Overcoming Counterfeiting by Design - · PDF fileFilm Coating Manager. ... Ideally the...

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


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


Anti – Counterfeiting Agenda

The ProblemOptions available to the formulatorProcess considerations for the options—Granulation—Compression—Film Coating—Printing

User recognitionConclusion


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


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.


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


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


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


Granulation


Granulating Agenda

Formulation

Methods

Process

Equipment


Formulation

Typical tablet formulationAPIFillerBinderDisintegrantLubricantFor anti counterfeiting purposes colour and flavour can also be considered, however the process can influence what is possible.


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


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


Methods of Granulating

Wet Granulation—Low Shear—High Shear—Fluidized Bed

Dry Granulation—Direct Compression—Roller Compaction


Granulation Process

Compact

Mill

Screen

Blend with lubricant

Blend


Compressed Tablet

Dry mix

Wet mix

Dry

Screen


API + Filler +Binder + Disintegrant

API + Filler +Binder + Disintegrant

API + Compressible Filler + Disintegrant + Flow Aid

Roller CompactionDirect CompressionWet Granulating

Blend


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


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.


Wet Granulation – colour migration

Coloured Wet Granule Coloured Dry Granule

White Core

Water loss

Coloured Edge

Drying

Screen –Granule

breakdown


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.


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.


Disintegrant

Active

Lubricant

Compressible Filler

Flow aid

Dry Blending - Colour Issues

Colour Flavour


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.


Compressing


Agenda

Tablet design— Shapes—Embossing—Layering

Process

Equipment


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.


Tablet design - Shapes


Tablet Design - Embossing


Tablet design - Bilayer Tablets


Process - Compression Cycle


Process - Laboratory Compressing Machines


Process - Production Compressing Machines


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


Disintegrant

Active

Lubricant

Compressible Filler

Flow aid

Compressing - Colour Issues

Colour Flavour


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. .


Film Coating


Agenda

FormulationProcess—Reconstitution—Coating

EquipmentOther Methods—Gel Dipping—Enrobing


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.


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).


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


Formulation - Candurin Microstructure

Photos courtesy of Merck.


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.


Formulation - Pearlescent effects


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


Formulation - Tablet Coating Application

Sub coat/top coat


Formulation - Taste

SaltSour (acidic)Bitter (actives)Sweet (sugar)Umami (meat)


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.


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


Formulation - Micro Taggants

Hair


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.


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.


Process - Film Coater Installation


Process - Fully Perforated, Side-vented Coating Pan

PerforatedPan

CoatingSpray

TabletBed

ExhaustPlenum

DryingAir Duct


Other technologies – Gel dip/Enrobing


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.


PRINTING


Agenda

FormulationMethods—Offset Gravure—Pad—Ink Jet

Process—Etch Design—Double siding

Printing examples


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


Process – Offset Gravure

Feed hopperGravure roll

Rubber transfer roller

Ink reservoir

Transport belt

Exit chute

Doctor blade

Multi-track offset-gravure printer


Process - Pad Printing

PI/450 MC

Input

Feedingsystem

Blowingsystem

Dryer

Exit

Operating panel

Output and sampling system

Brushbox

Control

Input

Print Station


Sealedink

reservoir

Pump

5 micronfilter

nozzleElectrostatic deflection

Objectbeing

printed

Computercontrol

Solvent reservoir

Process - Inkjet Printing


Process

Offset-gravure etched roller Pad printer transfer pad


Printing Examples


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.


USER RECOGNITION


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.


CONCLUSION


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.


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.


Conclusion

Which tablet doesthe counterfeiter

prefer


Questions?


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.

Overcoming Counterfeiting by Design - · PDF fileFilm Coating Manager. ... Ideally the...

Documents

Transcript of Overcoming Counterfeiting by Design - · PDF fileFilm Coating Manager. ... Ideally the...