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Simon Mills | April 20081 |
Pharmaceutical Development with Focus on Paediatric formulations
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
Simon Mills | April 20082 |
Pharmaceutical Development with Focus on Paediatric formulations
Pharmaceutical Development with Focus on Paediatric formulations
Pharmaceutical packaging – an overview including some considerations for paediatrics
Presented by:
Name: Simon Mills
Contact details:
Simon Mills | April 20083 |
• 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 Introduction
Simon Mills | April 20084 |
• 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 Specific paediatric considerations
Simon Mills | April 20085 |
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
Simon Mills | April 20086 |
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
Simon Mills | April 20087 |
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
Simon Mills | April 20088 |
Packaging: WVTRPackaging: 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.
Simon Mills | April 20089 |
Packaging: DesiccantsPackaging: 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.
Simon Mills | April 200810 |
Barrier Properties (typical MVTR g/m2/day 38°C/90%RH)
Cold Form Aluminium 0.00Aclar ® 33C 0.08Aclar ® UltRx2000 0.11 - 0.12Aclar ® 22C 0.22Aclar ® SupRx 900 0.23 - 0.26Aclar ® 22A 0.31 - 0.34PVC/80g PVDC 0.31Aclar ® Rx160 0.39 - 0.42Aclar ® 33C 0.42PVC/60g PVDC 0.47 - 0.6PVC/40g PVDC 0.7 - 0.75PP 0.7 - 1.47PVC 2.4 – 4
Aclar ® is a registered trade mark of Allied Signal
PACKAGING: Choosing the most appropriate pack
Simon Mills | April 200811 |
Packaging: OVTRPackaging: 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.
PackOVTR
(g. mm/(m2. day))
LDPE241
HDPE102
Polystyrene127
Polycarbonate114
Polypropylene89
PVC4
PET2
Simon Mills | April 200812 |
Packaging DevelopmentPackaging 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.
Simon Mills | April 200813 |
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
Simon Mills | April 200814 |
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
Simon Mills | April 200815 |
• 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 ComplexityMaintaining FlexibilityReduced ComplexityMaintaining Flexibility
CurrentCurrent
FutureFuture
First Intent: Bottles and Closures - Benefits
Simon Mills | April 200816 |
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 PACKAGING: Bottles
Simon Mills | April 200817 |
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 PACKAGING: Closures
Simon Mills | April 200818 |
THERMOFORM BLISTERS– plastic base web– blister formed with aid
of heating – low to high barrier
PACKAGING: Solid Dose – Blister Packs 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
Simon Mills | April 200819 |
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 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
Simon Mills | April 200820 |
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 PACKAGING: Solid Dose – Blister Packs
Film – e.g. PVC, PVC/PVDC
Product contact layers:For PVC = PVCFor PVC/PVDC = PVDCFor Lid foil = heat seal lacquer
Simon Mills | April 200821 |
Packaging challenges (4FDC)Packaging challenges (4FDC)
A 4-API combination anti-TB tablet:Rifampicin 150 mgIsoniazid 75mgPyrazinamide 400mgEthambutol 275mgTOTAL API weight: 900mgTablet 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 !
Simon Mills | April 200822 |
Packaging challenges (4FDC)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%)
Simon Mills | April 200823 |
Metered dose inhaler
Nebules
PACKAGING: IH and IN ProductsDry Powder Inhalers
Intranasal
Simon Mills | April 200824 |
PACKAGING: Key Regulatory Guidance - USGuidance for Industry, Container Closure Systems for Packaging of Human Drugs and Biologics
Guidance for Industry, Changes to an Approved NDA or ANDA
Simon Mills | April 200825 |
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)
Simon Mills | April 200826 |
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
Simon Mills | April 200827 |
EXTRACTABLES and LEACHABLES: DefinitionsEXTRACTABLES 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.
Simon Mills | April 200828 |
EXTRACTABLES and LEACHING: Practical examples of Issues
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
Simon Mills | April 200829 |
EXTRACTABLES and LEACHING: ConsiderationsEXTRACTABLES 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 robustrelationship with suppliers, e.g. change control. Leachables: comprehensive stability package – long-term storage condition andaccelerated stability assessment for drug product in pack to cover shelf-life ofthe product
• Consistency in materials/components (Specifications, DMFs)• Control of packing material and product manufacture • Control for unintended contaminants
Simon Mills | April 200830 |
Packaging DevelopmentPackaging 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.
Simon Mills | April 200831 |
Phase I – FTIH & Phase II Clinical SupplyPhase 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
Simon Mills | April 200832 |
Phase II – III, Commercial Pack DevelopmentPhase II – III, Commercial Pack DevelopmentObjective:
– 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
Simon Mills | April 200833 |
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
Simon Mills | April 200834 |
• 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
Simon Mills | April 200835 |
• 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
Simon Mills | April 200836 |
• 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
Simon Mills | April 200837 |
• 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
Simon Mills | April 200838 |
Phase 3 - LaunchPhase 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
Simon Mills | April 200839 |
Pack Changes? 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.
Simon Mills | April 200840 |
Summary 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?