CRITICAL SELECTION OF CRITICAL SELECTION OF PRIMARY PACKAGINGPRIMARY PACKAGING

Shams RustomShams RustomLabopharmLabopharmSr. Director, Product Development & ManufacturingSr. Director, Product Development & Manufacturing

OutlinesOutlines

What is primary packaging ?What is primary packaging ?Types of Primary PackagingTypes of Primary PackagingSelection criteria of primary pack mat for oral Selection criteria of primary pack mat for oral solid dosage formsolid dosage formPackaging materials variablesPackaging materials variablesPackaging process variables & troubleshootingPackaging process variables & troubleshootingPackaging process validation strategyPackaging process validation strategyAntiAnti--counterfeit packagingcounterfeit packagingGlobal strategy & Regulatory requirementsGlobal strategy & Regulatory requirements

Primary Packaging DefinitionPrimary Packaging Definition

Refers to packaging that immediately Refers to packaging that immediately envelopes a product. It provides most of the envelopes a product. It provides most of the strengthstrength

and and barrierbarrier

needed to safeguard a needed to safeguard a

productproduct’’s purity, potency and integrity from s purity, potency and integrity from the time it leaves the assembly line until itthe time it leaves the assembly line until it’’s s used by the consumer.used by the consumer.

Examples of primary packaging include Bottles, Examples of primary packaging include Bottles, blister packs, etc. blister packs, etc.

Healthcare Packaging & ProductsHealthcare Packaging & ProductsPharmaceutical PackagingPharmaceutical Packaging

BottlesBottlesBlister Films and FoilsBlister Films and FoilsClosure LinersClosure LinersAerosol/Pump System Aerosol/Pump System ComponentsComponentsPharma Rubber ComponentsPharma Rubber Components

Types of Primary PackagingTypes of Primary PackagingGlass Bottles (colored / transparent)Glass Bottles (colored / transparent)Polymer Bottles & Closures e.g. PET, Polymer Bottles & Closures e.g. PET, HDPE etcHDPE etcTubes & Pump System componentsTubes & Pump System componentsBlistersBlisters

PVC film with Aluminum foilPVC film with Aluminum foilPVC/PVDC film with Aluminum foilPVC/PVDC film with Aluminum foilAclar/ PVC or Aclar/PVC/PE with Al. FoilAclar/ PVC or Aclar/PVC/PE with Al. FoilCold Form Foil (CFF)Cold Form Foil (CFF)COC (PVC free barrier film)COC (PVC free barrier film)Aluminum / Aluminum blistersAluminum / Aluminum blisters

Selection CriteriaSelection CriteriaCompany Strategy & Goal (global or National?)Company Strategy & Goal (global or National?)

Trouble free global submissions (USA, EU, Japan) Trouble free global submissions (USA, EU, Japan) Global acceptance of supplier (DMF) & materials Global acceptance of supplier (DMF) & materials

Product stability & Required BarrierProduct stability & Required BarrierICH conditions for zoneICH conditions for zone--I to II or Zone II to II or Zone I--IVIV

Regulatory & Patient Compliance Regulatory & Patient Compliance Child resistant, Senior friendly etc.Child resistant, Senior friendly etc.

Cost & BenefitCost & BenefitPrice, Advantages & Compliances of the specific Price, Advantages & Compliances of the specific packaging system.packaging system.

Properties & Advantages of BottlesProperties & Advantages of BottlesGlass BottlesGlass Bottles

Convenience:Convenience:Glass is a perfect barrier to atmospheric oxygen, avoiding ranciGlass is a perfect barrier to atmospheric oxygen, avoiding rancidness, dness, changes of colour & taste.changes of colour & taste.Glass is inert. No migration of components Glass is inert. No migration of components

Inconvenience: Fragile & heavy weightInconvenience: Fragile & heavy weightPET bottlesPET bottles

Convenience: Light weight & not fragileConvenience: Light weight & not fragileInconvenience: Not a good barrier & migration of components may Inconvenience: Not a good barrier & migration of components may happen.happen.

HDPE BottlesHDPE BottlesConvenience:Convenience:

Light weight & UnbreakableLight weight & UnbreakableComparatively better barrierComparatively better barrier

Inconvenience:Inconvenience:Migration of components may happen & may affect on product stabMigration of components may happen & may affect on product stability,ility,

Types of Polymer BottlesTypes of Polymer Bottles*Type 1 *Type 1 --

PETE Polyethylene Terephthalate (PET) PETE Polyethylene Terephthalate (PET)

*Type 2 *Type 2 --

HDPE HighHDPE High--Density Polyethylene Density Polyethylene *Type 3 *Type 3 --

Polyvinyl Chloride (PVC) e.g. blistersPolyvinyl Chloride (PVC) e.g. blisters

*Type 4 *Type 4 --

LDPE LowLDPE Low--Density Polyethylene, Density Polyethylene, *Type 5 *Type 5 --

PP Polypropylene e.g. Most bottles caps. PP Polypropylene e.g. Most bottles caps.

*Type 6 *Type 6 --

PS Polystyrene e.g. Throwaway utensils,. PS Polystyrene e.g. Throwaway utensils,. *Type 7 *Type 7 --

OTHER Usually layered or mixed plastic. OTHER Usually layered or mixed plastic.

The number indicates the class of resin. Types 1 and 2 are The number indicates the class of resin. Types 1 and 2 are commonly recycled. Type 4 is less commonly recycled. commonly recycled. Type 4 is less commonly recycled. The ``Other`` types are generally not recycled because of The ``Other`` types are generally not recycled because of harmful chemicals, except perhaps in small test programs.harmful chemicals, except perhaps in small test programs.Common plastics polycarbonate (PC) and acrylonitrileCommon plastics polycarbonate (PC) and acrylonitrile--butadienebutadiene--styrene (ABS) do not have recycling numbers. styrene (ABS) do not have recycling numbers.

Identification SymbolsIdentification Symbols

PET Clarity, strength, toughness, barrier to gas and moisture.e.g. Soft drink, water, peanut butter etc.e.g. Soft drink, water, peanut butter etc.

HDPE Stiffness, strength, toughness, resistance to moisture, permeability to gas. e.g. widely used for pharmaceuticalse.g. widely used for pharmaceuticals

PVC Versatility, ease of blending, strength, toughness..e.g. widely used for blister filme.g. widely used for blister film

LDPE Ease of processing, strength, toughness, flexibility, ease of sealing, barrier to moisture. e.g. squeezable bottles & etc.e.g. squeezable bottles & etc.

PP Strength, toughness, resistance to heat, chemicals, grease and oil, versatile, barrier to moisture e.g. bottle e.g. bottle caps, caps,

PS Versatility, clarity, easily formede.g. Egg cartons, disposable cup & plates etc.e.g. Egg cartons, disposable cup & plates etc.

OTHER Dependent on polymers or combination of polymerse.g. Beverage bottle , baby milk bottles etce.g. Beverage bottle , baby milk bottles etc

Non packaging uses: Compact disc.Non packaging uses: Compact disc.

SYMSYMBOLBOL

NAMENAME PROPERTIESPROPERTIES

Comparison of Polymer Bottle propertiesComparison of Polymer Bottle properties

ResinDensity (g/ml)

MVTR1 Oxygen2 Stiffness3Impact Resist

Hot Fill Max (F)

PET-G 1.33 4.0 100 300 Fair 160O-PET 1.36 2.0 75 450 Excellent 160PET (hot fill) 1.37 1.8 55 550 Excellent 188

PP (polypropylene) 0.91 0.5 3,500 200 Fair 200

O-PP (oriented) 0.91 0.3 2,500 250 Good 220

PVC polyvinylchloride 1.35 3.0 150 300 Fair 160

HDPE (high density polyethylene)

0.96 0.5 4,000 150 Excellent 160

1 g/mil/100 sq in - 24 hrs, 2 cc/mil/sq m - 24 hrs, 3 Flexural modulus (jpsi x 1000)Source : Westbridge

Blister Films and FoilsBlister Films and Foils

Mono PPMono PPMono PVCMono PVCPVdCPVdC--coated PVCcoated PVCPCTFE laminationPCTFE laminationCOCCOC

coco--extrusionsextrusions

PETG/PCTFE laminationPETG/PCTFE laminationCFFCFF

Cold Form Foil (Alu / Alu)Cold Form Foil (Alu / Alu)

PTA film for aggressive liquids (Tekniflex)PTA film for aggressive liquids (Tekniflex)Lidding foilLidding foil

Film Layers Vs Product ContactFilm Layers Vs Product ContactSame product contact layer:Same product contact layer:

Mono PVCMono PVCPVdCPVdC--coated PVCcoated PVCPCTFE laminations (Aclar or Vaposhield)PCTFE laminations (Aclar or Vaposhield)ColdCold--Form FoilForm Foil

PVC Puretherm 1001 LHD

PVDC PCTFE AluoPA

Properties & Advantages of PVC Properties & Advantages of PVC

Pharmaceutical and Food grade onlyPharmaceutical and Food grade onlyHomopolymer type (more inert).Homopolymer type (more inert).Gauge range 125Gauge range 125µµ -- 500500µµ (5mil to 20mil).(5mil to 20mil).Common gauges: 200Common gauges: 200µµ -- 250250µµ (7.5mil & 10mil).(7.5mil & 10mil).Colors: Clear, UVColors: Clear, UV--blocker, White, Amber..blocker, White, Amber..Better adhesion with lidding foil Better adhesion with lidding foil Cheapest packaging optionCheapest packaging optionLimited barrierLimited barrier

Properties & Advantage of PVDCProperties & Advantage of PVDC

PVDC Coated Film:PVDC Coated Film:PVC Gauges 200PVC Gauges 200µµ & 250& 250µµ (7.5mil & 10mil).(7.5mil & 10mil).PVDC coatings: 40gsm, 60gsm, 90gsm & PVDC coatings: 40gsm, 60gsm, 90gsm & 120gsm.120gsm.Duplex or Triplex (25Duplex or Triplex (25µµ PE)PE)Colors: Clear and WhiteColors: Clear and WhiteMedium barrier for moisture and oxygenMedium barrier for moisture and oxygen

Duplex & Triplex PVDC coatingsDuplex & Triplex PVDC coatings

Triplex (example: VDC 250Triplex (example: VDC 250--2525--60) 60)

Duplex (example: VDC 250Duplex (example: VDC 250--40)40)

PVC 250 micronAdhesive

PVDC 60gsm

PE 25 micron

PVDC 40gsm

PVC 250micron

PCTFE is a flexible thermoplastic film made from PCTFE is a flexible thermoplastic film made from ((polyolycchlorohlorottririffluoroluoroeethylene) fluoropolymer resin thylene) fluoropolymer resin

F

C

F

F

C

Cl n

Homopolymer PCTFE filmHomopolymer PCTFE film--

100% PCTFE (additive free)100% PCTFE (additive free)

--

Less shrinkageLess shrinkage--

More cost effectiveMore cost effective

““CopolymerCopolymer””

PCTFE filmPCTFE film--

Historically firstHistorically first

--

~ 40 ~ 40 --

50 % less barrier 50 % less barrier (vs. Homopolymer)(vs. Homopolymer)

--

~95% PCTFE content~95% PCTFE content

Properties ofProperties of

PCTFE FilmPCTFE Film

PCTFE LaminationsPCTFE Laminations

Triplex LaminationTriplex Lamination

Duplex LaminationDuplex Lamination

PVC or alternative

Adhesive

PCTFE

PE

AdhesivePCTFE

PVC, PETG, BAREX®, PPOr even LDPE

Advantage of PCTFE LaminationAdvantage of PCTFE Lamination

Triplex lamination (PVC/PE/PCTFE )Triplex lamination (PVC/PE/PCTFE )More forgiving in thermoformingMore forgiving in thermoformingHistorically material of choiceHistorically material of choice

Duplex lamination (PVC/PCTFE )Duplex lamination (PVC/PCTFE )Higher yield (more area per unit weight)Higher yield (more area per unit weight)Lower cost (source reduction)Lower cost (source reduction)Better clarityBetter clarityUsed widely outside North AmericaUsed widely outside North AmericaGaining greater acceptanceGaining greater acceptance

0.000

0.005

0.010

0.015

0.020

0.025

0.030

0.035

0.040

0.045

PVC/PE/PVDC 90gsm PVC/PCTFE 15µ

Flat SheetFormed Blister

PVDC or PCTFE barrierPVDC or PCTFE barrier

??40gsm and 60gsm PVDC are best in class40gsm and 60gsm PVDC are best in class1515µµ

PCTFE is better than 90gsm PVDCPCTFE is better than 90gsm PVDC

PCTFE: long shelf life, does not yellowPCTFE: long shelf life, does not yellowPVDC: provides Oxygen barrier PVDC: provides Oxygen barrier

Properties & Advantages of CFFProperties & Advantages of CFF

–– 6060µµ PVC / 45PVC / 45µµ Aluminum / 25Aluminum / 25µµ oPA.oPA.–– 100100µµ PVC / 45PVC / 45µµ Aluminum / 25Aluminum / 25µµ oPA. oPA. –– Near absolute barrier for moisture and oxygen.Near absolute barrier for moisture and oxygen.–– Larger blisterpacks, Larger blisterpacks, –– Not transparent, Not transparent, –– Slower processing compared to thermoforming.Slower processing compared to thermoforming.

PVC 60 micron

Adhesive

oPA 25 micron

ALU 45 micron

Properties of COCProperties of COC

COC COC ((Cyclic Olefin Copolymer) FilmStandard range starts at 190 Standard range starts at 190 µµmm COC up to 300 COC up to 300 µµmm COCCOCCOC core starts at 120 COC core starts at 120 µµmm COC up to 350 COC up to 350 µµmm of COCof COC

MVTR barrier: depends on the thickness of the COC coreProduction Process: Coextrusion (most cost effective)

Polyolefine skin layer: PP, PE, …

COCCOCPolyolefine skin Polyolefine skin layer: PP, PE, layer: PP, PE, ……

The skin layers can be 20, 30 or 40 µm thick, depending on the customers’

requirements.

Properties & AdvantagesProperties & AdvantagesCOC: Cyclic Olefin CopolymerA halogen free & PVC free copolymerTotally amorphous offering excellent clarityHighest Moisture Barrier PolyolefineExcellent ThermoformabilityCompatible with standard olefin lidding foil

Remarks:Not the best oxygen barrierSensitive to non polar solvents (haze)Need a skin of a PP or PE…

Conclusions:

COCCOC

films are a viable alternative to PVdC (90 g up) or PCTFE high moisture barrier films (0.350.35

to 0.23 g/m2/day at 380.23 g/m2/day at 38ººC/90%RH)C/90%RH)COC COC films are suitable for containing polar liquids

Advantages of COC FilmsAdvantages of COC Films

MVTR before & after FormingMVTR before & after Forming--COCCOCNew & Improved COC Film StructuresNew & Improved COC Film StructuresPerformance evaluation (before & after) forming.Performance evaluation (before & after) forming.

0.0000.0050.0100.0150.0200.0250.0300.0350.0400.045

PVC/PE/PVDC 90

gsm

Flat Sheet WVTRFormed Blister WVTR

Process Variables & Validation StrategyProcess Variables & Validation Strategy

Blistering Critical Process VariablesBlistering Critical Process VariablesMachine Speed (Dwell time)Machine Speed (Dwell time)Forming TemperatureForming TemperatureSealing TemperatureSealing Temperature

Blistering Minor Process Variables:Blistering Minor Process Variables:Cooling TemperatureCooling TemperaturePerforation TemperaturePerforation Temperature

♦

Bottling Critical Process VariablesBottling Critical Process Variables

￭￭

Torque Pressure / Induction sealTorque Pressure / Induction seal￭￭

Tablet counter & Line speedTablet counter & Line speed

♠

Packaging Trial Strategy:Packaging Trial Strategy:Identify critical SKUs: based on unique size, shape & impact Identify critical SKUs: based on unique size, shape & impact by the critical parametersby the critical parametersEstablish critical parameters range: Low speed Vs High temperatuEstablish critical parameters range: Low speed Vs High temperatures and Vice versa.res and Vice versa.

☺☺

Packaging Process Validation Strategy:Packaging Process Validation Strategy:In case of multiple packaged SKUs, take a matrix approach to selIn case of multiple packaged SKUs, take a matrix approach to select the number of ect the number of batches or run of each SKU.batches or run of each SKU.Validate the range of each critical process parameter during theValidate the range of each critical process parameter during the runrun

Film Vs Blistering ProcessFilm Vs Blistering Process

VariablesVariables PVCPVC PVDCPVDC PCTFEPCTFE

Film heatingFilm heating Upper & Lower Upper & Lower same same

Lower than PVC Lower than PVC faceface

Lower than Lower than PVC facePVC face

Cavity Cavity FormationsFormations

At any cooling At any cooling temp.temp.

Require Teflon Require Teflon coated. Cold tools coated. Cold tools may cause PVDC may cause PVDC crackingcracking

Teflon avoided.Teflon avoided.RT & Plug RT & Plug assist assist recommendedrecommended

Sealing Sealing PropertiesProperties

Lidstocks Lidstocks seals very wellseals very well

Lidstocks seals Lidstocks seals adequatelyadequately

Lidstocks seals Lidstocks seals poorly except poorly except Novel lidstockNovel lidstock

Sealing Sealing TemperatureTemperature((°°C)C)

Generally 170Generally 170--

22002200Higher temp Higher temp may cause may cause curlingcurling

Lamination, Winding & Product ContactLamination, Winding & Product Contact

Troubleshooting of Aclar BlisteringTroubleshooting of Aclar BlisteringEasily thermoformed on all conventional thermoforming lines Easily thermoformed on all conventional thermoforming lines

e.g. Uhlmann, Noack, Klockner, IMA, Romanco etc.e.g. Uhlmann, Noack, Klockner, IMA, Romanco etc.Slightly more heat required to form cavities than with mono PVC Slightly more heat required to form cavities than with mono PVC filmfilmMachine speed comparable with mono PVC filmMachine speed comparable with mono PVC filmAppropriate gap between cavity & edge to avoid any partial leakaAppropriate gap between cavity & edge to avoid any partial leakagegeAppropriate blister sealing by maintaining uniform sealing & cooAppropriate blister sealing by maintaining uniform sealing & cooling templing tempUse plug assist for deep draw ratio if depth Use plug assist for deep draw ratio if depth >6 mm to avoid malformation.>6 mm to avoid malformation.Proper mold designProper mold design-- draft angle of 5draft angle of 5°° to avoid nonto avoid non--uniform forminguniform forming

ShrinkageShrinkage33--5% TD shrinkage for copolymer PCTFE5% TD shrinkage for copolymer PCTFE11--3% TD shrinkage for homopolymer PCTFE3% TD shrinkage for homopolymer PCTFE

CurlCurlTowards PCTFE side of blisterTowards PCTFE side of blister

CausesCausesHigher TD shrinkage of raw PCTFE compared to PVC film (Up to 15%Higher TD shrinkage of raw PCTFE compared to PVC film (Up to 15% Vs~0)Vs~0)

RecommendationsRecommendationsDecrease heat applied to PCTFE side of laminationDecrease heat applied to PCTFE side of lamination

Film Cost Vs Performance AnalysisFilm Cost Vs Performance Analysis

Product Yield (sq. in./lb.) Avg. $/lb. at 5M lbs.Avg. $/msi (1,000 sq

in) MVTR - g/m²/24 hrs. MVTR - g/100 in.²/24 hrs.

A 1,866 $11.90 $6.38 0.31 0.020

B 2,028 $9.50 $4.68 0.23 0.015

C 1,860 $9.75 $5.24 0.15 0.010

D 1,730 $10.75 $6.21 0.11 0.007

E 1,528 $14.00 $9.16 0.07 0.005

F 1,355 $15.50 $11.44 0.05 0.003

PRODUCTPRODUCT MVTR MVTR (g/100in(g/100in²²/24 hrs)/24 hrs) PRICE IN US$PRICE IN US$X: 7.5mil PVC/2.0 mil PE/ 1.5 mil PCTFEX: 7.5mil PVC/2.0 mil PE/ 1.5 mil PCTFE 0.0200.020 ~ $ 40 / Kg~ $ 40 / Kg

Y: 7.5mil PVC/2.0 mil PE/ 0.9 mil PCTFEY: 7.5mil PVC/2.0 mil PE/ 0.9 mil PCTFE 0.0150.015 ~ $ 27 / Kg~ $ 27 / Kg

M: 10.0 mil PVC/ 2.0 mil PE/ 1.5 mil PCTFEM: 10.0 mil PVC/ 2.0 mil PE/ 1.5 mil PCTFE 0.0200.020 ~ $ 33 / Kg~ $ 33 / Kg

N: 10.0 mil PVC/ 2.0 mil PE/ 0.9 mil PCTFEN: 10.0 mil PVC/ 2.0 mil PE/ 0.9 mil PCTFE 0.0150.015 ~ $ 23 / Kg~ $ 23 / Kg

Pharmaceutical Lidding FoilsPharmaceutical Lidding Foils

• 20µ hard or soft temper & 25µ hard or soft temper•“push-through” foils • Paper/Foil – “push-through” structure.• Paper/PET/Foil – CR “peel-push” structure.• Paper/PET/Foil – CR “peelable” structure.

Other lidding foils available with a variety of heat sealable layers & CR technology.

AntiAnti--CounterfeitCounterfeitAntiAnti--Counterfeiting Technology in Blister Counterfeiting Technology in Blister

Films:Films:

ACF films and foils incorporate ACF films and foils incorporate ““UV MarkersUV Markers”” to to protect against counterfeiting.protect against counterfeiting.Company logo or product brand logo can be Company logo or product brand logo can be combined in the film and foil such that when combined in the film and foil such that when exposed under a standard UV light, the logo and exposed under a standard UV light, the logo and blister film illuminate to verify authenticity.blister film illuminate to verify authenticity.

Covert Marker Technology for Product:Available form of Indicia containing logos or unique Available form of Indicia containing logos or unique mark, batch no, text etc can be embedded on the mark, batch no, text etc can be embedded on the product which are not easily visibleproduct which are not easily visible

AntiAnti--Counterfeit Counterfeit

Digital Imaging: e.g. Cryptoglyph‘‘onon--packagingpackaging’’ protection on folding cartons, blisters, labels and protection on folding cartons, blisters, labels and leaflets leaflets A unique pattern made by printed dots, invisible to naked eyeA unique pattern made by printed dots, invisible to naked eyeUsing existing holes on the varnish layer and Camouflaged withinUsing existing holes on the varnish layer and Camouflaged withinthe natural imperfections of the varnish layer the natural imperfections of the varnish layer Unique characters camouflaged within the structures of the Unique characters camouflaged within the structures of the aluminium foil aluminium foil

Fingerprints:‘‘onon--dosagedosage’’ or or ‘‘onon--productproduct’’ protection protection Use of existing antiUse of existing anti--counterfeit feature on counterfeit feature on molded caps, Vial flipmolded caps, Vial flip--off tops, bottle closures etc. off tops, bottle closures etc.

Several companies from USA & Europe have their patented technology

Global StrategyGlobal Strategy

Strategy for packaging materials based on

Compliance to different parts of the worldCompliance to different parts of the worldStability study at the early development stageStability study at the early development stageAssurance of protection against different climatic Assurance of protection against different climatic zoneszonesTarget markets requirement & their most popular SKUTarget markets requirement & their most popular SKUCostCost--effectiveness: Barrier (MVTR), Availability, Price, effectiveness: Barrier (MVTR), Availability, Price, Yield and Ease of thermoforming.Yield and Ease of thermoforming.

PackagingPackaging

Vendor InterchangeabilityVendor Interchangeability

For FDA approval follow the 4 steps:For FDA approval follow the 4 steps:

StepStep--11: Classification of Change ( Major / Moderate or : Classification of Change ( Major / Moderate or Minor ? )Minor ? )

StepStep--22: Is the packaging Material CDER approved?: Is the packaging Material CDER approved?

StepStep--33: Does the new package provide the same or : Does the new package provide the same or better protective properties ?better protective properties ?

StepStep--44: If the answer of the step: If the answer of the step--3 yes, then make the 3 yes, then make the Change Control and include in the Annual ReportChange Control and include in the Annual Report

Packaging Vendor InterchangeabilityPackaging Vendor Interchangeability

StepStep--1: 1: Classification of the Change in a reporting Category: Major / Moderate / Minor

The changes of supplier/material can be classified as Minor Change

since : “A change in the container

closure system of unit dose packaging (e.g., blister packs) for non-sterile solid dosage form products, as long as the new package provides the same or better protective properties and any new primary packaging component materials have been used in and been in contact with CDER-approved products of the same type (e.g., solid oral dosage form, rectal suppository).”

Packaging Vendor InterchangeabilityPackaging Vendor Interchangeability

Step 2: Is the Packaging CDER approved ?

If Yes for relevant product, then this certificate is to be included in the Annual Report.

Packaging Vendor InterchangeabilityPackaging Vendor Interchangeability

Step 3: Does the new package provide the same or better protective properties ?

Light Transmission: applicable for opaque blisters only.Moisture Transmission: to be documented via the official compendial test: USP <671> Containers -Permeation.

Use the test "Single Unit Containers and Unit-Dose Containers for Capsules and Tablets". Use Method II for blisters with multiple unit dose containers. The new blisters should have equal or better WVTR compared to the current blister. A tolerance of +/-10% is industry accepted as variation on the method. The WVTR data is to be included in the Annual Report.

Packaging Vendor InterchangeabilityPackaging Vendor Interchangeability

Step 4: Change Control and Annual Report

If the results from step 3 show the new blister offers equal (+/-10%) or better protection from moisture compared to the current blister the change can be made. Document the changes in the next Annual Report to the FDA for each Drug Product.

Example of InterchangeabilityExample of InterchangeabilityFDA Change Protocol

Example-1: Change from PVC/PVDC to Copolymer Aclar.Changing between the group based on MVTR & availabilityThe MVTR of PVC/PVDC is 0.65 g/m²/day & MVTR of PVC/PE/Aclar is 0.11 g/m²/day.

Eample-2: Change from Co-polymer to Homo-polymer AclarChanging within the group based on MVTR & price. The MVTR for 7.5mil PVC/2.0 mil PE/ 1.5 mil PCTFE is 0.020 and for 10.0 mil PVC/ 2.0 mil PE/ 0.9 mil PCTFE is 0.015 g/m²/day

Justification for minor change:The PVC/PE/Aclar offers 5 times more barrier protection than that of the PVC/PVDC, classified as a minor change.Same justification applies on other example. Product contact (PVC) is also remain same

Regulatory Compliance VerificationRegulatory Compliance Verification

Worldwide compliance For Film :Worldwide compliance For Film :USA food contact: 21CFRUSA food contact: 21CFREU food contact: 2002/72/ECEU food contact: 2002/72/ECJapanese Food and Sanitation Law, Ministry Japanese Food and Sanitation Law, Ministry

of Health and Welfare Notification 20.of Health and Welfare Notification 20.USP: <661>USP: <661>Ph.Eur. 3.1.11 and Ph.Eur. 3.2.Ph.Eur. 3.1.11 and Ph.Eur. 3.2.max VCM levelsmax VCM levelsHeavy Metal DirectivesHeavy Metal DirectivesCDER approval for oral solid dosage formsCDER approval for oral solid dosage forms

Regulatory GuidelinesRegulatory Guidelines

Web site of FDA guidelines for submitting Web site of FDA guidelines for submitting documentation for human drugs & Biologics.documentation for human drugs & Biologics.

http://www.fda.gov/cder/guidance/package.htmhttp://www.fda.gov/cder/guidance/package.htmFDA guideline FDA guideline ““Container Closure Systems for Packaging Container Closure Systems for Packaging Human Drugs and BiologicsHuman Drugs and Biologics””..

Child resistant packaging:Child resistant packaging:US CPSC (US Consumer Product Safety Commission)US CPSC (US Consumer Product Safety Commission)

EU guideline 3AQ10A EU guideline 3AQ10A ““Plastic Primary Packaging Plastic Primary Packaging MaterialsMaterials””..

RecappingRecappingSelect costSelect cost--effective pack mat at early stage of developmenteffective pack mat at early stage of development

Appropriate barrier (MVTR) required for product in target marketAppropriate barrier (MVTR) required for product in target marketHDPE bottle can be the best & cheapest choice if target market aHDPE bottle can be the best & cheapest choice if target market allowsllowsAppropriate thickness & thermoforming yield for blisterAppropriate thickness & thermoforming yield for blisterPVC/PCTFE blister can be cost effective than PVC/PVDC & CFFPVC/PCTFE blister can be cost effective than PVC/PVDC & CFFAvailability from multiple vendors to keep purchasing flexibilitAvailability from multiple vendors to keep purchasing flexibility & controly & controlCompliance to global regulatory requirements & interchange abiliCompliance to global regulatory requirements & interchange abilityty

Critical issues to consider for blister packaging developmentCritical issues to consider for blister packaging developmentDesigning the blister card, Forming mold design, Blister machineDesigning the blister card, Forming mold design, Blister machine operation, Sealing, Die cutting, Lid stock,operation, Sealing, Die cutting, Lid stock,Seal failure may not be seen in leak test but through ICH acceleSeal failure may not be seen in leak test but through ICH accelerated rated condition.condition.

AntiAnti--counterfeit Packagingcounterfeit PackagingSelect costSelect cost--effective antieffective anti--counterfeit packaging based on the needcounterfeit packaging based on the need

Packaging Process validation strategyPackaging Process validation strategyPerform packaging trials & establish parameters range prior to vPerform packaging trials & establish parameters range prior to validationalidationSelect costSelect cost--effective validation strategy by taking matrix approacheffective validation strategy by taking matrix approach

Comments & Questions ??Comments & Questions ??