Download 1st Medicon Valley Inhalation Symposium

1st Medicon Valley Inhalation Symposium
Explore the Inhalation Opportunity
17 October 2012
09.00–17.00
Medicon Village, Lund, Sweden
inhalationsymposium.com
Platinum sponsors
Gold sponsor
CI Informatics Ltd.
Nolato MediTech
Silver sponsors
Oxford Lasers
Pharmaterials Ltd
Det Medicinska Malmö
ExIS AB
Epsilon AB
QSCL Q Scientific Consulting
The secrets of dry
powder inhalation
from a solid state
perspective
Lars-Erik Briggner, 121017
Adroit Science
Medicon Village, Lund
Content






Particle size…
Consquences of size reduction…
Mitigation…
Humidity interaction…
Electrostatics…
In the best of worlds…
Dry Powder Inhalation of drugs need,
 Too large particles do not reach the
lung – impacts in the throat and is
then swallowed
 Too small particles do not reach the
lung – exits with the exhalations
100
Exhaled
Deposition, %
Throat
50
Lung
0
0.01
0.1
1
Particle size, µm
10
100
with some implications for the drug!
 Material intended for dry powder
inhalation administration has to…
1.…cope with the particle reduction
technique,
e.g. micronisation by a Jet mill, providing a
reasonable through put in the mill (yield, no
clogging etc)
2.…be possible to administer in an efficient
way into the lung.
Potential agglomerates have to deaggregate
into small aggregates and/or primary particles
during the actual inhalation process in order
to follow the airstream into the lung (and not
Particle size reduction
 Many different techniques in theory…





Micronisation
Spray drying
Super critical techniques
Specialized crystallization techniques
…
 …but with different drawbacks





Amorphicity
Scale of production
Universatility with respect to API properties
Stability/solubility/compatibility
…
 Micronisation is by far the most common…
Fluidized Jet milling (micronisation)
Consequences of micronisation…
Reducing particle size is a high energy process,
relying on collisions between walls and/or
particles, potentially resulting in…
around 50 °C
in mill!!
…specific particle size distribution
…more rounded shape
…aggregates and/or agglomerates
…solid state transitions
…local melting events
…drying out of semi stable hydrates
…charging of the powder (electrostatic)
…disordered/amorphous regions
Effect of milling pressure
Common region for
modern drug candidates
From Article (L-E Briggner et al) : Int J Pharm 105 (1994) 125-135)
μ-calorimetry, Glass ampoule exp.
P/mW
2.4
“Microhygrostate”
Saturated salt
Solution; EtOH,
H2O etc
1.8
II
1.2
Sample
0.6
I – Humidity adsorbtion
II - Crystallization
I
0.0
0
50
100
Time/min
150
Measure enthalpy
of crystallistion
(and sorption
effects)
High sensitivity
(<0.5%), with flow
cell <0.1%)
High
reproducability
Timescale ½-5
hours
FPF for micronised material
Examples from dose withdrawal at different RH
Conditioning (restore crystallinity)
 Conditioning is normally based on
plasticizing (lowering of Tg)…
 increasing molecular mobility) by means of
vapor (small molecules)
and/or increased temperatures leading
to controlled recrystallisation
 Concerns
 Specific surface area decreases significantly
 Issues with particle growth
 “bridge formation” between particles
 Hydrophilic or hydrophobic compounds
 Hydrate/solvate formation
 Chemical stability
Increasing RH on micronised mtrl
Crystallisation
H2O efficient
plasticizer due
to its low Tg,
 -135 °C
Increasing temp. on micronised mtrl
0.05
1.4
0.14
Rev Heat Flow (W/g)
Heat Flow (W/g)
0.00
Crystallisation
0.9
76.59°C
83.58°C
3.060J/g
73.16°C
0.05815J/g
Tg
0.4
98.63°C
0.12
-0.05
Nonrev Heat Flow (W/g)
168.46°C
78.08°C(I)
0.10
164.51°C
60.92J/g
-0.1
0
Exo Down
50
100
150
Temperature (°C)
200
-0.10
250
Universal V4.4A TA Instruments
Intensity (cps)
XRPD before and after conditioning
60
50
40
30
20
10
0
5
10
15
20
25
30
35
2Theta (°)
FPF after conditioning
Fine Particle Fraction (<5um of dd)
30
25
20
15
10
5
0
0% RH to 0% RH
0% RH to 75% RH
Examples from dose withdrawal at different RH
Humidity Interaction – GVS
Sample: AZD2230 fri bas
Size: 5.9940 mg
Method: HADES-metod 0.00005 %/min
Comment: Mikroniserad, SN1069901086 (ej nya hydratformen)
File: \\...\PoB_GVS\TA\HADES\AZD2230.001
Operator: ED/LAB
Run Date: 2007-07-04 10:50
Instrument: TGA Q5000 V3.3 Build 250
3
80
2
1
0.7552%
40
0
Relative Humidity (%)
Weight Change (%)
60
20
-1
-2
0
200
400
600
800
Time (min)
1000
1200
1400
0
1600
Universal V4.4A TA Instruments
Humidity Interaction – GVS cont.
Sample: AZD2230 fri bas
Size: 5.9940 mg
Method: HADES-metod 0.00005 %/min
Comment: Mikroniserad, SN1069901086 (ej nya hydratformen)
File: \\...\PoB_GVS\TA\HADES\AZD2230.001
Operator: ED/LAB
Run Date: 2007-07-04 10:50
Instrument: TGA Q5000 V3.3 Build 250
-0.6
-0.7
30
-0.9
20
-1.0
0.5953%/min
-1.1
Relative Humidity (%)
Weight Change (%)
-0.8
10
-1.2
690.36min
-1.3
689.5
690.5
Time (min)
0
691.5
Universal V4.4A TA Instruments
FPF for a Channel Hydrate
45
Fine Particle fraction
40
35
30
25
FPF (% of dd)
20
15
10
5
0
0-75%RH
D55190-0%RH
behaves quite
OK at dry conditions while a withdrawel at
weighed
weighed
75% RH induce a major decrease in FPF
Powder Properties Characterization
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
plastic adhesion
steel adhesion
cohesion
respirable fraktion
Electrostatics, example of results
Untreated Powder
”Discharged Powder
Ideally...
Particle generation possible...
•...especially micronisation “default method”.
Thermally stable to...
• ...avoid thermal transitions at low
(Requires ingoing material to be crystalline.)
•...using standard milling technologies for
formulation development
temperature
• ...facilitate Manufacturing/Synthesising..
• ...make processing (micronisation,
compression etc.) possible
• ...facilitate storage, transport
High Crystallinity to...
•...accurately assess Biopharm risk (i.e.
accurate solubility measurement)
• ...be easier to manufacture
• ...provides route for purification
• ...improved chemical & physical stability
Non-hygroscopic so that...
• ...the compound will have sufficient
chemical stability
• ...inhalation can be possible (otherwise risk
for agglomeration leading to non-inhalable
material)
• ...no analytical problems associated with
changing humidity will occur
“Formulability” in order to...
• ...prepare relevant solution/suspension
e.g. must not gel etc. (often the case for
amorphous compounds)
How to get high FPF – some thoughts
Low bulk density…
Beneficial morphology…
“Hedgehog” surfaces!?
Non-sticky surfaces (adhesivity
and cohesivity)…
Non deforming particle, no
“shear planes” in the structure…
Optimal particle size
distribution…
“Small” humidity dependence…
(channel hydrates!!)
No amorphous surfaces –
conditioned…
Low static charge built up
www.adroitscience.com
Inhalation – puts a new twist on pharmacology
1st MVIC symposia Lund 2012‐10‐17
Karin von Wachenfeldt
Whygoinhaled?
Maximize local exposure
Convenient administration route
Minimize systemic exposure
Positioning Localeffect‐ lungrelatedindications
• Local effect desired, e.g. for treatment of asthma and COPD.
• Rapid delivery to the right location
• Bronchodilators ‐ rapid onset of action is crucial
• Hit‐and‐run effect
• Long‐term exposure at the right location
• Glucocorticoids – long‐term “low” level exposure
• Mechanisms for lung retention
• +/‐ Systemic exposure
• Systemic exposure to beta‐agonists associated with side‐effects
• Some exposure to glucocorticoids desired for maximal efficacy.
DeliveringLungefficacy
Adapted from G. Hochhaus PATS 2004
Drugsmetabolizedboth inlungandliver
Lung metabolism
Smoking induces lung specific CYPs
Liver metabolism
Adapted from G. Hochhaus PATS 2004
Inhaleddrugsforsystemicexposure
① Inhalation circumvents the “hostile” gut environment.
② Delivery to the lungs for systemic exposure – provides a direct route to the brain. Frequently exploited for delivery of aneastetics.
Routes of Drug Administration Oakley, R. & Ksir, C. (1996) Drugs, Society, and Human Behavior, 7th Ed
….aswellascigarettesmoke.
Mode‐of‐Action
• What types of drugs are suitable for inhalation?
• Local exposure mostly agonists.
• Hit‐and run principle.
 Compounds that are rapidly cleared from lungs can still have good effect.
• Antagonist effects often require long‐term target inhibition.
• Compounds need to have long lung‐retention. Needs to be engineered into molecule from start.
• Several strategies can be used;
• Low solubility
• Active retention in lung cells
• Binding kinetics
Budesonide‐ theidealinhalationsteroid?
Epithelial Cell
Budesonide retained within epithelial cells. Increases duration of action.
BUD
Ciclesonide – thedesignerinhaledGCS
Ciclesonide
Pro‐drug
Des‐CIC
Active metabolite
Des‐CIC oleate
Retained
From Nave R, Meyer W, Fuhst
R, et al 2005. Wheredoyouneedtheeffect?
① Achieve exposure in the right place.
② Dry powder vs. nebulized solution.
③ Particle size
④ Device
Peripheral
deposition
Central “bronchial” deposition
Summary
• Inhalation – what do you want to achieve?
• Focus the effect, or simply deliver the drug?
• Reduction of systemic side‐effect profile.
• Important to consider need for systemic exposure.
• Different metabolism, lung vs. liver.
• Different metabolism in healthy vs. diseased lung.
• Where in the lung is the effect needed?
• Through a smart inhalation strategy you can reach your target.
• Differentiation
• An effective inhaled drug is less threatened by generic competition – also after patent expiration for your compounds.
1st Medicon Valley Inhalation Symposium
2012‐10‐17
SUCCESSFUL INHALATION
STARTS WITH
COMPOUND DESIGN
THOMAS BRIMERT
www.redglead.com
WHY INHALATION ?
1. For systemic effect:
• Large surface area
• Thin alveolar epithelium
• Less metabolism
• Active transport
• Consider making a prodrug
2. For local effect:
• Avoid side effects from
systemic exposure
• Poor oral availability
• Consider making a soft drug
Inhalation can turn
your
weaknesses
into
strenghts
www.redglead.com
DEFINITION OF PRODRUG
A prodrug is a
pharmacological substance
that is administered in an
inactive (or less than fully
active) form, and is
subsequently converted to an
active pharmacological agent
through normal metabolic
processes
• Injected or inhaled (free base)
• Passes bbb
• Metabolized to morphine (active)
www.redglead.com
MED. CHEM. DEFINITION OF
SOFTDRUG
Soft drugs are drugs which are
characterized by a predictable
and controllable in vivo
destruction (i.e. metabolism) to
non-toxic products after they
have achieved their therapeutic
role.
Budesonide is quickly oxidized in the liver to 16α‐hydroxyprednisolone
www.redglead.com
DESIGNED FOR INHALATION EXAMPLE 1
How to utilize specific transporters in the lungs through a prodrug
Transporters in the lung
Carnithine
From : P. Zarogoulidis et al. Int. J. Nanomedicine, 2012, 7, 1551–1572 Prednisolone
www.redglead.com
PDSC
•
PDSC = prednisolone linked
with carnitine
•
Actively transported by organic carnitine
transporters OCTN1 and OCTN2
•
PDSC displayed 1.79‐fold increase of uptake compared to prednisolone •
in vitro LPS‐induced IL‐6 production from BEAS‐2B was more and longer suppressed by PDSC than prednisolone
X. Sun et al., Mol. Pharmaceutics, 2011, 8 (5), 1629–1640
www.redglead.com
DESIGNED FOR INHALATION EXAMPLE 2
Soft drug long‐acting β2‐agonists (LABAs) for Asthma and COPD
• How to improve duration of action
• Minimize cardiovascular sideeffects
• Minimize risk for Drug‐Drug‐Interactions
Examples of current therapies:
Salmeterol
Formoterol
www.redglead.com
2 violations of Lipinski’s rule of 5
Rat in vivo clearance 103 ml/min/kg
Rat plasma protein binding 95%
Caco‐2 (B‐A)/(A‐B) > 13 (efflux)
Rat in vivo p.o. bioavailability < 5%
Dog in vivo
PF610335
Salmeterol
Formoterol
lung ED50 DoA at ED50 TI lung vs CV
0.1 µg
>8 h
≥10
1 µg
4 h
1
0.1 µg
4 h
1
Pfizer compound PF610355
Site for glucuronidation
=> mixed metabolism
Dimethyl to balance lipophilicity
And remove one chiral center
Acidic sulfonamide and basic amine form zwitterion
=> Excellent crystallinity
P.A. Glossop, C.A.L. Lane et al.,J. Med. Chem. 2010, 53 (18) 6640‐6652
www.redglead.com
DESIGNED FOR INHALATION EXAMPLE 3
Soft drug inhaled p38 kinase inhibitors
VX‐745
Clinical findings of oral p38 inhibitors
• Skin disorders
• Infections
• CNS‐toxicity
• Elevation of liver transaminases
• Lack of efficacy
 Improve selectivity and  Duration of Action (DoA)
BIRB‐796
Examples of oral p38 kinase inhibitors
www.redglead.com
BIRB‐796
Slow koff
Pfizer hit
Very potent and selective
• Potent
• Selective
• Slow koff
www.redglead.com
Site for glucuronidation
=> mixed metabolism Chlorine make phenol more acidic
•
•
CYP450 oxidation of sulfur
to less active metabolites
Rat i.v. Cl 33.8 ml/min/kg
Rat ppb 99.8%
Rat p.o. F <5%
Selectivity was >1000 x primary pharmacology
in 68 of 68 targets (CEREP ligand profiling)
Clean in 4 day rat tox 2.8 mg/kg/day
Hydroxyethylene
to increase solubility
D. S. Millan et al., J. Med. Chem. 2011, 54, 7797‐7814
www.redglead.com
• Lungs are different !
• You can design molecules to utilize
specific pharmacology in the lungs
• You can design a molecule with
local effect in the lung and low
systemic exposure
Thank you !
Physics in Inhalation Devices
Björn Ullbrand
Office Locations
1
Staffanstorp, Sweden. Head office.
3
2
Kista, Sweden.
2
1
3
Rognan, Norway.
Areas of Expertise
• Validus Engineering AB specializes in product development in combination with FEA, Finite Element Analyses, and CFD, Computational Fluid Dynamics
• Our competence is based on over 20 years of industrial experience and our connection to the academic society
• Member of MVIC
Outline
• Computational Fluid dynamics (CFD)
• Dry particle physics (DPI)
• Wet particle physics (pMDI)
• Moisture transport
Computational Fluid Dynamics (CFD)
• Standard tool for simulating airflow and particles in inhalation applications
• Powerful computers are required to allow massive parallel computations
CAD
MESH
CFD Process
Throat geometry from www.isam.org
RESULTS
Computational Fluid Dynamics (CFD)
• Important tool for analysing:
• Flow distributions within devices (by‐pass flow etc.)
• Pressure drop (inhalation resistance)
• Indirect methods (no particles)
• Turbulence intensity (de‐aggregation)
• Wall shear stress (retention analyses)
• Direct methods
• Multiphase flows with particles or droplets
• Cavity emptying
• Deaggregation
• Deposition
Flow distribution & pressure drop (DPI)
• DPI’s typically rely on the patient to provide the energy for dose delivery and deaggreagation during inhalation
• Goal: Max deaggregation and min retention for min pressure loss
• Simulation gives information about total flow rate, flow distribution and pressure loss locations
Total pressure distribution
Velocity distribution
Turbulence
• Turbulence is a very complex phenomenon
•
•
•
•
Transition from laminar to turbulent flow
Large range of scales Computationally expensive to resolve turbulence (DNS/LES)
Often approximated by using time averaged models (RANS)
LES
Large Eddy Simulation
RANS
Reynolds Averaged Navier Stokes
Flow optimisation
• Flow distribution and geometry is important for optimisation of performance
• Example: Cavity de‐aggregation and dose delivery optimisation
• Optimisation of Q1 flow (pipe dimension and direction)
• Increasing velocity in cavity to reduce retention.
Q1
Q2
Velocity magnitude
Baseline
Mod #1
Mod #2
Flow optimisation
• Increasing turbulent kinetic energy in cavity to increase de‐
aggregation
• Significant increase is seen for Mod #1 and #2
Turbulent kinetic energy
Baseline
Mod #1
Mod #2
Flow optimisation
• Wall shear stress can be used as an indicator of retention
• Low shear stress – high retention
• High shear stress – low retention
• Average wall shear stress along cavity wall is showing significant increases for Mod #1 and #2
Wall shear stress
0.34 N/m2
1.51 N/m2
Baseline
Mod #1
2.54 N/m2
Mod #2
Dry particles physics (dilute)
• Normally treated as a light phase not affecting the fluid flow
• 1‐way coupling (particles not affecting carrier fluid)
• Momentum transfer only
• Equation of motion solved in a Lagrangian
reference frame:
du p
dt
 FD (u  u p ) 
g ( p   )
p
F
• Used for DPI particle analyses
Dry particles (USP 100 l/min)
20 micron particle tracks
20 micron particle deposition pattern
Dry particles (USP 100 l/min)
• Validation of the numerical models are essential for successful application in inhalation projects
Experimental data from Blomgren C-H, Simulation of throat
deposition using Large Eddy Simulations, ISSN 0282-1990
Dry particles physics (dense)
• Situations with dense particles also occurs in inhalation devices, typically in cavities where particles are stored
• This leads to a stronger interaction between the two phases and can be analysed with e.g. two‐phase Eularian models where both phases are treated as a continuum
Analysis of optimised cavity
• Cavity partly filled with 30 micron lactose particles
• Findings from indirect method verified by two‐phase model analysis
Baseline
Mod #2
Dry particles physics (DEM)
• Discrete Element Methods (DEM) can also be used for dense particle systems where large number of particles are tracked including particle‐particle interaction
• 3rd party software can be used for particle models to simulate various shapes and agglomerates
• Could be used for de‐aggregation analyses Wet particle (droplets) physics
• Similar to dry particle physics but more interaction with light phase
• 2‐way coupling (droplets also affect carrier fluid)
• Momentum transfer • Mass transfer
• Heat transfer • Atomization process is very complex
• Initial size, velocity and direction at nozzle exit needs to be defined
pMDI spray
Wet particles (pMDI spray simulation)
• Rosin-Rammler droplet initial size distribution (1-20 micron)
• HFA propellant in liquid and gas phase
• Boiling point 255 K
• Rapid evaporation of droplets into vapour phase
• Instant evaporation upon wall impact (no bouncing or break-up)
• Volatile fraction set to 97% leaving a solid core particle
Throat geometry from www.isam.org
Wet particles (pMDI spray simulation)
• Rosin-Rammler droplet initial size distribution (1-20 micron)
• HFA propellant in liquid and gas phase
• Boiling point 255 K
• Rapid evaporation of droplets into vapour phase
• Instant evaporation upon wall impact (no bouncing or break-up)
• Volatile fraction set to 97% leaving a solid core particle
Throat geometry from www.isam.org
Wet particles (pMDI spray simulation)
Wall temperature
Instantaneous deposition pattern
Moisture transport in devices
• Important for drug stability (shelf‐life and in‐use)
• Many substances are sensitive to humidity
• Can be simulated by using analogy to heat transfer
• Temperature is replaced with relative humidity etc.
• Experimental data normally required for material properties
• Validation is performed by comparing to stability testing data Moisture transport in devices (example)
• Device with drug compartment placed in humid/hot condition Substance compartment
Al-foils
(seal)
40oC/75%RH
HDPE (plastic material)
Desiccant (Silica-Gel)
Moisture transport in devices (example)
• Moisture is transported through side walls
• RH level in substance compartment is increasing but remains relatively dry for long time
• Simulation time: 30 minutes for 1000 days of real time
Conclusions
• Fluid dynamics analysis is important in inhalation projects in order to visualize and understand the physics involved and as an aid in the optimization process
• Simulations needs to be performed in parallel with experimental work for validation and verification of the models applied
• Flow rate & distribution, pressure drop, turbulence intensity and wall shear stress are typical physical parameters of interest.
• Indirect methods can be a very effective alternative to more complex methods, reducing the time and cost requirement
• Dry and wet particle physics can be included in the flow analysis and be used for e.g. deposition and deaggregation analyses
• Using an analogy with heat transfer it is possible to efficiently simulate moisture ingress in inhalation devices
Formulation
Manufacturing
Challenges
A broader perspective
QbD
Product Development
Nils Ove Gustafsson, Galenica AB
Galenica AB
•
•
•
•
•
•
•
Contract Development Organization
Formulation and Process Development
Analytical Development
CTM Manufacturing
Tech Transfer
All Different Kinds of Dosage Forms
Located in Malmö, Sweden
Formulation Manufacturing Challenges
• Inhaled drugs are complex products!
• Their function is a combination of a formulation
and a device, both the device and the
formulation being complex
• Due to the complex nature of inhaled products,
the use of a Quality by Design approach in
development is encouraged
QbD Short Version
• Use good science when
developing your product
• Understand your product and
processes, use the knowledge
gained during development and
manufacturing and share it with
the regulatory agencies
QbD Slightly Longer Version
• Set the design target for the product
• Identify what critical attributes that describes the
quality of the product (safety and efficacy)
• Identify the factors with potential effects on the
critical quality attributes
• Use a risk based approach to rank the factors and
investigate the most critical factors further
• Use the gained knowledge to define the control
strategy of the product
• Use the gained knowledge during manufacturing for
continuous improvements
QbD Even Longer Version
• ICH Q8 (R2) Pharmaceutical Development
• ICH Q9 Quality Risk Management
• A number of presentations, seminars, courses,
workshops, mock-up papers etc….
Formulation Manufacturing Challenges
Armanni et al. http://www.ipacrs.com/PDFs/Posters/RESP_On-screen%20version_IPAC2008%20Poster.pdf
QbD, What’s new?
•
•
•
•
•
Encouraged by Regulatory Agencies
More Structured Approach
Common Language
Linking Risk Assessment to Science
Increased Regulatory Flexibility Post
Approval
Manufacturing Challenges
Manufacturing Challenges
Define the manufacturing scale!
What governs the
manufacturing scale
• Commercial considerations
– Future markets and estimated sales?
• Manufacturing site
– Current equipment?
– New equipment?
– CMO?
• Technical aspects
When do we know the
manufacturing scale?
A BROADER PERSPECTIVE
Two very good thing to have when
developing a product:
• Target Product Profile
• Product Development Plan
Target Product Profile
What do we want to develop?
Product Development Plan
How do we develop it?
Product Development Plan
Includes:
• API and Preformulation
• Formulation development
• Device development
• Preclinical development
• Clinical development
• Process development and scale up
• Regulatory strategy
• Manufacturing
• Market considerations
• …….
Product Development Plan
• Living document
• Refine and fill in as the development
progress
• Better to have something than nothing!
• A number of competences needed
when preparing the plan
• Might also be a valuable asset!
Product Development Plan
Start CTM
development
Unit Dose Device
New Multi Dose Device
POC /
Early stage
clinical trials
New Multi Dose Device
New Multi Dose Device
Late stage
clinical trials
Finished
Product
Product Development Plan
Start CTM
development
Development
Development
Unit Dose Device
New Multi Dose Device
Development
POC /
Early stage
clinical trials
Development
New Multi Dose Device
New Multi Dose Device
Finished
Product
Late stage
clinical trials
Conclusions
• It is important to know where you want
to go and the way to get there
• It takes a lot of different competences
involved in a project, already in an early
stage, to reach the goal in an efficient
way
• Do not forget to document your work
properly
Comments?
Questions?
- Confidential -
OUR INNOVATION STRENGTH BECOMES YOUR COMPETITIVENESS
WITHIN INJECTION, INHALATION AND CONNECTIVITY/COMPLIANCE
Device as the Strategic Weapon
in a Saturated Inhalation Market
Morten Nielsen, CEO
Bang & Olufsen Medicom a/s
MVIC Symposium - 17th October 2012
” Our innovation strength ...
... becomes your competitiveness”
1
- Confidential -
A few words on MEDICOM ...
Key figures
16.000.000 14.000.000 ~9,5 MEUR (2012)
Employees:
“We deliver solutions that are
not already out there”
10.000.000 8.000.000 6.000.000 4.000.000 2.000.000 ‐
2008
Revenue 12.903.000
2009
2010
2011
2012 forecast
2013 forecast
15.053.000
10.662.000
7.914.000 10.700.000
11.898.000
< 2007: 100% owned by Bang & Olufsen a/s
> 2007: 65%: Maj Invest Equity and Management
35%: Bang & Olufsen a/s
Copenhagen
•
•
•
•
Our Services
Device Strategy & Technology
Device Feasibility & Concept
Device Development
Pilot and low-volume production
•
•
•
•
•
Our Technology Innovation
Devices for Injection
Devices for Inhalation
Devices for Connectivity
Integrated Mechatronics
Design and User-Centricity
The Medicom Pulse
Injection >>
<< Connectivity
Inhalation >>
” Our innovation strength ...
... becomes your competitiveness”
60
12.000.000 Ownership
“We help our clients meet the
unmet needs in their markets”
Struer - HQ
8 MEUR (2011)
EUR
Revenue:
“We deliver innovative and benefit-driven
drug delivery device solutions”
2
Strategy &
Technology
Service Strength
• Specialist insight in
injection, inhalation
and connectivity
• Understanding endto-end technology
drivers and
consequences
• Understanding
combining drug and
device solutions
Feasibility &
Concept
Service Strength
• Integrated mechanics
and electronics
(including QA & RA
demands)
• Close integration with
clinical device
production
• Strong partner
network of industry
specialists
Highlights
• Technology and
Device mapping
• Device & Drug
assessment
• Device strategy
options
• Patent assessment
Development
Service Strength
• Strong design and
usability insight
• Strong device
architectural and
conceptual skills
within both
mechanics and
electronics
• Fast prototyping skills
(fast to demo)
Highlights
• Future electronic
injector concepts
• Future electronic
concepts
• Advanced pump
concepts
• Advanced dosing
concepts
Highlights
• Electronic autoinjectors
• Dual-shot autoinjectors
• Electronic
stethoscopes
• Advanced inhalers
Clinical
Low-volume
production
Service Strength
• Flexible and manual
• Experience from
electro-mechanical
production
• Outsource sub-parts
and sub-systems to
far-east suppliers
Highlights
• Auto injectors
• Pen injectors and
accessories
• Electronic
stethoscopes
• Inhalers
• Electronic compliance
devices
Device as the Strategic Weapon
in a Saturated Inhalation Market
Basic delivery
+ Industrial
design
+ Ease of use,
automation,
feedback
+ Connectivity
+ Service
- Confidential -
Let’s start with a little story on Asthma/COPD ...
Annual lost productivity resulting
from poor asthma control in the EU
is estimated to 9.8 billion € ***)
Annual cost of asthma in the EU is
estimated to 17.7 billion € ***)
In the UK it is estimated that 75%
of hospital admissions due to
asthma could be avoided *)
Successful management of asthma
preventing exacerbations would
reduce cost 3.5 times ****)
Hospitalization for acute
exacerbation of COPD is a major
annual cost contributor **)
http://www.asthma.org.uk/news-centre/facts-for-journalists, ** http://www.who.int/gard/publications/chronic_respiratory_diseases.pdf
*** ”The economic burdon of occupational asthma in Europe”, Huo Jinhai, Umeå university, 2010,
**** ”Risk factors and costs associated with an asthma attack”, Hoskins, G et al, Thorax
” Our innovation strength ...
... becomes your competitiveness”
4
- Confidential -
The step-change device innovations driven by industry is not impressive!
pMDI’s have been around
since the 50’ties
“Numerous studies have shown that
patients didn’t know that they
should keep track and patients
ended up calling 911”
Dose counters were only reluctantly
added to pMDI’s when FDA made a
requirement
Why so
reactive?
“The pharmaceutical companies
focus have traditionally been the
Drug”
DPI’s are inherently Breath Actuated
and dose counters are typically easy
to implement
”We will sell the Drug in a bucket if
possible”
No “new” thinking on
-Ease of use
-Adherence
“Old wine on new bottles” thinking
” Our innovation strength ...
... becomes your competitiveness”
5
- Confidential -
Paradigm shift in thinking ... Devices can be a strategic weapon!
• Improve adherence
• Improve Inhalation Technique
• Improve Quality of Life
• Increase productivity of patient
• Reduce hospitalization cost
• If DCT is high, numerous options are
available
• If DCT is low, options are reduced,
but they are still there and requires a
new thinking on device cost
structures
Market
Opportunities
Treatment and trends
Treatment and
context
Therapy
Value chain
Stakeholder
Network
Disease knowledge
Treatments and drugs
Diagnostics methods
Monitoring
Treatment environment
Geographic market segments
Work load distribution
Cost of treatment
Reimbursement
Major players
Roles (decision power and
competences)
Interactions (strong/weak)
Present device options
Future competition
Market
Technical solutions
Service solutions
Primary packaging
Delivery devices
Monitoring devices
Solutions maturity level
Patient f orums
Web based solutions
Social network
Support services
Known plans
Anticipated changes
Competitor pipeline
Future launches
Patent expiration
Anticipated competitor initiatives
Likely product launches
US / Western Europe
Far East (India)
Execution
Device (%) options
Product DCT
Technical
Product DCT
options
Device (%)
Segmentation aspects
• Breath actuation/coordination
• Training devices
• Dialogue tools between HCP and
patient
” Our innovation strength ...
... becomes your competitiveness”
< 0.1 %
Internal
Issues
0,1-4 %
100 $
Financial
Technical
Formal
Economical
Technical
Formal
Reimbursement
Outcome improvement
Time savings
Cost of treatment
Device expenses
Service expenses
Resources
Financial
Manning and capacity
Market maturity
Readiness
Expectations
Regulatory
Explicit requirements
Approval procedures
Competition
Existing IPR
Expected LCM initiatives
Timeline
Supply chain
Needed development time
Use of existing platforms
Feasibility of new equip.
Technical risk
Feasibility
6
Organization
Training ability
Sales and service skills
User segments
►
Entry product
►
Market segment
0.1-0.4 $
Added features
►
►
Added diversity
Competition aspects
New drugs
Expected LCM
►
►
Patent expiration
►
Design identity
Corporate aspects
Single product
►
Platforms
Timing aspects
Sequencial launch
Direct and
Indirect Constrains
External
Issues
Cystic Fibrosis
0.4 – 3.8 $
Internal
Issues
Asthma/COPD
External
Issues
One f its all
Evolution and LCM aspects
►
n/a
►
Added service
7-15%
n/a
Parallel execution
• Traditional thinking on cost
structures for Inhaler market have
put extreme cost pressures on the
device
- Confidential -
Device
categories
How mature are you in your inhalation device strategy?
Basic delivery
+ Industrial
design
+ Ease of use,
automation,
feedback
+ Connectivity
+ Service
Products
Asthma/
COPD in DK
Force reduction
Dose counting
pMDI
Breath actuation
Trainer, integrated/stand - alone
Dose confirmation, dose registration
Dose confirmation, dose registration, wireless connectivity
Services
Dose counting
Trainer, integrated/stand - alone
DPI
Dose confirmation, dose registration
Dose confirmation, dose registration, wireless connectivity
” Our innovation strength ...
... becomes your competitiveness”
7
Services
- Confidential -
Device
categories
Could there be a potential for other unmet needs ..
.... if we take a look at the entire “disease chain”
Basic delivery
+ Industrial
design
+ Ease of use,
automation,
feedback
Products
Asthma/
COPD in DK
+ Connectivity
+ Service
Unmet Needs to Explore
Force reduction
Dose counting
pMDI
Breath actuation
Trainer, integrated/stand - alone
Dose confirmation, dose registration
Dose confirmation, dose registration, wireless connectivity
Services
Dose counting
Trainer, integrated/stand - alone
DPI
Dose confirmation, dose registration
Dose confirmation, dose registration, wireless connectivity
” Our innovation strength ...
... becomes your competitiveness”
8
Services
- Confidential -
Food for Thought ...
To be competitive in a future cost-pressured market, the drug itself
is not enough. Means for assuring that the drug gets timely to
where it work will be essential to be a winner
The pharmaceutical industry should increase their focus on the
device and re-think the cost structure in an end-to-end setting
Other high value therapies with high DCT might pave the way for
new thinking, like it is happening in the injection field
” Our innovation strength ...
... becomes your competitiveness”
9
- Confidential -
Thanks for listening ...
Morten Nielsen
CEO
Bang & Olufsen Medicom a/s
Gimsinglundvej 20
DK-7600 Struer
DENMARK
Tel:
Mobile:
+45 70 30 16 00
+45 20 75 37 01
E-mail:
[email protected]
LinkedIn:www.linkedin.com/in/mortennielsen
” Our innovation strength ...
... becomes your competitiveness”
10
What Makes Inhalation Clinical Trials Special?
Lars Borgström, Ph.D.
Lund
[email protected]
The short answer:
The way of
administration
. . . and a longer one:
Inhaled medication
Device
(unfilled)
Formulation
(for filling)
Mechanical
aerodynamic
Physical
chemical
Product
properties
2012-10-18
Lars Borgström, Clin Pharm, Lund
3
Inhaled medication
Device
(unfilled)
Formulation
(for filling)
Mechanical
aerodynamic
Physical
chemical
Patient
behaviours
& patient
properties
Product
properties
Inhalation technique Throat geometry
Lung
deposition
2012-10-18
Lars Borgström, Clin Pharm, Lund
4
Types of clinical studies
•
•
•
•
Lung deposition, local pharmacokinetics
Systemic pharmacokinetics
Clinical effect
Bioequivalence
LUNG DEPOSITION
Pharmacokinetics of inhaled medication
Lung deposition
Vena
porta
Liver
Gut
Systemic
circulation
Metabolism
Borgström and Nilsson, 1990, Pharm Res, 7:1068‐1071 Pharmacokinetics of inhaled medication
Lung deposition
Charcoal
Vena
porta
Liver
Gut
Systemic
circulation
Borgström and Nilsson, 1990, Pharm Res, 7:1068‐1071 Charcoal block: substances
•
Terbutaline is hydrophilic. Systemic availability after charcoal block was 0.3%. –
–
•
Budesonide is lipophilic. Systemic availability after charcoal block was 2.6%.
–
–
•
Systemic availability without charcoal block is around 10%. Thus, 97% of the orally ingested drug was adsorbed on the charcoal. Systemic availability without charcoal block is around 13%.
Thus, 80% of the orally ingested drug was adsorbed on the charcoal.
Formoterol has an intermediate lipophilicity. No formoterol could be detected in urine after oral administration and charcoal block.
–
Thus, close to all orally ingested drug was adsorbed on the charcoal.
• Degree of adsorption needs to be validated for each substance under study.
Borgström and Nilsson, 1990, Pharm Res, 7:1068-1071
Thorsson, Edsbäcker and Conradson, 1994, Eur Respir J. 7:1839-1844
AstraZeneca, data on file.
Typical lung deposition values
• Pressurised metered dose inhalers (pMDI): 10 to 20 % of nominal dose
• Dry powder inhalers (DPI): 10 to 30 % of nominal dose.
• Small volume nebulisers: 30 to 40 % of nominal dose
• Thus a large variation.
Inhalers do differ!!
• Each device must be judged on its own merits
• A DPI ≠ DPI
• A pMDI ≠ pMDI
Systemic pharmacokinetics
• The systemic pharmacokinetics can be obtained in the same way as for orally given medication.
• With an intravenous infusion as the reference. Fluticasone
Budesonide
Harrison, T W et al. Thorax 2003;58:258‐260
Disease may influence
the balance between
absorption and
mucociliary clearance
differently for different
drugs and different
formulations.
Smoking may influence the rate of absorption of
drugs from the lung: inhaled terbutaline
smokers
Same AUC (Area Under the Curve)
Different Cmax
non-smokers
Schmekel B, Borgström L, Wollmer. 1991
Schmekel B, Borgström L, and Wollmer P. Thorax 1991; 46:225‐228
CLINICAL EFFECTS
Clinical effects
• The desired clinical effect is in most cases
local.
• The undesired clinical effect is in most cases
systemic. Can also be local.
• Systemic availability does not reflect lung
availability
• Thus, both local and systemic effects, and side effects, needs to be evaluated.
Clinical effects
• Measured by relevant clinical effect studies applying the usual treatment length and group
size calculations.
Inhalation for systemic treatment
• Use the same approach as for ”Inhalation for local treatment” but with a focus on systemic
effects/side effects.
• Regional deposition can influence the rate and degree of absorption, and thus the resulting
systemic effect. BIOEQUIVALENCE
Bioequivalence is defined as: • “ . . . the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of action . . . “
• A statement about doses.
• AUC and Cmax.
• 0.8 – 1.25; 2‐sided 90% conf. interval
• Systemic concentrations
FDA, 2003, orally administered drugs
Bioequivalence studies
• Applied in evaluating formulation changes
during development.
• Applied by ”generic” companies to compare
their own formulation with innovator
formulation.
• If new formulation found bioequivalent with
innovator formulation the new formulation
can be declared therapeutically equivalent
with innovator formulation.
Bioequivalence
Two formulations in two different studies. Values given as AUC‐ratios.
Mean AUC‐ratio
Two‐sided 90% confidence interval
Study I
1.18
1.13‐1.24
Study II
1.14
1.07‐1.22
Both studies showed a significant difference in AUC between the formulations.
Both studies showed that the formulations were bioequivalent with regard to AUC
AstraZeneca, data on file
Estimates of bioequivalence
Study A
Bioeq. interval
80%
100%
Study B
125%
Both studies A and B outcomes indicate
bioequivalence.
Bioequivalence, inhaled medication
•
“ . . . the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of action . . . “
• Both the local and the systemic exposure should be evaluated.
• AUC and Cmax
• 0.8 – 1.25; 2‐sided 90% conf. Interval
• This means that both the local and the systemic comparison needs to fulfil the BE criteria. • For two‐combination products all four comparisons need to fulfil the BE criteria. Design of clinical effect studies for therapeutic equivalence
• In analogy with the in vivo PK studies both the desired local effects and the undesired systemic effects needs to be evaluated.
• Two dose levels for at least the reference formulation need to be included. Also for combination products.
• Failure to show a significant difference in clinical effect between the two dose levels renders the study inconclusive. The same situation as for other administration forms.
Estimates of equivalence based on therapeutic ratio
Study A
Equivalence interval
X%
100%
Study B
Y%
The goal posts X and Y has to be agreed with the
regulatory agencies before study start.
Both studies A and B outcomes indicate
therapeutic equivalence.
Turbuhaler vs. pMDI
140
FEV (% of baseline)
1
TBH 0.50
TBH 0.25
pMDI 0.50
pMDI 0.25
120
100
0
1
2
3
4
Hours since dose administration
Borgström et al. Am J Resp Crit Care Med, 1996, 153:
5
6
Thank you for your attention!
1
Evaluation of inhalation devices using
human-like in vitro approaches
Mårten Svensson and Elna Berg, EMMACE Consulting AB
Dennis Sandell, S5 Consulting
2
Outline
•
•
•
Analytical testing on inhalation products
Pharmacopeia – how to perform the tests
More patient-like testing - improving the in-vitro in-vivo
correlation
•
•
•
Which parameters are important?
Experimental approaches
Examples
3
Unique analytical tests for inhalation products
•
•
•
•
•
Delivered dose uniformity (through inhaler life)
Aerodynamic characterisation (quality of the
aerosol cloud)
Spray pattern
Plume geometry
Droplet size distribution
4
Aerodynamic aerosol characterisation
•
Aerodynamic characterisation
(quality of the aerosol cloud)
•
•
•
Impactors are extensively used
Fractionating the aerosol
particles based on their
aerodynamic size
How particles behave in
different air flow pattern (eg
lung geometry)
5
Aerodynamic aerosol characterisation
•
Air flow according to
Pharmacopeia
•
•
•
•
pMDI: 30 lpm (NGI), 28.3 lpm
(Andersen)
Nebulizers: 15 lpm
DPI: flow that produce a
pressure drop of 4 kPa over the
inhaler, eg 30-100lpm
Air volume : 4 litres
4 kPa
6
Aerodynamic aerosol characterisation
•
Impactors, different types available (decribed in
Pharmacopeaia)
NGI
Twin Impinger
MLI
MMI
Andersen
7
Quality control vs prediction of In-vivo
•
The purpose of many of the tests is to control the quality
of the product
• The tests not necessarly good prediction tools for InVivo outcomes
 More sophisticated tools are available!
8
In-Vivo predicting tools
•
Two parameters are recognized important when
establish better IVIVC:
Throat geometry variation
Inhalation flow variation
flow
flow
time
time
9
The inhalation profile – the standard approach
•
With the pharmacopeia set-up
•
•
A square-wave air flow profile
Possibility to vary:
• Acceleration in the beginning (Flow Inspiratory Rate, (FIR))
• Maximum Flow, Plateau value (Peak inspiratory Flow, (PIF))
• Volume
Air Flow
PIF
FIR
Volume
Time
10
The inhalation profile – Lung Simulators
Weuthen, T. et. al., J.
Aerosol Med.,
15(2002) 297-303
Kamin, W.E.S. et.
al., J. Aerosol
Medicine,
15(2002) 65-73
Burnell, J. Aerosol
Sci. Vol 29, no 8,
p1011, 1998
11
Inhalation profiles – Mixing Inlet concept
•
•
Whole dose analysed
Impactor at fixed flow
OP model
•
•
Fairly simple
Commercially available
Piston
Pressurised air
Next Generation
Impactor
Mixing
Inlet
Vacuum
Bo Olsson,
RDD 2008
12
Throat inlets – Pharmacopeia throat
Pharmacopeia throat
13
Anatomical throat models
Alberta idealized throat
P. Byron group
The OP consortium throats
•
Different flows and throats will induce variability in “lung
dose” – What’s the meaning of that???
14
Lung deposition: variability vs lung dose
•
•
•
Borgström, 2006, JAM vol 19, No 4, 473
If high lung deposition is
wanted a low variability
is required
If you develop a product
with high variability – you
will never reach high
lung deposition
Different inhalation flows
and different throat
geometries will aid this
process
15
Example 1 – AstraZeneca Lung Dep
Bo Olsson, RDD 2008
DPI_A
DPI_B
80
% of mean delivered dose (MDD)
% of nominal delivered dose
90
70
60
90
80
70
60
DPI_A
DPI_B
50
40
30
20
10
0
in vivo EOM FPD
DM
Mean dose
passing throat
predicted
mean lung
deposition for
both DPIs
50
40
30
20
10
0
in vivo
Lung deposition
in vitro
Dose passing throat
16
Example 1 – AstraZeneca Lung Dep
Bo Olsson, RDD 2008
DPI_A
DPI_B
80
% of mean delivered dose (MDD)
% of nominal delivered dose
90
70
90
80
70
60
50
40
30
20
10
0
DPI_A
DPI_B
in vivo EOM FPD
DM
Similar in vivo
and in vitro
variability by
using OPC
throats with
different flows
60
50
40
30
20
10
0
in vivo
lung deposition
in vitro
impactor deposition
17
Example 2 - pMDI versus DPI
•
Fixed flows, different OPC throats
Förslag EB
Example 3 – Asmasal Clickhaler
•
•
•
Filtering capacity differ at 4 kPa, but not at 2 kPa (p = 0.03)
The smaller the cast, the more is captured in the cast
Low product variability?
19
Example 4: Design of clinical studies
•
Design of clinical studies of your novel drug/product
Pharmacopeia
4 kPa, cylinder throat
Data from
Emmace lab on
two salbutamol
(100µg) DPIs
20
Example 4: Design of clinical studies
•
Design of clinical studies of your novel drug/product
Pharmacopeia
4 kPa, cylinder throat
Variability
Different throats
and flows
Will the clinical study be successful….?
Data from
Emmace lab on
two salbutamol
(100µg) DPIs
21
Example 4: Design of clinical studies
•
Design of clinical studies of your Generic
Pharmacopeia
4 kPa, cylinder throat
Variability
Different throats
and flows
Data from
Emmace lab on
two salbutamol
(100µg) DPIs
22
Example 4: Design of clinical studies
•
Design of clinical studies of your Generic
Pharmacopeia
4 kPa, cylinder throat
Variability
Different throats
and flows
Data from
Emmace lab on
two salbutamol
(100µg) DPIs
Will the bioequivalence between Product 1 and
Product 2 be successful….?
23
Summary
•
•
In-Vivo realistic testing tools of inhalers are available
today
Using different inhalation flows (weak to strong) and
different throat geometries (e.g. small to large) offer:
• A guiding tool in product development
 Low lung dose variability in human population is a
prerequisite for high lung deposition
• Design input to clinical studies (new product and
bioequivalence)
24
Thank you for your attention
Biological Material – Your Treasure
Gun Persson, CEO Helene Sonesson, CFO
MVIC Symposium, Medicon Village, Lund‐Sweden, 17 October 2012
To reach the market…
in time…
Correct decisions must be made today!
Today…
• One substance – Many companies
• Biological materials ‐ Not always kept
• To have processes ‐ Cost
• Legal demands ‐ Difficult to understand?!
Tomorrow’s challenges!
• Competition increases…
‐ Time to market ‐ Quality
‐ Global co‐operation
• Legal demands will change and differ from country to country
Biological material will be one key…
The product’s sustainability from theory to practice
• Research costs ‐ important to ensure that investments are sustainable
• The clinic is not like normal clinical studies show
Biological Material gives
opportunities!
• Correct biomaker gives power
• Possibility to extend research…
‐ investigate AEs
‐ new biomarkers
‐ new indication
‐ multiple drugs
To the market…
Pre‐ Clinical
Clinical
Chain of Custody for samples
On Market
The Reality…
Chain of Custody for samples
Three major foundations
Feasible
Legal demands
Quality Assurance
What and How to do…
Right thing
Wrong way
Wrong thing
Right way
Wrong thing
Wrong way
RIGHT THING
RIGHT WAY
AT THE RIGHT TIME
Conclusion
Biological Material…
•
•
•
•
A company’s treasure
Lasts longer than a study or program
Possibilities for evidence & extended research
Important for investors
If you have global processes in place, it helps…
•
•
•
Your chain of custody
You to get what you want You to get where you want We can promise ‐ this will save you time & money!
Biological Material
Your Treasure
Treat it as it deserves!
www.nordicbiocube.com
Platinum sponsors
Gold sponsor
CI Informatics Ltd.
Nolato MediTech
Silver sponsors
Oxford Lasers
Pharmaterials Ltd
Det Medicinska Malmö
ExIS AB
Epsilon AB
QSCL Q Scientific Consulting
Organizing committee
Orest Lastow
Karin von Wachenfeldt
Charlott Brunmark
Stefan Ulvenlund
Martina Kvist Reimer
Kia Rönngard
Towa Carlsson
Caroline Formby
Sture Carlbom
Jessica Lastow
Thank you for attending
and see you all next year
2nd Medicon Valley Inhalation Symposium
16 October 2013
09.00–17.00
Medicon Village, Lund, Sweden
inhalationsymposium.com