New Generation Flexi-Q Auto-Injectors - DALI Medical Devices

New Generation
Flexi-Q Auto-Injectors
Novel Disposable Auto-
Injector Design for Injecting
High-Viscosity Liquid Drugs in
Pre-filled Syringes
Dr. Menachem Zucker, VP, I3D, Elcam Medical
David Daily, Director of R&D and BD, I3D, Elcam Medical
Management Forum, Injectable Drug Delivery
London, 24-25 March 2011

Contents
1. Short Introduction:
○
○
Elcam Medical
Flexi-Q Auto-Injector Platforms
2. Injecting High Viscosity Drugs Using
an Auto-Injector:
○
○
○
Studies Results and Analysis,
Injection Time Prediction Model
Design Implications
3. Conclusions & Summary
2

Elcam Medical
• Elcam Medical is a leading worldwide OEM
supplier of Fluid Management, Drug Delivery and
Vital Signs Monitoring systems and devices
• Our Quality System is in full accordance with the
FDA QSR, European Medical Devices Directive
and is ISO 9001, ISO 13485 certified
3

Elcam’s Manufacturing Facilities
• 27,000 sq. ft. of class 100,000 clean rooms at Kibbutz BarAm
• 10,000 sq. ft. of class 100,000 clean rooms at Dalton
• Manufacturing in the US via acquisition of Injectech
• Manufacturing in the EU via acquisition of Lucomed
• Precision injection molding processes, including 2C (Two
Components) and LSR (Liquid Silicon Rubber)
• Fully automated production floor utilizing custom made
assembly machines
4

Product Lines
• Stopcocks & Manifolds
• Needle-less
• Valves
• Disposable Pressure Transducer
• Injectable Drug Delivery Devices (I3D)

6
Some of Elcam’s Major Customers

Novel, Commercially Available
Flexi-Q PFS
Disposable
Auto-Injector
for
Pre-filled Syringes
MAF
(Device
Master File)
submitted
• Safe & Simple
• Reduced Pain Perception
• Injection starts only after
full needle penetration
• Easy & safe drug
reconstitution and
aspiration from vials
• Single or multiple vials
• Drug viscosity range
• Unique LCM tools
Flexi-Q DV
Disposable
Auto-Injector
for
Drugs in Vials
510(k)
submitted
7

Semi-Disposable Auto-injector
• The Semi-Disposable Auto-Injector features a
reusable driving unit and a cost-effective, automatic
needle protection disposable cassette for use with
standard pre-filled syringes and vials.
• For use with chronic diseases that require frequent
injections (e.g., multiple sclerosis), the partially
reusable design lowers the cost per injection and
reduces the volume for storage and disposal.
Disposable
Cassette
with
Pre-Filled
Syringe
Reusable
Driving Unit
8
Option: Reconstitution
using a Vial Adaptor with
the Disposable Cassette

Auto-injector design implications:
Injection of Pre-filled High
Viscosity Drugs

Background: Market
General:
• Growth at 2-digit percent/annum
• Investment in developing new drugs and
stabilizing dry formulations in liquid form
• Significant growth of self-administration
injectables/biologics and bio-similars segments
High viscosity results from:
• Development of sustained release /depot
formulations (e.g., PEGylation), mAb, other
• Trend towards SC injections (instead of IM and
IV), allowing self-administration limiting
dose volumes
10

Market Demands – some examples of
discussions with potential customers
Company
One of top 10
Medium
biotech
One of top 10
Small biotech
One of top 10
One of top 10
Small biotech
Viscosity, Dose etc.
10 cP, 1 mL; future: 1-25 cP , 0.1-1.0 mL
- 1 mL of the 70 cP drug
- delivered through a G27 needle in less than 10 sec.
~4 cP ; 1 mL @ 8 sec
50- 200 cP; 23-27G, 10 N /10 sec
- Typical liquid formulation viscosity is < 30 cP,
- Some formulation could be ~ 50 cP.
- Typical injection volume is 0.5 or 1 ml, but some is > 1 ml.
- SC injection.
1-30 cP ; 0.25-1.0 mL
- The dose should ideally be flexible in a range of 0.3 to 1.0 mL
- Highly viscous material (100-200 cP) in a reasonable short
timeframe

Some Examples of Disease Indications
Which Require Self-Injection
Diabetes
Oncology:
Anemia &
Neutropenia
Infertility
Psoriasis
Rheumatoid
Arthritis
Osteoporosis
Multiple
Sclerosis
Growth
Hormone
Deficiency
Acromegaly
Crohn’s
Disease
Hepatitis
B&C

Injecting High-Viscosity Drugs -
Injection Time Results with Flexi-Q PFS
Viscosity
[cP]
Notes:
Injection Time
[sec]
5 8-12*
37 7-9**
70 5-11**
140 21**
• Results with ½” long
needles, 1 mL
* 27G-29G needles
** 26G-27G, various
injection springs
• Injection time is significantly depending on each
specific drug characteristics!
• Injection time of the Flexi-Q PFS can be adjusted
as needed while modifying the injection spring and
proprietary friction mechanism characteristics
13

Challenges designing an auto-injector
for high-viscosity drugs:
@ given flow rate & needle diameter →
higher resistance to viscous fluids
• Much higher forces are involved!
implications:
○ Requires high rigidity device cost
○ High impact increased risk for glass
syringe breakage
○ Loud impact sound increase pain
perception & potential unintended premature
removal from the skin (resulting in incomplete
injection)
14

Challenges (cont.):
• Maintaining constant force during
injection
• Mechanical springs as energy source
Creep and cracking
• Keeping the design :
○ Simple and with acceptable dimensions
○ Reliable & robust
• Short development time & low device
cost
15

Injection Spring Design Process
Stage 1
• Objective: Analyze the average required
forces to inject viscous liquids using 1 mL
long glass syringe at various injection
speeds [used for design requirements characterization of
auto-injector for high viscosity drugs]
16
• Method: Average injection force
measurement on a Tensile-Compression
machine (w/o back pressure)
○ 5 - 870 cP: Different glycerin aqueous
solutions simulating high viscosity drugs
○ 1 mL long glass syringe with 23G, 26G and
27G normal-walled (NW) ½” long needles

17
Stage 1 - results

18
Stage 1 – results (cont.)

Injection Spring Design Process
Stage 2
• Objective: Propose a mathematical model
to predict high viscosity drugs’ injection
characteristics
• Method:
initial spring design
○ according to estimated force required to inject
the viscous drug (stage 1)
○ according to auto-injector design and
dimensional limitations
Compute estimated injection time
19

The Mathematical Model
• injection speed can be calculated by:
F
a,b
- force applied on the plunger-stopper
- constants taken from Fig. 2, at specific drug
viscosity
• The force generated by the spring at a specific
point along its stroke is given by:
F 0
k
- spring force at start of injection
- spring constant
aF
• Injection duration of the interval is given by:
t(
x)
dx
v
a(
F
0
dx
kx)
b
dx
v
F spring
b
x
( )
F 0
kx
20

The Mathematical Model (cont.)
• After integration, the total injection time is given
by:
t
total
1
ak
ln(
aF
a(
F
0
0
b
kx )
n
)
b
x n
where is the stroke of the spring, or the travel of the plungerstopper
to deliver the drug.
21

Injection Spring Design Process
Stage 3
• Objective: Validate the proposed
mathematical model
• Method: Injection time measurements of
Flexi-Q HV auto-injectors pre-filled with
liquids at different viscosities
22

Results: Flexi-Q HV Capability to
Inject High Viscosity Drugs
Flexi-Q HV design can allow injection spring
at least X3 stronger than maximum
Flexi-Q PFS injection spring force
Viscosity
[cP]
Injection Time
[sec]
Needle
Spring
Force
16 5 – 6* 27 – 29 G Medium
35 9 – 11 27 – 29 G Medium
77 2.5 – 13 26 – 27 G Strong**
150 5 – 6 26 G Strong**
○1 mL long glass syringe with 26-29G ½” long needles
○1 mL aqueous glycerin solution
23
* Model estimated 6.8 sec
** Spring force can be even stronger!
But – it can also be lowered for low viscosity drugs

Conclusions
For an auto-injector of high viscosity drugs,
two main approaches can be used while
keeping reasonable usability injection
duration:
1 st Approach:
Increase needle ID (25-27G thin-walled)
• Allowing manual injection -- reasonable force
• Available -- Elcam & other auto-injector vendors
-- No need for long and costly development
-- Low risks
• Potential logistic issue – sourcing glass syringe
24

Conclusions (cont.)
2 nd Approach:
Increasing the injection spring force, or, using
an alternative energy source for injection
• No manual injection -- unreasonable finger force
• Potential logistic issue -- glass COC/COP
syringe
• Significant design challenges – keeping the
auto-injector small, reliable, not noisy, keeping
the glass syringe integrity, and more…
• longer development time & cost (+device cost?)
potential usability issues
25

Other Approaches:
• IV pump (no self-administration, different
bioavailability)
• SC micro-infusion pump* (not yet available for
high viscosity)
• Reusable* (electrically powered, not yet available)
• Other…
* Contact us if such options are interesting
26

Flexi-Q HV – New auto-injector platform
allowing even higher viscosities
Elcam develops the Flexi-Q HV auto-injector for
Low to High-viscosity drugs in PFS:
• New proprietary damping mechanisms -
preventing impact on glass syringe:
○
○
low activation noise, no breakage issues
allowing use of extremely strong injection spring
• For use with 1 mL long glass syringe & staked needle
• Injection of 1 mL of high-viscosity drugs with 27G
NW /29G TW needles at < 10 sec
• Small Size: ø21 mm x 155 mm
• Two activation design options:
1. With a Trigger button and body sensing
2. Activation by pressing against skin (e.g. emergency use)
27

Summary: Elcam Medical
• Elcam has a broad line of innovative solutions for
easy-to-use self-administration of drugs - all are
customizable to meet your specific needs
• Elcam has a long history being a reliable partner
providing high quality and excellent service in the
disposable devices
• Experience working with major US pharma companies
in the fields of anemia, RA, MS, microspheres/high
viscosity
• Meet us to discuss potential collaboration options –
Flexi-Q line for low-high viscosity, liquid or lyophilized,
for both PFS & vials

Acknowledgement:
Lior Raday
Udi Carmel
Guy Keenan
Micha, Amit, Yuval, Avi…

Testimonials – from recent work with
pharma companies
Year /
Company* Description Testimonials
30
2010
One of top
10 pharma
Technical duediligence
performed by a US
professional
engineering
third-party on
behalf of a
pharma customer
for the use of the
Flexi-Q PFS
autoinjector for a
Phase III drug
(auto-immune
indication)
"The assembly steps as outlined here look relatively
easy to manage and tool for scale up activities..."
"One thing that jumps out of the design review is that in
general, clever and novel design approaches are
evident throughout the product...“
"The product uses the minimum number of
components to achieve the desired functionality,
without undue component complexity... “
"… we consider the device to be below average risk
for dose repeatability, and generalized functional
performance.“
"… our assessment of the “robustness” of the
design, its perceived fault tolerance, and ability
to function reliably and repeatably in a wide
variety of manufacturing and environmental
conditions is favorable.“
J.C., CEO, founder, major US-based engineering firm performing
technical due-diligence
* Due to confidentiality agreements, no disclosure of company names are possible

Testimonials – from recent work with
pharma companies (cont.)
Year /
Company* Description Testimonials
2010
Smallmedium
size biotech
2009
One of top
10 pharma
Stage I: Few concept
designs and drafting
a patent application
for the same
Feasibility project
for the use of one of
the Flexi-Q PFS
autoinjector for a
Phase III drug
“Very much satisfied from the work done; Well
done! Awaiting for the next stage of feasibility”;
R.L. , PhD, Patent Attorney, Director of Intellectual Property
“The engineering analysis David provided was
excellent. I would rate it on par with work we have
contracted in the past with ENGINEERING companies
who have ONLY THAT FOCUS AS THEIR BUSINESS
SERVICE. “
J.J., Senior Program Manager
31
2008
One of top
10 biopharma
companies
Feasibility project
for the use of one of
the Flexi-Q P-DVR
autoinjector for a
Phase II drug
“… Regarding the new prototype of the Flexi-Q
device, all of the people I have shown the device
to have been really pleased with the outcome.”
“As always, you have provided an exceptional
amount of quality with your work. Thank you
for all of your efforts.”
C.B., PhD, Senior Biologic Project Manager, R&D
* Due to confidentiality agreements, no disclosure of company names are possible