Packaging (1)

Simon Mills | April 20081 |

Pharmaceutical Development with Focus on Paediatric formulations


WHO/FIP Training Workshop Hyatt Regency Hotel

Sahar Airport Road

Andheri East, Mumbai, India

28 April 2008 – 2 May 2008




Pharmaceutical packaging – an overview including some considerations for paediatrics

Presented by:

Name: Simon Mills

Contact details:

[email protected]


• Choosing the most Appropriate Primary Pack• Blister Packs

• Containers & Closures

• General Overview• Bottles

• Blister Packs

• Inhalation / IntraNasal products

• Regulatory• US, EU, Pharmacopoeial

• Extractable & Leachables

• Packaging Development considerations through to Launch

Introduction Introduction


• As far as CMC considerations are concerned, paediatric and adult dosage forms can be treated in much the same way. There will be particular areas to focus attention on for paediatric products:

• There may be lower limits of acceptable levels of impurities, extractables and leachables resulting from product/pack interaction.

• Extra or novel devices to facilitate dosing or compliance can be associated with paediatric products, e.g. spacers with MDIs, syringes for oral dosing, nebulisers. It will be important to ensure that all contact materials are suitable and well controlled. For new materials/devices, this will necessitate extensive evaluation.

• Children must be protected from the risk of unsupervised access to medicines – this applies equally to paediatric and adult drug products. The need for child-resistant (CR) packaging will need to be assessed, balanced against the adjudged risk in accidental ingestion of the drug product itself; (some territories insist on CR packs; US requirements detailed in 16 CFR §1700).

Specific paediatric considerations Specific paediatric considerations


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


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 required

Global - Regional - Local packs

Anti-counterfeiting, illegal cross-border trading

Pharmacogenomics - Personalised medicines

Demographic change - Ageing population



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 prefers bottles• EU/RoW prefer blister packs

Child resistance requirements– US

• Legal requirement with few exceptions

– EU/RoW• Legal requirement in only 4 EU

member states & for very limited list of products



Packaging: WVTRPackaging: WVTR

The water vapour transmission rate (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

The theoretical rate of water permeation through a standard 60-cc HDPE bottle when stored at 40C/75%RH has been determined: – This equated to an uptake of 1mg of water per day. – So, even if a product is packed under low water vapour conditions the relative

humidity conditions within the container will re-equilibrate to 50% within 1 day.


Packaging: DesiccantsPackaging: Desiccants

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.

– Molecular sieve approved in EU for pharmaceuticals, not by FDA in US.

– 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.


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

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: OVTRPackaging: OVTR

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 here.

PackOVTR

(g. mm/(m2. day))

LDPE241

HDPE102

Polystyrene127

Polycarbonate114

Polypropylene89

PVC4

PET2


Packaging DevelopmentPackaging Development

The theoretical rate of oxygen permeation through a standard 30-cc HDPE bottle when stored in a well sealed container has been determined:– This equated to an uptake of 0.2 mMol 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.


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– Minimised R&D resource– Supports supply site transfers (like for like; identical)

PACKAGING: First Intent


MATERIALS (hierarchy of choice based on product stability)

– Material should preferably be opaque white unless clear is a specific market requirement (e.g. 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


• Reduction of complexity• Standardisation and rationalisation

of components• Reduced number of change-overs at

factory sites• Reduction in resource demand• 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 ComplexityMaintaining FlexibilityReduced ComplexityMaintaining Flexibility

CurrentCurrent

FutureFuture

First Intent: Bottles and Closures - Benefits


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 PACKAGING: Bottles


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

PACKAGING: Closures PACKAGING: Closures


THERMOFORM BLISTERS– plastic base web– blister formed with aid

of heating – low to high barrier

PACKAGING: Solid Dose – Blister Packs 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


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


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


Packaging challenges (4FDC)Packaging challenges (4FDC)

A 4-API combination anti-TB tablet:Rifampicin 150 mgIsoniazid 75mgPyrazinamide 400mgEthambutol 275mgTOTAL API weight: 900mgTablet weight: 1.3g

The technical challenges:

Big tablet

Problem APIs !! Rifampicin is vulnerable to oxidative degradation and hydrolysis, it is light sensitive

and it reacts with isoniazid. It also exhibits solid-state polymorphism. Isoniazid reacts with aldehydes/reducing sugars….& rifampicin → major degradant Ethambutol (2HCl) is hygroscopic, attracting moisture into the tablet to form a slightly

acidic solution that encourages the rifampicin/isoniazid interaction! Pyrazinamide…..seems to be OK !


Packaging challenges (4FDC)Packaging challenges (4FDC)

The solution:

Packaging:– Non-permeable (moisture and oxygen) material– Do not remove from primary packaging until use– Avoid repackaging– Protect from light

Also:

Excipients: no sugar/lactose (isoniazid)

Rifampicin used as “as is” powder (no granulation)

Maintain low water content of tablets (USP ≤ 3.0%)


Metered dose inhaler

Nebules

PACKAGING: IH and IN ProductsDry Powder Inhalers

Intranasal


PACKAGING: Key Regulatory Guidance - USGuidance for Industry, Container Closure Systems for Packaging of Human Drugs and Biologics

Guidance for Industry, Changes to an Approved NDA or ANDA


PACKAGING: Key Regulatory Guidance - EU

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)


FDA & CPMP (CHMP) Regulated

Baseline Statement of Safety– Defines

• acceptable starting materials• acceptable additives and processing aids• limits on residues• limits on leachables (e.g. 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


EXTRACTABLES and LEACHABLES: DefinitionsEXTRACTABLES and LEACHABLES: Definitions

Extractable– Compounds that can be extracted from

elastomeric, plastic components or coating of the container and closure system when in the presence of an appropriate solvent(s)

Leachable– Compounds that leach from the elastomeric,

plastic components or coatings of the container and closure system as a result of direct contact with the formulation of the drug product. Can get interaction with a product component to produce an impurity that requires stability monitoring.


EXTRACTABLES and LEACHING: Practical examples of Issues

EXTRACTABLES and LEACHING: Practical examples of Issues

Polyaromatic hydrocarbons (PAH) detected in CFC-filled MDIs (c.1990)– Prompted the first concerted efforts to look for leachables in MDIs

Vanillin detected in solutions for inhalation packed in LDPE containers– Source: migration through LDPE container wall from cardboard outer

packaging. Protective Al foil laminate overwrap introduced.

Di-ethylhexyl phthalate (DEHP)– Plasticizer in PVC; detected, for example, in TPN fat emulsions probably

via infusion tubing set– Neonates have particular sensitivity to DEHP


EXTRACTABLES and LEACHING: ConsiderationsEXTRACTABLES and LEACHING: Considerations

Clinical concerns:– A potentially sensitive, compromised (especially paediatric) patient population– Safety for both acute and chronic administration

Regulatory requirements: – FDA requirements– Included in CPMP guideline 3AQ10a and CPMP/QWP/4359

Extractables: control of quality of packaging materials and robustrelationship with suppliers, e.g. change control. Leachables: comprehensive stability package – long-term storage condition andaccelerated stability assessment for drug product in pack to cover shelf-life ofthe product

• Consistency in materials/components (Specifications, DMFs)• Control of packing material and product manufacture • Control for unintended contaminants


Packaging DevelopmentPackaging Development

Objective– To ensure timely and robust selection of the primary pack for

clinical trial and commercial supply.

Recommended approach:– To use, where possible, a limited range of standard,

well-characterised pack materials and packs.– To ensure thorough testing, characterisation and understanding

of these selected pack materials and packs.


Phase I – FTIH & Phase II Clinical SupplyPhase I – FTIH & Phase II Clinical Supply

Objective:– Selection of packs for clinical supply

Strategy:– Aim to use

• Limited range of standard, characterised packs, e.g. HDPE bottles for solid dose forms

• Inert packs, e.g. 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 DevelopmentPhase II – III, Commercial Pack DevelopmentObjective:

– 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


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


• 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

• Maximise 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


• 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, e.g. 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


• 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 for 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, e.g. dimensional and performance specifications, need for clean room manufacture, etc.

• Manufacturing controls for the packaging process

4. Controls Defined


• 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


Phase 3 - LaunchPhase 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? Pack Changes?

Recommended 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.

However, changes can occur at late stage due to, for example…– Unpredictable outcome in pivotal stability assessment

• Newly identified impurities• Requirement for tighter specification limits

These tend to drive need for more protective packs, e.g.– Inclusion of desiccant in bottle packs– Need for higher barrier (e.g. 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.


Summary Summary

• Choosing the most Appropriate Primary Pack• Blister Packs• Containers & Closures

• General Overview• Bottles• Blister Packs• Inhalation/IntraNasal products

• Regulatory• US, EU, Pharmacopoeial• Extractable/Leachables

• Packaging Development considerations through to Launch

ANY QUESTIONS PLEASE?

Documents

Packaging (1)