Slide1: Packaging Dr Dave Elder and Dr Simon Mills, GSK
Cape Town, South Africa
16-21st April, 2007
Introduction: 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
Slide3: 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
Slide4: 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
Slide5: 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
Packaging Development: 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.
Packaging Development: 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
Slide8:
Cold Form Aluminium 0.00
Aclar ® 33C 0.08
Aclar ® UltRx2000 0.11 - 0.12
Aclar ® 22C 0.22
Aclar ® SupRx 900 0.23 - 0.26
Aclar ® 22A 0.31 - 0.34
PVC/80g PVDC 0.31
Aclar ® Rx160 0.39 - 0.42
Aclar ® 33C 0.42
PVC/60g PVDC 0.47 - 0.6
PVC/40g PVDC 0.7 - 0.75
PP 0.7 - 1.47
PVC 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)
Slide9: 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
Packaging Development: 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
Packaging Development: 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.
Packaging Development: Packaging Development Impact of Oxidative Instability of Container-Closure
Slide13: 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
Slide14:
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)
Aclar® is registered trademark of Honeywell Inc PACKAGING First Intent – Blister base
Slide15:
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 Current Future Bottles and Closures: Benefits
PACKAGING Bottles: 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
PACKAGING Closures: 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
PACKAGING Closures - examples: PACKAGING Closures - examples Two piece Child Resistant (CR) with Induction Heat Seal Continuous thread (CT), plastic screw closure
PACKAGING Solid Dose – Blister Packs: THERMOFORM BLISTERS
plastic base web
blister formed with aid of heating
low to high barrier PACKAGING Solid Dose – Blister Packs Product contact layers: For PVC or PVC/Aclar = PVC For PVC/PVDC = PVDC For Lid foil = heat seal lacquer
PACKAGING Solid Dose – Blister Packs: 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 Product contact layers: For base = PVC (or PP) For lid foil = heat seal lacquer
PACKAGING Solid Dose – Blister Packs: 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 = PVC For PVC/PVDC = PVDC For Lid foil = heat seal lacquer
PACKAGING Injections: Vials Glass – type I
Plastic – e.g. LDPE Glass Plastic Syringe Rubber Vial Glass - type I
Plastics - PP, PC, COC
Stopper Rubber 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
Slide23: 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 NOTE:
Specific EU Directives limiting residues in epoxy coatings for food contact use
Slide24: Metered dose inhaler Nebules PACKAGING Inhalation and Intranasal Products Dry Powder Inhalers Intranasal
Slide25: 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
Slide26: 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)
Slide27: 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
Slide28: 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
EXTRACTABLES and LEACHING THE THEORY : EXTRACTABLES 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 exactly what to do or how to do it
Slide30: 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
Packaging Development: 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.
Phase I – FTIH & Phase II Clinical Supply: 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
Phase II – III, Commercial Pack Development: 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
Slide34: 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
Slide35: 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
Slide36: 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
Slide37: 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
Slide38: 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
Phase 3 - Launch: 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
Pack Changes? : 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.