Packaging

Dr Dave Elder and Dr Simon Mills, GSK Cape Town, South Africa 16-21st April, 2007
Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 1

Introduction

Chosing the most Appropriate Pack

Blister Packs Container/Closures Bottles Blister Packs Injectables Tubes Inhalation/IntraNasal products US, EU, Pharmacopoeial Extractable/Leachables

General Overview

Regulatory

Packaging Development

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 2

PACKAGING Choosing the most appropriate pack

BASIC REQUIREMENTS

Protection stability test conditions Compatibility

Regulatory Legislation E.g. EC Packaging and Packaging Waste Directive

Commercial image market requirements/trends dosing/patient compliance security/tamper evidence manufacturing economics - COG Corporate Global Quality Policies

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 3

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

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 4

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

Environment EU Packaging and Packaging Waste Directive US - no direct equivalent

EU/RoW Legal requirement in only 4 EU member states & for very limited list of products Push through blisters, opaque

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 5

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 40C/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.
Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 6

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 products shelf-life can be determined (4).

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

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 7

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 is a registered trade mark of Allied Signal
Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 8

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

PACKAGING Choosing the most appropriate pack

Barrier Performance versus Cost

Stability driver

COLD FORM FOIL ACLAR UltRx2000 ACLAR SupRx900

Barrier

ACLARRx160 PVC/PE/PVDC

PVC/PVDC 40gsm

PP
PVC Cost

Cost driver

COST IS AN IMPORTANT FACTOR

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 9

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)

Pack LDPE HDPE Polystyrene Polycarbonate Polypropylene PVC PET

OVTR (g. mm/(m2. day)) 241 102 127 114 89 4 2

References: (4) Y. Wang, A.J. Easteal, and X.D. Chen, Packag. Technol. Sci., 11 (1998) 169

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 10

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.

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 11

Packaging Development
Impact of Oxidative Instability of Container-Closure

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 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 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

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 13

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 (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)
Aclar is registered trademark of Honeywell Inc

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 14

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

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

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 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
Reseal liner Pulpboard Foil Wax Polyester Induction Liner Heatseal film/coating

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 17

PACKAGING Closures - examples

Two piece Child Resistant (CR) with Induction Heat Seal

Continuous thread (CT), plastic screw closure

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 18

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
Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 19

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

- 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
Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 20

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
Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 21

PACKAGING Injections
Ampoules Vials Syringe
Rubber, plastic
Glass type I Plastic PP, COC

Rubber

Glass type I

Vial Glass - type I Plastics - PP, PC, COC

Glass Plastic RUBBER

Stopper Rubber
Plastic e.g. LDPE

Butyl, chlorobutyl, bromobutyl, halobutyl, TPE ,natural*, buytl/polyisoprene* copolymer or blend; Coatings Flurotech, Omniflex, fluororesin/polymer

* Beware of concern over latex allergy. Need for Department of Medicines Policy and Standards, warning labelling EU & US
Health Technology and Pharmaceuticals 22

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 - White LDPE - PE - EMAA - Aluminium foil - EMAA - LDPE (product contact)

NOTE:
Specific EU Directives limiting residues in epoxy coatings for food contact use

Plastic PE, PVC

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 23

PACKAGING Inhalation and Intranasal 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

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 24

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

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

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)
Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 26

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)

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 27

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

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 28

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

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 29

PACKAGING Extractables & Leachables Expectation & Science

REGULATORY EXPECTATION

GOOD SCIENCE

Identify

Quantify Toxicological evaluation

Qualification exhaustive extraction to characterise (worst case) Avoids unnecessary stability qualitative and quantitative testing 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 detectionIf interaction is between the active and

a pack extractive, resultant compound is treated as an impurity (ICH Q3B)

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 30

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.

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 31

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

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 32

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
Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 33

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

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 34

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.

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 35

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.

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 36

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

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 37

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

Confirm compatibility and product stability Support product registration submission

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 38

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

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 39

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 Inclusion of desiccant in bottle packs Need for higher barier (eg foil/foil) blister packs

These tend to drive need for more protective packs, e.g.

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.

Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 40