Training Workshop on Pharmaceutical Development

with a Focus on Paediatric Medicines / 15-19 October 2007

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Training Workshop on
Pharmaceutical Development with
focus on Paediatric Formulations
Tallink City Hotel
Tallinn, South Africa
Date: 15 - 19 October 2007
Pharmaceutical Development
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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Pharmaceutical Development

Pharmaceutical packaging


Presenter: Simon Mills
Email: Simon.n.mills@gsk.com

Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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 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.
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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 products shelf-life can be determined.
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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Barrier Properties (typical MVTR g/m2/day 38C/90%RH)

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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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.

Pack OVTR
(g. mm/(m
2
. day))
LDPE 241
HDPE 102
Polystyrene 127
Polycarbonate 114
Polypropylene 89
PVC 4
PET 2
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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.
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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 Complexity
Maintaining Flexibility

Current
Future
First Intent: Bottles and Closures - Benefits
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
PACKAGING: Closures
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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 = PVC
For PVC/PVDC = PVDC
For Lid foil = heat seal lacquer
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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Drug suspension
in propellant
Gasket
Metering valve
Mouthpiece
Valve
stem
Atomising
nozzle
Actuator body
Aluminium
can
Metered dose inhaler
Nebules
PACKAGING: IH and IN Products
Dry Powder Inhalers
Intranasal
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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)
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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.

Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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.
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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?