Packaging
Dr Dave Elder and Dr Simon Mills, GSK
Cape Town, South Africa
16-21st April, 2007
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
1
Introduction
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Chosing the most Appropriate Pack
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General Overview
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Bottles
Blister Packs
Injectables
Tubes
Inhalation/IntraNasal products
Regulatory
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Blister Packs
Container/Closures
US, EU, Pharmacopoeial
Extractable/Leachables
Packaging Development
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
2
PACKAGING Choosing the most appropriate pack
BASIC REQUIREMENTS
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Protection
 stability test conditions
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Compatibility
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Regulatory
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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
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
3
PACKAGING Choosing the most appropriate pack
ADDITIONAL DRIVERS/FUTURE CHALLENGES
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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
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
4
PACKAGING Choosing the most appropriate pack
Some factors are territory specific, e.g.

Presentation
 e.g. for solid dose
 US prefer bottles
 EU/RoW prefer blister packs
• Environment
– EU Packaging and Packaging
Waste Directive
– US - no direct equivalent

Child resistance requirements
 US
 Legal requirement with few
exceptions
 Clear blisters, peel-push, tear
notch, secondary CR pack
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Health
Technology and Pharmaceuticals
5
EU/RoW
 Legal requirement in only 4 EU
member states & for very limited
list of products
 Push through blisters, opaque
Packaging Development
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The WVTR through the container is determined by
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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 40C/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.
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
6
Packaging Development
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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.
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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
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
7
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
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
8
PACKAGING Choosing the most appropriate pack
Barrier Performance versus Cost
• COLD FORM FOIL
•ACLAR® UltRx2000
Stability
driver
• ACLAR® SupRx900
• ACLAR®Rx160
• PVC/PE/PVDC
Barrier
• PVC/PVDC 40gsm
• PP
Cost
driver
• PVC
Cost
COST IS AN IMPORTANT FACTOR
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
9
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
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
10
Packaging Development
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Waterman et al (1) determined the theoretical rate of oxygen
permeation through a standard 30-cc bottle when stored in a
well sealed container
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This equated to an uptake of 0.2mMol of oxygen per year
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In addition to permeation through the container walls, the key
vulnerability in any container-closure system is the closure.
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With screw-topped closures leakage can be significant.
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Hence for oxidatively labile dosage forms an oxygen
impermeable seal is required, and induction heat sealed
containers are particularly useful.
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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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Health
Technology and Pharmaceuticals
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Packaging Development
Impact of Oxidative Instability of
Container-Closure
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Health
Technology and Pharmaceuticals
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PACKAGING First Intent
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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
 Minimises R&D resource
 Supports supply site transfers (like for like; identical)
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Global blister material first intent in place since 2003
Solid dose bottle and closure first intent under development
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Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
13
PACKAGING First Intent – Blister base
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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
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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
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
14
Bottles and Closures: Benefits
Current
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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
Future
Reduced Complexity maintaining
Flexibility
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
15
PACKAGING Bottles
BOTTLE
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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)
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
16
PACKAGING Closures
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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
Reseal liner
Pulpboard
Foil
Wax
Polyester
Induction Liner
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Heatseal film/coating
PACKAGING Closures - examples
Two piece Child Resistant (CR) with
Induction Heat Seal
Continuous thread (CT), plastic screw
closure
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
18
PACKAGING Solid Dose – Blister Packs
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THERMOFORM BLISTERS
 plastic base web
 blister formed with aid
of heating
 low to high barrier
- Overlacquer
- 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
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
19
PACKAGING Solid Dose – Blister Packs
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COLD FORM BLISTER
 blister formed mechanically (no heat)
 high barrier
Lidding Foil
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
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
20
PACKAGING Solid Dose – Blister Packs
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TROPICALISED BLISTER
 thermoform blister plus cold form tray
 once tray opened, in use life determined
by primary thermoform blister
 high barrier before use
Lidding Foil
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
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
21
PACKAGING Injections
Ampoules
Syringe
Vials
Rubber,
plastic
Glass – type I
Plastic – PP, COC
Glass – type I
Vial
Glass - type I
Plastics - PP, PC,
COC
Stopper
Rubber
Plastic – e.g. LDPE
Rubber
Glass
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
Department of Medicines Policy and Standards, warning labelling EU & US
Health
Technology and Pharmaceuticals
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PACKAGING Tubes
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Aluminium
Lacquered Aluminium
 lined with an epoxy phenolic lacquer
Laminate
 foil laminate body, plastic shoulder
 Eg, structure for Acyclovir topical ointment
- Clear LDPE
- White LDPE
- PE
- EMAA
- Aluminium foil
- EMAA
- LDPE (product contact)
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Plastic – PE, PVC
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
23
NOTE:
Specific EU Directives limiting residues in
epoxy coatings for food contact use
PACKAGING Inhalation and Intranasal Products
Dry Powder Inhalers
Metered dose inhaler
Drug suspension
in propellant
Aluminium
can
Gasket
Valve
stem
Metering valve
Atomising
nozzle
Actuator body
Nebules
Mouthpiece
Intranasal
Department of Medicines Policy and Standards,
Health
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24
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
Department of Medicines Policy and Standards,
Health
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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)
Department of Medicines Policy and Standards,
Health
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26
PACKAGING Food Contact Approval
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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
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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)
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PACKAGING Food Contact Approval - Relevance
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Baseline Statement of Safety
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Defines
 acceptable starting materials
 acceptable additives and processing aids
 limits on residues
 limits on leachables (eg specific migration limits)
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Based upon
 Acceptable or Tolerable Daily Intake in FOOD
NOTE US and EU do not use same calculations
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Health
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EXTRACTABLES and LEACHING
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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
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Health
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PACKAGING Extractables & Leachables Expectation & Science
REGULATORY
EXPECTATION
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GOOD SCIENCE
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Qualification
 exhaustive extraction
to characterise
(worst
case)
Avoids
unnecessary
stability
 qualitative and quantitative
testing chromatographic profiles
 show control at the material level (cf. synthetic impurities)
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Stability
 monitoring in real product, real time to establish equilibrium
concentration value
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Interaction
 early detectionIf interaction is between the active and
Identify
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Quantify
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Toxicological
evaluation
a pack extractive, resultant compound is
treated as an impurity (ICH Q3B)
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
30
Packaging Development
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Objective
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To ensure timely and robust selection of the primary pack for
clinical trial and commercial supply.
Our approach:
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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.
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
31
Phase I – FTIH & Phase II Clinical Supply
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Objective
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Selection of packs for clinical supply
Our approach:
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Will generally use
 Limited range of standard, characterised packs, eg, HDPE bottles for sold
dose forms
 Inert packs, eg, fluororesin laminated injection stoppers
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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
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32
Phase II – III, Commercial Pack Development
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Objective
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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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33
1. Identify Pack Options
Pack options are identified to meet:
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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
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
34
2. Material Selection & Testing
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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
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.
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
35
3. Development Stability Testing
Development stability testing used to
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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.
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
36
4. Controls Defined
Data from material and product testing used to identify critical
quality and process attributes for pack and packaging process,
e.g.:
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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
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Health
Technology and Pharmaceuticals
37
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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Health
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38
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
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
39
Pack Changes?
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Our aim:
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But changes can occur at late stage due to, for example,
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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.
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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
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.
Department of Medicines Policy and Standards,
Health
Technology and Pharmaceuticals
40