAGING MATERIAL OF COUNTERFEIT
PANADOL® VARIANTS AND CREOBIC® CREAM BY NON-DESTRUCTIVE
TESTS
TUHFAH ZAHIDAH BINTI SHAMSUDDIN
A dissertation submitted in partial fulfilment of the
requirements for the award of the degree of
Master of Science (Forensic Science)
Faculty of Science
Universiti Teknologi Malaysia
2014
iii
Especially to my beloved Mother with endless gratitude and admiration
iv
ACKNOWLEDGEMENT
The writer wishes to acknowledge the supervisors; Assoc. Prof. Dr. Azli Bin
Sulaiman and Assoc. Prof. Dr. Wan Aizan Binti Wan Abdul Rahman for their
guidance and patience alongside the journey in establishing this dissertation.
To Assoc. Prof. Dr. Umi Kalthom Binti Ahmad and Dr. Naji Arafat Bin
Mahat for their endless encouragement. Ministry of Health (MOH) and
Pharmaceutical Enforcement Division, MOH for the trust and financial support.
Infinite appreciation to Malaysia Fire and Rescue Department of Johor, UTM
lecturers, staffs and friends whom have contributed to this achievement.
v
ABSTRACT
The World Health Organization (WHO) has defined counterfeit drugs as
those which are “deliberately mislabelled with respect to identity and/or source”.
Packaging materials are ubiquitous and manufacturers are able to obtain them from
multiples of supplier. That is the reason for the unfeasible confiscation. There are a
few methods used to detect counterfeit products through its packaging: visual
inspection (visible light) and other optical methods such as infrared and ultraviolet
analysis as well as pattern recognition. The objective of this study is to differentiate
the features on the packaging material found from the original and the counterfeit of
the same fast-moving pharmaceutical products. There are four different product
packaging investigated obtained through over-the-counter purchase, from the
complainant or seized by the authority. Firstly, examination is carried out on the
direct paperboard packaging by comparison; physical examination on the basic
properties (viz. dimension, thickness and prints), microscopic, optical character
recognition (OCR) and near infrared analysis. Then, further investigation on the
information printed and hologram serial number was done. Determination of the
originality of the products upon procurement was done through authenticating the
hologram. Microscopic examination on the printed paperboard exhibited consistent
printing effect for all of the counterfeit and the genuine ones. Results on OCR for
certain parts of the prints show constant difference between the original and
counterfeit. However, the IR results indicated that such differences may prove
inconsistent and hence unreliable to be used for comparison. In conclusion, the
counterfeit pharmaceutical packaging may be distinguished from the genuine ones
through physical examination of its basic properties, microscopic observation and
OCR.
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ABSTRAK
Pertubuhan Kesihatan Sedunia (WHO) telah mentakrifkan ubat palsu sebagai
“kesilapan pelabelan yang disengajakan berkenaan dengan identiti dan/atau sumber”.
Bahan pembungkusan boleh didapati secara meluas daripada sumber pembekal yang
banyak. Oleh sebab itu, rampasan terhadap bahan mentah pembungkusan untuk
ubatan palsu sukar dilakukan. Terdapat beberapa kaedah yang biasa digunakan untuk
mengesan produk palsu melalui pembungkusan: pemeriksaan visual dan kaedah
optik lain seperti analisis inframerah dan ultralembayung serta pengecaman corak.
Objektif kajian ini adalah untuk membezakan ciri-ciri bahan pembungkusan yang
terdapat pada produk tulen dan palsu daripada produk farmaseutikal tertentu.
Terdapat empat bahan pembungkusan produk yang berbeza diperolehi melalui
pembelian di kaunter, daripada pengadu atau disita oleh pihak berkuasa. Pemeriksaan
dijalankan terhadap bungkusan kotak luar dengan membuat perbandingan;
pemeriksaan fizikal ke atas sifat-sifat asas (dimensi, ketebalan dan cetakan),
pemeriksaan mikroskopik, pengecaman aksara optik (OCR) dan analisis inframerah.
Kemudian, siasatan lanjut mengenai maklumat yang tercetak dan nombor siri
hologram dilakukan. Penentuan awal ketulenan produk dilakukan semasa perolehan
melalui pengesahan hologram. Pemeriksaan sifat-sifat asas serta mikroskopik ke atas
kualiti percetakan boleh membezakan antara produk palsu dan tulen. Hasil analisa
OCR untuk bahagian-bahagian tertentu pada percetakan di luar kotak pembungkusan
menunjukkan perbezaan antara produk tulen dan palsu. Walau bagaimanapun,
analisis inframerah menunjukkan spektrum yang tidak dapat membezakan antara
produk palsu dan produk tulen. Kesimpulannya, bahan pembungkusan produk
farmaseutikal palsu dan tulen boleh dibezakan menggunakan sifat-sifat asas,
pemeriksaan mikroskopik dan OCR.
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TABLE OF CONTENT
CHAPTER TITLE PAGE
DECLARATION ii
DEDICATION iii
ACKNOWLEDGEMENT iv
ABSTRACT v
TABLE OF CONTENT vii
LIST OF TABLES x
LIST OF FIGURES xi
LIST OF ABBREVIATIONS xv
LIST OF APPENDICES xvi
CHAPTER 1 INTRODUCTION 1
1.1 Introduction 1
1.2 Research Background 1
1.3 Problem Statement 2
1.4 Research Objectives 3
1.5 Scope of the Research 3
1.6 Significance of Research 4
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CHAPTER 2 LITERATURE REVIEW 6
2.1 Background Study 6
2.2 Pharmaceutical Supply and Distribution 7
2.3 Regulatory Body, Laws and
Enforcement Division
8
2.4 Anti-counterfeiting Measures 9
2.5 Types of Counterfeiting 12
2.6 Packaging Material 13
2.7 Forensic Perspective 14
2.8 Paperboard Focussed 15
CHAPTER 3 METHODOLOGY 19
3.1 Introduction 19
3.2 Products Selection 19
3.3 Sampling Pattern and Procurement 21
3.4 Apparatus 22
3.5 Instrumentation 23
3.6 Procedure 23
3.6.1 Physical Evaluation 23
3.6.1.1 Special Feature(s)
Detection
23
3.6.1.2 Dimension and
Thickness
Measurement
23
3.6.2 Fourier Transform Infrared –
Attenuated Total Reflectance
(FTIR-ATR)
25
3.6.3 Microscope Observation on
Print Quality
25
ix
3.6.4 MeditagTM Serial Number
Investigation
26
3.6.5 Pattern Recognition 26
CHAPTER 4 RESULTS AND DISCUSSION 27
4.1 Introduction 27
4.2 Procurement and Distribution Pattern 27
4.3 Physical Evaluation 31
4.3.1 Special Feature(s) Detection 31
4.3.2 Dimension and Thickness
Measurement
34
4.4 Fourier Transform Infrared – Attenuated
Total Reflectance (FTIR-ATR)
36
4.5 Microscope Observation on Print
Quality
45
4.6 MeditagTM Serial Number Investigation 48
4.7 Pattern Recognition 50
4.8 Limitations 54
CHAPTER 5 CONCLUSIONS AND
RECOMMENDATIONS
55
5.1 Conclusions 55
5.2 Recommendations 57
REFERENCES 58
APPENDICES 62
x
LIST OF TABLES
NO. TITLE PAGE
4.1 Dimension and Thickness Measurement 35
4.2 Missing Hologram Reported from a Pharmaceutical
Company
50
4.3 Comparison text recognized in Panadol® Actifast
(Based on Figure 4.22)
52
4.4 Comparison text font in Panadol® Actifast
(Based on Figure 4.22)
53
xi
LIST OF FIGURES
NO. TITLE PAGE
2.1 Phases in implementing the registration scheme 11
2.2 Sheet-fed offset printing unit 16
2.3 Gravure printing 16
2.4 Flexographic printing 17
3.1 MeditagTM Decoder 20
3.2 MeditagTM Hologram; (a) Second Generation (b)
Third Generation
20
3.3 Second Generation Hologram Positive Identification;
(a) Before – KKM visible, (b) After – KKM invisible
21
3.4 Second Generation Hologram Negative Identification;
(a) Before – KKM visible, (b) After – KKM remain
visible
21
3.5 Reverse Tuck End with Tab used in Creobic® Cream 24
3.6 Straight Seal End used in Panadol® 24
3.7 Reverse Tuck End used in Panadol® Actifast and
Panadol® Extend
25
4.1 Counterfeit samples procured according to districts in
Johor
28
4.2 Genuine samples procured according to districts in
Johor
29
4.3 Counterfeit samples scattering pattern 29
4.4 Distribution of products procured according to
originality
32
4.5 Comparison of the shadow effect on each alphabet on
the brand name in PR (a) Counterfeit (b) Genuine
32
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4.6 Comparison of the bullet position and capitalization of
alphabet ‘I’ in the suitability statement in Panadol®
Actifast (a) Counterfeit (b) Genuine
33
4.7 Comparison of image sharpness of the human figure
on Panadol® Extend (a) Counterfeit (b) Genuine
33
4.8 Comparison of the existent of the mole/black colour
dot of the partial face on Creobic® Cream
(a) Counterfeit (b) Genuine
34
4.9 Comparison of common peaks from IR spectrum of
the coat surface of the paperboard packaging for
Panadol® (a) Counterfeit (b) Genuine
37
4.10 Comparison of common peaks from IR spectrum of
the inner side of the paperboard packaging for
Panadol® (a) Counterfeit (b) Genuine
38
4.11 Comparison of common peaks from IR spectrum of
the coat surface of the paperboard packaging for
Panadol® Actifast (a) Counterfeit (b) Genuine
39
4.12 Comparison of common peaks from IR spectrum of
the inner side of the paperboard packaging for
Panadol® Actifast (a) Counterfeit (b) Genuine
40
4.13 Comparison of common peaks from IR spectrum of
the coat surface of the paperboard packaging for
Panadol® Extend (a) Counterfeit (b) Genuine
41
4.14 Comparison of common peaks from IR spectrum of
the inner side of the paperboard packaging for
Panadol® Extend (a) Counterfeit (b) Genuine
42
4.15 Comparison of common peaks from IR spectrum of
the coat surface of the paperboard packaging for
Creobic® Cream (a) Counterfeit (b) Genuine
43
4.16 Comparison of common peaks from IR spectrum of
the inner side of the paperboard packaging for
Creobic® Cream (a) Counterfeit (b) Genuine
44
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4.17 Comparison of the print of the shadow effect from the
alphabet on the brand name of Panadol®;
Magnification 10 x 3.2 (a) Counterfeit (b) Genuine
45
4.18 Comparison of the print of the shadow effect from the
trademark of Panadol® Actifast; Magnification 10 x
3.2 (a) Counterfeit (b) Genuine
46
4.19 Comparison of the print of the caplet on Panadol®
Extend; Magnification 10 x 3.2 (a) Counterfeit (b)
Genuine
46
4.20 Comparison of the location of the mole/black colour
dot of the partial face on Creobic® Cream;
Magnification 10 x 3.2 (a) Counterfeit (b) Genuine
47
4.21 Genuine hologram serial number bought by
companies legitimately for their pharmaceutical
products found on counterfeit samples
49
4.22 OCR output for Panadol® Actifast (a) Genuine
(b) Counterfeit 1 (c) Counterfeit 2
50
xiv
LIST OF ABBREVIATIONS
API - Active pharmaceutical ingredient
CC - Creobic® Cream
cm - Centimeter
DCA - Drug Control Authority
DUNAS - Dasar Ubat Nasional
FTIR-ATR - Fourier Transform Infrared – Attenuated Total Reflectance
MOH - Ministry of Health
mm - Millimeter
MTDCC - Ministry of Domestic Trade, Co-operatives and Consumerism
nm - Nanometer
NPCB - National Control Pharmaceutical Bureau
OCR - Optical character recognition
OTC - Over-the-counter
PA - Panadol® Actifast
PCA - Principal Component Analysis
PE - Panadol® Extend
PED - Pharmaceutical Enforcement Division
ppi - Pixel per inch
PR - Panadol®
RFID - Radio frequency identification
SD Standard Deviation
TDM - Toxicity Drug Monitoring
USFDA United State Food and Drug Administration
WHO World Health Organization
xv
LIST OF APPENDICES
NO. TITLE PAGE
A Abstract: Oral presentation at 11th Indo Pacific
Association of Law, Medicine and Science
(INPALMS) Congress 2013
62
B1 IR spectrum coat surface of genuine Panadol®
(Example)
63
B2 IR spectrum inner side of genuine Panadol®
(Example)
64
B3 IR spectrum coat surface of counterfeit Panadol®
(Example)
65
B4 IR spectrum inner side of counterfeit Panadol®
(Example)
66
C1 IR spectrum coat surface of genuine Panadol®
Actifast (Example)
67
C2 IR spectrum inner side of genuine Panadol®
Actifast (Example)
68
C3 IR spectrum coat surface of counterfeit Panadol®
Actifast (Example)
69
C4 IR spectrum inner side of counterfeit Panadol®
Actifast (Example)
70
xvi
D1 IR spectrum coat surface of genuine Panadol®
Extend (Example)
71
D2 IR spectrum inner side of genuine Panadol® Extend
(Example)
72
D3 IR spectrum coat surface of counterfeit Panadol®
Extend (Example)
73
D4 IR spectrum inner side of counterfeit Panadol®
Extend (Example)
74
E1 IR spectrum coat surface of genuine Creobic®
Cream (Example)
75
E2 IR spectrum inner side of genuine Creobic® Cream
(Example)
76
E3 IR spectrum coat surface of counterfeit Creobic®
Cream (Example)
77
E4 IR spectrum inner side of counterfeit Creobic®
Cream (Example)
78
CHAPTER 1
INTRODUCTION
1.1 Introduction
Throughout the chapter, discussion will be from the investigation on the
information on the paperboard packaging such as the manufacturing date and
hologram serial number search using the Mediharta Sdn. Bhd. official web site,
observations using microscope, Fourier transform infrared – attenuated total
reflectance (FTIR-ATR) and optical character recognition (OCR). The findings of
the sampling pattern and procurement of the samples will also be discussed.
1.2 Research Background
In this study, focussed is on the paperboard packaging. There are several
analysis to be used on this material. Since the information pertaining to the medicine
is printed on the paperboard, there is also of importance to analyse this as a way to
recognize its authenticity. In Malaysia, a medicinal product will only be recognized
as registered when there are two (2) features; product registration number and
MeditagTM hologram. Thus, the hologram will also be investigated through its unique
serial number.
2
1.3 Problem Statement
Counterfeit medicine has flooded Malaysia market and has been an issue
among healthcare professionals. Public seem to have easy access to counterfeit
medicine rather than the authentic due to the vast availability and cheaper price.
Usage of counterfeit medicine will endanger lives due to the unknown ingredient in
the products.
Although the better way to ensure a fake drug is by direct analysis of the
active pharmaceutical ingredient (API), but this is not feasible due to short course
therapies and what only remains is the packaging material. Nevertheless, most
patients/customers will discard the packaging materials as thought to be unimportant
although it contain most of the information pertaining to the medication.
Furthermore, modus operandi of modern criminals’ separately ship packaging
materials of the fake and the raw materials for the pharmaceutical dosages makes it
even harder for the perpetrators to be caught.
Counterfeiting is also a form of intellectual property infringement. Even
though this is not of forensic significance but this may be the main reason if a jointly
effort to be applied in further studies.
The importance to precede such study is to prepare the authorities, stake
holders and public in differentiating fake medicinal products. For the authorities to
know that there are such analyses to be done on the packaging and possibly
determining its source; for the stakeholders to cooperate and challenge the current
situation on counterfeiting and for the public to be more careful in purchasing their
health care products to ensure its safety, efficacy and quality.
3
1.4 Research Objectives
The objectives of this study are:
i. To determine the features on the packaging material found in the original
and the counterfeit on the same fast-moving pharmaceutical products by
visual examination.
ii. To create a simple, reproducible, reliable and applicable method viz.
infrared analysis, microscopy observation and pattern recognition for
early detection of counterfeit in the department.
1.5 Scope of the Research
The samples for this study was procured in the state of Johor and only
accounts for the centre of each districts and regions. Samples consist of three (3)
Panadol® variant; namely Panadol®, Panadol® Actifast and Panadol® Extend as
well as one (1) topical antifungal, Creobic® Cream.
Analysis of the packaging material is via visual examination of the printed
side of the paperboard, microscope observation of the print quality, attenuated total
reflectance infrared analysis on the paperboard box and the coated surface as well as
optical character recognition of the printed side of the paperboard.
4
1.6 Significance of Research
The need to conduct this research is to point out the manifestation of
counterfeit pharmaceuticals in the market from a scientific point of view. Currently,
there is no study pertaining to the investigation of these counterfeit from the
packaging material use in Malaysia. Since there are countless of packaging materials
suppliers and manufacturers, a better framework must be implemented in the
packaging material procurement process to reduce the counterfeit products.
There is no provision under the laws enforced by Pharmacy Enforcement
Division to try cases pertaining to counterfeits. At present, the fake medicinal
products were prosecuted under different Acts and for offences not mentioning
counterfeiting; and the practice as stated below:
1. Section 13 Possession for sale of poison and sale of poison, Poisons Act 1952
which only can try cases where the content has been confirmed containing
poison as listed in the First Schedule, Poisons List.
2. Section 15 Adulteration, Sales of Drugs Act 1952 which needs to analyse the
ingredients and to be compared with the declared content and does not
provide any means to charge the counterfeiter.
3. Regulation 29 Directions, Control of Drugs and Cosmetics Regulation 1984
which states that the Director of Pharmaceutical Services may issue written
guidelines pertaining to labelling, storage including requirement of the
containers etc. The labelling includes the use of hologram at point of sale.
Unfortunately, according to Mediharta Sdn. Bhd., the maker for MeditagTM
hologram there has not been a case relating to the counterfeit holograms.
5
Recently, Pharmacy Enforcement Johor received information pertaining to
the supply of packaging material and enquires whether there are any way(s) to
determine the culprit of this counterfeiting activity. Since the core function of the
department is to investigate offences made under the act and forensic science may
contribute to finding the probable source, no doubt this study should be conducted.
58
Azzi, A., Battini D., Persona, A. and Sgarbossa, F. (2012). “Packaging Design:
General Framework and Research Agenda.” Packaging Technology Science. 25.
435 – 456.
Been, F., Roggo, Y., Degardin, K., Esseiva, P. and Margot, P. (2011). “Profiling of
Counterfeit Medicines by Vibrational Spectroscopy.” Forensic Science
International. 211. 83 – 100.
Berman, B. (2008). “Strategies to Detect and Reduce Counterfeiting Activity.”
Business Horizon. 51. 191 – 199.
Bosco, G.L. (2010). “James L. Waters Symposium 2009 on Near-Infrared
Spectroscopy.” TrAC Trends in Analytical Chemistry. 29. 197 – 208.
Bourbakis, N. G. and Burton, M. (1991). “OCR Technique for the Design of Non-
conventional Typed Text Reading Systems”. Engineering Application Artificial
Intelligent. 4. 191 – 204.
Butler, M. (2004). “Pack to the Future.” Manufacturing Chemist. September Edition.
Davison, M. (2011). “Pharmaceutical Anti-Counterfeiting: Combating the Real
Danger from Fake Drugs.” Haboken N. J.: John Wiley and Sons Inc. 113 – 126.
Department of Statistics Malaysia (2010). “Population Distribution and Basic
Demographic Characteristics.”
European Union (2011). “Q&A: Directive on Falsified Medicines”
Gällstedt, M. and Hedenqvist, M. S. (2005). “Packaging-related Mechanical and
Barrier Properties of Pulp-Fiber-Chitosan Sheets.” Carbohydrate Polymer. 63. 46
– 53.
59
Janrógiewicz, M. (2012). “Application of Near-infrared Spectroscopy in the
Pharmaceutical Technology.” Journal of Pharmaceutical and Biomedical
Analysis. 66. 1 – 10.
Johnson, B. (2011). “A Pharmaceutical Company's View on Supply-Chain Security:
A Perspective from Pfizer.” Pharmaceutical Technology. 35.
Kiphan, H. (2001). “Handbook of Print Media: Technologies and Production
Methods.” Berlin, Germany: Springer-Verlag. 641.
Kwok, K. and Taylor, L. S. (2012). “Analysis of the Packaging Enclosing a
Counterfeit Pharmaceutical Tablet Using Raman Microscopy and Two-
dimensional Correlation Spectroscopy.” Vibrational Spectroscopy. 61. 176 – 182.
Kwok, K.M., Ho, S.H., Zhang, W.B., Day, R. and Ho, C.M. (2013). “Characteristics
of Overdose and Non-Overdose Suicide Attempts in a Multi-ethnic Asian
Society.” Asian Journal of Psychiatry. 6. 373 – 379.
Lacy, C.F., Armstrong, L.L., Goldman, M.P., Lance, L.L. (2005). “Drug Information
Handbook International with Canadian and International Drug Monographs.” 13th.
ed. Hudson, Ohio. Lexi-Comp Inc. 28 – 30.
Lodha, R.M. (2000). “ORDER Bombay High Court - Procter and Gamble India Ltd.
And Richardson-Vicks Inc. Against Endolabs Limited and Shree Mangesh
Medical Stores on 16 December 1999.” Bombay Law Reporter. 1. 938. Retrieved
December 1, 2013, from http://indiankanoon.org/doc/588725/
Malaysia (1952). “Control of Drugs and Cosmetics Regulations 1984”: PU (A)
477/09.
Malaysia (1997). “Penal Code”: Act 574.
Malaysia (1952). “Poisons Act”: Act 366.
60
Malaysia (1952). “Sales of Drugs Act”: Act 368.
Malaysia (2011). “Trade Description Act”: Act 730.
Malaysian National Medicines Policy (2007). Ministry of Health Malaysia.
Mathialagan, A. and Kaur, S. (2012). “Community Perception on the Use of Over the
Counter (OTC) Medications in Malaysia.” International Journal of Scientific &
Engineering Research. 3.
Možina, K., Černič, M. and Demšar, A. (2007). “Non-destructive Methods for
Chemical, Optical, Colorimetric and Typographic Characterisation of a Reprint.”
Journal of Cultural Heritage. 8. 339 – 349.
Rodionova, O.Y. and Pomerantsev, A.L. (2010).”NIR-based Approach to Counterfeit
Drug Detection.” TrAC Trends in Analytical Chemistry. 29. 795 – 803.
Sumimoto, M. (1990). “Paper and Paperboard Containers.” Kadoya T. “Food
Packaging.” Sandiago, Ca: Academic Press Inc. 53 – 56.
The Star (2002). “Help Check Fake Medicines, Local Governments Told.”
Toxicity Drug Monitoring (TDM) Services Sultanah Aminah Hospital Johor Bahru
(2013). “Aktiviti Farmakokinetik Klinikal - Pemonitoran Ubat Terapeutik (TDM)
Negeri Johor.” Unpublished.
United State Food and Drug Administration (2006). “What is the Status of Electronic
Track and Trace across the Drug Supply Chain?” FDA Counterfeit Drug Task
Force Reports: Section IV.
World Health Organization (2002). “WHO Expert Committee on Specifications for
Pharmaceutical Preparations.” WHO Technical Report Series.