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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 20071 |
Training Workshop on Pharmaceutical Development
with focus on Paediatric Formulations
Tallink City HotelTallinn, South Africa
Date: 15 - 19 October 2007
Pharmaceutical Development
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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 20072 |
Pharmaceutical Development
Pharmaceutical packaging
Presenter: Simon Mills
Email: [email protected]
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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 20073 |
• Choosing the most Appropriate Primary Pack• Blister Packs• Containers & Closures
• General Overview• Bottles• Blister Packs• Inhalation / IntraNasal products
• Regulatory• US, EU, Pharmacopoeial• Extractable / Leachables
• Packaging Development considerations through to Launch
Introduction
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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 20074 |
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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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 20075 |
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 required
Global - Regional - Local packs
Anti-counterfeiting, illegal cross-border trading
Pharmacogenomics - Personalised medicines
Demographic change - Ageing population
PACKAGING: Choosing the most appropriate pack
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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 20076 |
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 prefers bottles• EU/RoW prefer blister packs
Child resistance requirements– US
• Legal requirement with few exceptions
– EU/RoW• Legal requirement in only 4 EU member
states & for very limited list of products
PACKAGING: Choosing the most appropriate pack
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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 20077 |
Packaging: WVTRThe water vapour transmission rate (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
The theoretical rate of water permeation through a standard 60-cc HDPE bottle when stored at 40C/75%RH has been determined: – This equated to an uptake of 1mg of water per day. – So, even if a product is packed under low water vapour conditions the relative
humidity conditions within the container will re-equilibrate to 50% within 1 day.
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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 20078 |
Packaging: Desiccants
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.– Molecular sieve approved in EU for pharmaceuticals, not by FDA in US. – 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.
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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 20079 |
Barrier Properties (typical MVTR g/m2/day 38°C/90%RH)
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
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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 200710 |
Packaging: OVTR
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 here.
PackOVTR
(g. mm/(m2. day))
LDPE241
HDPE102
Polystyrene127
Polycarbonate114
Polypropylene89
PVC4
PET2
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Packaging Development
The theoretical rate of oxygen permeation through a standard 30-cc HDPE bottle when stored in a well sealed container has been determined:– This equated to an uptake of 0.2 mMol 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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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– Minimised R&D resource– Supports supply site transfers (like for like; identical)
PACKAGING: First Intent
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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 200713 |
MATERIALS (hierarchy of choice based on product stability)
– Material should preferably be opaque white unless clear is a specific market requirement (e.g. 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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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 200714 |
• Reduction of complexity• Standardisation and rationalisation of
components• Reduced number of change-overs at
factory sites• Reduction in resource demand• 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 ComplexityMaintaining Flexibility
Current
Future
First Intent: Bottles and Closures - Benefits
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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 200715 |
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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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 200716 |
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
PACKAGING: Closures
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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 200717 |
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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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 200718 |
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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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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Metered dose inhaler
Nebules
PACKAGING: IH and IN ProductsDry Powder Inhalers
Intranasal
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PACKAGING: Key Regulatory Guidance - USGuidance 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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PACKAGING: Key Regulatory Guidance - EU
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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FDA & CPMP (CHMP) Regulated
Baseline Statement of Safety– Defines
• acceptable starting materials• acceptable additives and processing aids• limits on residues• limits on leachables (e.g. 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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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
Interaction between API & pack extractive – resultant compound is an impurity
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Packaging Development
Objective– To ensure timely and robust selection of the primary pack for
clinical trial and commercial supply.
Recommended approach:– To use, where possible, a limited range of standard,
well-characterised pack materials and packs– To ensure thorough testing, characterisation and understanding
of these selected pack materials and packs.
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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 200726 |
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, e.g. HDPE bottles for solid dose forms • Inert packs, e.g. 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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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 200727 |
Phase II – III, Commercial Pack DevelopmentObjective:
– 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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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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• 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
• Maximise 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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• 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, e.g. 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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• 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 for 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, e.g. dimensional and performance specifications, need for clean room manufacture, etc.
• Manufacturing controls for the packaging process
4. Controls Defined
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• 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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Phase 3 - LaunchBetween 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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Pack Changes? Recommended 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.
However, changes can occur at late stage due to, for example…– Unpredictable outcome in pivotal stability assessment
• Newly identified impurities• Requirement for tighter specification limits
These tend to drive need for more protective packs, e.g.– Inclusion of desiccant in bottle packs– Need for higher barrier (e.g. 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.
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Summary
• Choosing the most Appropriate Primary Pack• Blister Packs• Containers & Closures
• General Overview• Bottles• Blister Packs• Inhalation/IntraNasal products
• Regulatory• US, EU, Pharmacopoeial• Extractable/Leachables
• Packaging Development considerations through to Launch
ANY QUESTIONS PLEASE?