Pharmaceutical Development
Training Workshop on
Pharmaceutical Development with
focus on Paediatric Formulations
Tallink City Hotel
Tallinn, South Africa
Date: 15 - 19 October 2007
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Pharmaceutical Development
Pharmaceutical packaging
Presenter:
Simon Mills
Email:
Simon.n.mills@gsk.com
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Introduction
• 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
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PACKAGING: Choosing the most appropriate pack
BASIC REQUIREMENTS
Protection
– stability test conditions
Compatibility
Regulatory
Legislation
– E.g. EC Packaging and
Packaging Waste Directive
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Commercial
– image
– market requirements/trends
– dosing/patient compliance
– security/tamper evidence
– manufacturing
– economics - COG
Corporate
– Global Quality Policies
PACKAGING: Choosing the most appropriate pack
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
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PACKAGING: Choosing the most appropriate pack
Some factors are territory-specific, e.g.
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
• Environment
– EU Packaging and Packaging
Waste Directive
– US - no direct equivalent
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• Legal requirement in only 4 EU member
states & for very limited list of products
Packaging: WVTR
 The 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 40C/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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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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PACKAGING: Choosing the most appropriate pack
Barrier Properties (typical MVTR g/m2/day 38°C/90%RH)
Cold Form Aluminium
Aclar ® 33C
Aclar ® UltRx2000
Aclar ® 22C
Aclar ® SupRx 900
Aclar ® 22A
PVC/80g PVDC
Aclar ® Rx160
Aclar ® 33C
PVC/60g PVDC
PVC/40g PVDC
PP
PVC
0.00
0.08
0.11 - 0.12
0.22
0.23 - 0.26
0.31 - 0.34
0.31
0.39 - 0.42
0.42
0.47 - 0.6
0.7 - 0.75
0.7 - 1.47
2.4 – 4
Aclar ® is a registered trade mark of Allied Signal
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Packaging: OVTR
Pack
 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.
OVTR
(g. mm/(m2. day))
LDPE
241
HDPE
102
Polystyrene
127
Polycarbonate
114
Polypropylene
89
PVC
4
PET
2
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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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PACKAGING: First Intent
 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)
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PACKAGING: First Intent – Blister base
 MATERIALS (hierarchy of choice based on product stability)
1. PVC 250m
2. PVC/PVDC 250m/60gsm
3. Cold Form 25 OPA/45 Al/ 60 PVC
4. PVC/Aclar® UltRx 2000
– 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)
Aclar® is registered trademark of Honeywell Inc
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First Intent: Bottles and Closures - Benefits
Current
• 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
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Future
Reduced Complexity
Maintaining Flexibility
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)
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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
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PACKAGING: Solid Dose – Blister Packs
- Overlacquer
 THERMOFORM BLISTERS
– plastic base web
– blister formed with aid
of heating
– low to high barrier
- Print
- Aluminium
- Primer
- Heat seal lacquer
Lidding Foil – typically 20 micron Al
Film - eg PVC, PVC/PVDC, PVC/PE/PVDC, PVC/Aclar®
- PVC
- PVDC or Aclar®
Product contact layers: For PVC or PVC/Aclar® = PVC
For PVC/PVDC
= PVDC
For Lid foil = heat seal lacquer
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PACKAGING: Solid Dose – Blister Packs
COLD FORM BLISTER
Lidding Foil
– blister formed mechanically (no heat)
– high barrier
Foil Laminate – e.g. OPA/foil/PVC, or
OPA/foil/PP
- OPA Film
- Primer/Adhesive
- Aluminium foil
- Primer/Adhesive
- PVC (may be PP)
Product contact layers:
For base = PVC (or PP)
For lid foil = heat seal lacquer
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PACKAGING: Solid Dose – Blister Packs
TROPICALISED BLISTER
Lidding Foil
– thermoform blister plus cold form tray
– once tray opened, in use life determined by
primary thermoform blister
– high barrier before use
Film – e.g. PVC, PVC/PVDC
Foil Laminate – e.g. OPA/foil/PVC
Product contact layers:
For PVC = PVC
For PVC/PVDC = PVDC
For Lid foil = heat seal lacquer
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PACKAGING: IH and IN Products
Dry Powder Inhalers
Metered dose inhaler
Drug suspension
in propellant
Aluminium
can
Gasket
Valve
stem
Metering valve
Atomising
nozzle
Actuator body
Mouthpiece
Nebules
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Intranasal
PACKAGING: Key Regulatory Guidance - US
Guidance for Industry, Container
Closure Systems for Packaging of
Human Drugs and Biologics
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Guidance for Industry, Changes to an
Approved NDA or ANDA
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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PACKAGING: Food Contact Approval - Relevance
 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
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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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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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Phase II – III, Commercial Pack Development
 Objective:
– Identification, development and testing of commercial pack options
 Approach:
1. Identify Pack Options
2. Material Selection & Testing
3. Development Stability Testing
4. Controls Defined
5. Pack Selection
6. Pivotal Stability Testing
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1. Identify Pack Options
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
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2. Material Selection & Testing
•
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.
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3. Development Stability Testing
•
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.
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4. Controls Defined
•
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
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5. Pack Selection
•
Data from the previous steps, together with the clinical,
patient, commercial and manufacturing requirements, are
used to identify and agree the intended market packs.
6. Pivotal Stability Testing
•
Pivotal stability testing conducted in the selected markets
packs, to
•
•
Confirm compatibility and product stability
Support product registration submission
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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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Pack Changes?
 Recommended aim:
– to avoid pack changes between pivotal stability and launch by ensuring a Quality-byDesign 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?
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