Packaging.ppt

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

2
• 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
 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

4
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

5
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

6
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.

7
 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

8
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
Barrier Properties (typical MVTR g/m2/day 38 C/90%RH)

9
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
Barrier Performance versus Cost
• COLD FORM FOIL

10
 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

11
 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.

12
Impact of Oxidative Instability of
Container-Closure

13
 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

14
 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
PACKAGING First Intent – Blister base

15
• 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
Current
Future
Bottles and Closures: Benefits

16
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

17
 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

18
PACKAGING Closures - examples
Two piece Child Resistant (CR) with
Induction Heat Seal
Continuous thread (CT), plastic screw
closure

19
 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

20
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

21
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 = PVC
For PVC/PVDC = PVDC
For Lid foil = heat seal lacquer

22
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
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

24
Drug suspension
in propellant
Gasket
Metering valve
Mouthpiece
Valve
stem
Atomising
nozzle
Actuator body
Aluminium
can
Metered dose inhaler
Nebules
PACKAGING Inhalation and Intranasal Products
Dry Powder Inhalers
Intranasal

25
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
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
 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

28
 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

29
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

30
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

31
 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.

32
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

33
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

34
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

35
• 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
• 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
• 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
• 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
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

40
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.ppt

Recommandé

Recommandé

Contenu connexe

Similaire à Packaging.ppt

Similaire à Packaging.ppt (20)

Plus de HafizurRahman130404

Plus de HafizurRahman130404 (19)

Dernier

Dernier (20)

Packaging.ppt