Emerging and established inhaler markets: Can one size ... · Emerging and established inhaler markets: Can one size ever fit all? David Howlett ... Dr Reddys Redihaler ACME . Revolizer

Emerging and established inhaler markets: Can one size ever fit all?

David Howlett PharmaDelivery Solutions Ltd

IPAC-RS/UF Orlando Inhalation Conference 18 March 2014

A quick game of Global Inhaler Markets “Top

Trumps”

Argentina Bangladesh Brazil China Colombia Egypt India Mexico Russia TurkeyUnited

KingdomUnited States

Population42.6 163.7 201 1349.6 45.7 85.3 1220.9 118.8 142.5 80.7 63.4 316.4

GDP Per Capita$17,900 $2,000 $11,700 $9,100 $10,700 $6,500 $3,800 $15,400 $17,500 $14,800 $36,600 $51,700

No. Domestic HFA MDI producers

2 4 1 3 2 2 8 2 1 1 4 2

No. Domestice developed/ Manufactured DPIs

1 3 2 2 0 0 6 0 1 2 2 1

Specific Inhalation Detail in Pharmacopoeia

M N L L N N H H N N H H

Published Regulatory requirements

L N L L L L M M N N H H

Un-Published regulatory Requirements

N N L M N L N N N N L H

• Protectionism • Geography • Import Duties • IP concerns • Affordability • Market presence

• Protectionism • Regulatory

Requirements • Regulatory

expectations • Market presence

The common focus

DPIs Key differences Eu Vs USA

European Perspective FDA PerspectiveDesign Control Indirectly expected by virtue of MDD Mandated with publication of FDA final RuleDesign History File Not a specific requirement in Eu Mandated with publication of FDA final RuleDevice Master Record Not a specific requirement in Eu Mandated with publication of FDA final Rule

Extractables and LeachablesNot a requirement in Europe

Requirement to demonstrate extractables routine controls on "critical components. Leachables study in deevelopment only.

Emitted dose and PSD Typically based on Pharmacopoeial approach of 4.0 litres volume.

Specific requirement for performance based on 2.0 litres of air.

Device resistance Performance understood for 10th to 90th percentile of patient population.

Routine release specification for device resitance. Performance at justified flow rates (30,60,90 for generic ADVAIR).

Human Factors Indirectly expected by virtue of MDD Specifically mandated

Foreign ParticulatesData is now being requested

Release specification for finished product mandataed based on EPA with significant safety margin.

BiocompatibilityISO 10993 fully recognised

CDER still prefer references to USP, but can be bridged.

Type III DMF Does not exist in European system Regularly used in USA

Comparison of minimum Salaries

30

32

34

36

38

40

42

44

46

48

50

The working week

Obviously translates in to Affordability

Sources include: Bulletin of the World Health Organization Print version ISSN 0042-9686 2007

0 1 2 3 4 5 6 7 8 9 10

Bangladesh

Malawi

Nepal

Pakistan

Sri-lanka

India

India

UK*

UK Prescrip

US non insured

Days equivalent (minimum wage)

Affordability of one months Asthma Therapy

The international Reference Price IRP (200 dose Albuterol MDI)

0

0.5

1

1.5

2

2.5

1 2 3 4 5 6 7 8 9

Pric

e/ u

nit U

S$

Median prices for Salbutamol MDIs (source International Drug Price Indicator Guide 2012)

Median selling

Median Purchase

03 04 05 06 07 08 09 10 11

Defines the ecomomics

0

5

10

15

20

25

30

35

USA 1 USA 2 USA 3 BNF 1 BNF 2 IRP seller IRP Buyer India 1 India 2 India 3 HongKong

RussiaDom

RussiaImport

RussiaImport

ChinaImport

ChinaDom

Pric

e £

per u

nit

Price comparison 2011/2012 for Salbutamol MDI

But equally Labor costs are lower

MaterialsOEMPowerLaborROI/ Dep

But how significant is that?

Import Duty

0

20

40

60

80

100

120

140

160

Average Duty

Maximum Duty

How Far?

There are at least Ten commercial “Brands” of Salmeterol + Fluticasone in

India, in the following presentations • Capsule DPI • Multi-Dose DPI • HFA MDI • Breath Actuated HFA MDI • HFA MDI with Dose Counter • HFA MDI with integral spacer

Diversity of Capsule based DPIs increasing

Cipla Rotahaler Respihaler Zydus Cadilla

Lupin Lupihaler

Lupin Transhaler

Kopran Easehaler

Myhaler

Dr Reddys Redihaler

Revolizer ACME Rotahaler

Sava Medica SavaHaler

Outlay more of a concern than cost effectiveness

0

0.02

0.04

0.06

0.08

0.1

0.12

MDI MDI MDDPI MDDPI SDDPI SDDPI SDDPI

Cost

per

dos

e £

Cost/ dose for Salmeterol - Fluticasone Inhalation products in India

Low strength

Mid strength

High Strength

The challenge isn’t always a copy!

You have to start Somewhere? • Development, Registration and Launch

strategies. – Staged – Planned – Opportunistic – Chaotic

The development Blunderbuss - Bound to hit the target (but at what cost?)

Of growing importance

Could they ever? • Passive (breath-actuated)

device • Pre-metered multi-dose format • 60 doses • External operating procedures

consisting of (1) Open, (2) Click, (3) Inhale, and (4) Close

• Similar size and shape to the R product

• Comparable device resistance to the R product

• Dose counter

What does this mean?

21CFR § 820.30. Design controls (The Headlines)

• Development Planning • Design History File (DHF) • Design Inputs • Design Reviews • Risk Management • Design Verification • Design Validation

Not unusual Project Plan

Worse if the inventor also ha control of the budget.

Compiling the DHF in retrospect, (always good fun!!)

Material Selection Strategies • Selection Criteria

– Food Contact – Heavy Metals – BSE/TSE – Phthalates/ Latex – Biocompatibility – A current and active Drug Master File – Security

• What about local supply?

Sometimes change is difficult to manage

• Accidents • Mergers • Rationalization

The local molder • Often an engineering focus (changing) • cGMP not core • Equipment Qualification • Change Control

Equipment Qualification often a challenge

Ever wondered what these poor ignorant creatures were in awe of?

Open Mouth technique!!

New child inflation apparatus?

Will things change?

Harmonization Initiatives • The International Conference on

Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)

• The Pharmaceutical Inspection Convention/Cooperation Scheme (PIC/S)

• Pharmacopoeial Working Group (PWG) of the Pan American Network for Drug Regulatory Harmonization

• The APEC Harmonization Center (AHC)

The Pharmaceutical Inspection Convention/Cooperation Scheme

(PIC/S) PIC and the PIC Scheme, operating together as PIC/S, provide an active and constructive co-operation in the field of GMP (Good Manufacturing Practice). The purpose of PIC/S is to facilitate the networking between participating authorities and the maintenance of mutual confidence, the exchange of information and experience in the field of GMP and related areas, and the mutual training of GMP inspectors. http://www.picscheme.org/publication.php

PIC/S Participating Authorities and

Partners • Including • USA/ Americas • Europe • Eastern

Europe • Asia • Australasia

A good example of pharmacopoeial harmonization USP <1151>

• Extractable Substances • Since pressurized inhalers and aerosols are normally formulated with organic solvents as the

propellant or the vehicle, leaching of extractables from the elastomeric and plastic components into the formulation is a potentially serious problem. Thus, the composition and the quality of materials used in the manufacture of the valve components (e.g., stem, gaskets, housing, etc.) must be carefully selected and controlled. Their compatibility with formulation components should be well established so as to prevent distortion of the valve components and to minimize changes in the medication delivery, leak rate, and impurity profile of the drug product over time. The extractable profiles of a representative sample of each of the elastomeric and plastic components of the valve should be established under specified conditions and should be correlated to the extractable profile of the aged drug product or placebo, to ensure reproducible quality and purity of the drug product. Extractables, which may include polynuclear aromatics, nitrosamines, vulcanization accelerators, antioxidants, plasticizers, monomers, etc., should be identified and minimized wherever possible.

• Specifications and limits for individual and total extractables from different valve components may require the use of different analytical methods. In addition, the standard USP biological testing (see the general test chapters Biological Reactivity Tests, In Vitro 87 and Biological Reactivity Tests, In Vivo 88) as well as other safety data may be needed.

Mexican Pharmacopoeia (translated)

• Extractable substances. Since aerosols and pressurized inhalers are usually formulated with organic solvents, such as the propellant or the carrier, the leaching of removable material from the plastic and elastomeric components in the formulation poses a serious problem. Therefore the formulation and material quality used for the manufacture of the valve parts must be carefully selected and controlled. Its compatibility with the components of the formulation must be well established in order to prevent valve parts fault and minimize the changes in the medicine spray. The extractable material in a representative sample of each plastic or elastomeric component of the valve must be evaluated under specific conditions and must be consistent with the drug or placebo extractable profile in order to guarantee the reliable quality of the medicine. The extractable substances, including polynuclear aromatic compounds, nitrosamines, vulcanization catalysers, antioxidants, plasticisers, monomers, etc. must be identified and minimised as much as possible.

Argentinian Pharmacopoeia

Sustancias extraibles - La composición y la calidad de los materiales empleados en la elaboración de los componentes de las válvulas (como por ej. vástago, juntas, etc.) deben seleccionarse con cuidado debido a que en la formulación de aerosoles se emplean solventes orgánicos como propelentes o vehículos que pueden extraer materiales de los componentes elastoméricos y plásticos a la formulación. Las sustancias extraibles, entre las cuales se pueden incluir hidrocarburos aromáticos, nitrosaminas, aceleradores de vulcanización, antioxidantes, plastificantes, monómeros, etc., deben identificarse y minimizarse en lo posible.

Korean Pharmacopoeia

In Summary

• From a Technology perspective “One size clearly can fit all”.

• From a market/ commercial perspective it’s a different story.

• Regulatory Harmonization a long way to go, but!

• Planning Vs After the event is always easier, regardless of where development starts.

And the USP is?