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

1| Simon Mills | April 2008

Pharmaceutical Development with Focus
on Paediatric formulations
Pharmaceutical packaging an overview
including some considerations for paediatrics

Presented by:

Name: Simon Mills

Contact details:

Simon.n.mills@gsk.com

2| Simon Mills | April 2008

 Introduction
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

3| Simon Mills | April 2008

 Specific paediatric considerations
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).

4| Simon Mills | April 2008

 PACKAGING: Choosing the most appropriate pack
BASIC REQUIREMENTS

Protection Commercial
stability test conditions image
market requirements/trends
Compatibility dosing/patient compliance
security/tamper evidence
Regulatory manufacturing
economics - COG
Legislation
e.g. EC Packaging and Corporate
Packaging Waste Directive Global Quality Policies

5| Simon Mills | April 2008

 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 required

Global - Regional - Local packs

Anti-counterfeiting, illegal cross-border trading

Pharmacogenomics - Personalised medicines

Demographic change - Ageing population

6| Simon Mills | April 2008

 PACKAGING: Choosing the most appropriate pack
Some factors are territory-specific, e.g.

Presentation Child resistance requirements

e.g. for solid dose US
US prefers bottles Legal requirement with few
exceptions
EU/RoW prefer blister
packs EU/RoW
Legal requirement in only 4 EU
Environment member states & for very limited
EU Packaging and list of products
Packaging Waste Directive
US - no direct equivalent

7| Simon Mills | April 2008

 Packaging: 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.

8| Simon Mills | April 2008

 Packaging: 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 products shelf-life can be determined.

9| Simon Mills | April 2008

 PACKAGING: Choosing the most appropriate pack

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

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

10 | Simon Mills | April 2008

 Packaging: OVTR

Pack OVTR

Similar considerations are (g. mm/(m2. day))

relevant to protection of LDPE 241
products that are labile to
oxidative degradation. The HDPE 102
permeability of plastic
containers to oxygen Polystyrene 127
ingress has also been
evaluated (OVTR), and is Polycarbonate 114
summarised here.
Polypropylene 89

PVC 4

PET 2

11 | Simon Mills | April 2008

 Packaging 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.

12 | Simon Mills | April 2008

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

13 | Simon Mills | April 2008

 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 (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)
Aclar is registered trademark of Honeywell Inc

14 | Simon Mills | April 2008

 First Intent: Bottles and Closures - Benefits
Current

Reduction of complexity
Standardisation and rationalisation
of components
Reduced number of change-overs at Future
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 Reduced Complexity
Commercial Leverage Maintaining Flexibility

15 | Simon Mills | April 2008

 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)

16 | Simon Mills | April 2008

 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

17 | Simon Mills | April 2008

 PACKAGING: Solid Dose Blister Packs
- Overlacquer
THERMOFORM BLISTERS - Print
plastic base web - Aluminium
- Primer
blister formed with aid
- Heat seal lacquer
of heating
low to high barrier
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

18 | Simon Mills | April 2008

 PACKAGING: Solid Dose Blister Packs
COLD FORM BLISTER Lidding Foil
blister formed mechanically (no heat)
high barrier
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

19 | Simon Mills | April 2008

 PACKAGING: Solid Dose Blister Packs

TROPICALISED BLISTER Lidding Foil

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

Foil Laminate e.g. OPA/foil/PVC

Product contact layers:

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

20 | Simon Mills | April 2008

 Packaging challenges (4FDC)
A 4-API combination anti-TB tablet:
Rifampicin 150 mg
Isoniazid 75mg
Pyrazinamide 400mg
Ethambutol 275mg
TOTAL API weight: 900mg
Tablet 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 !

21 | Simon Mills | April 2008

 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%)

22 | Simon Mills | April 2008

 PACKAGING: IH and IN Products
Metered dose inhaler Dry Powder Inhalers

Drug suspension
in propellant
Aluminium
can Gasket

Valve Metering valve

stem

Atomising
nozzle
Mouthpiece
Actuator body

Nebules
Intranasal

23 | Simon Mills | April 2008

 PACKAGING: Key Regulatory Guidance - US
Guidance for Industry, Container Guidance for Industry, Changes to an
Closure Systems for Packaging of Approved NDA or ANDA
Human Drugs and Biologics

24 | Simon Mills | April 2008

 PACKAGING: Key Regulatory Guidance - EU
CPMP/QWP/4359/03 Guideline on Plastic Guideline on Dossier Requirements for Type
Immediate Packaging Materials - specific to 1A and Type 1B Notifications
plastics only

KEY POINT TO NOTE

EU does NOT have a consolidated
container/closure guideline (cf FDA)

25 | Simon Mills | April 2008

 PACKAGING: Food Contact Approval - Relevance
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

26 | Simon Mills | April 2008

 EXTRACTABLES 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.

27 | Simon Mills | April 2008

 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

28 | Simon Mills | April 2008

 EXTRACTABLES 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 robust
relationship with suppliers, e.g. change control.
Leachables: comprehensive stability package long-term storage condition and
accelerated stability assessment for drug product in pack to cover shelf-life of
the product
Consistency in materials/components (Specifications, DMFs)
Control of packing material and product manufacture
Control for unintended contaminants

29 | Simon Mills | April 2008

 Packaging 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.

30 | Simon Mills | April 2008

 Phase 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

31 | Simon Mills | April 2008

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

32 | Simon Mills | April 2008

 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

33 | Simon Mills | April 2008

 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

Maximise pack and product knowledge and understanding and achieve

commercial efficiency by using a limited range of First Intent, preferred pack
materials, wherever possible.

34 | Simon Mills | April 2008

 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, 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.

35 | Simon Mills | April 2008

 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 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

36 | Simon Mills | April 2008

 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

37 | Simon Mills | April 2008

 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

38 | Simon Mills | April 2008

 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.

39 | Simon Mills | April 2008

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

General Overview
Bottles ANY QUESTIONS PLEASE?
Blister Packs
Inhalation/IntraNasal products

Regulatory
US, EU, Pharmacopoeial
Extractable/Leachables

Packaging Development considerations through to Launch

40 | Simon Mills | April 2008