packaging
TRANSCRIPT
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Packaging
Dr Dave Elder and Dr Simon Mills, GSKCape Town, South Africa16-21st April, 2007
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
• Chosing the most Appropriate Pack• Blister Packs• Container/Closures
• General Overview• Bottles• Blister Packs• Injectables• Tubes• Inhalation/IntraNasal products
• Regulatory• US, EU, Pharmacopoeial• Extractable/Leachables
• Packaging Development
Introduction
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Protection stability test conditions
Commercial image market requirements/trends dosing/patient compliance security/tamper evidence manufacturing economics - COG
BASIC REQUIREMENTS
Legislation E.g. EC Packaging and Packaging
Waste Directive
Compatibility
PACKAGING Choosing the most appropriate pack
Regulatory
Corporate Global Quality Policies
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
ADDITIONAL DRIVERS/FUTURE CHALLENGES
Moisture sensitive drugs increasing barrier requirements Novel delivery systems Emphasis on speed to market Control of R&D Expenditure/resource - number of stability studies Global - Regional - Local packs Anti-counterfeiting, illegal cross border trading Multiple studies for different packs vs. Year-on-Year manufacturing costs Pharmacogenomics - Personalised medicines Demographic change - Ageing population
PACKAGING Choosing the most appropriate pack
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Some factors are territory specific, e.g.
• Environment– EU Packaging and Packaging
Waste Directive– US - no direct equivalent
Presentation e.g. for solid dose
US prefer bottles EU/RoW prefer blister packs
Child resistance requirements US
Legal requirement with few exceptions
Clear blisters, peel-push, tear notch, secondary CR pack
EU/RoW Legal requirement in only 4 EU
member states & for very limited list of products
Push through blisters, opaque
PACKAGING Choosing the most appropriate pack
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Packaging Development The WVTR through the container is determined by
container wall thickness permeability of the packaging material difference between the external and internal relative humidity environments
Driving force for the water flux through the container
Waterman et al (1) determined the theoretical rate of water permeation through a standard 60-cc bottle when stored at 40C/75%RH.
This equated to an uptake of 1mg of water per day. They commented that even if the product had been packed under low water
vapour conditions the relative humidity conditions within the container would be re-equate to 50%RH within 1 day. The WVTRs (see Table) for some common packaging materials were reported by Waterman et al (2).
References:
(1) K.C. Waterman, R.C. Adami, K.M. Alsante, A.S. Antipas, D.R. Arenson, R. Carrier, J. Hong, M.S. Landis, F. Lombardo, J.C. Shah, E. Shalaev, S.W. Smith and H. Wang, Pharm. Dev. and Tech., 7 (2002b) 113.
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Packaging Development Desiccants have been utilised to control the exposure of products to
the ingress of moisture. Desiccants vary in their capacity and the rate that they
adsorb/absorb ingressed moisture. Silica gel is very efficient at absorbing moisture at high relative
humidities, but comparatively poor at lower relative humidities Molecular sieve desiccants - the opposite scenario prevails As a consequence, more molecular sieve is required at higher relative
humidities, and the greater the handling precautions that are required during packaging operations.
Based on the calculated WVTR of known container components and the rate of moisture adsorbed by desiccants, the amount of desiccant that would be required to maintain a specified relative humidity over the product’s shelf-life can be determined (4).
References:(4) L. Dobson, J. Packag. Technol., 1 (1987) 127-131
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Cold Form Aluminium 0.00Aclar ® 33C 0.08Aclar ® UltRx2000 0.11 - 0.12Aclar ® 22C 0.22Aclar ® SupRx 900 0.23 - 0.26Aclar ® 22A 0.31 - 0.34PVC/80g PVDC 0.31Aclar ® Rx160 0.39 - 0.42Aclar ® 33C 0.42PVC/60g PVDC 0.47 - 0.6PVC/40g PVDC 0.7 - 0.75PP 0.7 - 1.47PVC 2.4 - 4
Aclar ® is a registered trade mark of Allied Signal
PACKAGING Choosing the most appropriate pack Barrier Properties (typical MVTR g/m2/day 38 C/90%RH)
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Cost
Barrier
• PVC
• PVC/PVDC 40gsm
• ACLAR®Rx160• PVC/PE/PVDC
•ACLAR® UltRx2000
• ACLAR® SupRx900
• PP
COST IS AN IMPORTANT FACTOR
Stability driver
Cost driver
PACKAGING Choosing the most appropriate pack Barrier Performance versus Cost
• COLD FORM FOIL
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Packaging Development
Similar considerations are relevant to protection of products that are labile to oxidative degradation. The permeability of plastic containers to oxygen ingress has also been evaluated (OVTR), and is summarised. Derived from Wang et al, 1998 (4)
References:(4) Y. Wang, A.J. Easteal, and X.D.
Chen, Packag. Technol. Sci., 11 (1998) 169
Pack OVTR
(g. mm/(m2. day))
LDPE 241
HDPE 102
Polystyrene 127
Polycarbonate 114
Polypropylene 89
PVC 4
PET 2
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Packaging Development Waterman et al (1) determined the theoretical rate of oxygen
permeation through a standard 30-cc bottle when stored in a well sealed container
This equated to an uptake of 0.2mMol of oxygen per year In addition to permeation through the container walls, the key
vulnerability in any container-closure system is the closure. With screw-topped closures leakage can be significant. Hence for oxidatively labile dosage forms an oxygen
impermeable seal is required, and induction heat sealed containers are particularly useful.
Levels of oxygen in the headspace of the container-closure can be significant, and packaging under an inert atmosphere although doable is problematical.
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Packaging Development
Impact of Oxidative Instability of Container-Closure
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
What is First Intent? Preferred range of pack/material options to be used for new products Agreed between R&D and factory Identical global materials Fully aligned with Procurement sourcing strategies Secure/robust sourcing Minimises R&D resource Supports supply site transfers (like for like; identical)
Global blister material first intent in place since 2003 Solid dose bottle and closure first intent under development
PACKAGING First Intent
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
MATERIALS (hierarchy of choice based on product stability)
Material should preferably be opaque white unless clear is a specific market requirement (eg US, Japan)
Aclar should be restricted to applications where cold form is not technically or commercially acceptable due to product or pack size, ie larger products (further guidance to be defined)
1. PVC 250m
2. PVC/PVDC 250m/60gsm
4. PVC/Aclar® UltRx 2000
3. Cold Form 25 OPA/45 Al/ 60 PVC
Aclar® is registered trademark of Honeywell Inc
PACKAGING First Intent – Blister base
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
• Complexity reduction• Standardisation and rationalisation
of components• Reduced number of change-overs
at factory sites• Resource demand reduction• R&D, Pack Dev, Procurement, Sites
use ‘off the shelf’ solution for majority of products.
• Flexibility across factory sites without increased Regulatory activity.
• Risk Mitigation• Commercial Leverage Reduced Complexity maintaining
FlexibilityReduced Complexity maintaining
Flexibility
CurrentCurrent
FutureFuture
Bottles and Closures: Benefits
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
BOTTLE Glass
type III (solids) type I (for inhaled solutions)
Plastic low density polyethylene LDPE high density polyethylene HDPE polypropylene PP polyester PET, PETG Cyclo-olefin copolymer (COC)
PACKAGING Bottles
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Plastic - wadless or lined, CR (child resistant), CT (continuous thread), snap fit
Metal - screw, ROPP Liner – cork, pulpboard, EPE; flowed in gasket
product contact materials/facings : PVDC, Saran, Saranex, Melinex, EPE, Vinyl, Foamed PVC
Induction heat seals
Pulpboard
Wax
Foil
Polyester
Heatseal film/coating
PACKAGING Closures
Reseal liner
Induction Liner
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
PACKAGING Closures - examples
Two piece Child Resistant (CR) with Induction Heat Seal
Continuous thread (CT), plastic screw closure
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
THERMOFORM BLISTERS plastic base web blister formed with aid
of heating low to high barrier
PACKAGING Solid Dose – Blister Packs
- PVC
- PVDC or Aclar
Lidding Foil – typically 20 micron Al
Film - eg PVC, PVC/PVDC, PVC/PE/PVDC, PVC/Aclar
- Overlacquer
- Heat seal lacquer
- Print- Aluminium- Primer
Product contact layers: For PVC or PVC/Aclar = PVC For PVC/PVDC = PVDC For Lid foil = heat seal lacquer
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Foil Laminate – e.g. OPA/foil/PVC, or OPA/foil/PP
Lidding Foil COLD FORM BLISTER blister formed mechanically (no heat) high barrier
PACKAGING Solid Dose – Blister Packs
- PVC (may be PP)
- OPA Film
- Aluminium foil
- Primer/Adhesive
- Primer/Adhesive
Product contact layers:For base = PVC (or PP)For lid foil = heat seal lacquer
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Lidding Foil
Foil Laminate – e.g. OPA/foil/PVC
TROPICALISED BLISTER thermoform blister plus cold form tray once tray opened, in use life determined
by primary thermoform blister high barrier before use
PACKAGING Solid Dose – Blister Packs
Film – e.g. PVC, PVC/PVDC
Product contact layers:For PVC = PVCFor PVC/PVDC = PVDCFor Lid foil = heat seal lacquer
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Vials
Glass – type I
Plastic – e.g. LDPE
GlassPlastic
Syringe
Rubber
VialGlass - type I
Plastics - PP, PC, COC
StopperRubber
Ampoules
Glass – type I Plastic – PP, COC
Rubber, plastic
RUBBER
Butyl, chlorobutyl, bromobutyl, halobutyl, TPE ,natural*, buytl/polyisoprene* copolymer or blend; Coatings – Flurotech, Omniflex, fluororesin/polymer
* Beware of concern over latex allergy. Need for warning labelling EU & US
PACKAGING Injections
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
PACKAGING Tubes
Aluminium Lacquered Aluminium
lined with an epoxy phenolic lacquer
Laminate foil laminate body, plastic shoulder Eg, structure for Acyclovir topical ointment
Plastic – PE, PVC
- Clear LDPE
- Aluminium foil
- White LDPE
- PE- EMAA
- LDPE (product contact)- EMAA
NOTE:
Specific EU Directives limiting residues in epoxy coatings for food contact use
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Metered dose inhaler
Nebules
PACKAGING Inhalation and Intranasal Products
Dry Powder Inhalers
Intranasal
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
PACKAGING Key Regulatory Guidance - US
Guidance for Industry, Container Closure Systems for Packaging of Human Drugs and Biologics
Guidance for Industry, Changes to an Approved NDA or ANDA
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
PACKAGING Key Regulatory Guidance - EUROPE
CPMP/QWP/4359/03 – Guideline on Plastic Immediate Packaging Materials - specific to plastics only
Guideline on Dossier Requirements for Type 1A and Type 1B Notifications
KEY POINT TO NOTE
EU does NOT have a consolidated container/closure guideline (cf FDA)
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Regulatory requirement FDA
Container Closure Systems for Packaging of Human Drugs and Biologics, Chemistry, Manufacturing and Controls Documentation, III,B,I,c Safety
Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products, Manufacturing and Controls Documentation, III,G,1.
Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products Chemistry, Manufacturing, and Controls Documentation, III,G,a
CPMP CPMP Note for Guidance III/9090/EN (3AQ10a) Plastic Primary Packaging Materials,
Introduction CPMP Note for Guidance CPMP/QWP/4359, Plastic Immediate Packaging Materials
(effective 1 December 2005)
PACKAGING Food Contact Approval
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Baseline Statement of Safety
Defines acceptable starting materials acceptable additives and processing aids limits on residues limits on leachables (eg specific migration limits)
Based upon Acceptable or Tolerable Daily Intake in FOOD
NOTE US and EU do not use same calculations
PACKAGING Food Contact Approval - Relevance
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
EXTRACTABLES and LEACHING THE THEORYEXTRACTABLES and LEACHING THE THEORY
FDA guidelines make significant reference Included in CPMP guideline 3AQ10a and
CPMP/QWP/4359 Pack/product interaction Label adhesive migration
But no guidance tells you exactlywhat to do or how to do it
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
REGULATORY
EXPECTATION
Identify
Quantify
Toxicological evaluation
GOOD SCIENCE Qualification
exhaustive extraction to characterise (worst case) qualitative and quantitative chromatographic profiles show control at the material level (cf. synthetic impurities)
Stability monitoring in real product, real time to establish equilibrium
concentration value Interaction
early detection
Avoids unnecessary stability testing
If interaction is between the active and a pack extractive, resultant compound is treated as an impurity (ICH Q3B)
PACKAGING Extractables & Leachables Expectation & Science
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Packaging Development
Objective To ensure timely and robust selection of the primary pack for
clinical trial and commercial supply.
Our approach: To use, where possible, a limited range of standard, well
characterised pack materials and packs To ensure thorough testing, characterisation and understanding of
our pack materials and packs.
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Phase I – FTIH & Phase II Clinical Supply
Objective Selection of packs for clinical supply
Our approach: Will generally use
Limited range of standard, characterised packs, eg, HDPE bottles for sold dose forms
Inert packs, eg, fluororesin laminated injection stoppers
Packs and materials chosen to ensure pharmacopoeial and regulatory compliance is well understood
Material performance is well characterised or known Pack selection is supported by stability testing for each product
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Phase II – III, Commercial Pack Development
Objective Identification, development and testing of commercial pack options
Approach:
3. Development Stability Testing
2. Material Selection & Testing
1. Identify Pack Options
6. Pivotal Stability Testing
5. Pack Selection
4. Controls Defined
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Pack options are identified to meet:
Product attributes, e.g., dosage form, physical and chemical robustness Product protection needs, e.g., moisture & gas sensitivity, thermal stability,
photostability, chemical compatibility etc Clinical requirements, e.g., dosing regimen, titration dosing, route of administration,
need for dosing device Patient requirements, e.g., specific handling requirements, patient handling studies Commercial requirements, e.g., market presentation, pack sizes, market specific
needs, patient handling needs Manufacturing requirements, e.g., equipment capability, critical process parameters, Regulatory requirements, e.g., material compliance, pharmacopeial monographs
1. Identify Pack Options
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
• Product contact materials chosen to meet global and local regulations. • Product contact materials, particularly, plastics confirmed as compliant with relevant food
contact regulations, e.g. US, EU etc• Pharmacopoeial compliance established, e.g. USP, Ph Eur, JP • Performance testing conducted, e.g., moisture permeation, light transmission• Chemical characterisation, e.g., extractables and leachables studies, especially for
parenteral, ophthalmic and inhalation products• Toxicological assessment of extractables and leachables conducted
• We maximise our pack and product knowledge and understanding and achieve commercial efficiency by using a limited range of First Intent, preferred pack materials, wherever possible.
2. Material Selection & Testing
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
• Development stability testing used to • Understand and explore stability in selected pack option• Predict long term stability• Confirm product protection or need for more protective packs, eg, need for
• Inclusion of desiccants for moisture protection• Higher barrier blister films or need for foil/foil blisters• protective overwrap
• Confirm compatibility• Identify and explore pack/product interaction
• These are key data used to make a final pack selection.
3. Development Stability Testing
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
• Data from material and product testing used to identify critical quality and process attributes for pack and packaging process, e.g.:
• Need for RH controls during packing• Need to inert gassing of pack headspace• Seal integrity testing• Need for extractables testing as a routine control• Manufacturing controls/specifications for the pack components and suppliers,
eg, dimensional and performance specifications, need for clean room manufacture etc
• Manufacturing controls for the packaging process
4. Controls Defined
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
• Data from the previous steps, together with the clinical, patient, commercial and manufacturing requirements, are used to identify and agree the intended market packs.
• Pivotal stability testing conducted in the selected markets packs, to• Confirm compatibility and product stability• Support product registration submission
5. Pack Selection
6. Pivotal Stability Testing
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Phase 3 - Launch
Between Phase 3 and Launch
Secondary packaging is defined note, if needed for product protection, this will be defined with the primary
pack and included in pivotal stability
Define market presentations, graphics, patient information leaflets
Conduct line, engineering and technical trials on pack components and equipment
Conduct any necessary validation of packaging processes
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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals
Pack Changes?
Our aim: to avoid pack changes between pivotal stability and launch by ensuring a quality
by design approach to pack selection and understanding of product stability and packaging
But changes can occur at late stage due to, for example, Unpredictable outcome in pivotal stability Newly identified impurities or need for tighter specification limits
These tend to drive need for more protective packs, e.g. Inclusion of desiccant in bottle packs Need for higher barier (eg foil/foil) blister packs
By use of First Intent pack materials and packs, we aim to have a thorough understanding of our materials to minimise impact of change and have readily available, well characterised pack options.