Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Tallink City Hotel Tallinn, South

1. Pharmaceutical Development Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Tallink City Hotel Tallinn, South Africa Date: 15 - 19 October 2007

2. Pharmaceutical Development Pharmaceutical packaging Presenter: Simon Mills Email: Simon.n.mills@gsk.com

3. 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

4. Protection stability test conditions Commercial image market requirements/trends dosing/patient compliance security/tamper evidence manufacturing economics - COG PACKAGING: Choosing the most appropriate pack BASIC REQUIREMENTS • Compatibility • Regulatory • Legislation • E.g. EC Packaging and Packaging Waste Directive • Corporate • Global Quality Policies

5. 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. Presentation e.g. for solid dose US prefers bottles EU/RoW prefer blister packs PACKAGING: Choosing the most appropriate pack Some factors are territory-specific, e.g. • 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 • Environment • EU Packaging and Packaging Waste Directive • US - no direct equivalent

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.

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.

9. PACKAGING: Choosing the most appropriate pack Barrier Properties (typical MVTR g/m2/day 38°C/90%RH) Cold Form Aluminium 0.00 Aclar ® 33C 0.08 Aclar ® UltRx2000 0.11 - 0.12 Aclar ® 22C 0.22 Aclar ® SupRx 900 0.23 - 0.26 Aclar ® 22A 0.31 - 0.34 PVC/80g PVDC 0.31 Aclar ® Rx160 0.39 - 0.42 Aclar ® 33C 0.42 PVC/60g PVDC 0.47 - 0.6 PVC/40g PVDC 0.7 - 0.75 PP 0.7 - 1.47 PVC 2.4 – 4 Aclar ® is a registered trade mark of Allied Signal

10. 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.

11. 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. 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. 1. PVC 250m 2. PVC/PVDC 250m/60gsm 3. Cold Form 25 OPA/45 Al/ 60 PVC 4. PVC/Aclar® UltRx 2000 PACKAGING: First Intent – Blister base • 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) Aclar® is registered trademark of Honeywell Inc

14. 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 Future Reduced ComplexityMaintaining Flexibility

15. 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)

16. 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. PACKAGING: Solid Dose – Blister Packs - Overlacquer - Print - Aluminium - Primer - Heat seal lacquer Lidding Foil – typically 20 micron Al Film - egPVC, PVC/PVDC, PVC/PE/PVDC, PVC/Aclar® - PVC - PVDC or Aclar® • THERMOFORM BLISTERS • plastic base web • blister formed with aid of heating • low to high barrier Product contact layers: For PVC or PVC/Aclar® = PVC For PVC/PVDC = PVDC For Lid foil = heat seal lacquer

18. PACKAGING: Solid Dose – Blister Packs - OPA Film - Primer/Adhesive - Aluminium foil - Primer/Adhesive - PVC (may be PP) Lidding Foil • COLD FORM BLISTER • blister formed mechanically (no heat) • high barrier Foil Laminate –e.g. OPA/foil/PVC, or OPA/foil/PP Product contact layers:For base = PVC (or PP)For lid foil = heat seal lacquer

19. PACKAGING: Solid Dose – Blister Packs • TROPICALISED BLISTER • thermoform blister plus cold form tray • once tray opened, in use life determined by primary thermoform blister • high barrier before use Lidding Foil Film –e.g.PVC, PVC/PVDC Foil Laminate – e.g.OPA/foil/PVC Product contact layers:For PVC = PVCFor PVC/PVDC = PVDCFor Lid foil = heat seal lacquer

20. PACKAGING: IH and IN Products Dry Powder Inhalers Metered dose inhaler Nebules Intranasal

21. 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

22. PACKAGING: Key Regulatory Guidance - EU Guideline on Dossier Requirements for Type 1A and Type 1B Notifications CPMP/QWP/4359/03 – Guideline on Plastic Immediate Packaging Materials- specific to plastics only KEY POINT TO NOTE EU does NOT have a consolidated container/closure guideline (cf FDA)

23. 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 FOODNOTE: US and EU do not use same calculations PACKAGING: Food Contact Approval - Relevance

24. 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

25. 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.

26. 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

27. 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

28. 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

29. 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.

30. 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.

31. 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

32. 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. • Pivotal stability testing conducted in the selected markets packs, to • Confirm compatibility and product stability • Support product registration submission 6. Pivotal Stability Testing

33. 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

34. 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.

35. 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?