Upload
trinhnguyet
View
214
Download
1
Embed Size (px)
Citation preview
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Overcoming Counterfeiting by Design
James GilmourFilm Coating Manager
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Anti – Counterfeiting
This presentation is given on behalf of the Drug Product Engineering and ProcessingFocus Group set up by the APS.
Is there a way to "formulate out" or "process out“counterfeiting? Solid oral dosage forms
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Anti – Counterfeiting Agenda
The ProblemOptions available to the formulatorProcess considerations for the options—Granulation—Compression—Film Coating—Printing
User recognitionConclusion
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
The Problem of Counterfeit Products
Consumers—Potential Illness or loss of life—Higher overall costs for pharmaceuticals
Drug Manufacturers—Lost revenues—Increased Liability—Damage to Brand Integrity—Decrease in Company Reputation
Governments—Decline in public confidence in health care—Lost tax revenues—Increased enforcement costs
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Overt Protection
Do you recognize this drug?
NO:
Distinctive shape and colourMemorable imageNo trademark protectionBrand identityCounterfeit protection
Ideally the security of the product should be with the product and the consumer should be able to check authenticity before use.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Overt options available to the formulator
For the consumer overt technology can be used - a simple visual test of identity is required, however for visual id they must know what the product should look like – this is for the manufacturer to educate/implement.Current /typical methods of tablet identification:—Colour—Shape—Embossing—Printing
Other possibilities include:—Flavours/odours in the core/coating—Gel dipping—Enrobing
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Covert options available to the formulator
Chemical taggants—Trace chemicals only detected by highly specific reagent
systems. Requires destruction of the tablet.Biological taggants— Very low level in product or coating. Only detected by highly
specific reagent systems. Requires destruction of the tablet.DNA taggants—Highly specific “lock and key” reagent system.
Isotope ratios—Naturally occurring isotopes can be determined by laser
fluorescence or NMR. Requires expensive lab equipment.Micro-taggants—Microscopic markers
Source: Anti-counterfeit and Anti-tampering Technologies for the Protection of Medicines (2010) Technology Working Group, International Medical Products Anti-Counterfeiting Task-Force
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Processing Options
Granulation— Colour— Flavour
Compression— Shape— Embossing— Layering
Film Coating— Pearlescent colour— Flavour— Taggants - Physical-chemical identifiers (PCiDs)
Printing— Logos— Bar codes— Physical-chemical identifiers (PCiDs)
Others— Gel dipping— Enrobing
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Granulation
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Granulating Agenda
Formulation
Methods
Process
Equipment
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Formulation
Typical tablet formulationAPIFillerBinderDisintegrantLubricantFor anti counterfeiting purposes colour and flavour can also be considered, however the process can influence what is possible.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Colourants
Water soluble dyes—FD&C yellow no 5 (Tartrazine)—FD&C blue no 2 (Indigo Carmine)
FD&C Aluminium Lakes—FD&C yellow no 5—FD&C blue no 2
Inorganic Pigments—Iron Oxides
Non Synthetic Pigments—Carmine—Riboflavine
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Flavours
Salty: —cinnamon, orange, cherry, citric acid,
cocoa, raspberryBitter: —cocoa, raspberry, cherry, licorice, orange
Sour: —raspberry and other fruit syrups
Oily: —rhubarb, and lemon syrups; wintergreen
and peppermint oils
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Methods of Granulating
Wet Granulation—Low Shear—High Shear—Fluidized Bed
Dry Granulation—Direct Compression—Roller Compaction
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Granulation Process
Compact
Mill
Screen
Blend with lubricant
Blend
Blend with lubricant
Compressed Tablet
Dry mix
Wet mix
Dry
Screen
Blend with lubricant
API + Filler +Binder + Disintegrant
API + Filler +Binder + Disintegrant
API + Compressible Filler + Disintegrant + Flow Aid
Roller CompactionDirect CompressionWet Granulating
Blend
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Wet Granulation - High Shear
High Shear— API; diluent; disintegrant; binder
added to mixer and dry mixed (blended) together.
— Liquid addition either gravity fed or pumped/sprayed, can be a binder solution or solvent (water) only.
— Granulating to end point.— Discharge/delumping into fluid bed
drier (FBD); or Tray Dryer; or Microwave and dried.
Anticounterfeit option: — Pigments and/or flavour can be
added in the dry mix or can be used in the granulating solution.
— Problems are flavour loss on FBD/tray drying, microwave effects, colour uniformity, colour migration, cleaning.
Impellor
Chopper
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Wet Granulation - Fluid Bed
Filters
Spray gun
Fluidising Air
Discharge
Fluidised Powder
Fluid Bed—API; filler; disintegrant;
possibly binder added to FBD and fluidised together.
—Granulating liquid sprayed onto fluidised bed, can be a binder solution or solvent (water) only.
—Granulating to end point.—Discharge into hopper.
Anticounterfeit option: —Pigments and/or flavour can
be added at process start or can be used in the granulating solution.
—Problems are flavour loss, colour uniformity, cleaning.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Wet Granulation – colour migration
Coloured Wet Granule Coloured Dry Granule
White Core
Water loss
Coloured Edge
Drying
Screen –Granule
breakdown
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Roller compaction
Rollers
Feed Augers
Mill
Screen
Powder Blend
Roller Compactor—This is controlled feeding of
pre blended API; filler; disintegrant; possibly binder through a set of directly opposed, counter-rotating rollers with a controllable aperture (roller gap) between the rollers.
—Anticounterfeit option: Possible problems are flavour and colour change due to pressure application, cleaning.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Direct Compression / Blending
Direct Compression—API; filler; disintegrant; binder
added to blender and mixed together to end point.
—Lubricant added to blender and mixed together to end point.
—Discharge into hopper.Anticounterfeit option: —Pigments and/or flavour can be
added at initial blending stage.—As small quantities of pigment
or flavour are used a pre mix with another formula material (i.e. filler) for uniformity is ideal.
—Problems are colour uniformity, cleaning.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Disintegrant
Active
Lubricant
Compressible Filler
Flow aid
Dry Blending - Colour Issues
Colour Flavour
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Conclusion
Colouring and Flavouring in GranulatingFor the Originator— Simple to formulate in.— If tablet is colour coated - only detected by destruction of the tablet.— Darker coloured cores can affect pale coloured coatings— Quantity of colour could be a problem - regulatory— Stability can be problematic— Relies on users sense of taste— Cleaning issues— Both colouring and flavouring of the granule can cause problems
during granulation, adding at the blending stage is the simplest option
Anticounterfeiting— Both colouring and flavouring of the granule would be problematic for
counterfeiters.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Compressing
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Agenda
Tablet design— Shapes—Embossing—Layering
Process
Equipment
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Tablet design
Shapes—Many shapes are possible.—This complicates manufacture for the originator and
the counterfeiter. Very noticable to the user.Embossing—Huge range of options, letters numbers, names and
logo’s. Very noticable to the user.Bilayer—Typically done for technical reasons of incompatibility
or release profile.—This complicates manufacture for the originator and
the counterfeiter. Very noticable to the user.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Tablet design - Shapes
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Tablet Design - Embossing
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Tablet design - Bilayer Tablets
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Process - Compression Cycle
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Process - Laboratory Compressing Machines
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Process - Production Compressing Machines
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Process - scale-up of tablet compression
Independent Variables(process variables)
Dependent Variables(product attributes)
Precompression forceCompression force (upper and lower)Machine speedDwell timeForce feeder settingEjection force
Tablet hardnessTablet weight variationDisintegration timeDissolutionColour variation
Lab Scale Output Production Scale OutputSingle punchMinimal
Multiple punch1,000,000 tablets/hour
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Disintegrant
Active
Lubricant
Compressible Filler
Flow aid
Compressing - Colour Issues
Colour Flavour
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Conclusion
Shapes, Embossing and Layering in CompressingFor the Originator —Simple shapes and logos are currently regularly used, more
complex shapes and logos could be used —Layering is possible but problematic.—Coloured cores are possible but cause problems i.e. shade
changes may occur with varying pressure applied.—Getting the user to recognise the product is critical.
Anticounterfeiting—Complex shapes and logos are harder for the counterfeiter.
Also dependant on core formulation, i.e. poor formulation may not work well with these complex shapes.
—Layering is much harder for the counterfeiter – special machinery, colour matching.
—Coloured cores – harder for the counterfeiter. .
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Film Coating
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Agenda
FormulationProcess—Reconstitution—Coating
EquipmentOther Methods—Gel Dipping—Enrobing
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Formulation – Immediate Release
Polymer
—Hydroxypropyl methylcellulose (HPMC); Hydroxypropyl cellulose (HPC); Hydroxyethyl cellulose (HEC); Polyvinyl alcohol (PVA)
Plasticiser
—Polyethylene glycols; Glycerol; Propylene glycol; Glyceryl triacetate (Triacetin); Triethyl citrate; Acetyl triethyl citrate; Diethylphthalate; Acetylated monoglyceride
Pigment/Opacifier
—Aluminium Lakes; Titanium Dioxide; Iron Oxides
Anticounterfeit
—Pearlescents (Candurin), flavours, micro taggants.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Formulation - Pearlescent Pigments
Definition: Pearlescent pigments are optical filters whichreflect and transmit light which falls upon them.
Requirements for a good pearlescent pigment are:high refractive indexgood transparencysmooth surfaces and a platy structure with lengths between 5 and 60 micronsoptimum plate thickness of 60-160 nm
Ref: L. Armanini, Basic Optics and Pearlescent Pigments (Technical Bulletin No. 1 - The Mearl Corporation).
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Formulation - Candurin Basic Structure
0.5 µ MicaMica0.1-0.5 µ
TiO2 and/or Fe2O3 (0.06 - 0.16 µ)
5-60 µ
TiO2 only: Silver, Green, Blue, Red, YellowTiO2 and Fe2O3: Gold
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Formulation - Candurin Microstructure
Photos courtesy of Merck.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Formulation - Observed Colours
Plate Thickness (nm) Optical Thickness (nm)* Observed Colour
60 140 white/silver84 210 gold106 265 red118 295 violet132 330 blue159 395 green
*Optical thickness = plate thickness x plate refractive index.
Ref: Encyclopedia of Polymer Science & Technology, Vol. 10 (1969)., pp. 197, 203.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Formulation - Pearlescent effects
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Formulation - Pearlescent effects
Red Purple Green Blue Yellow
1.5
2.0
3.0
Effect of Increasing Weight Gain of Pearlescent coating on a Blue Subcoat
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Formulation - Tablet Coating Application
Sub coat/top coat
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Formulation - Taste
SaltSour (acidic)Bitter (actives)Sweet (sugar)Umami (meat)
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Formulation - Flavours
Vanilla, Bubble gum, Lemon, Lime, Orange,Cherry, Grapefruit, Grape, Liquorice, Coffee,Chocolate, Mint, Cherry, Peach, Raspberry,Cinnamon, Citric acid, Cocoa, Licorice,Rhubarb and Peppermint.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Formulation - Micro Taggants
Rapid authenticationNon-destructive Covert marker reconstituted with aqueous film coat
100 micron micro-tag Invisible to naked eye on tablet surface. Enlarged view -140X magnification
Detector
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Formulation - Micro Taggants
Hair
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Process – Coating Reconstitution
For flavour/taggants:• Add the film Coating system to water anddisperse.
• Add flavouring• Add taggants• Mix to end point
For pearlescents: • Add the pearlescentfilm coating formulato water and mix toend point.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Process – Film Coating
1. Load tablets into pan.2. Warm tablets with hot air until they are ready to coat.3. Rotate pan to give tablets movement. 4. Spray moving tablets with coating. 5. Continue coating to end point - weight gain.6. Cool tablets7. Remove tablets from pan .8. Store in well sealed containers.9. Clean equipment thoroughly.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Process - Film Coater Installation
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Process - Fully Perforated, Side-vented Coating Pan
PerforatedPan
CoatingSpray
TabletBed
ExhaustPlenum
DryingAir Duct
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Other technologies – Gel dip/Enrobing
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Conclusion
Pearlescent Colours, Flavours and Taggants in CoatingFor the Originator— Pearlescents simple to formulate into formulation.— Flavours and taggants need to be added at coating reconstitution— Possible loss of flavour due to atomisation, air flow in coating machine.— Flavours rely on users sense of taste— Product recognition by the user is critical.— Cleaning issues
Anticounterfeiting— Incorporating flavours is harder for the counterfeiter to copy.— The use of a colour coat with a pearlescent top coat means the
counterfeiter has to know the sub coat colour and the quantity of the pearlescent top coat - much harder for the counterfeiter
— Taggants are a higher level of anti-counterfeiting but requires the user to employ special equipment.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
PRINTING
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Agenda
FormulationMethods—Offset Gravure—Pad—Ink Jet
Process—Etch Design—Double siding
Printing examples
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Formulation
Polymer—Shellac Ester, Shellac, PVAP, HPMC
Pigments —Oxides, Lakes
Solvents —Ethanol; Ethyl Acetate; IPA; N-butanol, Propylene Glycol
Additives—Wetting agents; Ph modifiers; Defoamers; Plasticizers
Anticounterfeiting—Taggants
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Process – Offset Gravure
Feed hopperGravure roll
Rubber transfer roller
Ink reservoir
Transport belt
Exit chute
Doctor blade
Multi-track offset-gravure printer
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Process - Pad Printing
PI/450 MC
Input
Feedingsystem
Blowingsystem
Dryer
Exit
Operating panel
Output and sampling system
Brushbox
Control
Input
Print Station
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Sealedink
reservoir
Pump
5 micronfilter
nozzleElectrostatic deflection
Objectbeing
printed
Computercontrol
Solvent reservoir
Process - Inkjet Printing
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Process
Offset-gravure etched roller Pad printer transfer pad
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Printing Examples
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Conclusion
Logos, letters, numbers and Bar Codes—Printing simple logo/letters/numbers are currently
regularly used—Product recognition by the user is critical.
Anticounterfeiting—Complex images are harder for the counterfeiter to
copy.—Bar coding can give individual identity to the tablet but
requires a reader, this could be a mobile phone app or a pharmacy/shop based reader.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
USER RECOGNITION
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
User Recognition
Options for the user areRecognising the tablet from colour, flavour shape and logoReading the bar code using a mobile phone app or a pharmacy/shop based reader.Reading the taggants using a pharmacy/shop based reader.
This relies on the user knowing what the products features areFor visual recognition/description the manufacturer can put an accurate description with pictures on their web site for the user to easily access.Bar code or taggants information should give the user information – references that can be checked with the manufacturer through an anticounterfeiting contact.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
CONCLUSION
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Anti – Counterfeiting Conclusion - 1
Counterfeiting poses risks to patients, pharmaceutical companies and government agenciesRegarding "formulating out" or "processing out“ counterfeiting we see we can add other materials and use more complex processes to make it more difficult for the counterfeiter.Use of colour and flavour in the core for granulation and compression is problematic for the originator and not ideal. Use of complex shapes and logos in compression is problematic for the originator and counterfeiter. Use of bilayering in compression is problematic for the originator and counterfeiter.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Anti – Counterfeiting Conclusion - 2
Use of pearlescent colour and flavour in the film coating is already achievable for the originator and problematic for the counterfeiter to match. Use of Micro Taggants in the film coating is possible for the originator and problematic for the counterfeiter. Use of Gel dipping or enrobing is possible for the originator and problematic for the counterfeiter. Use of complex logos and bar coding in printing is already achievable for the originator and problematic for the counterfeiter. Packaging solutions only address part of the problemWe need to apply a multi layer approach Everyone is responsible for authentication and education of the end user is paramountThese choices have impact on manufacturing and have to be commercially viable.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Conclusion
Which tablet doesthe counterfeiter
prefer
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Questions?
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Anti-counterfeiting Technologies
The information contained in this document is not intended as legal advice, and should not be relied upon for that purpose.
The information in this document has been compiled by Colorcon, Inc. from a variety of sources, and is believed to be as accurate as reasonably possible, but no warranty, expressed or implied, is made with regard to such information.
All trademarks are property of BPSI Holdings LLC.
© BPSI Holdings LLC, 2012.