Pharmaceutical Development Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Tallink City Hotel Tallinn, South Africa Date: 15 - 19 October 2007 Training Workshop on Pharmaceutical Development | 1 with a Focus on Paediatric Medicines / 15-19 October 2007 Pharmaceutical Development Pharmaceutical packaging Presenter: Simon Mills Email: Simon.n.mills@gsk.com Training Workshop on Pharmaceutical Development | 2 with a Focus on Paediatric Medicines / 15-19 October 2007 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 Training Workshop on Pharmaceutical Development | 3 with a Focus on Paediatric Medicines / 15-19 October 2007 PACKAGING: Choosing the most appropriate pack BASIC REQUIREMENTS Protection – stability test conditions Compatibility Regulatory Legislation – E.g. EC Packaging and Packaging Waste Directive Training Workshop on Pharmaceutical Development | 4 with a Focus on Paediatric Medicines / 15-19 October 2007 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 Training Workshop on Pharmaceutical Development | 5 with a Focus on Paediatric Medicines / 15-19 October 2007 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 Child resistance requirements – US • Legal requirement with few exceptions – EU/RoW • Environment – EU Packaging and Packaging Waste Directive – US - no direct equivalent Training Workshop on Pharmaceutical Development | 6 with a Focus on Paediatric Medicines / 15-19 October 2007 • 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 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 | 7 with a Focus on Paediatric Medicines / 15-19 October 2007 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 | 8 with a Focus on Paediatric Medicines / 15-19 October 2007 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 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 Aclar ® is a registered trade mark of Allied Signal Training Workshop on Pharmaceutical Development | 9 with a Focus on Paediatric Medicines / 15-19 October 2007 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. OVTR (g. mm/(m2. day)) LDPE 241 HDPE 102 Polystyrene 127 Polycarbonate 114 Polypropylene 89 PVC 4 PET 2 Training Workshop on Pharmaceutical Development | 10 with a Focus on Paediatric Medicines / 15-19 October 2007 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 | 11 with a Focus on Paediatric Medicines / 15-19 October 2007 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) Training Workshop on Pharmaceutical Development | 12 with a Focus on Paediatric Medicines / 15-19 October 2007 PACKAGING: First Intent – Blister base MATERIALS (hierarchy of choice based on product stability) 1. PVC 250m 2. PVC/PVDC 250m/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 Training Workshop on Pharmaceutical Development | 13 with a Focus on Paediatric Medicines / 15-19 October 2007 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 Training Workshop on Pharmaceutical Development | 14 with a Focus on Paediatric Medicines / 15-19 October 2007 Future Reduced Complexity Maintaining Flexibility PACKAGING: Bottles 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) Training Workshop on Pharmaceutical Development | 15 with a Focus on Paediatric Medicines / 15-19 October 2007 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 Training Workshop on Pharmaceutical Development | 16 with a Focus on Paediatric Medicines / 15-19 October 2007 PACKAGING: Solid Dose – Blister Packs - Overlacquer THERMOFORM BLISTERS – plastic base web – blister formed with aid of heating – low to high barrier - 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 Training Workshop on Pharmaceutical Development | 17 with a Focus on Paediatric Medicines / 15-19 October 2007 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 Training Workshop on Pharmaceutical Development | 18 with a Focus on Paediatric Medicines / 15-19 October 2007 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 Training Workshop on Pharmaceutical Development | 19 with a Focus on Paediatric Medicines / 15-19 October 2007 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 Training Workshop on Pharmaceutical Development | 20 with a Focus on Paediatric Medicines / 15-19 October 2007 Intranasal PACKAGING: Key Regulatory Guidance - US Guidance for Industry, Container Closure Systems for Packaging of Human Drugs and Biologics Training Workshop on Pharmaceutical Development | 21 with a Focus on Paediatric Medicines / 15-19 October 2007 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) Training Workshop on Pharmaceutical Development | 22 with a Focus on Paediatric Medicines / 15-19 October 2007 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 Training Workshop on Pharmaceutical Development | 23 with a Focus on Paediatric Medicines / 15-19 October 2007 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 | 24 with a Focus on Paediatric Medicines / 15-19 October 2007 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 | 25 with a Focus on Paediatric Medicines / 15-19 October 2007 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 | 26 with a Focus on Paediatric Medicines / 15-19 October 2007 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 Training Workshop on Pharmaceutical Development | 27 with a Focus on Paediatric Medicines / 15-19 October 2007 1. Identify Pack Options 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 Training Workshop on Pharmaceutical Development | 28 with a Focus on Paediatric Medicines / 15-19 October 2007 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. Training Workshop on Pharmaceutical Development | 29 with a Focus on Paediatric Medicines / 15-19 October 2007 3. Development Stability 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. Training Workshop on Pharmaceutical Development | 30 with a Focus on Paediatric Medicines / 15-19 October 2007 4. Controls Defined • 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 Training Workshop on Pharmaceutical Development | 31 with a Focus on Paediatric Medicines / 15-19 October 2007 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 • • Confirm compatibility and product stability Support product registration submission Training Workshop on Pharmaceutical Development | 32 with a Focus on Paediatric Medicines / 15-19 October 2007 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 | 33 with a Focus on Paediatric Medicines / 15-19 October 2007 Pack Changes? Recommended aim: – to avoid pack changes between pivotal stability and launch by ensuring a Quality-byDesign 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 | 34 with a Focus on Paediatric Medicines / 15-19 October 2007 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? Training Workshop on Pharmaceutical Development | 35 with a Focus on Paediatric Medicines / 15-19 October 2007