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Measurement andoptimization ofinjection force:Two case studies onmaterial selection anduser perceptionJakob Lange, Ulm,October 17, 2018

Outline1.2.3.4.Introduction to Ypsomed and devices for self injectionCase study 1: Modelling, measurement and material selectionCase study 2: Force measurement versus perceptionConclusions2 Ypsomed Zwick Seminar Ulm October 17, 2018

1. Ypsomed – Key facts Turnover CHF 466 M R&D-Investment CHF 41 M Listed at SWX, majority shareholderand founder family owning 75% 1‘450 employees- 990 in Switzerland- 460 in Sales Affiliates Manufacturing & assembly- Reusable devices 1 million units- Disposable devices 80 million units- Pen needles 600 million units3 Ypsomed Zwick Seminar Ulm October 17, 2018

1. Devices for self-injection – IntroductionAutoinjectorPre-filled syringeSyringe and vialCartridge4 Ypsomed Zwick Seminar Ulm October 17, 2018Pen Injector

1. Devices for self-injection – DriversEase of useIncreased complianceImproved convenienceIncreased safetyDifferentiation / marketingHigher dose accuracy5 Ypsomed Zwick Seminar Ulm October 17, 2018

1. Devices for self-injection – Markets8 millionreusable pens1000 milliondisposable pensDiabetes hormones:Insulins, GLP-1sPCSK-9sOther hormones:hGH, infertility,osteoporosis6 Ypsomed Zwick Seminar Ulm October 17, 2018MABs: Autoimmunediseases, MS, RA,psoriasis, IBD, asthmaCancer, hep C80 milliondisposableautoinjectorsEmergency drugs:Anaphylactic shock,migraine, military

1. Devices for self-injection – Disposable pens Single use, come with the cartridge already inside Simple dial and dose or pull-push operation Range of devices for different applications– Variable dose– Fix-dose Insulin and diabetes largest marketEfficient gearing mechanisms foroptimized user handling forces7 Ypsomed Zwick Seminar Ulm October 17, 2018

1. Injection force – Overview Everybody agrees injection force isimportant, is touted as the single mostimportant performance parameterLots of studies on mechanical injectionforce measurement have beenconducted and published in theliteratureNo systematic method comparison oragreement on how to best measureinjection force – tensile tester is usedbut test setup / method notstandardizedFew people have studied how usersactually inject or what they perceive8 Ypsomed Zwick Seminar Ulm October 17, 2018F

2. Case study 1 – The problem How can injection force be minimized?Optimize the efficiency of the pen mechanism through material selection!75% of the frictionalresistance comes fromthis interface9 Ypsomed Zwick Seminar Ulm October 17, 2018

2. Case study 1 – The method Zwick Roell Z 2.5 universal testmachine with custom fittingsMeasurement of force and torque over450 degrees rotation 15 times backand forth at 90 degrees/sForce and torque converted to CoFthrough a simple analytical modelThreaded sleeveννcircνaxνDose sleeveyνcircνaxPitchαx2RπJ Lange, L Urbanek, S Burren; Development of devices for self-injection: using tribological analysis to optimize injection force, Medical Devices: Evidence and Research2016:9 93–10310 Ypsomed Zwick Seminar Ulm June 13, 2018

2. Case study 1 – Data evaluationCalculation of the average coefficient of friction for each individual pair of up and down runs,gives 15 data points per tested sample. 10 samples were tested for each materialcombinationCoF Angle [degrees]11 Ypsomed Zwick Seminar Ulm June 13, 2018

2. Case study 1 – The tests Testing was performed on a range of materials and combinations with differentadditives and lubricants:J Lange, L Urbanek, S Burren; Development of devices for self-injection: using tribological analysis to optimize injection force, Medical Devices: Evidence and Research2016:9 93–10312 Ypsomed Injection force optimization

2. Case study 1 – The results 1Combination 1Combination 3Combination 11Combination 70.2000.175CoF0.1500.1250.1000.0750.050024 68 10 12 14 16 0Cycle no24 68 10 12 14 16Cycle no024 68 10 12 14 16Cycle no024 68 10 12 14 16Cycle noJ Lange, L Urbanek, S Burren; Development of devices for self-injection: using tribological analysis to optimize injection force, Medical Devices: Evidence and Research2016:9 93–10313 Ypsomed Injection force optimization

2. Case study 1 – The results 2PolymersExternal lubricationInternal lubricationSystem force nbimo0.480.380.30.590.55mConabimConabi0.02nt io3mConabint io4mConabint io0.390.150.12-0.01nt oat0.655mConabi0.006nit omConabint io0.850.840.820.810.770.770.460.237mConabint io8mConabint io9Cnbimonioat10mConabint io11J Lange, L Urbanek, S Burren; Development of devices for self-injection: using tribological analysis to optimize injection force, Medical Devices: Evidence and Research2016:9 93–10314 Ypsomed Injection force optimization

3. Case study 2 – Force measurement versus perception Questions to be adressed:– Which is the best way to measure injection force?– Under what test conditions can / should pens be compared?– How do users actually perceive pens with differentmeasured forces?15 Ypsomed Zwick Seminar Ulm October 17, 2018

3. Case study 2 – Force measurements1. Three pens tested– Disposable pen (UnoPenTM)– Reusable pen with the same gearing ratio (4:1)– Prototype disposable pen with different gearing ratio (3:1)2. Injection force evaluated in different ways– Constant mechanical rate [mm/s]– Constant volumetric flow rate [U/s]3. Tests with controlled rate– 2 different needle gauges (31G and 29G)– 25 measurements per pen type / condition(provides a resolution of at least 1N)Andreas E. Schneider & Jakob Lange (2018) Pen devices for self-injection: contrasting measured injection force withusers’ perceived ease of injection, Expert Opinion on Drug Delivery, 15:2, 115-125, DOI:10.1080/17425247.2018.141588416 Ypsomed Zwick Seminar Ulm October 17, 2018

3. Case study 2 – Force raw data Force profiles aresimilar between pensForce level is differentbetween pensForce increaseswith ratePlateau values canbe used to comparebetweenmeasurementsForce increases withneedle gauge (thinnerneedle, data notshown)17 Ypsomed Zwick Seminar Ulm October 17, 2018Injection force 29G needleReusable 5 IU/s / 2.75 mm/sReusable 15 IU/s / 8.25 mm/sDisp. 1 5 IU/s / 2.75 mm/sDisp. 1 15 IU/s / 8.25 mm/sDisp. 2 5 IU/s / 2.065 mm/sDisp. 2 15 IU/s / 6.20 mm/s1260Force [N] 1260126001020300Travel [mm]102030Andreas E. Schneider & Jakob Lange (2018) Pen devices for self-injection: contrasting measured injection force withusers’ perceived ease of injection, Expert Opinion on Drug Delivery, 15:2, 115-125, DOI:10.1080/17425247.2018.1415884

3. Case study 2 – Force results 1Constant push-button rate3525Reusable 29GDisposable 1 29GDisposable 2 29GReusable 31GDisposable 1 31GDisposable 2 31G302520155 1510100Reusable 29GDisposable 1 29GDisposable 2 29GReusable 31GDisposable 1 31GDisposable 2 31G20Force [N]Force [N]Constant flow rate5123456Injection rate [mm/s]78924681012Injection rate [IU/s]1416The two ways of comparing pens are not equivalent!Constant flow rate is considered the most appropriate (closest to user behaviour)18 Ypsomed Zwick Seminar Ulm October 17, 2018

3. Case study 2 – Force results 2Comparison between pen types16ReusableDisposable 1Disposable 214121210108644225 IU/s 29G5 IU/s 31G10 IU/s 29GFlow rate / needle gauge10 IU/s 31G5 IU/s 29G5 IU/s 31G10 IU/s 29G10 IU/s 31G860 16Force [N]Force [N]14Comparison between needle gauges / flow rates0ReusableDisposable 1Pen typeDisposable 2Larger differences between needle gauges (for a given pen and rate) than betweenpens (at a given rate and needle gauge) !19 Ypsomed Zwick Seminar Ulm October 17, 2018

3. Case study 2 – Patient perception study Simulated injections into an injection pad– All three pens tested, reusable pen included twice– Injection of 20 units (small dose) with 31G needle and 60 units (large / max dose) with29G needle– Each participant performed every injection 2 times, in random order Participant rating of injection experience directly after each injection on a five-levelLikert-Scale (1 strongly disagree; 5 strongly agree):– “How would you rate the handling comfort during the injection?”– “Please respond to the following statement: I had a pleasant feeling when performing aninjection with this pen.” Participants– 39 participants, 19 female and 20 male– Age distribution 11-60 years– All injection naïve20 Ypsomed Zwick Seminar Ulm October 17, 2018

3. Case study injection force – Perception resultsHandling / comfort score (n 39*)*n 38 for Di s posable 1 31GDisposable 2 31G2Disposable 2 29G2 12911Disposable 1 31G 0 2Reusable A 29G 010%12183132161415517184152010%20%Score 1 11177Reusable B 29G 01Reusable A 31G 015147Disposable 1 29G 01Reusable B 31G 012130%Score 240%Score 31450%60%Score 470%80%90%100%Score 5Smaller differences between needle gauges (for a given pen) than between pens(at a given needle gauge) !21 Ypsomed Zwick Seminar Ulm October 17, 2018

3. Case study 2 – Force versus perceptionFeeling / convenience vs injection forceHandling / comfort vs injection force5.05.04.54.54.0Mean scoreMean score4.03.53.02.52.0 2468Force [N]103.02.5Force 5 IU/s, R squared 25.3%Force 10 IU/s, R squared 27.5%03.51214162.0Force 5 IU/s, R squared 17.0%Force 10 IU/s, R squared 27.0%02468Force [N]10121416Very little correlation is observed, other factors than measurable injection forcemust be at play!22 Ypsomed Zwick Seminar Ulm October 17, 2018

4. Conclusions Self-injection devices is an important and growing marketEverybody agrees injection force is important but– There is no agreed standard for how to measure– Nobody has studied how users actually inject and what they prefer! Injection force is heavily influenced by the materials used in the pen– Frictional testing combined with modelling is a useful development tool– There are large differences between different materials– Additives / lubricants have as much influence on performance as the material itself Force measurement and perceptions– Measured forces / outcome depend strongly on the needle gauge, rate of injection andhow pens are compared (constant push-button or flow rate)– Patients do perceive differences, but perception is only indirectly related to measuredforces23 Ypsomed Zwick Seminar Ulm October 17, 2018

3. Case study 2 - Force raw data Force profiles are similar between pens Force level is different between pens Force increases with rate Plateau values can be used to compare between measurements Force increases with needle gauge (thinner needle, data not shown) 17. Ypsomed Zwick Seminar Ulm October 17, 2018. 12 6 0 12 6 0 0 10 20 30 12 6 0 .