Packaging

Simon Mills | April 20081 |
Pharmaceutical Development with Focus
on Paediatric formulations
WHO/FIP Training Workshop
Hyatt Regency Hotel
Sahar Airport Road
Andheri East, Mumbai, India
28 April 2008 – 2 May 2008

Pharmaceutical Development with Focus
on Paediatric formulations
Pharmaceutical packaging – an overview
including some considerations for paediatrics
Presented by:
Name: Simon Mills
Contact details:
Simon.n.mills@gsk.com

• 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

• As far as CMC considerations are concerned, paediatric and adult
dosage forms can be treated in much the same way. There will be
particular areas to focus attention on for paediatric products:
• There may be lower limits of acceptable levels of impurities, extractables and
leachables resulting from product/pack interaction.
• Extra or novel devices to facilitate dosing or compliance can be associated with
paediatric products, e.g. spacers with MDIs, syringes for oral dosing, nebulisers.
It will be important to ensure that all contact materials are suitable and well
controlled. For new materials/devices, this will necessitate extensive evaluation.
• Children must be protected from the risk of unsupervised access to medicines –
this applies equally to paediatric and adult drug products. The need for child-
resistant (CR) packaging will need to be assessed, balanced against the
adjudged risk in accidental ingestion of the drug product itself; (some territories
insist on CR packs; US requirements detailed in 16 CFR §1700).
Specific paediatric considerations

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

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

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: 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.

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.

Barrier Properties (typical MVTR g/m2/day 38°C/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: 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/(m2
. day))
LDPE 241
HDPE 102
Polystyrene 127
Polycarbonate 114
Polypropylene 89
PVC 4
PET 2

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.

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

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 250µm
2. PVC/PVDC 250µm/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

• 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
Reduced Complexity
Maintaining Flexibility
CurrentCurrent
FutureFuture
First Intent: Bottles and Closures - Benefits

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

 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

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

Foil Laminate – e.g. OPA/foil/PVC, or
OPA/foil/PP
Lidding FoilCOLD FORM BLISTER
– blister formed mechanically (no heat)
– high barrier
- 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

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
Film – e.g. PVC, PVC/PVDC
Product contact layers:
For PVC = PVC
For PVC/PVDC = PVDC
For Lid foil = heat seal lacquer

Packaging challenges (4FDC)
A 4-API combination anti-TB tablet:
Rifampicin 150 mg
Isoniazid 75mg
Pyrazinamide 400mg
Ethambutol 275mg
TOTAL API weight: 900mg
Tablet weight: 1.3g
The technical challenges:
 Big tablet
 Problem APIs !!
 Rifampicin is vulnerable to oxidative degradation and hydrolysis, it is light sensitive
and it reacts with isoniazid. It also exhibits solid-state polymorphism.
 Isoniazid reacts with aldehydes/reducing sugars….& rifampicin → major degradant
 Ethambutol (2HCl) is hygroscopic, attracting moisture into the tablet to form a slightly
acidic solution that encourages the rifampicin/isoniazid interaction!
 Pyrazinamide…..seems to be OK !

Packaging challenges (4FDC)
The solution:
Packaging:
– Non-permeable (moisture and oxygen) material
– Do not remove from primary packaging until use
– Avoid repackaging
– Protect from light
Also:
 Excipients: no sugar/lactose (isoniazid)
 Rifampicin used as “as is” powder (no granulation)
 Maintain low water content of tablets (USP ≤ 3.0%)

Metered dose inhaler
Nebules
PACKAGING: IH and IN Products
Dry Powder Inhalers
Intranasal

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

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)

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

EXTRACTABLES and LEACHABLES: Definitions
 Extractable
– Compounds that can be extracted from
elastomeric, plastic components or coating
of the container and closure system when in
the presence of an appropriate solvent(s)
 Leachable
– Compounds that leach from the elastomeric,
plastic components or coatings of the
container and closure system as a result of
direct contact with the formulation of the
drug product. Can get interaction with a
product component to produce an impurity
that requires stability monitoring.

EXTRACTABLES and LEACHING:
Practical examples of Issues
•Polyaromatic hydrocarbons (PAH) detected in CFC-filled
MDIs (c.1990)
– Prompted the first concerted efforts to look for leachables in MDIs
• Vanillin detected in solutions for inhalation packed in LDPE
containers
– Source: migration through LDPE container wall from cardboard outer
packaging. Protective Al foil laminate overwrap introduced.
 Di-ethylhexyl phthalate (DEHP)
– Plasticizer in PVC; detected, for example, in TPN fat emulsions probably
via infusion tubing set
– Neonates have particular sensitivity to DEHP

EXTRACTABLES and LEACHING: Considerations
 Clinical concerns:
– A potentially sensitive, compromised (especially paediatric) patient population
– Safety for both acute and chronic administration
Regulatory requirements:
– FDA requirements
– Included in CPMP guideline 3AQ10a and CPMP/QWP/4359
Extractables: control of quality of packaging materials and robust
relationship with suppliers, e.g. change control.
Leachables: comprehensive stability package – long-term storage condition and
accelerated stability assessment for drug product in pack to cover shelf-life of
the product
• Consistency in materials/components (Specifications, DMFs)
• Control of packing material and product manufacture
• Control for unintended contaminants

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.

Phase I – FTIH & Phase II Clinical Supply
Objective:
– Selection of packs for clinical supply
Strategy:
– Aim to 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

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

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

• 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

• 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

• 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

• 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
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?
 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.

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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