Andy Fry delivered this presentation at the PDA Universe of Pre-filled Syringes conference in Basel on November 8th 2011

1. Parenteral Drug Delivery in the
PDA: A Global
Future:
A View of Developments,
Association
Implications and Opportunities
Andy Fry
Founder, Team Consulting Ltd
8th November 2011

2. Parenteral Drug Delivery in the Future
• The parenteral delivery device
• HFE, Compliance and usability – what„s the connection?
• Mature optimisation– influential improvements
• Disruptive change - transforming technologies
• Implications for the future
2

3. The Parenteral Delivery Device
• Tablets we can swallow – mostly
• Ointment we can rub on – usually
• For virtually all other prescription medications :
‘The delivery device is the drug to patient interface’
(Georg Rößling, February 2011)
3

4. „the drug to patient interface‟
• Some fundamental points arise when we consider the device this way;
– No device, no therapy
– Bad device = Bad therapy
– Bad drug = Bad therapy
• The right device is as important as the right drug
4

5. Parenteral Drug Delivery in the Future
• The parenteral delivery device
• HFE, Compliance and Usability – what„s the connection?
• Mature optimisation– influential improvements
• Disruptive change - transforming technologies
• Implications for the future
5

6. Compliance – some research data
side change
effects delivery reduce
route dose
freq
53%
to 35%
50% 67% 30% 52% to
41% 25%
to to 45%
35% 35%
estimated measured compliance compliance with compliance with compliance with compliance with
compliance compliance with oral inflximab infusion adalimumab daily oral weekly oral
across chronic with oral methotrexate for for RA4 autoinjector for bisphosphonate bisphosphonate
illnesses & medications for RA3 RA4 for osteoporosis5 for osteoporosis5
lifestyle changes1 Type 2 diabetes2
1 - Haynes et al (1979) Compliance in health care. Johns Hopkins University Press, 1979
2 - Paes et al (1997) Impact of dosage frequency on patient compliance. Diabetes Care 20:1512 -1517
3 - Viller et al (1999) Compliance to drug treatment of patients with rheumatoid arthritis: a 3 year longitudinal study. J
Rheumatol 10: 2114-22
4 - Hetland et (2010) Arthritis & Rheumatism 62: 22–32
5 - Cramer et al (2007) A systematic review of persistence and compliance with bisphosphonates for osteoporosis.
Osteoporos Int 18:1023–103

7. compliance
Compliance – influencing factors
poor
education
disability poor perceived
treatment
side effects effectiveness/
understanding
of disease dosing lack of
chronic regime confidence/
conditions complexity perceived
younger age / ability to take
male gender medication
treatment
cost
lack of social /
forgetting professional
support
relationships
driving wilful non-compliance
driving unintentional non-compliance

8. What can device developers influence?
compliance
poor
education
poor perceived
disability
treatment demands on user
side effects effectiveness/
understanding
of disease dosing lack of
chronic regime confidence/
conditions complexity perceived
younger age / ability to take
male gender medication
treatment
cost
lack of social /
forgetting professional
support
relationships
support of user
• what can‟t we change?
– the disease condition
– the drug: side effects, symptomatic relief
– the patient‟s age / gender / disabilities / socioeconomic status
• what can we influence?
– the formulation: e.g. dosing frequency
– the delivery route: e.g. from IV to SC, depot implants, wearable devices/patches
– the demands on the user associated with dose delivery
– the support provided to the patient to help them adhere to dosing regime
– the patient‟s perceptions of and attitudes to their treatment

9. Mature Optimisation; Improve Compliance through
Usability - Reduce Demands on Users
Minimise the core physical and cognitive burden of
delivering therapy
• Target - eliminate the negatives
– perfect device reliability / consistency of performance in
hands of users
•
–
–
–
no significant use-related risks
accommodate full range of user input
•
•
grip styles, operation styles
maximise ease of use
minimise delivery pain / anxiety
But there are some conflicts
?
– clarity of feedback vs. discretion/privacy
– some users want to be in „control‟, others want „distance‟
• Excellent usability = zero “delivery task” burden …
…. but usability alone cannot address the “self-
management task” burden (i.e. we have to accept that
total compliance can never be achieved)
9

10. Disruptive Change; Improve Compliance through
Additional Functionality – Support Users
Reduce the cognitive and emotional burden of managing
treatment. Opportunities include :
• Wearable / implantable devices
• New formulation enabled by new device
– reduced dosing frequency
– reduced dose size
– reduced dose discomfort
• On-board electronic features
– reminders
– dose logging / memory
• Links to other devices
– smartphone self-management apps
– diagnostic devices – theranostics
• Links to social networks
– e.g. www.patientslikeme.com/
10

11. HFE, Usability, Compliance and Regulation
• Follow usability engineering / human factors
process with passion and creativity Design
Concept
Phase
Design
Input
Design
Output
Verification Validation
Control Perform
–
Activities Design Design Test Output Test Against
FDA guidance Studies &
Analysis
Requirements Specifications Against Input User Needs
– ISO/IEC 62366 (incl. ANSI/AAMI HE74) Contextual
Inquiry
Task Analysis Prototyping /
Simulations
Expert
Reviews
Production
Units (or
User Profiles Equivalent)
–
Literature Iterative Design Cognitive
ANSI/AAMI HE75:2009 Human
Factors
Reviews
Complaints
Use Environment
Heuristic Review
Formative
Usability
Walkthroughs
Summative
Summative
Usability
Testing
Activities Analysis Testing Usability
Risk Analysis Testing Field Studies
Market Risk Analysis
Research Usability Risk Analysis
Objectives Cognitive
Walkthroughs
• This is not a ‘Nice to have’ but a regulatory
necessity
• Reduce risk and improve compliance

12. HFE as part of a balanced process
• Three essential attributes for success;
– Usability The patient must be able to use the device without difficulty or errors
– Functionality The device must address needs and function reliably and consistently
– Manufacturability The device must be manufacturable at acceptable cost
• All three attributes must be in balance
– Get the first two right to satisfy the regulators and benefit the patients
– Get the last one right to satisfy prescribers and payers (and get it to the patient)
• Dominance of one attribute at the expense of others may spoil
an otherwise good device
• Failure to hit the mark in any one area is usually terminal for the device
(and possibly the therapy concerned)

13. Parenteral Drug Delivery in the Future
• The Parenteral Delivery Device
• HFE, Compliance and Usability – what„s the connection?
• Mature optimisation – Influential improvements
• Disruptive change - transforming technologies
• Implications for the future
13

14. Mature optimisation;
„Established‟ product types – Autoinjectors
• A new generation of autoinjectors is
emerging
• Different manufacturers, different designs but
some fundamental objectives in common;
– consistent and reliable
– designed for manufacture
– competitively priced
– compact in size
– wide applicability for a range of therapies
– simple and intuitive in use
14

15. Mature optimisation;
Next generation glass pre-filled syringes
• BD Hypak™ has a long and admirable pedigree
– But not originally designed for autoinjector use
– Integration of formed glass with precision mechanisms is challenging,
demanding tighter tolerances
• BD continue to develop the Hypak™ family
– BD Physiolis™ syringe
• Current product
– BD Hypak™ for Biotech
• New specification for autoinjector compatibility
– BD Neopak™ - in development
• 6σ quality vision, new production process
Images by kind permission of BD Medical – Pharmaceutical Systems 15

16. Mature optimisation;
Alternatives to glass as a syringe material
COC / COP cyclic polyolefin syringes
• Injection moulded, designed to replace glass
– Much tighter dimensional control than glass
– Reduced need for siliconisation
– No tungsten issues
– Robust; greater safety, no breakage losses
West Daikyo Crystal Zenith
Image by kind permission of West Pharmaceutical Services
• In many ways a very promising design alternative
• Several leading producers already offering prefilled syringes
– West, BD, Schott, Gerresheimer and others
• Some resistance to adoption
– For drug product approved in glass, time and cost to change material
– Lower oxygen barrier than type 1 Borosilicate glass
• In Japan, 65% of all syringes are COC/COP and have been for several years

17. Mature optimisation;
Improved Syringe Siliconisation Control
Bad syringe Good syringe
Images by kind permission of ZebraSci 17

18. Mature optimisation;
Improved Syringe Lubrication
• silicone-free lubrication system for
syringe-barrels, plungers and needles
• Perfluoropolyether (PFPE) chemistry
– atmospheric plasma crosslinking process immobilises PFPE
lubricant onto the device surface
• Glass and plastic (COC, COP, PP) cartridges
and syringes (Luer and staked needle)
• FDA 510(k) approval for use in piston syringe
applications received in 2007
• Multiple benefits
– Low break-free force
– Low, uniform extrusion force
– Minimal protein aggregation
– Low friction coating on needles
Images by kind permission of TriboGlide 18

19. Parenteral Drug Delivery in the Future
• The parenteral delivery device
• Compliance and usability – what„s the connection?
• Mature optimisation – influential improvements
• Disruptive change - transforming technologies
• Implications for the future
19

20. Disruptive Change; EEDDs
(Electronically Enabled Delivery Devices)
easypod® image by kind permission of Merck Serono
EEDDs are already becoming established - examples
• easypod® for delivery of HGH
– simple in use (attach needle, position against skin, press button)
– device keeps track of daily therapy
– preset dosing
– GUI
• OmniPod ® system for delivery of insulin
– wearable insulin pump („pod‟)
– wireless management unit („PDM‟)
– integrated glucose meter
– downloads to health management system
• Both products
– reduce demands on the user associated with dose delivery
– provide support to help patient comply with dosing regime
– respond to the particular needs of the patient groups concerned
• The number of EEDDs applications is growing OmniPod ® images by kind permission of Ypsomed
20

21. Disruptive Change; EEDDs - Opportunities
• Potential for improved compliance through reduced
cognitive, physical and emotional burden
– Reminders for infrequent therapies
– Prompts to aid correct use
– Rewards e.g. for children
– Fully automated, invisible needle
– Usage trends / history
– Complex functions simplified e.g. titration
• Sophisticated interface will not suit all user groups
– One size won‟t fit all
– Just because functions are possible they aren‟t necessarily desirable
21

22. Disruptive Change;
Wearable devices SmartDose ® image by kind permission of West Pharmaceutical Services
• Increasing range of :
– Names – patch pumps, infusers, bolus delivery devices
– Technologies – electromechanical, spring driven, elastomeric
– Devices – from an increasing number of established and emerging
organisations
• Common theme
– SQ delivery of high viscosity and/or high volume meds
– e.g. biopharm/macromolecules
• Up to 10 ml in 60 mins typical with no / minimal pain
• Convenient
– adhere to skin, then automated sequence;
– insert needle / cannula, deliver dose, disable, then remove / dispose
• Suited to chronic therapy where dose size, viscosity
or both preclude autoinjector delivery
SteadyMed ® image by kind permission of SteadyMed Therapeutics, Inc
22

23. Disruptive Change;
Novel delivery technologies
• Needle-free („jet„) injection
• No sharps hazard, no needle phobia
• Delivery <100msec; no issue of „hold„ time
• Small molecule delivery well established
• Sumavel® DoseproTM for migraine since Q1 2010
• Needle-free delivery is unaffected by viscosity
• same injection time from 1cP to 3000cP
• Delivery of macromolecules without denaturation
• MAb„s, proteins, vaccines
Delivery technology enables formulation opportunities
to be realised
Images by kind permission of Zogenix Inc.
23

24. Disruptive Change;
Novel formulations
• Xeris; ultra-low volume, ready-to-use bio-pharmaceuticals
• Non-aqueous paste – no reconstitution
• Suited to peptides, proteins, antibodies and small molecules
• No cold chain, stable as pre-mixed paste or liquid at room temperature
• Ultra-low injected volume hence very low discomfort
• Ideal for self-administration
Formulation opportunity enabled via the right delivery technology
Aqueous Non- Aqueous Aqueous Non- Aqueous
Images by kind permission of Xeris Pharmaceuticals, Inc
24

25. Parenteral Drug Delivery in the Future
• The parenteral delivery device
• Compliance and usability – what„s the connection?
• Mature optimisation – influential improvements
• Disruptive change - transforming technologies
• Implications for the future
25

26. Implications for the future
• The delivery device is the drug to patient interface
– Devices will remain a fundamental part of parenteral product offering
• HFE ensures that user issues are given appropriate weight
– Regulators will assess usability, user should benefit from improved compliance
• Plenty of scope to improve current technologies further
– Products, materials and processes
• Emerging technologies are presenting new opportunities
– Delivery technology and formulation enablers
26

27. Acknowledgements
Many thanks for images, data and permissions granted by;
• BD Medical – Pharmaceutical Systems
• Merck Serono S.A.
• Oval Medical Ltd
• Owen Mumford Ltd
• SHL Group AB
• SteadyMed Therapeutics, Inc.
• TriboGlide, Inc.
• West Pharmaceutical Services, Inc.
• Xeris Pharmaceuticals, Inc.
• Ypsomed AG
• ZebraSci, Inc.
• Zogenix, Inc.
27

28. Thank you
Andy Fry
Founder
Email: andy.fry@team-consulting.com
Tel: +44 1799 532739
Mob: +44 7764 178439
28