1. 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

2. Pharmaceutical Development with Focus on Paediatric formulations
World Health Organization
Pharmaceutical Development with Focus on Paediatric formulations
1 April, 2017
Pharmaceutical packaging – an overview including some considerations for paediatrics
Presented by:
Name: Simon Mills
Contact details:

3. World Health Organization
1 April, 2017
Introduction
Choosing the most Appropriate Primary Pack
Blister Packs
Containers & Closures
General Overview
Bottles
Inhalation / IntraNasal products
Regulatory
US, EU, Pharmacopoeial
Extractable & Leachables
Packaging Development considerations through to Launch

4. Specific paediatric considerations
World Health Organization
1 April, 2017
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).

5. World Health Organization
1 April, 2017
PACKAGING: Choosing the most appropriate pack
BASIC REQUIREMENTS
Protection
stability test conditions
Commercial
image
market requirements/trends
dosing/patient compliance
security/tamper evidence
manufacturing
economics - COG
Compatibility
Regulatory
Legislation
e.g. EC Packaging and Packaging Waste Directive
Corporate
Global Quality Policies

6. World Health Organization
1 April, 2017
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

7. World Health Organization
1 April, 2017
PACKAGING: Choosing the most appropriate pack
Some factors are territory-specific, e.g.
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
Environment
EU Packaging and Packaging Waste Directive
US - no direct equivalent

8. 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 40C/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.

9. 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 product’s shelf-life can be determined.

10. World Health Organization
1 April, 2017
PACKAGING: Choosing the most appropriate pack
Barrier Properties (typical MVTR g/m2/day 38°C/90%RH)
Cold Form Aluminium 0.00
Aclar ® 33C 0.08
Aclar ® UltRx
Aclar ® 22C 0.22
Aclar ® SupRx
Aclar ® 22A
PVC/80g PVDC 0.31
Aclar ® Rx
Aclar ® 33C 0.42
PVC/60g PVDC
PVC/40g PVDC PP
PVC – 4
Aclar ® is a registered trade mark of Allied Signal

11. Packaging: OVTR Pack OVTR (g. mm/(m2. day)) LDPE 241 HDPE 102
Polystyrene
127
Polycarbonate
114
Polypropylene 89
PVC 4
PET 2
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.

12. 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.

13. 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)

14. PACKAGING: First Intent – Blister base
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 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

15. First Intent: Bottles and Closures - Benefits
Current
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
Future
Reduced Complexity Maintaining Flexibility

16. World Health Organization
1 April, 2017
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)
At the opposite extreme - For Perfumes then development of the pack is as important as development of the product.
The same is true for pharmaceuticals, and we need to be nearer this end of the spectrum and not the end game.
Pack should be developed and tested alongside the product
Treat no different to product. As we will see in a minute in numerous cases the same guidelines, eg, ICH Q6A, CPMP DPS and Stability guidelines, are equally applicable to packaging.
Perhaps a useful an would be excipient compatibility and to GMP.
Just as GMP is not something you can add at the end of a process, if looking for effective ST’s, then same is true for is packaging.

17. World Health Organization
1 April, 2017
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
Let’s start with Packaging is not an end game activity.
What do I mean by this?
I have worked in this industry for 30 years, most of my career having been spent in packaging. Whilst I have seen many changes in that time, one thing which has tended to remain constant is that for many people in the industry packaging is something that is bolted on at the end, or something which somebody else sorts out for you.

18. PACKAGING: Solid Dose – Blister Packs
World Health Organization
1 April, 2017
PACKAGING: Solid Dose – Blister Packs
- Overlacquer
- Heat seal lacquer
- Print
- Aluminium
- Primer
THERMOFORM BLISTERS
plastic base web
blister formed with aid of heating
low to high barrier
Lidding Foil – typically 20 micron Al
Film - eg PVC, PVC/PVDC, PVC/PE/PVDC, PVC/Aclar®
At the opposite extreme - For Perfumes then development of the pack is as important as development of the product.
The same is true for pharmaceuticals, and we need to be nearer this end of the spectrum and not the end game.
Pack should be developed and tested alongside the product
Treat no different to product. As we will see in a minute in numerous cases the same guidelines, eg, ICH Q6A, CPMP DPS and Stability guidelines, are equally applicable to packaging.
Perhaps a useful an would be excipient compatibility and to GMP.
Just as GMP is not something you can add at the end of a process, if looking for effective ST’s, then same is true for is packaging.
- PVC
- PVDC or Aclar®
Product contact layers: For PVC or PVC/Aclar® = PVC For PVC/PVDC = PVDC For Lid foil = heat seal lacquer

19. PACKAGING: Solid Dose – Blister Packs
World Health Organization
1 April, 2017
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
- PVC (may be PP)
- OPA Film
- Aluminium foil
- Primer/Adhesive
At the opposite extreme - For Perfumes then development of the pack is as important as development of the product.
The same is true for pharmaceuticals, and we need to be nearer this end of the spectrum and not the end game.
Pack should be developed and tested alongside the product
Treat no different to product. As we will see in a minute in numerous cases the same guidelines, eg, ICH Q6A, CPMP DPS and Stability guidelines, are equally applicable to packaging.
Perhaps a useful an would be excipient compatibility and to GMP.
Just as GMP is not something you can add at the end of a process, if looking for effective ST’s, then same is true for is packaging.
Product contact layers: For base = PVC (or PP) For lid foil = heat seal lacquer

20. PACKAGING: Solid Dose – Blister Packs
World Health Organization
1 April, 2017
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
At the opposite extreme - For Perfumes then development of the pack is as important as development of the product.
The same is true for pharmaceuticals, and we need to be nearer this end of the spectrum and not the end game.
Pack should be developed and tested alongside the product
Treat no different to product. As we will see in a minute in numerous cases the same guidelines, eg, ICH Q6A, CPMP DPS and Stability guidelines, are equally applicable to packaging.
Perhaps a useful an would be excipient compatibility and to GMP.
Just as GMP is not something you can add at the end of a process, if looking for effective ST’s, then same is true for is packaging.
Foil Laminate – e.g. OPA/foil/PVC
Product contact layers: For PVC = PVC For PVC/PVDC = PVDC For Lid foil = heat seal lacquer

21. Packaging challenges (4FDC)
A 4-API combination anti-TB tablet: Rifampicin 150 mg
Isoniazid mg
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 !
WHO thought this was a good idea?

22. 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%)

23. PACKAGING: IH and IN Products
Metered dose inhaler
Dry Powder Inhalers
Nebules
Intranasal

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

25. PACKAGING: Key Regulatory Guidance - EU
Guideline on Dossier Requirements for Type 1A and Type 1B Notifications
CPMP/QWP/4359/03 – Guideline on Plastic Immediate Packaging Materials - specific to plastics only
KEY POINT TO NOTE
EU does NOT have a consolidated container/closure guideline (cf FDA)

26. World Health Organization
1 April, 2017
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

27. EXTRACTABLES and LEACHABLES: Definitions
World Health Organization
1 April, 2017
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.

28. EXTRACTABLES and LEACHING: Practical examples of Issues
World Health Organization
EXTRACTABLES and LEACHING: Practical examples of Issues
1 April, 2017
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

29. EXTRACTABLES and LEACHING: Considerations
World Health Organization
1 April, 2017
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

30. 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.

31. 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

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

33. Pack options are identified to meet:
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

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
Maximise pack and product knowledge and understanding and achieve commercial efficiency by using a limited range of First Intent, preferred pack materials, wherever possible.

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, 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.

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 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

37. 6. Pivotal Stability Testing
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.
Pivotal stability testing conducted in the selected markets packs, to
Confirm compatibility and product stability
Support product registration submission
6. Pivotal Stability Testing

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

39. 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.

40. World Health Organization
Summary
1 April, 2017
Choosing the most Appropriate Primary Pack
Blister Packs
Containers & Closures
General Overview
Bottles
Inhalation/IntraNasal products
Regulatory
US, EU, Pharmacopoeial
Extractable/Leachables
Packaging Development considerations through to Launch
ANY QUESTIONS PLEASE?