Pharmaceutical Development with Focus on Paediatric formulations WHO/FIP Training Workshop Hyatt Regency Hotel
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 1| 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: Simon.n.mills@gsk.com 2| 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 3| 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). 4| 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 5| 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 6| 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 7| 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 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. 8| 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. 9| 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 10 | 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. 11 | 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. 12 | 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) 13 | Simon Mills | April 2008 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 14 | 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 15 | Simon Mills | April 2008 Future Reduced Complexity Maintaining Flexibility PACKAGING: Bottles BOTTLE Glass – type III (solids) – type I (for inhaled solutions) Plastic – – – – – 16 | 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 17 | 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 18 | 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 19 | 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 20 | 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 ! 21 | 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%) 22 | 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 23 | Simon Mills | April 2008 PACKAGING: Key Regulatory Guidance - US Guidance for Industry, Container Closure Systems for Packaging of Human Drugs and Biologics 24 | 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) 25 | 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 26 | 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. 27 | 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 28 | 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 29 | 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. 30 | 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 31 | 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 32 | Simon Mills | April 2008 1. Identify Pack Options Pack options are identified to meet: 33 | – 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. 34 | Simon Mills | April 2008 3. Development Stability Testing • Development stability testing used to • • • • • • 35 | 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. • • • • • • 36 | 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 • • 37 | 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 38 | 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. 39 | Simon Mills | April 2008 Summary 40 | • 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?
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