Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / October |1 | Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Tallink City Hotel Tallinn, South Africa Date: October 2007 Pharmaceutical Development

Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / October |2 | Pharmaceutical Development Pharmaceutical packaging Presenter:Simon Mills

Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / October |3 | 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 / October |4 | 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 / October |5 | 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 / October |6 | 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 / October |7 | 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.

Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / October |8 | 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.

Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / October |9 | Barrier Properties (typical MVTR g/m2/day 38°C/90%RH) Cold Form Aluminium0.00 Aclar ® 33C0.08 Aclar ® UltRx Aclar ® 22C0.22 Aclar ® SupRx Aclar ® 22A PVC/80g PVDC0.31 Aclar ® Rx Aclar ® 33C0.42 PVC/60g PVDC PVC/40g PVDC PP PVC2.4 – 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 / October | 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. PackOVTR (g. mm/(m 2. day)) LDPE241 HDPE102 Polystyrene127 Polycarbonate114 Polypropylene89 PVC4 PET2

Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / October | 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 / October | 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 / October | 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 250  m 2. PVC/PVDC 250  m/60gsm 4. PVC/Aclar® UltRx 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 / October | 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 / October | 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 / October | 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 / October | 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 / October | 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 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 / October | 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 / October | Metered dose inhaler Nebules PACKAGING: IH and IN Products Dry Powder Inhalers Intranasal

Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / October | 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 / October | 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 / October | 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 / October | 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 / October | 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 / October | 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 / October | 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 / October | 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 / October | 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 / October | 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 / October | 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 / October | 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 / October | 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 / October | 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 / October | 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?