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
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Simon Mills | April 2008
Pharmaceutical Development with Focus
on Paediatric formulations
Pharmaceutical packaging – an overview
including some considerations for paediatrics
Presented by:
Name: Simon Mills
Contact details:
[email protected]
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Simon Mills | April 2008
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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Simon Mills | April 2008
Specific paediatric considerations
• 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 childresistant (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).
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Simon Mills | April 2008
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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Simon Mills | April 2008
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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Simon Mills | April 2008
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
• Environment
– EU Packaging and
Packaging Waste Directive
– US - no direct equivalent
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Simon Mills | April 2008
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.
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Simon Mills | April 2008
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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Simon Mills | April 2008
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
Aclar
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Simon Mills | April 2008
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
® is a registered trade mark of Allied Signal
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.
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Simon Mills | April 2008
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.
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Simon Mills | April 2008
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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Simon Mills | April 2008
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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Simon Mills | April 2008
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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Simon Mills | April 2008
Future
Reduced Complexity
Maintaining Flexibility
PACKAGING: Bottles
BOTTLE
Glass
– type III (solids)
– type I (for inhaled solutions)
Plastic
–
–
–
–
–
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Simon Mills | April 2008
low density polyethylene LDPE
high density polyethylene HDPE
polypropylene PP
polyester PET, PETG
Cyclo-olefin copolymer (COC)
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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Simon Mills | April 2008
PACKAGING: Solid Dose – Blister Packs
 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
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Simon Mills | April 2008
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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Simon Mills | April 2008
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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Simon Mills | April 2008
Packaging challenges (4FDC)
A 4-API combination anti-TB tablet:
Rifampicin
Isoniazid
Pyrazinamide
Ethambutol
TOTAL API weight:
Tablet weight:
150 mg
75mg
400mg
275mg
900mg
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 !
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Simon Mills | April 2008
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%)
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Simon Mills | April 2008
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
Intranasal
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Simon Mills | April 2008
PACKAGING: Key Regulatory Guidance - US
Guidance for Industry, Container
Closure Systems for Packaging of
Human Drugs and Biologics
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Simon Mills | April 2008
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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Simon Mills | April 2008
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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Simon Mills | April 2008
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.
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Simon Mills | April 2008
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
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Simon Mills | April 2008
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
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Simon Mills | April 2008
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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Simon Mills | April 2008
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
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Simon Mills | April 2008
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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Simon Mills | April 2008
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
Simon Mills | April 2008
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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Simon Mills | April 2008
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, 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.
Simon Mills | April 2008
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 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
Simon Mills | April 2008
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
•
•
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Confirm compatibility and product stability
Support product registration submission
Simon Mills | April 2008
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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Simon Mills | April 2008
Pack Changes?
 Recommended aim:
– to avoid pack changes between pivotal stability and launch by ensuring a Qualityby-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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Simon Mills | April 2008
Summary
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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
Simon Mills | April 2008
ANY QUESTIONS PLEASE?