Packaging Dr Dave Elder and Dr Simon Mills, GSK Cape Town, South Africa 16-21st April, 2007

Introduction Chosing the most Appropriate Pack General Overview Blister Packs Container/Closures General Overview Bottles Injectables Tubes Inhalation/IntraNasal products Regulatory US, EU, Pharmacopoeial Extractable/Leachables Packaging Development

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

ADDITIONAL DRIVERS/FUTURE CHALLENGES 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 Global - Regional - Local packs Anti-counterfeiting, illegal cross border trading Multiple studies for different packs vs. Year-on-Year manufacturing costs Pharmacogenomics - Personalised medicines Demographic change - Ageing population

Some factors are territory specific, e.g. PACKAGING Choosing the most appropriate pack Some factors are territory specific, e.g. Presentation e.g. for solid dose US prefer bottles EU/RoW prefer blister packs Child resistance requirements US Legal requirement with few exceptions Clear blisters, peel-push, tear notch, secondary CR pack EU/RoW Legal requirement in only 4 EU member states & for very limited list of products Push through blisters, opaque Environment EU Packaging and Packaging Waste Directive US - no direct equivalent

Packaging Development The 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 Waterman et al (1) determined the theoretical rate of water permeation through a standard 60-cc bottle when stored at 40C/75%RH. This equated to an uptake of 1mg of water per day. They commented that even if the product had been packed under low water vapour conditions the relative humidity conditions within the container would be re-equate to 50%RH within 1 day. The WVTRs (see Table) for some common packaging materials were reported by Waterman et al (2). References: (1) K.C. Waterman, R.C. Adami, K.M. Alsante, A.S. Antipas, D.R. Arenson, R. Carrier, J. Hong, M.S. Landis, F. Lombardo, J.C. Shah, E. Shalaev, S.W. Smith and H. Wang, Pharm. Dev. and Tech., 7 (2002b) 113.

Packaging Development 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. 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 (4). References: (4) L. Dobson, J. Packag. Technol., 1 (1987) 127-131

Aclar ® is a registered trade mark of Allied Signal 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

COST IS AN IMPORTANT FACTOR PACKAGING Choosing the most appropriate pack Barrier Performance versus Cost COLD FORM FOIL Stability driver ACLAR® UltRx2000 ACLAR® SupRx900 Barrier ACLAR®Rx160 PVC/PE/PVDC PVC/PVDC 40gsm PP Cost driver PVC Cost COST IS AN IMPORTANT FACTOR

Packaging Development 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. Derived from Wang et al, 1998 (4) References: (4) Y. Wang, A.J. Easteal, and X.D. Chen, Packag. Technol. Sci., 11 (1998) 169 Pack OVTR (g. mm/(m2. day)) LDPE 241 HDPE 102 Polystyrene 127 Polycarbonate 114 Polypropylene 89 PVC 4 PET 2

Packaging Development Waterman et al (1) determined the theoretical rate of oxygen permeation through a standard 30-cc bottle when stored in a well sealed container This equated to an uptake of 0.2mMol 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.

Packaging Development Impact of Oxidative Instability of Container-Closure

Preferred range of pack/material options to be used for new products 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 Minimises R&D resource Supports supply site transfers (like for like; identical) Global blister material first intent in place since 2003 Solid dose bottle and closure first intent under development

Aclar® is registered trademark of Honeywell Inc 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 (eg 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 2000 3. Cold Form 25 OPA/45 Al/ 60 PVC Aclar® is registered trademark of Honeywell Inc

Reduced Complexity maintaining Bottles and Closures: Benefits Current Complexity reduction Standardisation and rationalisation of components Reduced number of change-overs at factory sites Resource demand reduction 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 Complexity maintaining Flexibility

type I (for inhaled solutions) Plastic low density polyethylene LDPE 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) At the opposite extreme - For Perfumes then development of the pack is as important as development of the product. The same is true for pharmaceuticals, and we need to be nearer this end of the spectrum and not the end game. Pack should be developed and tested alongside the product Treat no different to product. As we will see in a minute in numerous cases the same guidelines, eg, ICH Q6A, CPMP DPS and Stability guidelines, are equally applicable to packaging. Perhaps a useful an would be excipient compatibility and to GMP. Just as GMP is not something you can add at the end of a process, if looking for effective ST’s, then same is true for is packaging.

Liner – cork, pulpboard, EPE; flowed in gasket 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 Reseal liner Pulpboard Foil Let’s start with Packaging is not an end game activity. What do I mean by this? I have worked in this industry for 30 years, most of my career having been spent in packaging. Whilst I have seen many changes in that time, one thing which has tended to remain constant is that for many people in the industry packaging is something that is bolted on at the end, or something which somebody else sorts out for you. Wax Polyester Heatseal film/coating Induction Liner

PACKAGING Closures - examples Two piece Child Resistant (CR) with Induction Heat Seal Continuous thread (CT), plastic screw closure Let’s start with Packaging is not an end game activity. What do I mean by this? I have worked in this industry for 30 years, most of my career having been spent in packaging. Whilst I have seen many changes in that time, one thing which has tended to remain constant is that for many people in the industry packaging is something that is bolted on at the end, or something which somebody else sorts out for you.

PACKAGING Solid Dose – Blister Packs THERMOFORM BLISTERS plastic base web blister formed with aid of heating low to high barrier - Overlacquer - Heat seal lacquer - Print - Aluminium - Primer Lidding Foil – typically 20 micron Al Film - eg PVC, PVC/PVDC, PVC/PE/PVDC, PVC/Aclar - PVC - PVDC or Aclar At the opposite extreme - For Perfumes then development of the pack is as important as development of the product. The same is true for pharmaceuticals, and we need to be nearer this end of the spectrum and not the end game. Pack should be developed and tested alongside the product Treat no different to product. As we will see in a minute in numerous cases the same guidelines, eg, ICH Q6A, CPMP DPS and Stability guidelines, are equally applicable to packaging. Perhaps a useful an would be excipient compatibility and to GMP. Just as GMP is not something you can add at the end of a process, if looking for effective ST’s, then same is true for is packaging. Product contact layers: For PVC or PVC/Aclar = PVC For PVC/PVDC = PVDC For Lid foil = heat seal lacquer

PACKAGING Solid Dose – Blister Packs COLD FORM BLISTER blister formed mechanically (no heat) high barrier Lidding Foil Foil Laminate – e.g. OPA/foil/PVC, or OPA/foil/PP - PVC (may be PP) - OPA Film - Aluminium foil - Primer/Adhesive At the opposite extreme - For Perfumes then development of the pack is as important as development of the product. The same is true for pharmaceuticals, and we need to be nearer this end of the spectrum and not the end game. Pack should be developed and tested alongside the product Treat no different to product. As we will see in a minute in numerous cases the same guidelines, eg, ICH Q6A, CPMP DPS and Stability guidelines, are equally applicable to packaging. Perhaps a useful an would be excipient compatibility and to GMP. Just as GMP is not something you can add at the end of a process, if looking for effective ST’s, then same is true for is packaging. Product contact layers: For base = PVC (or PP) For lid foil = heat seal lacquer

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 = PVC For PVC/PVDC = PVDC For Lid foil = heat seal lacquer At the opposite extreme - For Perfumes then development of the pack is as important as development of the product. The same is true for pharmaceuticals, and we need to be nearer this end of the spectrum and not the end game. Pack should be developed and tested alongside the product Treat no different to product. As we will see in a minute in numerous cases the same guidelines, eg, ICH Q6A, CPMP DPS and Stability guidelines, are equally applicable to packaging. Perhaps a useful an would be excipient compatibility and to GMP. Just as GMP is not something you can add at the end of a process, if looking for effective ST’s, then same is true for is packaging.

Syringe Ampoules Vials Rubber, plastic Rubber Glass – type I PACKAGING Injections Syringe Ampoules Vials Rubber, plastic Glass – type I Plastic – PP, COC Rubber Glass – type I Plastic – e.g. LDPE Vial Glass - type I Plastics - PP, PC, COC Stopper Rubber Glass Plastic RUBBER Butyl, chlorobutyl, bromobutyl, halobutyl, TPE ,natural*, buytl/polyisoprene* copolymer or blend; Coatings – Flurotech, Omniflex, fluororesin/polymer * Beware of concern over latex allergy. Need for warning labelling EU & US At the opposite extreme - For Perfumes then development of the pack is as important as development of the product. The same is true for pharmaceuticals, and we need to be nearer this end of the spectrum and not the end game. Pack should be developed and tested alongside the product Treat no different to product. As we will see in a minute in numerous cases the same guidelines, eg, ICH Q6A, CPMP DPS and Stability guidelines, are equally applicable to packaging. Perhaps a useful an would be excipient compatibility and to GMP. Just as GMP is not something you can add at the end of a process, if looking for effective ST’s, then same is true for is packaging.

lined with an epoxy phenolic lacquer PACKAGING Tubes Aluminium Lacquered Aluminium lined with an epoxy phenolic lacquer Laminate foil laminate body, plastic shoulder Eg, structure for Acyclovir topical ointment - Clear LDPE - Aluminium foil - White LDPE - PE - EMAA - LDPE (product contact) NOTE: Specific EU Directives limiting residues in epoxy coatings for food contact use Plastic – PE, PVC

Metered dose inhaler Dry Powder Inhalers Nebules Intranasal PACKAGING Inhalation and Intranasal Products Metered dose inhaler Dry Powder Inhalers Nebules Intranasal

Guidance for Industry, Changes to an Approved NDA or ANDA 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

EU does NOT have a consolidated container/closure guideline (cf FDA) PACKAGING Key Regulatory Guidance - EUROPE 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)

Regulatory requirement FDA PACKAGING Food Contact Approval Regulatory requirement FDA Container Closure Systems for Packaging of Human Drugs and Biologics, Chemistry, Manufacturing and Controls Documentation, III,B,I,c Safety Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products, Manufacturing and Controls Documentation, III,G,1. Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products Chemistry, Manufacturing, and Controls Documentation, III,G,a CPMP CPMP Note for Guidance III/9090/EN (3AQ10a) Plastic Primary Packaging Materials, Introduction CPMP Note for Guidance CPMP/QWP/4359, Plastic Immediate Packaging Materials (effective 1 December 2005)

Baseline Statement of Safety Defines acceptable starting materials PACKAGING Food Contact Approval - Relevance Baseline Statement of Safety Defines acceptable starting materials acceptable additives and processing aids limits on residues limits on leachables (eg specific migration limits) Based upon Acceptable or Tolerable Daily Intake in FOOD NOTE US and EU do not use same calculations

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 But no guidance tells you exactly what to do or how to do it

Avoids unnecessary stability testing PACKAGING Extractables & Leachables Expectation & Science GOOD SCIENCE Qualification exhaustive extraction to characterise (worst case) qualitative and quantitative chromatographic profiles show control at the material level (cf. synthetic impurities) Stability monitoring in real product, real time to establish equilibrium concentration value Interaction early detection REGULATORY EXPECTATION Identify Quantify Toxicological evaluation Avoids unnecessary stability testing If interaction is between the active and a pack extractive, resultant compound is treated as an impurity (ICH Q3B)

Packaging Development Objective To ensure timely and robust selection of the primary pack for clinical trial and commercial supply. Our approach: To use, where possible, a limited range of standard, well characterised pack materials and packs To ensure thorough testing, characterisation and understanding of our pack materials and packs.

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, eg, HDPE bottles for sold dose forms Inert packs, eg, 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

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

Pack options are identified to meet: 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

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 We maximise our pack and product knowledge and understanding and achieve commercial efficiency by using a limited range of First Intent, preferred pack materials, wherever possible.

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, eg, 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.

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 to 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, eg, dimensional and performance specifications, need for clean room manufacture etc Manufacturing controls for the packaging process

6. Pivotal Stability Testing 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

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

Pack Changes? Our 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 But changes can occur at late stage due to, for example, Unpredictable outcome in pivotal stability Newly identified impurities or need for tighter specification limits These tend to drive need for more protective packs, e.g. Inclusion of desiccant in bottle packs Need for higher barier (eg 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.