Pharmaceutical DevelopmentTraining 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: Email: Simon Mills [email protected] 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 g.PACKAGING: Choosing the most appropriate pack BASIC REQUIREMENTS Protection – stability test conditions Compatibility Regulatory Legislation – E. 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 .Regional .Ageing population Training Workshop on Pharmaceutical Development | 5 with a Focus on Paediatric Medicines / 15-19 October 2007 .number of stability studies required Global .Personalised medicines Demographic change .Local packs Anti-counterfeiting. illegal cross-border trading Pharmacogenomics . PACKAGING: Choosing the most appropriate pack Some factors are territory-specific.no direct equivalent 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 Training Workshop on Pharmaceutical Development | 6 with a Focus on Paediatric Medicines / 15-19 October 2007 .g. Presentation – e. for solid dose • US prefers bottles • EU/RoW prefer blister packs • Environment – EU Packaging and Packaging Waste Directive – US .g. e. – 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: 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. the opposite scenario prevails. – Based on the calculated WVTR of known container components and the rate of moisture adsorbed by desiccants. Desiccants vary in their capacity and the rate that they adsorb/absorb ingressed moisture. but comparatively poor at lower relative humidities. not by FDA in US. and the greater the handling precautions that are required during packaging operations. – Molecular sieve desiccants . more molecular sieve is required at higher relative humidities. Training Workshop on Pharmaceutical Development | 8 with a Focus on Paediatric Medicines / 15-19 October 2007 . the amount of desiccant that would be required to maintain a specified relative humidity over the product’s shelf-life can be determined. – Silica gel is very efficient at absorbing moisture at high relative humidities. – Molecular sieve approved in EU for pharmaceuticals.Packaging: Desiccants Desiccants have been utilised to control the exposure of products to the ingress of moisture. – As a consequence. 23 .7 .26 0.31 0.0.22 0.00 0.0.0.0.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 0.31 .39 .42 0.08 0.34 0.6 0.1.11 .47 2.7 .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 .75 0.0.47 .42 0.0.12 0. Packaging: OVTR Pack Similar considerations are relevant to protection of products that are labile to oxidative degradation. mm/(m2. OVTR (g. day)) LDPE HDPE Polystyrene Polycarbonate Polypropylene PVC PET 241 102 127 114 89 4 2 Training Workshop on Pharmaceutical Development | 10 with a Focus on Paediatric Medicines / 15-19 October 2007 . The permeability of plastic containers to oxygen ingress has also been evaluated (OVTR). and is summarised here. 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. is problematical. Levels of oxygen in the headspace of the container-closure can be significant. Hence for oxidatively labile dosage forms an oxygen-impermeable seal is required and induction heat-sealed containers are particularly useful. With screw-topped closures. leakage can be significant. and packaging under an inert atmosphere. although doable. the key vulnerability in any container-closure system is the closure.2 mMol of oxygen per year In addition to permeation through the container walls. Training Workshop on Pharmaceutical Development | 11 with a Focus on Paediatric Medicines / 15-19 October 2007 . identical) Training Workshop on Pharmaceutical Development | 12 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. g.PACKAGING: First Intent – Blister base MATERIALS (hierarchy of choice based on product stability) 1. PVC/PVDC 250m/60gsm 3. US. Japan) – Aclar® should be restricted to applications where cold form is not technically or commercially acceptable due to product or pack size. PVC 250m 2. 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 . 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. 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. Sites use ‘off the shelf’ solution for majority of products. Procurement. • Risk Mitigation • Commercial Leverage Future Reduced Complexity Maintaining Flexibility Training Workshop on Pharmaceutical Development | 14 with a Focus on Paediatric Medicines / 15-19 October 2007 . • Flexibility across factory sites without increased Regulatory activity. PETG Cyclo-olefin copolymer (COC) Training Workshop on Pharmaceutical Development | 15 with a Focus on Paediatric Medicines / 15-19 October 2007 .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. snap fit Metal . pulpboard. Melinex.wadless or lined. flowed in gasket – product contact materials/facings : PVDC. Saran. CT (continuous thread). EPE. CR (child resistant). ROPP Liner – cork. Foamed PVC Induction heat seals Training Workshop on Pharmaceutical Development | 16 with a Focus on Paediatric Medicines / 15-19 October 2007 . Vinyl.PACKAGING: Closures Plastic . EPE.screw. Saranex. Heat seal lacquer Lidding Foil – typically 20 micron Al Film .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 . PVC/Aclar® .Aluminium .PACKAGING: Solid Dose – Blister Packs THERMOFORM BLISTERS – plastic base web – blister formed with aid of heating – low to high barrier .eg PVC. PVC/PE/PVDC.Primer . PVC/PVDC.Overlacquer .PVC .Print . Aluminium foil .g.PACKAGING: Solid Dose – Blister Packs COLD FORM BLISTER – blister formed mechanically (no heat) – high barrier Lidding Foil Foil Laminate – e.OPA Film . OPA/foil/PVC. or OPA/foil/PP .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 .Primer/Adhesive .Primer/Adhesive . in use life determined by primary thermoform blister – high barrier before use Lidding Foil Film – 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: Solid Dose – Blister Packs TROPICALISED BLISTER – thermoform blister plus cold form tray – once tray opened.g. PVC. PVC/PVDC Foil Laminate – e. PACKAGING: IH and IN Products Metered dose inhaler Drug suspension in propellant Gasket Metering valve Dry Powder Inhalers Aluminium can Valve stem Atomising nozzle Actuator body Mouthpiece Nebules Intranasal Training Workshop on Pharmaceutical Development | 20 with a Focus on Paediatric Medicines / 15-19 October 2007 . PACKAGING: Key Regulatory Guidance . Container Closure Systems for Packaging of Human Drugs and Biologics Guidance for Industry.US Guidance for Industry. Changes to an Approved NDA or ANDA Training Workshop on Pharmaceutical Development | 21 with a Focus on Paediatric Medicines / 15-19 October 2007 . PACKAGING: Key Regulatory Guidance .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 .EU CPMP/QWP/4359/03 – Guideline on Plastic Immediate Packaging Materials . 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. 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 .PACKAGING: Food Contact Approval .g. 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 . Training Workshop on Pharmaceutical Development | 25 with a Focus on Paediatric Medicines / 15-19 October 2007 . characterisation and understanding of these selected pack materials and packs. well-characterised pack materials and packs – To ensure thorough testing. where possible. Recommended approach: – To use.Packaging Development Objective – To ensure timely and robust selection of the primary pack for clinical trial and commercial supply. a limited range of standard. g.Phase I – FTIH & Phase II Clinical Supply Objective – Selection of packs for clinical supply Our approach: – Will generally use • • Limited range of standard.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 . characterised packs. HDPE bottles for solid dose forms Inert packs. e. e. Controls Defined 5. Material Selection & Testing 3. Pivotal Stability Testing Training Workshop on Pharmaceutical Development | 27 with a Focus on Paediatric Medicines / 15-19 October 2007 . development and testing of commercial pack options Approach: 1. Commercial Pack Development Objective: – Identification. Development Stability Testing 4.Phase II – III. Pack Selection 6. Identify Pack Options 2. photostability. patient handling needs Manufacturing requirements. moisture & gas sensitivity. Identify Pack Options Pack options are identified to meet: – – – – – Product attributes. thermal stability. material compliance. route of administration.g.g. titration dosing. e. market presentation. pack sizes. equipment capability.g. patient handling studies Commercial requirements.g. dosage form. e. market specific needs.g. etc Clinical requirements. pharmacopeial monographs – – Training Workshop on Pharmaceutical Development | 28 with a Focus on Paediatric Medicines / 15-19 October 2007 .g. e. specific handling requirements. e. critical process parameters. need for dosing device Patient requirements.g.1. e. chemical compatibility. physical and chemical robustness Product protection needs. e. dosing regimen. Regulatory requirements. e. e. e. Product contact materials. light transmission Chemical characterisation. moisture permeation. USP. Training Workshop on Pharmaceutical Development | 29 with a Focus on Paediatric Medicines / 15-19 October 2007 . particularly. preferred pack materials. e. extractables and leachables studies. wherever possible.g.2. US. Material Selection & Testing • • • • • • • Product contact materials chosen to meet global and local regulations. JP Performance testing conducted.g. Ph Eur.. plastics confirmed as compliant with relevant food contact regulations.g. 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.g. especially for parenteral. EU etc Pharmacopoeial compliance established. e. Training Workshop on Pharmaceutical Development | 30 with a Focus on Paediatric Medicines / 15-19 October 2007 . e. 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. 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.3.g. need for clean room manufacture. Controls Defined • Data from material and product testing used to identify critical quality and process attributes for pack and packaging process. e. dimensional and performance specifications.4.g.g. Manufacturing controls for the packaging process • Training Workshop on Pharmaceutical Development | 31 with a Focus on Paediatric Medicines / 15-19 October 2007 . e. etc. • • • • • 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. 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 . are used to identify and agree the intended market packs. Pack Selection • Data from the previous steps. commercial and manufacturing requirements. 6. together with the clinical. Pivotal Stability Testing • • • Pivotal stability testing conducted in the selected markets packs.5. patient. 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 .Launch Between Phase 3 and Launch – Secondary packaging is defined • note. patient information leaflets – Conduct line.Phase 3 . graphics. if needed for product protection. this will be defined with the primary pack and included in pivotal stability – Define market presentations. – Inclusion of desiccant in bottle packs – Need for higher barrier (e. changes can occur at late stage due to. foil/foil) blister packs By use of First Intent pack materials and packs. Training Workshop on Pharmaceutical Development | 34 with a Focus on Paediatric Medicines / 15-19 October 2007 . e.g. 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. we aim to have a thorough understanding of our materials to minimise impact of change and have readily available.g. However. well characterised pack options.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. Pharmacopoeial • Extractable/Leachables • • ANY QUESTIONS PLEASE? • Packaging Development considerations through to Launch Training Workshop on Pharmaceutical Development | 35 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.