packaging

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Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

Packaging

Dr Dave Elder and Dr Simon Mills, GSKCape Town, South Africa16-21st April, 2007

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• 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

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Protection stability test conditions

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

BASIC REQUIREMENTS

Legislation E.g. EC Packaging and Packaging

Waste Directive

Compatibility

PACKAGING Choosing the most appropriate pack

Regulatory

Corporate Global Quality Policies

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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


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Some factors are territory specific, e.g.

• Environment– EU Packaging and Packaging

Waste Directive– US - no direct equivalent

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


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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.

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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

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Cold Form Aluminium 0.00Aclar ® 33C 0.08Aclar ® UltRx2000 0.11 - 0.12Aclar ® 22C 0.22Aclar ® SupRx 900 0.23 - 0.26Aclar ® 22A 0.31 - 0.34PVC/80g PVDC 0.31Aclar ® Rx160 0.39 - 0.42Aclar ® 33C 0.42PVC/60g PVDC 0.47 - 0.6PVC/40g PVDC 0.7 - 0.75PP 0.7 - 1.47PVC 2.4 - 4

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)

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Cost

Barrier

• PVC

• PVC/PVDC 40gsm

• ACLAR®Rx160• PVC/PE/PVDC

•ACLAR® UltRx2000

• ACLAR® SupRx900

• PP

COST IS AN IMPORTANT FACTOR

Stability driver

Cost driver

PACKAGING Choosing the most appropriate pack Barrier Performance versus Cost

• COLD FORM FOIL

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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

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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.

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Impact of Oxidative Instability of Container-Closure

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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

PACKAGING First Intent

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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 250m

2. PVC/PVDC 250m/60gsm

4. PVC/Aclar® UltRx 2000

3. Cold Form 25 OPA/45 Al/ 60 PVC

Aclar® is registered trademark of Honeywell Inc

PACKAGING First Intent – Blister base

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• 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

FlexibilityReduced Complexity maintaining

Flexibility

CurrentCurrent

FutureFuture

Bottles and Closures: Benefits

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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)

PACKAGING Bottles

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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

Pulpboard

Wax

Foil

Polyester

Heatseal film/coating

PACKAGING Closures

Reseal liner

Induction Liner

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PACKAGING Closures - examples

Two piece Child Resistant (CR) with Induction Heat Seal

Continuous thread (CT), plastic screw closure

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THERMOFORM BLISTERS plastic base web blister formed with aid

of heating 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

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Foil Laminate – e.g. OPA/foil/PVC, or OPA/foil/PP

Lidding Foil COLD FORM BLISTER blister formed mechanically (no heat) high barrier


- PVC (may be PP)

- OPA Film

- Aluminium foil

- Primer/Adhesive

- Primer/Adhesive

Product contact layers:For base = PVC (or PP)For lid foil = heat seal lacquer

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Lidding Foil

Foil Laminate – e.g. OPA/foil/PVC

TROPICALISED BLISTER 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

Product contact layers:For PVC = PVCFor PVC/PVDC = PVDCFor Lid foil = heat seal lacquer

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Vials

Glass – type I

Plastic – e.g. LDPE

GlassPlastic

Syringe

Rubber

VialGlass - type I

Plastics - PP, PC, COC

StopperRubber

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

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PACKAGING Tubes

Aluminium Lacquered Aluminium

lined with an epoxy phenolic lacquer

Laminate foil laminate body, plastic shoulder Eg, structure for Acyclovir topical ointment

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

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Metered dose inhaler

Nebules

PACKAGING Inhalation and Intranasal Products

Dry Powder Inhalers

Intranasal

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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

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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)

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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)

PACKAGING Food Contact Approval

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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

PACKAGING Food Contact Approval - Relevance

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EXTRACTABLES and LEACHING THE THEORYEXTRACTABLES 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 exactlywhat to do or how to do it

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REGULATORY

EXPECTATION

Identify

Quantify

Toxicological evaluation

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

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

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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.

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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

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Phase II – III, Commercial Pack Development

Objective Identification, development and testing of commercial pack options

Approach:

3. Development Stability Testing

2. Material Selection & Testing

1. Identify Pack Options

6. Pivotal Stability Testing

5. Pack Selection

4. Controls Defined

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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

1. Identify Pack Options

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• 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

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• 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

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• 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

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• 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

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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

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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.

packaging

Documents

packaging

product contact

material selection

development

pack selection

pack components

product stability

packaging