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1 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Packaging Dr Dave Elder and Dr Simon Mills, GSK Cape Town, South.

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Presentation on theme: "1 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Packaging Dr Dave Elder and Dr Simon Mills, GSK Cape Town, South."— Presentation transcript:

1 1 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Packaging Dr Dave Elder and Dr Simon Mills, GSK Cape Town, South Africa st April, 2007

2 2 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Chosing the most Appropriate Pack Blister Packs Container/Closures General Overview Bottles Blister Packs Injectables Tubes Inhalation/IntraNasal products Regulatory US, EU, Pharmacopoeial Extractable/Leachables Packaging Development Introduction

3 3 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals n Protection ä stability test conditions n Commercial ä image ä market requirements/trends ä dosing/patient compliance ä security/tamper evidence ä manufacturing ä economics - COG BASIC REQUIREMENTS n n Legislation ä ä E.g. EC Packaging and Packaging Waste Directive n n Compatibility PACKAGING Choosing the most appropriate pack n n Regulatory n n Corporate ä ä Global Quality Policies

4 4 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals ADDITIONAL DRIVERS/FUTURE CHALLENGES n Moisture sensitive drugs increasing barrier requirements n Novel delivery systems n Emphasis on speed to market n Control of R&D Expenditure/resource - number of stability studies n Global - Regional - Local packs n Anti-counterfeiting, illegal cross border trading n Multiple studies for different packs vs. Year-on-Year manufacturing costs n Pharmacogenomics - Personalised medicines n Demographic change - Ageing population PACKAGING Choosing the most appropriate pack

5 5 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Some factors are territory specific, e.g. Environment – – EU Packaging and Packaging Waste Directive – – US - no direct equivalent n Presentation ä e.g. for solid dose l US prefer bottles l EU/RoW prefer blister packs n n Child resistance requirements ä ä US l l Legal requirement with few exceptions l l Clear blisters, peel-push, tear notch, secondary CR pack ä ä EU/RoW l l Legal requirement in only 4 EU member states & for very limited list of products l l Push through blisters, opaque PACKAGING Choosing the most appropriate pack

6 6 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Packaging Development n The WVTR through the container is determined by ä container wall thickness ä permeability of the packaging material ä difference between the external and internal relative humidity environments l Driving force for the water flux through the container n Waterman et al (1) determined the theoretical rate of water permeation through a standard 60-cc bottle when stored at 40  C/75%RH. n This equated to an uptake of 1mg of water per day. n 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.

7 7 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Packaging Development n Desiccants have been utilised to control the exposure of products to the ingress of moisture. n Desiccants vary in their capacity and the rate that they adsorb/absorb ingressed moisture. ä Silica gel is very efficient at absorbing moisture at high relative humidities, but comparatively poor at lower relative humidities ä Molecular sieve desiccants - the opposite scenario prevails ä As a consequence, more molecular sieve is required at higher relative humidities, and the greater the handling precautions that are required during packaging operations. ä 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)

8 8 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Cold Form Aluminium0.00 Aclar ® 33C0.08 Aclar ® UltRx Aclar ® 22C0.22 Aclar ® SupRx Aclar ® 22A PVC/80g PVDC0.31 Aclar ® Rx Aclar ® 33C0.42 PVC/60g PVDC PVC/40g PVDC PP PVC Aclar ® is a registered trade mark of Allied Signal PACKAGING Choosing the most appropriate pack Barrier Properties (typical MVTR g/m 2 /day 38 C/90%RH)

9 9 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Cost Barrier PVC PVC/PVDC 40gsm ACLAR ® Rx160 PVC/PE/PVDC ACLAR ® UltRx2000 ACLAR ® SupRx900 P COST IS AN IMPORTANT FACTOR Stability driver Cost driver PACKAGING Choosing the most appropriate pack Barrier Performance versus Cost COLD FORM FOIL

10 10 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Packaging Development n 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 PackOVTR (g. mm/(m 2. day)) LDPE241 HDPE102 Polystyrene127 Polycarbonate114 Polypropylene89 PVC4 PET2

11 11 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Packaging Development n Waterman et al (1) determined the theoretical rate of oxygen permeation through a standard 30-cc bottle when stored in a well sealed container n This equated to an uptake of 0.2mMol of oxygen per year n In addition to permeation through the container walls, the key vulnerability in any container-closure system is the closure. n With screw-topped closures leakage can be significant. n Hence for oxidatively labile dosage forms an oxygen impermeable seal is required, and induction heat sealed containers are particularly useful. n Levels of oxygen in the headspace of the container-closure can be significant, and packaging under an inert atmosphere although doable is problematical.

12 12 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Packaging Development Impact of Oxidative Instability of Container-Closure

13 13 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals n What is First Intent? ä Preferred range of pack/material options to be used for new products ä Agreed between R&D and factory ä Identical global materials ä Fully aligned with Procurement sourcing strategies ä Secure/robust sourcing ä Minimises R&D resource ä Supports supply site transfers (like for like; identical) n Global blister material first intent in place since 2003 n Solid dose bottle and closure first intent under development PACKAGING First Intent

14 14 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals n n MATERIALS (hierarchy of choice based on product stability) ä ä Material should preferably be opaque white unless clear is a specific market requirement (eg US, Japan) ä ä 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 Cold Form 25 OPA/45 Al/ 60 PVC Aclar® is registered trademark of Honeywell Inc PACKAGING First Intent – Blister base

15 15 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 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 Reduced Complexity maintaining Flexibility Reduced Complexity maintaining Flexibility Current Future Bottles and Closures: Benefits

16 16 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals BOTTLE n n Glass ä ä type III (solids) ä ä type I (for inhaled solutions) n n Plastic ä ä low density polyethylene LDPE ä ä high density polyethylene HDPE ä ä polypropylene PP ä ä polyester PET, PETG ä ä Cyclo-olefin copolymer (COC) PACKAGING Bottles

17 17 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals n Plastic - wadless or lined, CR (child resistant), CT (continuous thread), snap fit n Metal - screw, ROPP n Liner – cork, pulpboard, EPE; flowed in gasket ä product contact materials/facings : PVDC, Saran, Saranex, Melinex, EPE, Vinyl, Foamed PVC n Induction heat seals Pulpboard Wax Foil Polyester Heatseal film/coating PACKAGING Closures Reseal liner Induction Liner

18 18 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals PACKAGING Closures - examples Two piece Child Resistant (CR) with Induction Heat Seal Continuous thread (CT), plastic screw closure

19 19 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals n n THERMOFORM BLISTERS ä ä plastic base web ä ä blister formed with aid of heating ä ä low to high barrier PACKAGING Solid Dose – Blister Packs - PVC - PVDC or Aclar Lidding Foil – typically 20 micron Al Film - eg PVC, PVC/PVDC, PVC/PE/PVDC, PVC/Aclar - Overlacquer - Heat seal lacquer - Print - Aluminium - Primer Product contact layers: For PVC or PVC/Aclar = PVC For PVC/PVDC = PVDC For Lid foil = heat seal lacquer

20 20 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Foil Laminate – e.g. OPA/foil/PVC, or OPA/foil/PP Lidding Foil n n COLD FORM BLISTER ä ä blister formed mechanically (no heat) ä ä high barrier PACKAGING Solid Dose – Blister Packs - PVC (may be PP) - OPA Film - Aluminium foil - Primer/Adhesive Product contact layers: For base = PVC (or PP) For lid foil = heat seal lacquer

21 21 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Lidding Foil Foil Laminate – e.g. OPA/foil/PVC n n TROPICALISED BLISTER ä ä thermoform blister plus cold form tray ä ä once tray opened, in use life determined by primary thermoform blister ä ä high barrier before use PACKAGING Solid Dose – Blister Packs Film – e.g. PVC, PVC/PVDC Product contact layers: For PVC = PVC For PVC/PVDC = PVDC For Lid foil = heat seal lacquer

22 22 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Vials Glass – type I Plastic – e.g. LDPE Glass Plastic Syringe Rubber Vial Glass - type I Plastics - PP, PC, COC Stopper Rubber Ampoules Glass – type I Plastic – PP, COC Rubber, 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 PACKAGING Injections

23 23 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals PACKAGING Tubes n Aluminium n Lacquered Aluminium ä lined with an epoxy phenolic lacquer n n Laminate ä ä foil laminate body, plastic shoulder ä ä Eg, structure for Acyclovir topical ointment n n Plastic – PE, PVC - Clear LDPE - Aluminium foil - White LDPE - PE - EMAA - LDPE (product contact) - EMAA NOTE: Specific EU Directives limiting residues in epoxy coatings for food contact use

24 24 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Metered dose inhaler Nebules PACKAGING Inhalation and Intranasal Products Dry Powder Inhalers Intranasal

25 25 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 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

26 26 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals PACKAGING Key Regulatory Guidance - EUROPE 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)

27 27 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals n Regulatory requirement ä FDA l Container Closure Systems for Packaging of Human Drugs and Biologics, Chemistry, Manufacturing and Controls Documentation, III,B,I,c Safety l Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products, Manufacturing and Controls Documentation, III,G,1. l Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products Chemistry, Manufacturing, and Controls Documentation, III,G,a ä CPMP l CPMP Note for Guidance III/9090/EN (3AQ10a) Plastic Primary Packaging Materials, Introduction l CPMP Note for Guidance CPMP/QWP/4359, Plastic Immediate Packaging Materials (effective 1 December 2005) PACKAGING Food Contact Approval

28 28 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals n Baseline Statement of Safety ä Defines l acceptable starting materials l acceptable additives and processing aids l limits on residues l limits on leachables (eg specific migration limits) ä Based upon l Acceptable or Tolerable Daily Intake in FOOD NOTE US and EU do not use same calculations PACKAGING Food Contact Approval - Relevance

29 29 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals EXTRACTABLES and LEACHING THE THEORY n n FDA guidelines make significant reference n n Included in CPMP guideline 3AQ10a and CPMP/QWP/4359 n n Pack/product interaction n n Label adhesive migration But no guidance tells you exactly what to do or how to do it

30 30 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals REGULATORY EXPECTATION n Identify n Quantify n Toxicological evaluation GOOD SCIENCE n n Qualification ä ä exhaustive extraction to characterise (worst case) ä ä qualitative and quantitative chromatographic profiles ä ä show control at the material level (cf. synthetic impurities) n n Stability ä ä monitoring in real product, real time to establish equilibrium concentration value n n Interaction ä ä early detection Avoids unnecessary stability testing If interaction is between the active and a pack extractive, resultant compound is treated as an impurity (ICH Q3B) PACKAGING Extractables & Leachables Expectation & Science

31 31 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Packaging Development n Objective ä To ensure timely and robust selection of the primary pack for clinical trial and commercial supply. n Our approach: ä To use, where possible, a limited range of standard, well characterised pack materials and packs ä To ensure thorough testing, characterisation and understanding of our pack materials and packs.

32 32 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Phase I – FTIH & Phase II Clinical Supply n Objective ä Selection of packs for clinical supply n Our approach: ä Will generally use l Limited range of standard, characterised packs, eg, HDPE bottles for sold dose forms l Inert packs, eg, fluororesin laminated injection stoppers ä Packs and materials chosen to ensure pharmacopoeial and regulatory compliance is well understood ä Material performance is well characterised or known ä Pack selection is supported by stability testing for each product

33 33 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Phase II – III, Commercial Pack Development n Objective ä Identification, development and testing of commercial pack options n Approach: 3. Development Stability Testing 2. Material Selection & Testing 1. Identify Pack Options 6. Pivotal Stability Testing 5. Pack Selection 4. Controls Defined

34 34 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Pack options are identified to meet: ä Product attributes, e.g., dosage form, physical and chemical robustness ä Product protection needs, e.g., moisture & gas sensitivity, thermal stability, photostability, chemical compatibility etc ä Clinical requirements, e.g., dosing regimen, titration dosing, route of administration, need for dosing device ä Patient requirements, e.g., specific handling requirements, patient handling studies ä Commercial requirements, e.g., market presentation, pack sizes, market specific needs, patient handling needs ä Manufacturing requirements, e.g., equipment capability, critical process parameters, ä Regulatory requirements, e.g., material compliance, pharmacopeial monographs 1. Identify Pack Options

35 35 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 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. 2. Material Selection & Testing

36 36 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 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. 3. Development Stability Testing

37 37 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 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 4. Controls Defined

38 38 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 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 5. Pack Selection 6. Pivotal Stability Testing

39 39 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Phase 3 - Launch n Between Phase 3 and Launch ä Secondary packaging is defined l note, if needed for product protection, this will be defined with the primary pack and included in pivotal stability ä Define market presentations, graphics, patient information leaflets ä Conduct line, engineering and technical trials on pack components and equipment ä Conduct any necessary validation of packaging processes

40 40 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Pack Changes? n Our aim: ä 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 n But changes can occur at late stage due to, for example, ä Unpredictable outcome in pivotal stability ä Newly identified impurities or need for tighter specification limits n These tend to drive need for more protective packs, e.g. ä Inclusion of desiccant in bottle packs ä Need for higher barier (eg foil/foil) blister packs n 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.


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