1053 Ondrugdelivery Wearable Bolus Injectors Issue 51 01.08.Indd

PHARMA PERSPECTIVE: SELECTING A WEARABLE INTEGRATED SOLUTIONS THE JOURNEY HAS INJECTOR TECHNOLOGY FOR THE DELIVERY OF HIGH- P07 JUST BEGUN... P08 & PARTNER P26 VOLUME BIOLOGICS

INJECTABLE DELIVERY: WEARABLE BOLUS INJECTORS

OUTSTANDING ISSUE SPONSOR 51 O ISSUE N • , 2014 , 2014 RD JULY 23 JULY Contents

ONdrugDelivery Issue No 51, July 23rd, 2014 Injectable Delivery: CONTENTS Wearable Bolus Injectors This edition is one in the ONdrugDelivery series of publications from Frederick Furness Publishing. Each Editorial Comment issue focuses on a specific topic within the field of Guy Furness drug delivery, and is supported by industry leaders 4 - 5 in that field. Introduction: Pharma Perspective EDITORIAL CALENDAR 2014/15 Paul Jansen, Associate Vice-President, Sep: Prefilled Syringes 7 Medical Device Development Oct: Drug Formulation & Delivery Solutions Sanofi & Services Criteria for Selecting a Wearable Injector Nov: Pulmonary & Nasal Drug Delivery Technology and Partner Dec: Delivering Biotherapeutics Alan Shortall, Chief Executive Officer Jan: Ophthalmic Drug Delivery 8 - 13 Feb: Prefilled Syringes Unilife Corporation March: Transdermal Delivery, Microneedles Large-Volume Injector Enables Anytime & Needle-Free Injection Anywhere Delivery of Parenteral Drugs April: Pulmonary & Nasal Drug Delivery Dr Pieter Muntendam, President and CEO May: Injectable Drug Delivery: Devices Focus scPharmaceuticals Inc SUBSCRIPTIONS: Dr Gerhard Mayer, Vice-President, Business Development North America To arrange your FREE subscription (pdf or print) 16 - 19 to ONdrugDelivery Magazine: Sensile Medical, USA E: [email protected] Dr Lars Krinelke, Head Product Management, Head Medical Affairs SPONSORSHIP/ADVERTISING: Sensile Medical AG Contact: Guy Furness, Proprietor & Publisher PatchPump: Expanding the Limits of T: +44 (0) 1273 78 24 24 Parenteral Administration E: [email protected] Marylyn Rigby, Director of Business 22 - 24 Development & Marketing MAILING ADDRESS: SteadyMed Therapeutics, Inc Frederick Furness Publishing Ltd The Candlemakers, West Street, Lewes, Integrated Solutions for the Delivery East Sussex, BN7 2NZ, United Kingdom of High-Volume Biologics ONdrugDelivery Magazine is published by Mr Graham Reynolds, Vice-President, Frederick Furness Publishing Ltd. Registered Office: 26 - 28 Marketing & Innovation, Pharmaceutical The Candlemakers, West Street, Lewes, Delivery Systems East Sussex, BN7 2NZ, United Kingdom. West Pharmaceutical Services, Inc Registered in England: No 8348388. People Power: Inspiring & Delivering a Unique VAT Registration No: GB 153 0432 49. Wearable Bolus Injector ISSN 2049-145X print 30 - 33 Enable Injections, LLC ISSN 2049-1468 pdf Safe & Reliable Primary Drug Copyright © 2014 Frederick Furness Publishing Ltd All rights reserved Container Manufacturing 34 Gerresheimer AG

The views and opinions expressed in this issue are those of the authors. Due care has been used in producing this publication, but the publisher makes no claim that it is free of error. Nor does the publisher accept liability for the consequences of any decision or action taken (or not taken) as a result of any information contained in this publication.

Front cover image: “A wearable injector applied to the abdomen.”, kindly provided by Unilife Corporation (see this issue, page 8).

Peel, Stick, Click.

Wearable Injectors

T: +1 717 384 3400 E: [email protected] W: www.unilife.com

These products have not yet been evaluated by the FDA Editorial

EDITORIAL COMMENT

I’m pleased to present to you here the first the usual detailed and lengthy regulatory button”. NuPrivo- ever issue of ONdrugDelivery Magazine requirements by using, or only incrementally SC is due to enter to focus wholly on the topic: “Wearable modifying, existing components, especially clinical trials shortly, making it the most Bolus Injection Devices”. These devices, those that contact the drug formulation itself. advanced in Ratio’s portfolio of patch-injec- also known as patch pumps or high-volume So a game-changing new class of delivery sys- tion devices, which includes an intradermal injectors, typically carry out automated sub- tems can be realised using highly intelligent injector and a continuous infusion system. cutaneous (SC) delivery of large volumes of and innovative, yet relatively incremental The first of the companies contribut- potentially highly viscous drug formulation technological advances. ing to this issue which should be men- whilst worn like a patch, adhered to the skin. tioned is Unilife, to which I’m most grateful They are distinguished from long-term infu- for its strong support for this edition of sion devices which have existed for many ONdrugDelivery as our Outstanding Issue years now in that, rather than delivering “I have never been able Sponsor. Company CEO Alan Shortall has a constant amount of drug per minute or to say this about a class written an insightful piece (Page 8), which sequential small regular doses in order to of novel (pre-approval) sets Unilife’s two electronic wearable bolus maintain specified drug plasma levels over injectors – Flex-Therapy and Precision- time, wearable bolus injectors deliver a sin- drug delivery systems with Therapy – in the context of an integrated gle bolus SC dose and are then removed and such certainty before, but offering as part of Unilife’s highly customis- disposed of or recycled. wearable bolus injection able range of injectable drug delivery devices I’ve heard of, read about and written on and safety syringes. a number of “hot topics” over the decade devices … will change the Continuing the theme of wearable-bolus or so since drug delivery became my career pharmaceutical industry injection devices as part of an integrated focus – some of them weren’t hot at all forever, and they will drug delivery offering, Graham Reynolds it turned out, others were important but of West Pharmaceutical Services argues that destined for failure, and a fair few of them do it relatively soon” as self-injection at home becomes more have changed the pharmaceutical industry commonplace, it becomes increasingly clear forever. I have never been able to say this that there is no “one size fits all” device about a class of novel (pre-approval) drug More detailed explanations as to exactly solution (Page 26). Preferences differ from delivery systems with such certainty before, why this is such a particularly important area one patient to another, with some people but wearable bolus injection devices belong of drug delivery today and why it will have feeling more confident and in control using in the latter category. They will change the such an impact can be found in the articles a “naked” prefilled syringe with simple pharmaceutical industry forever, and they that follow in this issue, beginning with the needle-safety device, for example, while oth- will do it relatively soon. Pharma Perspective article from Paul Jansen, ers prefer everything to be taken care of by a Why so sure? In short, this class of devices Vice-President, Medical Device Development wearable injector. But Reynolds also points has found the sweetest of sweet spots for at Sanofi Aventis (Page 7). Jansen is positive out that an individual patient’s preference a major technological innovation. On one in his assessment of the potential of what he could change over the long time (perhaps hand, a cluster of wearable bolus injectors calls “large volume delivery (LVD) devices” a lifetime) that they could be taking an are coming through their own development saying that industry is competing aggressively injected therapy for a chronic condition. process timed perfectly to be available and for access to LVD technology. For each pharmaceutical product, a variety ready to fulfil a huge need in the market as it I’m very pleased indeed to have such a of integrated injection devices is essential, arises – in this case the need comes from the great spread of device feature articles in this therefore, to cater for these changing inter- wave of biologics moving through the latter issue, contributed by the majority of the main and intra-patient preferences. stages of their clinical development towards players in this closely competitive sector of Enable Injections is taking a unique approval, combined with the rapidly increas- the injectable drug delivery sector. Before approach as it races towards US approval ing emphasis being placed on Human Factors going on briefly to introduce those compa- with its wearable bolus injector. I had and Usability, and the mere acceptance of nies and technologies which do appear here the privilege of meeting Enable Injections’ self/home subcutaneous administration in this issue, I should mention a couple of Founder and CEO, Mike Hooven, ear- evolving into a requirement. On the other those which have been unable to contribute. lier this year after one of Management hand, wearable bolus injectors can fulfil this Firstly, BD is developing its MicroInfuser Forum’s many excellent London confer- massive market demand without themselves – recently rebranded as the Libertas Patch ences. I was genuinely inspired, not only needing to be especially far advanced, tech- Injector – a single-use, disposable system, by Mr Hooven’s formidable track-record nologically-speaking, from their predeces- hands-free during drug delivery, the duration in other medical device-related business sors. No wild leaps into the unknown. Clever of which can range from seconds to sev- endeavours, but also by the complete grasp design approaches in safe pairs of hands have eral minutes. Secondly, Ratio Drug Delivery, he has of very precisely where and why enabled companies to bring forward this new which said it couldn’t contribute to this issue wearable injection devices slot in to the cur- class of devices very rapidly. To a greater or for confidentiality reasons, is developing rent parenteral drug delivery arena, and also lesser extent many of them are able to avoid NuPrivo-SC, which it calls a “bandage with a by the passion he has for his current project,

the mechanical Enable Injection Device. PatchPump for pulmonary arterial hyper- existing components, including a standard Enable’s very high volume, small, wearable tension, for which US NDA submission is primary drug container, to which the same bolus injection device is described in this planned for the second half of 2015. rigorous inspection standards will apply dur- issue on Page 30, together with the reasons The final wearable bolus injector tech- ing scale-up to commercial manufacturing. why Enable has avoided a prefilled system nology to introduce here is the result of At the rate things are moving, full-scale and gone for a patient-loaded drug transfer a successful classic pharma/drug delivery commercial manufacturing of approved and system. These reasons are backed by robust partnership. Swiss device company Sensile marketed wearable bolus injectors is just data from numerous intensive user studies. Medical together with US pharmaceutical around the corner. All of the drug delivery technologies fea- company scPharmaceuticals are collaborat- The next issue of ONdrugDelivery tured in this issue of ONdrugDelivery have ing on the development of a bolus injec- Magazine focusing wholly on this excit- their own unique and particularly interest- tor device built around Sensile’s SenseCore ing topic will be out in July 2015. By that ing characteristics and, for SteadyMed’s micropump, for the delivery of scPharma- time, as well has having published various PatchPump device (Page 22), this is the ceuticals’ pipeline of products (Page 16). further issues, each focusing on specific top- E-Cell, which provides the driving force The companies highlight advanced safety ics within drug delivery, such as “Prefilled for delivering the drug. The E-Cell is simi- features made possible only with their pump Syringes”, “Transdermal, Microneedles & lar to a normal alkaline battery and it mechanism and electronic device. The focus NFIs”, “Ophthalmic Delivery” and others does generate the electric power for the is on enabling a portfolio of pharmaceutical (see the Editorial Calendar on Page 15), PatchPump’s electronics. However, unlike a products suitable for “anytime-anywhere” ONdrugDelivery Magazine will have also normal alkaline battery, as current flows the delivery – specifically SC administration celebrated its Tenth Anniversary (in early E-Cell’s electrolytic materials expand in a via a wearable device – which, among 2015). To coincide with our one decade flexible housing, thus generating a mechani- other applications, could either completely milestone, we are launching some exciting cal force which drives the delivery of drug replace, or supplement, IV delivery. new information and intelligence offerings formulation from the device to the patient. Also featured in this issue of for you, fit for the next decade to come, all Unlike the other companies featured in this ONdrugDelivery Magazine is a brief article still tightly focused as ever on the global issue, SteadyMed is developing its device for from Gerresheimer on the manufacture of drug delivery industry … watch this space!! incorporation into its own specialty pharma glass primary parenteral drug containers business model. The lead internal prod- (Page 34). As mentioned at the top of this Guy Furness uct development programme is treprostinil piece, many wearable bolus injectors use Publisher, ONdrugDelivery Magazine

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The Parenteral Drug Association presents the... 2014 PDA Universe of Pre-filled Syringes and Injection Devices Improving Patient Outcomes through Innovation October 6-7, 2014 HYATT REGENCY HUNTINGTON BEACH RESORT AND SPA HUNTINGTON BEACH, CALIFORNIA

EXHIBITION: OCTOBER 6-7 2014 PDA DRUG DELIVERY COMBINATION PRODUCTS WORKSHOP: OCTOBER 8 COURSES: OCTOBER 9-10 www.pda.org/preﬁlled2014 Introduction

INTRODUCTION PHARMA PERSPECTIVE

By Paul Jansen, PE The current status of LVD includes a Pharmaceutical industry pipeline trends reflect plethora of emerging technologies focused a significant increase in biologicals, namely on delivering >1.0 ml volumes of viscous “The emergence monoclonal antibodies (mAbs), in clinical drugs/biologics with lower complexity and of biosimilar and development with most being in Phase II lower cost as compared with conventional interchangeable mAbs may clinical trials. The majority of these mAbs in infusion pumps. The primary packaging of the drug pipeline are highly viscous and need some of these technologies are being devel- actually be diff erentiated to be administered subcutaneously with drug oped with novel materials and containers. based on these delivery delivery systems in volumes that exceed the It is important to remember that primary device off erings” standard fill of a 1.0 ml prefilled syringe. The packaging is an essential interface between emergence of biosimilar and interchangeable drug/biologic formulation and a deliv-

Viscosity FDA focuses on addressing safe use of medical up to Autoinjector 1 ml devices for home or self use. This, combined 30 cP Area 2 LV with regulatory feedback will determine specif- Autoinjector 2 ml 20 Autoinjectors ic usability and safety requirements for LVD. Area 1 Electronic Micro-Needle Reusable Var. LVD may provide significant advantages 1 mL Disposable Dose s.c. System Autoinjectors and options to patients with regard to home Injectors Safety Syringes Bolus Injectors use based upon usability and safety as well Variable Dose Pens as the integration of wireless connectivity 10 Area 3 for monitoring and information capture and Large Volume Patchable Pumps (up to 10 ml) exchanges which will ultimately improve Intradermal pump (up to 5 ml) drug adherence, healthcare outcomes and the lives of people living with chronic disease. The market will sort out proven and 1 ml 2 ml 3 ml Volume acceptable delivery mechanisms which may up to 10 ml Large Volume 1.2 ml differ based on patient group drug requirements, based upon patient group (e.g. rheu- Figure 1: LVD Landscape: Subcutaneous Large Volume Delivery Devices are becoming more diverse. matoid arthritis as compared with asthma). Patient acceptance is based on the adoption mAbs may actually be differentiated based on ery device. Meanwhile, the International of wearable injectors due to form factor, these delivery device offerings. Organization for Standardization (ISO) has complexity and duration of drug delivery. The evolution of subcutaneous drug deliv- taken the initiative to create a new standard The journey has just begun…. ery devices includes: syringes, pen injectors, on such bolus injectors as an extension autoinjectors, infusion pumps and, most to their standard series 11608 (“Needle- REFERENCES: recently, also so-called large volume delivery based injection systems for medical use – (LVD) devices (see Figure 1). The group of Requirements and test methods”) to provide 1. Parenteral Drug Association this emerging device class is still heterogeneous guidance in technical terms. (PDA); Monograph on Parenteral but it seems that LVD devices are typically Industry is competing aggressively for Administration Policies, Section 2.1. electromechanical with low complexity and use access to LVD technology that can be indus- 2. Spratto GR, Woods AL, “PDR Nurse’s standard primary packaging (containers). On trialised for a variety of platform and drug- Drug Handbook”, 2000. the other hand, over the last few years, infusion specific options. While this is an exciting pump technology has evolved to being tube- horizon for subcutaneous delivery of mAbs, Mr Paul Jansen less, integrated systems reflecting the migration it is not without risk with regard to potential Associate Vice-President, Medical toward bolus injectors and patch technologies. issues with Intellectual Property (IP). For Device Development Currently, the acceptable volume of sub- example, LVD automatic needle/cannula T: +1 617 665 4601 cutaneous injections as a bolus is defined as insertion can be a minefield of IP challenges. E: [email protected] injections of 1.0-2.5 ml.1 When reviewing the Regulatory evolution includes drug/biolog- PDR Nurse’s Drug Handbook 2 and nurse ic development requirements such as “to-be- Sanofi guidelines in different institutes and hospi- marketed” devices to be used in clinical studies 640 Memorial Drive Cambridge tals, injection volumes up to 1.0 ml appear to as well as in Phase III. For example, US FDA MA 02139 be considered standard and volumes >1.0 ml Center for Devices and Radiological Health United States up to 2.5 ml are acceptable in special patient (CDRH) requirements of usability/human fac- populations, such as palliative care. tors validation studies have increased as the www.sanofi.com

CRITERIA FOR SELECTING A WEARABLE INJECTOR TECHNOLOGY AND PARTNER

In this article, Alan Shortall, Chief Executive Officer, Unilife, provides a detailed account of the significant opportunities that wearable injection devices present pharmaceutical and biotech companies, the specific criteria that such devices must meet, and how Unilife’s Precision-Therapy® and Flex-Therapy® ranges have been designed to fulfil these requirements comprehensively.

Pharmaceutical and biotechnology com- Conventional hand-held devices such as panies continue to shift their investment prefilled syringes and auto-injectors are towards the development and supply of bio- designed to deliver doses no greater than logics and other drugs that are targeted for 2 ml over injection periods of up 20 sec- subcutaneous self-administration by well- onds. When used with drugs that require defined patient populations. In addition to larger dose volumes or longer durations, the commercialisation of a new wave of these types of hand-held devices may create patient-centric biologics such as monoclonal risks including drug wastage, misalignment antibodies, pharma companies are seeking of the needle and patient discomfort result- to convert a multitude of approved therapies ing in sub-optimal therapy outcomes. At the from IV infusion to subcutaneous injection. other end of the device spectrum, reusable insulin pumps are too expensive and complicated for the injec- “More than 1,000 people in tion of these drugs, which typically only require the periodic the US, Europe and Asia have injection of a fixed-dose volume participated in user and marketing of drug every one, two, four, six studies undertaken either by Unilife weeks or beyond. In recent years, a number of or its pharmaceutical partners” device manufacturers including Unilife have created single-use wearable device technologies These efforts by pharma companies cre- that are designed to deliver large volume ate a significant opportunity to redefine the drugs to the patient over long durations. provision of healthcare and reduce treat- Known as wearable injectors, this relatively Alan Shortall ment costs across a range of chronic disease new but fast-growing segment of the device Chief Executive Officer areas including oncology, auto-immune dis- industry is poised to enable and enhance the orders, cardiovascular diseases and respira- delivery of countless injectable therapies over tory ailments. the coming decade. Unilife Corporation However, gaps in the traditional device As an industry leader for injectable drug 250 Cross Farm Lane market have impeded the commercialisa- delivery systems, Unilife is building long- York tion and lifecycle management of many of term relationships with a multitude of phar- PA 17406 these drugs, which come in a liquid format maceutical and biotechnology companies United States T: +1 717 384 3400 and are best suited to large dose volumes who have each identified up to a dozen or E: [email protected] requiring subcutaneous injection over a pre- more approved and pipeline molecules that programmed period from minutes to hours. are being targeted for use with wearable www.unilife.com

Simple to Customise Unilife

Dose Volume 2 ml to 10 ml (or greater)

Viscosity up to 100 cP (or greater)

Delivery duration Seconds to hours (up to 24 hours)

Delivery rate Bolus, basal or variable

External design Customisable look and feel

Product disposal Optional removable electronics

Needle type Flexwear comfort catheter or needle operational, sales, marketing, and thera- Patient wear On-body (adhesive patch) or off-body (belt clip) peutic needs? 2. Simple to Commercialise: How seam- Simple to Commercialise Unilife lessly can it be integrated with approved Platform architecture Ability to customise one part without redesigning manufacturing methods and materials, others allowing rapid development to get a customer’s drug onto the market quickly and Primary drug container Standard glass and elastomer materials minimise regulatory risk? Maintaining sterility Sterilisation only required for drug and human 3. Simple to Use: How well does it enable contacting surfaces (no terminal sterilisation) an intuitive, effective, comfortable and Fluid Path Only accessed at commencement of injection confident user experience by the target patient population? Container closure integrity Maintains drug integrity throughout shelf-life

Supply for filling Standard syringe handling processes To facilitate the long-term needs of pharmaceutical companies who are evaluating Filling equipment Standard syringe filling equipment prospective wearable injector technologies Material selection Open architecture (multiple options from range of and device partners, Unilife has created a suppliers) list of selection criteria that cover important factors across each of these three key areas. Simple to Use Unilife The criteria are summarised in the table Final supply to user Pre-filled. Pre-assembled. Ready for injection. shown in Figure 1, and detailed below.

Attachment to body By patient at time of use SIMPLE TO CUSTOMISE Environment of use Clinical and non-clinical environments (home etc.) For a pharmaceutical company with a Insertion site Subcutaneous tissue (abdomen, arm, buttock, thigh) broad portfolio of injectable therapies, a No. of steps of use Three (peel, stick and click) wearable injector platform should provide it with the flexibility to have devices individual- User Interface Electronic (audible, tactile, visual indicators) ly customised for optimal configuration with Drug security Safety lock prevents premature activation each target molecule and patient population. Criteria that should be used in the selec- Sharps protection Needle auto-retracts after soft cannula insertion tion process for customisability include dose Type of cannula for injection Soft cannula for comfort during wear volume, drug viscosity, delivery duration, View to medication Large window with wide viewing angle delivery rate, external shape and feel, user notifications, user initiation, product dis- Figure 1: Table summarising key criteria for a wearable injection device. posal, needle type and mode of patient wear. Pharmaceutical companies evaluating injectors. With every drug having specific requirements. That is why Unilife has pio- prospective wearable injector technologies formulation, patient and commercial require- neered a new customer-centric model for and partners should assess the modular ments, these pharmaceutical companies have injectable drug delivery systems that enables design flexibility of a device platform to taken a platform-based approach towards the efficient customisation of each product ensure it can deliver the right therapy, user the appointment of a preferred device partner within a platform to address specific cus- experience and brand message for a portfo- and wearable injector technology. tomer, drug and patient needs. lio of target drugs. Unilife recognises that the conventional When it comes to selecting a preferred “one-size-fits-all” approach to device devel- partner and device technology for wearable DOSE VOLUME opment is too inflexible to accommodate injectors, Unilife recognises that pharmaceu- the breadth of customer requirements for tical companies have three key criteria: Many pharmaceutical companies recog- portfolios of biologics, small molecules 1. Simple to Customise: How does it allow nise the therapeutic and commercial ben- and vaccines that can each have particular customisation to fit all of the customer’s efits of striking the right balance between

a) b)

rate and duration period specifications for each drug within a customer’s portfolio to best serve the therapy needs of a target patient population.

EXTERNAL DESIGN

Drug delivery systems are increasingly Figure 2: The Precision-Therapy™ range (a), for delivering large dose volumes over being used by pharma companies to gen- a few minutes, and the Flex-Therapy™ range (b), for long-duration therapies that erate brand differentiation against com- require delivery of large volumes with a specific rate profile. petitors. Furthermore, human factors have become integral to securing the regulatory dose volume, drug viscosity and injection Typically, it is those molecules which are approval of drug-device combinations, as frequency. A common goal is to select the considered too viscous for a liquid dose of 1 ml well as optimising rates of therapy adher- formulation that is least invasive to the user or less that are selected for use with wear- ence. A platform technology for wearable experience and requires a less frequent dos- able injectors. Based upon the requirements injectors must therefore not only be simple ing regimen. of many pharmaceutical companies engaged to use, but also easily customisable with One recent survey of physicians in a sig- with Unilife, the standard range of viscosities respect to look, feel and functionality. nificant disease area being targeted for both being targeted for use with wearable injectors Unilife’s platform of wearable injectors auto-injectors and wearable injectors high- is between one and 100 cP. Unilife’s wear- provides pharmaceutical customers with lighted that, when all other things are equal, able injectors have been proven to accommo- the flexibility to have the external design 76% would prescribe the drug with a large date viscosities of greater than 100 cP. and functionality of each device tailored to dose volume for once-a-month dosing as match their requirements in several impor- opposed to a competitor product requiring DELIVERY RATE AND DURATION tant ways. Options extend far beyond brand dosing of a smaller volume every two weeks. labelling or colors to include single button In such cases, wearable injectors represent A wearable injector should be pre-pro- or dual-button activation, the button force a significant opportunity to drive patient grammable to facilitate the accurate delivery required for activation, button size for or physician preference and differentiate a of a fixed dose at the controlled rate and population needs, and an ergonomic and drug from its competitors. duration that can provide the best clinical distinctive external design that best fits the While Unilife has received enquiries to uti- outcome for the patient. The selection of grip of the user and enables comfortable lise wearable injectors for drugs with target rate-controlled or duration-controlled for wear during the injection period. dose volumes of between 30 ml and 100 ml, a target therapy will be determined by the the overwhelming majority of customer specific delivery rate profile, or the delivery PRODUCT DISPOSAL requirements range between 2 ml and 10 ml. volume requirements. A platform of wearable injectors should Unilife works with its customers to adopt Unilife has developed its platform of be able to accommodate the full spectrum the simplest solution for their needs to avoid wearable injectors with the option of remov- of target dose volumes required by a phar- them having to pay for added complexity able electronics to enable the recovery, maceutical customer across its portfolio of that is ultimately unnecessary. Customer reuse and recycling of electronic waste. This injectable therapies. With some other wear- options that are provided by Unilife include removable electronics option enables phar- able injector technologies marketed by other bolus, basal or variable rates over very maceutical companies to strike the right pharmaceutical companies being limited to tightly controlled delivery durations. The balance between patient usability and green use with doses of 2-3 ml, it’s important for a option to pre-programme the device for an disposal and recycling. pharmaceutical company to understand the immediate or delayed start to the injection range of anticipated dose volumes expected is also available. OTHER CUSTOMISATION OPTIONS across a drug portfolio. Unilife’s Precision-Therapy™ range of wearable injectors (Figure 2a) is best suited Other customisation options include the DRUG VISCOSITY to short-duration therapies that require gauge of needle used for automatic insertion of the delivery of large dose volumes over the Flexwear comfort catheter (see Figure 3), Viscosity is a common factor that can pre-programmed periods such as a few on-body or off-body wear options, and influence the decision of a pharmaceutical minutes. The Flex-Therapy™ range of wear- packaging design. company as to whether to utilise a hand- able injectors (Figure 2b) is best suited to held device such as a prefilled syringe or long-duration therapies that require delivery SIMPLE TO USE auto-injector, or a wearable injector. As a of large volumes with a specific rate pro- general rule, the lower the viscosity of the file. This platform-based flexibility enables Unilife is committed to the design, devel- drug, the more comfortable and easy it will Unilife to ensure each of its devices can be opment and customisation of injectable be to use by a target patient population. pre-programmed to the optimal delivery drug delivery systems that are as safe, com-

fortable and easy to use as possible. As a general rule, intuitive devices with fewer usage steps are most likely to reduce the risk of error, minimise the need and cost of training, optimise rates of therapy compliance and drive patient preference rates amongst patients, prescribers and payers. Such device-related benefits can be leveraged by a pharmaceutical company to build or protect market share and differentiate a drug brand from the competition. Figure 3: A metal needle automatically retracts into the device after insertion of the FlexWear comfort catheter to maximise patient comfort during the injection. FINAL SUPPLY TO USER USER STUDIES In one user study, 100% of users under- To overcome the inability of most wear- stood and successfully executed proper device able injector technologies to be terminally Usability and human factors represent activation with only a basic description of the sterilised (see under Sterilisation Method), a strong area of focus for pharmaceuti- goal. The presence of user-vetted visual and many device manufacturers have developed cal companies evaluating wearable injector audio-indicators that are designed to convey products that cannot be supplied in a pre- technologies. Common criteria for pharma the status of the device clearly at all times dur- filled, pre-assembled and read-to-inject for- companies conducting user studies for wearing use was also strongly favoured. mat. Such products require the user to load able injectors include: ease of use, but- a prefilled cartridge into the device prior to ton force for activation, sharps protection, ERGONOMICS AND PATIENT WEAR use or they may require the user to first load insertion comfort, wear comfort, premature the drug from a vial with a syringe, and then activation, user interface simplicity and con- As a new technology platform, wearable fill a reservoir in the injection device. venience of disposal. injectors have significant potential to enable Delivery systems with multiple parts that Data generated through these user or enhance the self-injection of injectable place an extra burden on the user are not studies can be of critical importance therapies by patient populations or demo- only less convenient, but they may create in the successful clinical development, graphic groups where hand-held devices additional risks of error, result in sub-opti- regulatory submission and lifecycle man- such as syringes may not be appropri- mal rates of therapy adherence and reduce agement of a therapy. To develop the ate. With wearable injectors ergonomically levels of acceptability amongst patients or most intuitive design with the simplest designed to be comfortably attached, acti- prescribers. Some wearable injector prod- user interface for its wearable injectors, vated and worn on the body, the level of ucts have failed user studies conducted by various iterations of Unilife’s devices have dexterity required to maintain control dur- pharmaceutical companies evaluating vari- undergone extensive human factor testing ing an injection is relatively low. ous technologies due to these extra steps of and device evaluations across a wide vari- Such benefits may create opportuni- use associated with a patient having to load the drug into the device at the time of use. Unilife’s platform of wearable injectors can be pre-filled and pre-assembled “The level of dexterity required to maintain in their final-packaging by the pharma- control during an injection is relatively low” ceutical manufacturer and then supplied to the patient in a ready-to-inject format. Compared with some other technologies that necessitate seven, twelve or even more ety of patient populations and geographic ties to convert IV infusion drugs or other steps of use, Unilife’s wearable injectors territories. In total, more than 1,000 injectable therapies previously recommend- require only three simple steps to deliver people in the US, Europe and Asia have ed only for administration by healthcare a therapy that are commonly described as participated in user and marketing studies workers into a subcutaneous injection for- “Peel, Stick and Click”. undertaken either by Unilife or its phar- mulation ready for intuitive self-injection by This convenient, ready-to-use format maceutical partners during the evaluation the patient. Areas of the body suitable for has been found to be strongly accepted of its wearable injectors. the subcutaneous administration of a drug and preferred in user studies. It can also A key finding of these user studies was using a wearable injector may include the help to minimise the need for additional that the minimal steps of use, as well as anterior abdomen, rear upper arm, upper training and associated overheads that a other integrated features, associated with outer quadrant of the buttock and the ante- pharmaceutical company may otherwise Unilife’s wearable injectors can help mini- rior upper thigh. incur which can impair its broader accept- mise the risk of user error and maximise When used to deliver drugs over peri- ance into the market. levels of acceptability and preference. ods longer than a few minutes, wearable

may exacerbate levels of patient discomfort ness. An audio status feature, which informs over duration periods longer than a few the patient of the commencement, status seconds and upon removal. Unilife is able and completion of an injection, is able to to provide either rigid needle or soft can- be silenced for discreet use. Various light nula options depending upon the specific colours, illumination patterns and tone fre- customer and target therapy requirements. quencies can also be customised based upon Most pharma customers working with customer and brand requirements and user Unilife have cited a preference for its study outcomes. proprietary FlexWear comfort catheter™ technology, a compact self-contained nee- DRUG SECURITY dle insertion mechanism that automatically inserts a FlexWear comfort catheter A wearable injector technology should into the administration site. The needle not only protect the drug during shipment is then automatically retracted following and storage but prevent potential drug the insertion of the catheter for opti- wastage prior to the point at which the user mal patient comfort during the period of is ready to commence the injection of the administration, and sharps-free disposal of dose. Unilife’s wearable injector technology Figure 4: The proprietary safety the used device. features a robust, tamper-evident external interlock mechanism, which must be Factors such as patient comfort and casing and is suitable for final shipment in depressed on the body prior to the confidence can greatly impact rates of user sturdy yet easy-to-open packaging. A pro- start of an injection. acceptance and preference for a therapy. prietary safety interlock mechanism must In line with the growing trend towards also be depressed on the body (Figure 4) injectors should enable the user to wear personalised medicine, Unilife provides its prior to the start of an injection, to prevent the device discreetly underneath clothing. pharmaceutical customers with a multitude premature activation. These safety features Conceivably, any routine behaviour that a of other customisation options including help to minimise the risk of drug wastage, patient may undertake during their normal on-body or off-body wear, button position- and enable clear and confident use during daily life should be feasible during the ing or a one or two-button design. This the injection period. period of use. Environments where a wear- flexibility can enable a customer to have able injector could conceivably be used by the look and feel of each wearable injector SIMPLE TO COMMERCIALISE a patient include home, work, cafes, restau- tailored to the specific requirements of a rants, gymnasiums and outdoors. drug, its commercial brand strategy and A fundamental goal of any wearable The ability to wear a device in itself is target patient population. injector business is to ensure that each however insufficient to help optimise rates pharma customer can easily get its products of therapy adherence and drive patient pref- USER INTERFACE to market with as minimal risk as possible. erence towards a particular drug product. The incorporation of new materials, new Factors that can influence the level of user An effective user interface for a wear- filling processes or novel methods of delivery acceptance towards a particular therapy able injector should enable a patient to represent examples of unnecessary risk that can include the degree of ease and comfort visually inspect the drug before and during can be mitigated through the upfront devel- associated with the attachment, activation, administration, facilitate the initiation of an opment of a robust, modular platform that is customer-centric in design and fully scalable. Unilife’s philosophy is that wearable injectors should leverage well understood “Wearable injectors should leverage well materials and fit seamlessly into approved understood materials and ﬁ t seamlessly into manufacturing methods to mitigate the approved manufacturing methods to mitigate the need for a customer to change any of its standard processes and preferred equip- need for a customer to change any of its standard ment suppliers. processes and preferred equipment suppliers” PLATFORM ARCHITECTURE

To support the rapid commercialisation wearing and removal of the device from injection with minimal force and provide of several injectable molecules in parallel the body. In addition to the size, shape and accurate visual, audio or tactile indicators for a customer, Unilife has developed its adhesive of a wearable injector, the method relating to the status of an injection. wearable injector platform under a modular at which a needle or cannula is inserted Unilife’s wearable injectors provide a framework that enables customisation to into the body during the period of injection 180° viewing window to the medication one component without the need to redesign can be a particularly important factor for during all stages of use. Likewise, electronic the other components. Unilife can therefore patient comfort. and mechanical systems can provide visual, efficiently customise each product to a range Some wearable injector technologies are audio or vibratory indicators to facilitate of customer specifications such as dose vol- restricted to the use of a rigid needle, which user confidence and under-clothing aware- ume, drug viscosity and duration rate.

PRIMARY DRUG CONTAINER Technologies which require a pharmaceuti- OTHER FACTORS TO CONSIDER IN cal manufacturer to modify existing pro- THE SELECTION PROCESS Unilife follows an open architecture cesses, purchase extra equipment or invest in model in the selection of components and new or unconventional filling processes may The selection of a wearable injector suppliers to provide customers with a level encounter customer resistance and potential- platform should not only be based on how of flexibility that is typically not possible ly impact commercialisation timelines for a simple it is to customise, commercialise and with traditional device suppliers. Rather programme. To support regulatory processes use. As a preferred wearable injector tech- than having to rely on a device to sell a and enable modular scale-up during clini- nology will ultimately play a significant role specific material, each of Unilife’s prod- cal trials and commercial rollout, wearable in the approval and commercial success of ucts exists to meet the specific needs of injector technologies should also be designed a target therapy, pharma companies should customer, its target drugs and associated to enable filling to occur on multiple scales. carefully consider how a device manufac- patient populations. Most importantly, the Unilife has developed a robust and turer can serve their long-term requirements primary drug container for Unilife’s plat- modular-based design platform to ensure with speed, agility and reliability. form of wearable injectables is designed to each product is thoroughly engineered and In addition to having world-class, US utilise standard materials including stand- aligned with established manufacturing pro- manufacturing facilities and unparalleled ard borosilicate type I glass and commonly cesses. Unilife’s wearable injectors can be innovation credentials, Unilife has devel- used elastomers. integrated seamlessly into filling and inspec- oped a company structure and culture Customisable aspects of the primary tion equipment with no major changes. that is highly customer-centric. The com- drug container include the use of silicone Filling and stoppering can be conducted pany strives to understand customer needs oil, baked silicone or coated elastomers. in high-speed syringe filling equipment fully and to ensure that the right balance Unilife can also provide products with a in aseptic operations. Unilife can provide of resources and expertise are applied plastic (polymer)-based primary container pharma customers with an in-depth evalu- to meet them. Each wearable injector should the customer desire it. ation of how its devices can be integrated team established for a customer is com- into established syringe filling equipment, prised of engineers, scientists and other STERILISATION METHOD and to be filled on multiple scales up to experts from the drug delivery industry, hhundredsundreds ooff ununitsits per mminute.inute. UUnilife’snilife’s withwiw th mmanyany hhavingaving experexperienceienc in class- Many biologicsics andandn other injectables areare existing relationships with well-knowell-knownwn three devices and infusion pupumps.m Unilife not recommendeded to go through a terminalterminal CMOs aandnd filling equipmentequipment manufacturersmanufacturers hashaas established arguably the llargest team sterilisation cyclele due to the risk of caus- can also be leveraged to supportsupportt the com- in the wearable injectorinjectorr mamarket, which ing damage to the molecule. Unilife hashas mercialisation pathway forfor a customer’scustomer’s boastsboasts deep technical knoknowledgew and developed a unique,que, proprietary system thathatt target drugdrug products. advanced industry expertise.expertise. enables sterilisationtion onlyonly ofof thethe requiredrequired UnlikeUnlike otherother companies wherewh the busi- components whichich are exposedexposed to thethe ness is predominantlypredominantly basedbased aroundaro materi- drug or the patient.ent. alsals or commoditycommmodity components,components, Unilife was Unilife wearablerable injectorsinjectors createdcreated fromfrom thethe groundground up as a developer, can be asepticallyally filled andand manufacturermanun facturer and supplier of sophisticateds then pre-assembledbled in a non- injectableinjectable drugdrug deliverydelivery systems.systet m It has a aseptic environmentment without anyany deepdeep understandingunderstanding of primaryprimar container special processes.es. SterilisationSterilisation technologies,technologies, and how theythey mustm be inte- of all drug contactingacting and flu- ggratedrated into the effective productionpro and id-path componentsents can occuroccur functionalitfunctionalityy of a drugdrug deliverydeliv system. without full terminalerminal dedevicevice From a customer pperspective,erspective this trans- sterilisation orr sosophisticatedphisticated lates into havinghaving a partnerpartner that has the assembly steps. eexpertise,xpertise, processesprocesses and capabilitiesca to The primaryy drugdrug containercontainer ttakeake fullfulu l responsibilityresponsibility for alla aspects of is only accessedd once the injectioninjection tthehe device andandd its integrationintegration within the sequence has beenen initiated byby the user. overall drug-devicedrug-device combinationcombinat product. The successful developmentdevelopment of a wear- With Unilife also havinhavingg a broad port- able injector technologyhnology that can be pre-pre- foliofof lio of ininjectablejectable drugdrug deliverydelive systems, it filled and pre-assembledssembled without terminalterminal also has the neutrality to helphelp pharmaceu- sterilisation allowsws a great deal of flexibilityflexibility ticaltical customerscustommers determine whetherwh a par- in the supply chainhain without creating newnew ticularticular molecule is best suitedsuited for use with manufacturing technologiesechnologies or compromis- a wearable injector, prefiprefilledl syringe, ing the biologic or drug. auto-injectorauto-injector or a combinationcombina of two oro more platforms. UniUnilife is ready SUPPLY FOR FFILLINGILLING tot serve pharmaceuticalpharmaceutica customers underunu der long-term papartnershipsr to Wearable injectorjector technologies shoulshouldd enableene able and enhanceenhance the delivery be designed to eenablenable seamless integratiintegrationon andaand commercialcommercial successsu of their into standard fillingllingyg ssystemsystems and pprocesses.rocesses. injectableini jpjectable therapies.therapi

International conference on polymers in medical devices for parenteral drug administration

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ONdrugDelivery 2014/15 EDITORIAL CALENDAR

Publication Month Issue Topic Materials Deadline

September Preﬁ lled Syringes August 11th

October Drug Formulation & Delivery, Services & Solutions September 15th

November Pulmonary & Nasal Drug Delivery (OINDP) October 13th

December Delivering Biotherapeutics November 10th

January 2015 Ophthalmic Drug Delivery December 8th

February 2015 Preﬁ lled Syringes January 12th

March 2015 Transdermal Patches, Microneedles & Needle-Free Injection February 3rd

April 2015 Pulmonary & Nasal Drug Delivery March 2nd

May 2015 Injectable Drug Delivery: Devices Focus April 13th

June 2015 Novel Oral Delivery Systems May 4th

July 2015 Wearable Bolus Injectors June 1st scPharmaceuticals / Sensile Medical

LARGE-VOLUME INJECTOR ENABLES ANYTIME ANYWHERE DELIVERY OF PARENTERAL DRUGS Dr Pieter Muntendam President and CEO In this piece, Pieter Muntendam, MD, President and CEO, scPharmaceuticals; Gerhard E: [email protected] Mayer, PhD, Vice-President, Business Development North America, Sensile Medical USA; and Lars Krinelke, MD, PhD, Head Product Management, Head Medical Affairs, Sensile scPharmaceuticals Inc Medical AG describe how their large-volume injection device allows subcutaneous self- 131 Hartwell Ave. Suite 215 administration, an important part of the “anytime-anywhere” model for drug delivery. Lexington, MA 02421 United States Many important drugs must be administered loop diuretic, furosemide, for heart failure. parenterally because they are not orally active Novel technology allows for simple, con- www.scpharmaceuticals.com or are insufficiently orally active to remedy venient and comfortable SC administration a specific condition. With rare exceptions, of parenteral pharmaceuticals in larger vol- parenteral administration requires intrave- umes than has been possible before. scPhar- nous (IV) or intramuscular (IM) administra- maceuticals partnered with Sensile Medical tion by a specially trained clinician. To date, to develop an easy-to-use, full-featured patch subcutaneous (SC) administration has not pump device that permits SC drug admin- been an option for many pharmaceuticals istration over durations, rates and volumes despite the conceptual appeal of a simpler, that can be tailored to specific drugs. less invasive drug delivery option. scPharma- Dr Gerhard Mayer ceuticals aims to change that – using innova- PART OF THE ANYTIME-ANYWHERE Vice-President, Business Development North America tive technology to enable anytime-anywhere MEDICAL MODEL Sensile Medical, USA treatment options that benefit patients, clini- E: [email protected] cians, healthcare facilities and payers. SC administration of parenteral drugs, SC administration is appealing in several and eventually self-administration of those ways. It provides nearly 100% bioavailabil- drugs, is an important part of the emerging ity, in most cases offers a preferred pharma- anytime-anywhere medical model that seeks cokinetic profile over the standard IV bolus, to align medical treatments and processes and does not require special skills. From a more closely with the fluidity of daily life. patient’s perspective it is also less invasive Technology enables patients to communi- than IV administration. However, its use cate with clinical staff in real time. Clinical for parenteral drugs has been restricted by data and even results of blood tests can be technology. SC delivery by injection is lim- transmitted allowing the physician to make Dr Lars Krinelke ited to 1-1.5 ml. Larger volumes of a drug informed clinical decisions. Head Product Management, Head would require a slower rate of administra- We are at the dawn of a new medical Medical Affairs tion that is not possible with a syringe and model where time and place are almost irrel- T: +41 62 209-7100 needle. Except for insulin and treatments evant. In this model physicians can authorise E: [email protected] for certain orphan disorders, none of the use of more advanced therapies and patients commonly used parenteral medications have can self-administer medications that previ- Sensile Medical AG been developed for slow SC administration. ously required visits to a medical facility or Fabrikstrasse 10 Hagendorf scPharmaceuticals was formed to devel- home visits from a healthcare professional. CH-4614 op new SC treatments based on existing and SC self-administration of critical medica- Switzerland widely used parenteral drugs. The first such tions as envisioned by scPharmaceuticals is a therapy will be a novel formulation of the natural component of this new model. www.sensile-medical.com

In the emerging model there are two distinct clinical scenarios or use cases where SC administration offers clear and obvious benefits:

1. Supplementing IV with SC SC administration offers effective parenteral therapy that bridges current treatments. The use of furosemide in heart failure provides an illustration. Oral furosemide at home and intravenous furosemide in the emergency room or hospital are currently essential in heart failure treatment. SC furosemide for use at home offers an intermedi- ate treatment to prevent the exacerbation Figure 1: The heart of SenseCore Technology: Sensile’s micropump consisting of of symptoms that now require emergency two plastic components. room or in-hospital treatment, and avert the need for IV treatment. SC furosemide can also be used to continue treatment at A) B) C) home following a patient’s discharge so as to extend parenteral treatment without the need to prolong the in-patient stay. In this case SC treatment is not used to replace IV, but to supplement existing options and give patients the kind of therapeutic response that was previously available only in an emergency room or hospital.

2. Substituting SC for IV Many parenteral antibiotics are administered IV. Instead of daily administration of an antibiotic in a peripherally inserted central line (PIC line or PICC), a patient could receive SC treatment using a patch pump Figure 2: A) As the pump rotates, the upward motion draws in the exact dose. whilst continuing to go about normal daily B) The dose resides in the pump with both valves closed, preventing uncontrolled living. Thus, instead of driving to an infusion free-flow. C) With continued rotation and the downward stroke, the drug is centre, for example, the patient can drive to expelled toward the needle and the patient. work while the small patch pump on the abdominal wall conveniently and comfort- Determined to overcome the technology the device had to contain a filled medica- ably provides the same dose of the same barrier, scPharmaceuticals explored a range tion reservoir using non-standard primary drug. The benefits are distinct and important of technologies and options for large vol- containers and closures. These devices were – avoidance of the cost and complications of ume injectors. After evaluating all available complex, expensive and difficult to manu- the PIC line, and avoidance of the cost and options, scPharmaceuticals selected Sensile facture, and thus not suitable for routine personal burden of the administration in an Medical’s SenseCore technology for its wear- widespread use. infusion centre or doctor’s office. able patch pump. SenseCore is a micro piston The SenseCore technology allows for pump, smaller than the size of a US “quar- the development of a small two-component UNTAPPED OPPORTUNITY WITH ter” coin, comprising two pieces of precision device comprising a single-use disposable unit LARGE POTENTIAL moulded medical grade plastics (see Figure 1). and a reusable unit (see Figure 3). The dis- The piston is rotated by a small electric posable unit contains the SenseCore pump, a The safety of most widely used paren- motor and the rotation provides the pump- drug reservoir, the fluid path, needle insertion teral medications is well established but their ing force (see Figure 2). The pumping can be and retraction mechanism, and the patch that use has been restricted to a clinical setting bi-directional allowing the device both to fill adheres to the skin during drug delivery. The because intravenous or intramuscular admin- itself from a standard primary container and reusable unit consists of a motor, control- istration requires clinical skills and has inher- to deliver the medication SC. ler and electronics in plastic housing. After ent risks. SC administration of parenteral Until now devices used a single compo- inserting the disposable cartridge in the reus- drugs has simply not been an option with nent design wherein the mechanism that able unit, a mechanical drive shaft connects existing technologies, making the benefits of provided the force and energy was part the two to transfer the energy and force. convenient comfortable anytime-anywhere of the component that delivered the drug, As mentioned previously, Sensile’s tech- administration of parenteral prescription thus the entire device had to be discarded nology is being developed to deliver scP- pharmaceuticals unobtainable. after use. In most designs this also meant harmaceuticals’ furosemide heart failure

device can be filled with multiple doses that, if administered IV, would require multiple Disposable: Drug Reservoir | Micropump resource-intensive drug administrations by a clinician.

• Platform for Multiple Applications: This design includes capability to auto-fill from a standard container and delivery controlled by a pre-programmed computer chip. These features permit a single device to be used across a broad range of therapies by changing only the software programming that controls the fill and delivery.

• Optimising Pharmacokinetics: For some drugs, such as antibiotics, maintaining plasma levels is critical to achiev- ing therapeutic effects. For other drugs, a rapid loading dose is desirable followed Reuseable: by a steady-state delivery. The electronic Motor | Electronics | Battery control allows for optimisation of delivery to achieve the desired therapeutic effects. In many cases the controlled delivery with the Figure 3: The Sensile pump is a customised delivery device. In this configuration, it patch pump can offer an improved pharma- consists of two major parts. In the disposable part, a micropump draws the product codynamic response when compared with out of the reservoir and delivers it through a needle on the underside of the device (not shown). Key high-value components are retained for repeated use in the the same dose administered by the standard reusable part. During administration, only the disposable part is in contact with the once-a-day IV bolus. drug or the patient. After injection, only the disposable is discarded. • Cost Efficiency: treatment. Figure 3 shows an overview In general, the SenseCore technology Many of the clinical situations where con- of the disposable and reusable compo- offers a number of important benefits: version from IV to SC offers important nents of the furosemide delivery system. In advantages require frequent drug adminis- Figure 4, the disposable and reusable com- • Auto-fill from standard primary container: tration over extended periods. For example, ponents are combined and the drug vial has The device for scFurosemide has an auto- antibiotics usually require daily doses for been attached for automatic transfer of the fill feature that allows it to fill itself from a weeks or even months. This puts pres- drug into the internal reservoir. Finally, in standard primary container such as a vial. sure on the cost of goods associated with Figure 5, the vial has been removed and the This eliminated the need to design a new the components that are discarded after furosemide patch is ready for use. primary container and closure system, and each administration. With a two-component avoided the associated development and design, the reusable component can be used regulatory risks. Additionally, it eliminates for the entire treatment period and only a the need bring the device into the pharma- low-cost, single-use component is discarded ceutical manufacturing process. The drug after each drug administration. and device have separate manufacturing processes and come together in a much sim- • Advanced Proprietary Features: pler kitting process. One important feature of the SenseCore technology is the built-in opportunity to • Controlled Delivery of Large Volume: monitor its pumping function. As the micro Furosemide and other therapies in the pipe- piston pump operates, the piston will make line will require administration of larger short up-and-down movements with every volumes than possible with syringes and rotation in the housing. The piston’s up- needles – up to 20 ml. The electromotor and and-down movements can easily be moni- controller allow full control over the deliv- tored using an electronic sensor in the ery. The device has a dynamic range that reusable unit. This enables important safety spans a range from 50 μl over 24 hours to features typically not possible with other 5 ml per minute. The electromotor and con- technologies. In case of blockage of the troller permit every possible required deliv- fluid path, for example, the sensor would Figure 4: The patient transfers the drug ery profile, including one that provides mul- register impaired piston movement which from the vial into the device’s internal tiple distinct administrations – for example could trigger a “malfunction” alarm. These reservoir. Upon completion of transfer, it is possible to administer four doses of features would be complex and expensive the vial is removed. 5 ml at six-hour intervals. In this case the to match with most other technologies

since they would require fluid path sensors. Another important feature is that needle insertion and retraction are electronically controlled and do not use a mechanical spring for release. The advanced features of the system are patent protected. scPHARMACEUTICALS’ PIPELINE

The company’s lead product is scFuro- semide - a novel formulation of furosemide injection optimised for SC delivery. The Affordable Care Act provides unprece- dented financial incentives for hospitals to improve management of patients with heart failure and reduce readmission rates following patient discharge. scFurosemide allows physicians to increase diuresis in heart failure patients and reduce fluid Figure 5: Now ready for use, the device is placed on the skin and the drug overload to prevent the acute form of heart administered. After injection, disposable and reusable parts are separated and only failure known as acute decompensated the disposable is discarded. heart failure. It can also be used to finish a treatment regimen at home that was TIME TO CLINIC OR MARKET ABOUT scPHARMACEUTICALS INC started in the hospital. The patient would be discharged after a short stay in a medi- The option to use a standard primary scPharmaceuticals was formed in cal facility and continue SC furosemide at container, combined with the auto fill feature, 2013 to develop innovative pharmaceu- home for 3-5 days until fluid overload has eliminates the need for development and test- tical products for SC delivery based been resolved. ing of a novel primary container and a separate on widely-used and proven APIs. scP- A second product that scPharmaceuti- fill facility for the container. This can reduce harmaceuticals is pursuing the largely cals plans to bring to market will be the time to clinical use or market by several years, untapped opportunity of treating patients first ever cephalosporin antibiotic for SC as new primary packaging alone will typically for serious and life-threatening condi- administration. This will offer convenient take 4-5 years.. It also removes an important tions with convenient anytime-anywhere and comfortable administration, and even- component and risk to the regulatory review. SC drug administration. scPharmaceuti- tually self-administration, that will replace cals is developing a portfolio of innova- the need for a PIC line, and daily trips to TRAIL-BLAZING ON A PATH TO tive drug-device combination products an infusion centre or clinic for intravenous THE MARKET that use the SenseCore micro piston administration. Similarly, it will avoid the technology for delivery. This technology costs and complications associated with PIC A patch pump straddles the domains allows for a cost-effective two-compo- lines for outpatient parenteral antimicrobial between auto-injectors and infusion pumps. nent design. For further information see treatment in the home-setting. It acts as an advanced large form of auto- www.scpharmaceuticals.com. scPharmaceuticals expects to file US injector with controls and safety features NDAs for both products in 2015 and to that are typically absent from auto-injec- ABOUT SENSILE MEDICAL AG launch the products in 2016. tors. However, structurally it resembles an infusion pump. In the case of the Sensile Sensile Medical AG is a leading com- MEETING HEALTHCARE PROVIDER system it contains a mechanical pump driv- pany in the area of advanced micro pump AND PATIENT NEEDS en by an electromotor controlled by a technology developing a broad range circuit board. Infusion pumps are subject of customer-specific delivery and dos- Human factor considerations are playing to increased scrutiny by the regulatory ing solutions. These pumps are increas- an ever-increasing role, especially as novel agencies in response to errors and malfunc- ingly being used to enable for instance drug delivery systems are coming to market. tions that have caused injury or death. Pre- Large-Volume SC delivery of modern Professionals, patients and caregivers may programmed delivery using a patch pump pharmaceutical and biotech products need to be able to safely prepare, place, acti- that is easy to use should avoid the problems for self-administration by patients. Due vate and remove the device with minimal associated with the programmable pumps. to Sensile’s SenseCore technology the difficulty. The SenseCore technology allows As is often the case, release of a first-of- products are highly cost-efficient, for single-button operation with visual and its-kind product for use will define a path accurate, and safe. Theyare increasingly audible signals that are easy to understand. making it easier for others to follow. The used in drug delivery, medical and consumer The devices are pre-programmed at the time SenseCore technology is well suited to blaze applications. Founded in 2004, Sensile of manufacturing for the drug delivery pro- the trail and set the standard because of Medical is located in Haegendorf, file. This eliminates the risk of programming its combination of precision, controls and Switzerland. For further information consult: errors by user or clinician. advanced safety features. www.sensile-medical.com.

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Applications for the SenseCore Technology

Patch pump for up to 20 ml drug delivery Key beneﬁts

Highly accurate volumetric dosing from simple to complex ﬂow rates Primary container independent solution Automated needle insertion and retraction mechanism Sophisticated, but simple sensor technology Well- known rotary piston pump technology with proven production capabilities Economical reusable – disposable designs with all ﬂuid- contact items in the disposable

Home care Hospital care Diagnostics Drug preparation

SMART Sensile Medical AG SIMPLE Fabrikstrasse 10 | CH-4614 Hagendorf | Switzerland Tel: +41 62 209 71 00 | Fax: +41 62 209 71 01 SUSTAINABLE [email protected] | www.sensile-medical.com SteadyMed Therapeutics

PATCHPUMP: EXPANDING THE LIMITS OF PARENTERAL ADMINISTRATION

Here, Marylyn Rigby, Director of Business Development & Marketing, SteadyMed Therapeutics, introduces the company’s PatchPump device, its design, mechanism of action, steps of use and current status of clinical development.

SteadyMed Therapeutics is a specialty phar- The core technology inside the PatchPump maceutical company redefining the paren- is the E-Cell, which is comparable to an teral delivery experience and is committed to alkaline battery but with a flexible hous- expanding the limits of injectable therapeu- ing. The key difference between the E-Cell tics to restore freedom, joy, and dignity to and a conventional alkaline battery is patients’ lives. The company is actively devel- that as the E-Cell discharges, the housing oping a portfolio of PatchPump™-enabled expands. In the PatchPump, the expansion drug products and intends to submit its first of the E-Cell is precisely controlled by its US NDA in the second half of 2015, as fur- electrical discharge rate, and as the E-Cell ther described below. expands against a flexible drug reservoir, the liquid formulation is expelled from the INTRODUCTION TO PATCHPUMP™ device and delivered either subcutaneously or intravenously. PatchPump is a proprietary system The PatchPump utilises either an exter- developed by SteadyMed, to enable easier, nal infusion set as used with insulin infusion more convenient and less error-prone drug pumps (see Figure 1), or an integrated can- administration via a single-use, disposable, nula (see Figure 2) to deliver the medication. prefilled (at the site of manufacture under In addition to the E-Cell, the other major aseptic conditions), pre-programmed drug- components of the PatchPump include: a device combination product. flexible container for the prefilled sterile drug PatchPump is highly customisable, and formulation; a programmable circuit board, is intended to deliver volumes up to 10 ml, containing the hardware and software that over a period of minutes or a number of control the discharge/expansion rate and days depending on the delivery needs of other device functions; various sensors to the particular therapy and disease state. assist in flow control and occlusion detec-

Marylyn Rigby Director of Business Development & Marketing T: +1 925-272-4999 E: [email protected]

SteadyMed Therapeutics, Inc 2410 Camino Ramon, Suite 285 San Ramon CA 94583 United States Figure 1: PatchPump configured for Figure 2: The PatchPump together with external subcutaneous infusion set. integrated cannula. www.steadymed.com

abdomen but sites may also include the Buzzer upper arm, hip, thigh and upper buttocks. The product is intended to be self-adminis- LED’s Shut down button tered, and it is intended to be applied, used and worn throughout the course of normal Infusion set connector daily activities. Hence the product may experience the environments associated with working, exercising, sleeping and be worn both indoors and outdoors. In addi- Status button tion, PatchPump is designed to be water resistant and can be worn while bathing or swimming. Figure 3: The PatchPump incorporates a number of sensors, and indicators that provide feedback to the patient. (Infusion set configuration shown here.) E-CELL™ tion, and other indicators to tell the patient a controlled rate and as it does it displaces The E-Cell is a patented electrochemical the status of the drug delivery (Figure 3). the piston, which applies positive pressure actuation unit invented and developed by In the configuration developed for to the drug container. The pressure on the SteadyMed. The materials of construction SteadyMed’s lead internal development pro- container forces drug solution through the of the E-Cell are comparable with a stand- gramme; treprostinil PatchPump for pul- delivery channel of the container and into ard alkaline battery cell , with the excep- monary arterial hypertension (PAH), the the infusion line at a controlled rate. tion that the cell materials are contained PatchPump will utilise an external infusion The rate of expansion of the E-Cell in a flexible polymer housing to allow for set, and will be programmed to deliver drug is related to its discharge current. The expansion. Figure 5, a schematic of the continuously for a number of days. At the movement of the piston is measured using E-Cell, shows the anode and cathode mate- end of the dosing period, PatchPump will standard sensor technology, and a control rials contained in a flexible housing that alert the patient that it is out of drug; the circuit in the electronics ensures that the also contains the electrolyte solution. When patient removes and disposes of the empty piston moves at the required rate by regu- the product is activated, current is allowed device, and replaces it with a new unit to lating the discharge current (and hence the to flow via the electrical connectors to resis- continue the chronic, around-the-clock infu- rate of expansion) of the E-Cell. If there tors in the control circuit on the PCB. This sion treatment. are any occlusions in the delivery line, causes the electrochemical reaction inside This multi day replacement frequency is or site of infusion, they are detected by the E-Cell to take place, which results in a consistent with, or better than; the interval a force sensor positioned on the printed change in volume of the anode and cath- currently used for refilling other pumps circuit board (PCB) underneath the E-Cell ode materials. The geometric design of the used for PAH infusion therapy. Further, in (Figure 4). The increase in force produced anode and cathode along with the flexible contrast to the existing parenteral therapies by an occlusion is sensed by the control housing ensure linear, unidirectional expan- for this indication, the use of SteadyMed’s system, which triggers an alarm and stops sion of the E-Cell (in the vertical direction PatchPump-enabled product will eliminate the E-Cell expansion. as oriented in Figure 5). The quantities of the need for users to handle or fill the During basal delivery the product is anode and cathode material ensure that the pump with drug, as well as the need for any silent unless the status button is pressed, in E-Cell has sufficient capacity to support dose programming. which case the buzzer sounds and the LEDs expansion throughout the entire infusion Future PatchPump configurations for flash green. Near the end of the delivery cycle for the product. other products may run for shorter or period the product will beep and LEDs will Given the E-Cell acts as its own power longer periods, and may have the same be illuminated to instruct the user that deliv- source and the driving motor that effects existing external infusion set or may have ery will soon end. drug delivery the PatchPump can deliver vis- an integrated infusion set. It is expected that the PatchPump will cous drugs and large volumes from a small usually be positioned on the patient’s compact form factor. PRINCIPLE OF OPERATION

To activate the treprostinil PatchPump PAH product, the user removes a cap from the discharge port and attaches an infusion set at that location. This action pierces the septum of the primary drug container and simultaneously turns on the product. (For the integrated PatchPump configuration, which may be used to deliver biologic compounds, pressing a small button, which inserts the soft cannula into the subcuta- Figure 4: Cross-sectional view Figure 5: Schematic cross-section of neous tissue, activates the device.) Once showing the components layered the E-Cell. activated, the E-Cell begins to expand at within the PatchPump.

during the aseptic filling process, to maintain use. Several URS and PRS requirements were the cleanliness of the exterior surface of the derived from these studies as well as a deeper septum, up to the point of use of the product. understanding of users’ acceptance and sub- The container has been tested for drug jective preferences around the key principles compatibility, long-term stability and leach- of the drug device combination concept. In able compounds, and results have all been addition these studies provided the direction to favourable. Additional studies by third party help develop the PatchPump and Instructions biopharmaceutical companies have been con- for Use (IFU) design and provided good insight ducted for compatibility with biologic com- into the potential patient interaction with the pounds, with favorable results for adsorption design. This series of studies led to further Figure 6: The primary drug container and leachables as well as drug stability. refinement of the user interface and IFU. comprises a flexible multi-laminate SteadyMed has conducted proof-of-con- blister heat-sealed to a rigid base plate, with integrated filling/discharge channel, CLINICAL AND HUMAN FACTOR cept clinical studies in healthy volunteers in sealed with a butyl rubber septum. STUDIES. order to evaluate the safety, tolerability and technical aspects of the PatchPump. Data PRIMARY DRUG CONTAINER As a part of PatchPump development a from these studies is undisclosed. series of Human Factors (HF) studies have The primary drug container is circular in been completed with physicians, specialist DEVELOPMENT STATUS design and made up of several components. healthcare practitioners (HCPs), patients A flexible, thermoformed multi-laminate and healthy volunteers. This empirical work SteadyMed’s PatchPump is in late-stage blister is heat-sealed to a rigid, injection- has been informed and supported by an development with the supply chain in place moulded base plate with an integrated filling/ iterative program of design risk assessment to manufacture registration batches of its discharge channel. The blister and base-plate activities, including risk reviews of existing treprostinil PatchPump product prior to materials have been used in prior pharma- devices and Use FMEA studies. NDA submission in the second half of 2015. ceutical and medical device applications, and The series of HF studies has provided The company is also working with biop- were selected because of their low levels of a foundation of understanding of the users harmaceutical companies that are assessing extractables, and compatibility with biologic (patients and HCPs), and their current experi- stability and compatibility of certain bio- drugs. The container is sealed with a butyl ences in order to inform device design features logic drugs with the PatchPump as well as rubber septum. An additional cap is fitted and parameters to support safe and effective the performance of market research studies.

Pre-Filled Syringes Summit 2014

Device and Combination Product Innovation Ensure Regulatory Compliance Optimize Supply Chain Control

2nd-4th September 2014 | Washington DC

www.preﬁlled-syringes.com

West Pharmaceutical Services

INTEGRATED SOLUTIONS FOR THE DELIVERY OF HIGH-VOLUME BIOLOGICS

Highlighting the advantages for pharma companies of partnering early in the development process with packaging and delivery device partners, Graham Reynolds, Vice-President, Marketing & Innovation, West Pharmaceutical Services, Inc, introduces the company’s wearable bolus injector, SmartDose, in the context of a fully integrated self injection technology platform offering using a standard primary container.

Chronic conditions, such as diabetes and years. In fact, more than 907 biotechnology autoimmune diseases, continue to be treated medicines were in development as of 2013 by a variety of therapies, although side-effects – nearly 30% of all drugs in the pipeline.2 and challenges of patient self-administration Medicines derived from biotechnology have can affect adherence and therefore effective- aided those suffering from chronic condi- ness of these therapies in improving patient tions, including cancer, diabetes and auto- outcomes. In fact, according to the World immune diseases such as multiple sclerosis Health Organization, adherence to long- and rheumatoid arthritis (RA). term treatment recommendations for chronic Derived from living cells, biologic drugs conditions hovers at just 50%.1 Patients include genetically engineered proteins may choose not to follow their healthcare known as monoclonal antibodies (mAbs) that can be formulated to target specific components of a disease. “Changing a device can be easier For example, biologics designed to treat RA may target com- than changing the primary ponents of the immune system containment for a drug, so an that play a role in inflammation. understanding of how to create a In addition, injectable biologic drugs are being developed for platform of devices around a single conditions previously treated by drug container is essential” non-injectable means, such as Mr Graham Reynolds asthma and cholesterol-related Vice-President, conditions. When these drugs Marketing & Innovation, providers’ recommendations for a variety of reach the market, it is likely that the major- Pharmaceutical Delivery Systems reasons, including painful, inconvenient or ity will be presented to patients an injectable T: +1 610 594 2900 difficult administration. As chronic condi- format, and many will require regular self- E: [email protected] tions continue to rise, and patients take on injection in a non-clinical environment. the responsibility of administration in the Typically large in size, biologic molecules West Pharmaceutical Services, Inc home environment, it is increasingly impor- may require a higher concentration of the 530 Herman O. West Drive tant that delivery and administration systems drug product for efficacy. In addition, bio- Exton are designed with the patient in mind. logic molecules tend to be sensitive to prod- PA 19341 The success of biologics, which offer ucts commonly found in traditional glass T: +1 610 594 2900 patients better long-term outcomes and prefillable syringe systems, such as metal F: +1 610 594 3000 fewer side-effects than traditional, chemical- ions and silicone oil, substances that may E: [email protected] based therapies, has led to a rise in the num- impact the drug product’s efficacy and a bers of biologic drugs over the past several delivery system’s performance. The result is a www.westpharma.com

drug product whose viscosity is significantly recommendations, easy to use, safe and cartridge-based system may offer more con- higher than currently approved self-injected effective integrated delivery systems are an venience. Patients who must be on long-term products. In a traditional system, such high essential part of any drug product. A suc- therapies often find their own level of comfort viscosity may require clinical administration, cessful integrated delivery system should through varying degrees of drug delivery con- multiple dosing or more frequent injections, combine the following four key elements: trol. Many may be comfortable determining which can be less convenient for the patient. 1) The needs of the patient, caregiver and their own rate or angle of injection with a Many biologics in use today are admin- healthcare professional: Clinical benefit, prefilled syringe system, while others prefer istered via intravenous (IV) infusion in an as well as the ease-of-use and ability to the speed and simplicity of an auto-injector. acute care setting. However, trends toward adhere to a treatment schedule, should Offering delivery choices to the patient self-injection and home care have increased be considered. may help to ensure adherence at any stage of the demand for products that are eas- 2) The drug: A drug product must provide the patient’s therapeutic journey. Currently, ily injected by patients or caregivers in a effective treatment in an appropriate form Rebif® (interferon beta-1a), a self-injection home setting. At present there are several that enables effective administration with therapy for relapsing multiple sclerosis from approved biologic products intended for self- an optimum delivery rate and frequency. Merck Serono, offers the same drug pack- injection by patients, such as Johnson and 3) A primary containment system: The aged in a variety of different systems. Such Johnson’s Simponi® (golimumab), Amgen’s drug must be held in a container that options provide the patient with a choice of Enbrel® (etanercept), and Abbvie’s Humira® maintains effectiveness, safety and opti- delivery methods based on comfort level. (adalimumab). These injections are typically mum quality over a period of time. Rebif is available as a stand-alone syringe designed for delivery into the subcutaneous 4) A delivery device or system: The drug for those comfortable with self-injection. space, require a relatively low dose for effica- should be compatible with the contain- It is also available in either a disposable or cy and have a reduced risk of life-threatening ment system and designed to enhance reusable auto-injector system. adverse reactions. Both Simponi and Humira the drug delivery experience for the There is no “one-size-fits-all” device or are packaged in 1 ml “long” prefilled syring- patient or caregiver. system for patients suffering from chronic es and dosed on a weekly, semi-monthly or By collaborating with a packaging and conditions, so a variety of choices for self- monthly basis, depending on the patient’s device partner early in the development injection may soon become the norm for particular indication. Delivery of the medica- process, pharmaceutical and biotech com- many biologic therapies. Early-stage planning tion can be via manual injection from the panies can design and develop an integrated for such choices can help pharmaceutical com- prefilled syringe, or by incorporating the system that can help bring the four elements panies select materials for containment that syringe into a disposable auto-injector. of effective delivery system together sooner. can be used for multiple options. Changing a As pharmaceutical companies create and This will help to ensure that the biologic device can be easier than changing the primary clinically test large-molecule antibodies for drug product reaches the market in a deliv- containment for a drug, so an understanding new therapeutics that may require larger ery system that not only helps to protect the of how to create a platform of devices around doses given over a longer period of time, drug product’s efficacy, but will also help a a single drug container is essential. packaging and delivery challenges can arise. patient adhere to treatment during any part of the therapeutic lifecycle. EVOLVING TECHNOLOGY FOR DESIGNING A SUCCESSFUL INTEGRATED DELIVERY SYSTEMS INTEGRATED SYSTEM UNDERSTANDING PATIENT NEEDS As the biologic market has grown, so While the primary focus of most pharma- To create an effective and easy-to-use too has the use of prefillable syringe and ceutical companies is on the drug product delivery system, the patient-use cycle must be cartridge systems, moving from 3.1 billion itself, early collaboration with a packaging considered early in the development process. units in 2012 to an expected 4.7 billion in and device partner during the lengthy devel- From initial diagnosis to long-term adher- 2016.4 Such systems offer convenience and opment stages can result in a delivery system ence, the patient passes through a variety of ease of use. Many biologics in the pipeline that meets the needs of both the drug and emotional and physical phases. Human fac- will require high dose-volumes, and patients the patient. Research and development for tors testing can help establish the emotional who require long-term treatment may prefer a biologic drug product can typically last as and physical needs of patients at each stage of options that allow for higher doses to be given long at 15 years and cost as much as US$1.2 their therapeutic journey. For example, upon over longer periods. Since cyclic olefin poly- billion (£0.7 billion).3 So, when the product initial diagnosis, a patient may be fright- mers can be molded into a variety of shapes reaches the market, the originator may have ened and unsure of the delivery mechanism, and designs, unique systems with larger fill only a few years remaining on the patent. and may require guidance from a healthcare volumes and tighter dimensional tolerance Often, the delivery system is considered dur- professional to deliver the prescribed dose. can be used while still remaining compatible ing the final stages of development. If the Delivery systems for a person at this stage with established filling technologies. drug product cannot be effectively stored or should be designed to ease that burden of fear Proprietary systems, including West’s reacts chemically with the containment mate- by being simple to use and intuitive in design. SmartDose® electronic wearable injector*, are rials, or if the system does not function well It should also provide clear indications that being developed to aid patients with self- with a high-viscosity drug or is not a good fit the dose has been delivered successfully. administration. The SmartDose system, which for the intended audience, issues may arise As the patient learns to cope with the features a drug containment system based on a can be costly for the manufacturer. condition, other factors such as accessibility Daikyo Crystal Zenith® cyclic olefin polymer Since a drug product cannot be effective and portability may rise in importance. At cartridge and Flurotec® plunger, designed spe- if the patient does not adhere to therapeutic this stage, an auto-injector, pen device or cifically to hold high-volume doses of sensitive

ensure the optimum speed to market. West is continuing our “By your side” philosophy by working closely with several pharmaceutical companies that are currently performing drug stability studies in the Crystal Zenith cartridge, and evaluation of the system. Early collaborations between pharmaceutical manufacturers and packaging experts can help to create a platform of delivery options for patients. While the drug development journey may be long and expensive, the patient journey can last a lifetime. To ensure adherence and brand loyalty throughout that journey, pharmaceutical manufacturers should consider delivery alternatives as early as possible. By working with an integrated packaging and delivery system partner from R&D stages through commercialisation and Figure 1: West’s SmartDose® electronic wearable injector provides a solution for the beyond, the biopharmaceutical manufactur- challenge of delivering a large dose of a drug product. er can present patients with options that will last a lifetime and encourage adherence for biologics, offers a subcutaneous, program- allows it to be optimised for use with the as long as the patient requires medication. mable electronic injection system that adheres SmartDose system and makes it possible to to the skin and can deliver the drug over time use this technology for the next generation (see Figures 1-3). User interfaces such as elec- of self-administered protein-based drugs. REFERENCES tronic indicators optimised through human In 2013, West completed a preliminary factors studies can aid in patient adherence study of its SmartDose wearable patch injec- 1. World Health Organization, and caregiver monitoring. tion system, which incorporates a Daikyo “Adherence to Long-Term Therapies The SmartDose system is an excellent Crystal Zenith cartridge. The study evalu- – Evidence for Action,” 2003. (www. example of the balance between an effective ated multiple attributes of the technology who.int/chp/knowledge/publications/ drug containment system and a user-friend- and subjects’ experience with the self-appli- adherence_full_report.pdf, accessed on ly delivery system. The SmartDose system cation process. April 4, 2014.) has been designed for ease of use and patient The June 2013 study, entitled: “First-in- 2. PhRMA, “2013 Report: Medicines in comfort, while facilitating the delivery of Man, Single Center, Open, Two Periods, Development – Biologics”. (ww.phrma. innovative drug products. Self-Application clinical Study to Evaluate org/sites/default/files/pdf/biologics2013. The SmartDose system meets a need for the Safety, performance and tolerability pdf, accessed on April 4, 2014.) high-volume subcutaneous delivery of vis- of SmartDose 2.5 using Saline in Healthy 3. PhRMA slide pack cous or sensitive drug products, which may Subjects at Two Delivery Rates,” was con- “Biopharmaceuticals in Perspective”. require longer injections times. The use of a ducted in Israel. This milestone, following 4. “Injectable Drug Delivery Through Crystal Zenith cartridge offers the ability to extensive scale-up and validation of the 2016,” Greystone Research Associates. deliver a higher dose using an option based system, has helped to confirm the readiness on quality, stability and performance con- of the system to support customers’ clinical * For investigational use only by our siderations. The flexibility of Crystal Zenith studies with their drug product, and will help pharmaceutical and biotechnology development partners. West seeks partners for its SmartDose® injector technology platform. This platform is intended to be used as integrated systems with drug filling and final assembly completed by the pharmaceutical/biotechnology company.

Daikyo Crystal Zenith® is a registered trademark of Daikyo Seiko, Ltd. Daikyo Crystal Zenith and FluroTec technologies are licensed from Daikyo Seiko, Ltd. ConfiDose® and FluroTec® are registered Figure 2: SmartDose® uses a Daikyo Figure 3: The SmartDose® electronic trademarks of West Pharmaceutical Services, Crystal Zenith® cartridge that is filled wearable injector fulfills a need for by the pharmaceutical company high-volume subcutaneous delivery of Inc, in the US and other jurisdictions. using conventional filling equipment, modern biologics, which may require SmartDose® is a registered trademark of and is easily inserted into the injector longer injection times. Medimop Medical Projects Ltd., a subsidi- by the patient. ary of West Pharmaceutical Services, Inc.

With SmartDose® Electronic Wearable Injector, the only bolus injector system of its kind to have been successfully tested in a ﬁrst-in-human clinical study, your patients can leave their treatment center—and its costs and interruptions—behind.

www.smartdose.com I (800) 345-9800 Advancing Care, Improving Lives

West seeks partners for its SmartDose electronic wearable injector technology platform. This platform is intended to be used as an integrated system with drug ﬁlling and ﬁnal assembly completed by the pharmaceutical/biotechnology company.

West and the diamond logo and By your side for a healthier world ™ are registered trademarks or trademarks of West Pharmaceutical Services, Inc., in the United States and other jurisdictions. SmartDose® is a registered trademark of Medimop Medical Projects Ltd., a subsidiary of West Pharmaceutical Services, Inc.

PEOPLE POWER: INSPIRING & DELIVERING A UNIQUE WEARABLE BOLUS INJECTOR

In this article we describe the highly customisable wearable bolus injection device developed by Enable Injections to provide the most comfortable, simple and discreet patient experience whilst allowing more biologics, including lyophilised products and previously IV-only therapies, to be brought into the home/self-administration setting earlier for safe SC delivery.

Written by ONdrugDelivery Magazine for and on behalf of Enable Injections

These are exciting times for parenteral drug bolus injectors for high-volume subcutane- delivery – an entirely new class of drug ous (SC) injection are on their way is not delivery device is nearing the market and in doubt. The questions remaining are more will soon be out there, improving quality about which technologies will make it to the of life for patients suffering from chronic market and what will be the final form these technologies take. There exists a broad variety of device approaches cur- “The ability to bring drug rently in development at differ- mixing and reconstitution into ent stages, all racing towards the market, all with unique, the home self-administration innovative and clever charac- setting in this way brings with it teristics in their designs, mecha- manifold advantages” nisms and modes of use. Enable Injections’ wholly mechanical wearable bolus injector (see Figure 1) is no exception. But diseases. As part of the evolution of self- before going on to describe the device, how injection technologies, itself driven by the it works and how it is used in more detail, it rise of biologics, the fact that wearable is important to make a point about people. Enable Injections is all about people. Firstly, let’s consider its own people: the team that President and CEO Michael Hooven has assembled is formi- Contact: dable. Hooven himself is the founder of Michael D Hooven two previous successful medical device President and CEO businesses, including the surgical atrial E: [email protected] fibrillation treatment firm, AtriCure, in 2000. AtriCure is now a close competi- Enable Injections, LLC tor with global giant Medtronic, and is 301 Industrial Drive Franklin a publically traded company (NASDAQ: Figure 1: The Enable Injector device OH 45005 in 1-10 ml (right) and 1-20 ml (left) ATRC) with a market capitalisation in United States formats. The 10 ml device is about the excess of US$500 million. Hooven’s stellar size of an “Oreo” biscuit. board at Enable Injections includes such www.enableinjections.com

• 2,000 sq ft (186 m2) controlled environment injection moulding • High-volume injection moulding capabilities • Second manufacturing site identified for occupancy late 2015/early 2016.

THE DEVICE

At the outset, Enable defined its broad goals as follows: Figure 2: Fully equipped US manufacturing facilities are already in place. names as: Mark Collar, former President project through to market. • Development of a bolus injection system of Proctor & Gamble’s Pharmaceuticals As Gary Ansel, MD, Associate Medical • Utilise the pain-free injection technology and Personal Health business; Norman Director of the OhioHealth Research and • Deliver very high volumes and viscosities Weldon, PhD, founder of and investor in Innovation Institute (Columbus, OH, US) • Utilise standard vial/cartridge container more than 20 medical device companies, put it: “Having an injector like this, espe- closure who has also served as President and CEO cially one that decreases pain, opens the • Automatically reconstitute lyophilised of numerous companies in the field includ- door to new pharmaceuticals that wouldn’t solutions ing, amongst others, Cordis Corporation; be possible without this revolutionary • Deliver the highest volume using the Karen Robards, former Head of Healthcare device. We’re talking potential for huge smallest possible device. Investment Banking at Morgan Stanley; cost savings, reduced hospital stays, and and Don Harrison, MD, former Chief of increased patient compliance—all at the Since defining those targets just a few Cardiology at Stanford University, for- push of a button.” years ago, Enable Injections has devel- mer Head of the University of Cincinnati The initial technology development for oped a fully automated, mechanical drug Medical School, and former President of Enable’s devices took place at the Children’s delivery system that allows the user to the American Heart Association. Hospital Medical Center in Cincinnati, self-administer any volume of drug from Likewise, the design team working on OH, US, and were focused on a painless 1 to 20 ml by SC injection. The patient Enable’s devices are top-drawer. In total injection system. Multiple studies showed simply inserts the drug vial or cartridge the team has worked on the development of significant pain reduction and, whilst tem- into the system, places the device on the more than 100 products with combined sales perature was found to be one key factor, body, and presses a button. The drug is topping $10 billion, they have more than 200 the deep understanding of all the causes automatically and comfortably delivered patents between them, and count amongst of injection pain gained through Enable’s at a pre-programmed flow rate into the their ranks a J&J Chairman’s Medal Winner. partnership with the hospital means that subcutaneous tissue over a timeframe that Similarly, the company’s clinical, regulatory the Enable Injector addresses all of these can range from minutes to hours. After and human factors teams are of the same causes, delivering the most comfortable delivery is complete, the needle is auto- experienced, seasoned high calibre. injection experience possible. matically retracted and locked out, and People. Always uppermost in the Enable’s admin and finance is still head- the user is notified with a primarily tactile thoughts of this top-flight team as they quartered in Cincinnati with design and feedback which is discreet, being only felt bring Enable’s products to fruition are, manufacturing now taking place at its and heard by the patient, who can look once again, people. Specifically, they are thinking about the patients who will eventually be using and benefiting from Enable’s devices. As one learns more about Enable “The system automatically warms the Injections and begins to examine the device drug to room temperature, meaning that design in-depth, the constant consideration given as the absolute top priority to the instead of waiting the usual 30 minutes ... detailed wants, concerns and needs (clinical the dose is ready to inject immediately” and personal) of the patient becomes appar- ent. This is the thread that runs through every aspect of what Enable Injections does and the devices it is developing. extensive facilities in Franklin, OH, US. at the device for visual confirmation too. Along with a steadfast focus on patients, Enable plans to continue to manufacture all The needle is never seen or exposed, and a clear understanding of the cold, hard device components onsite at its US manufac- the device is fully recyclable having no science and engineering, plus the capabili- turing facilities (Figure 2), which comprise: electronic components. ties and business acumen to operate in the From the point of view of the patient pharma industry, and the experience and • 5,000 sq ft (465 m2) pilot manufacturing using the Enable device, the first thing they knowledge to navigate the regulatory proce- space are presented with is a small box (approxi- dures, are all requirements for successfully • 5,000 sq ft controlled environment man- mately 15 cm by 12 cm, and quite flat at bringing a drug delivery device development ufacturing only 4.5 cm high). On opening the box (see

injector, the necessity to incorporate a prefilled drug container such as a vial or cartridge inside the device, together with plunger and power source (often a spring) to drive the injection, represents a considerable limitation of design options with the addition of bulk being amongst them. Also, the force required to drive the plunger increases as the as the volume and/or viscosity of drug increases, usually resulting either in an increase in delivery time or an increase in the size of the cannula. A B C With the Enable device, the force required Remove Vial Flip Cap Insert Vial Remove Injector to deliver the drug does not change with the volume and the delivery rate and can- Figure 3: Drug transfer process: three simple patient steps. nula size remain the same meaning that the Enable system delivers volumes and viscosi- Figure 3a) the patient sees inside: on the left, completely removed from the mixing pro- ties substantially higher than devices that use a standard vial or cartridge containing their cess and the three-step instructions for the a cartridge and plunger. Specifically Enable medication; and to the right, the injector dual-vial system remain exactly the same is more than comfortable claiming routinely device (roughly the size of an “Oreo” biscuit for the patient as for the single vial system. to be able to achieve effective delivery of – just over 4cm across) in a plastic housing. Enable’s automated mixing system can be 10 ml of 100 cP formulation through a 29g One-word instructions with simple graphic pre-configured to mix powder/liquid or liq- needle at a rate of 1 ml/min, but in most illustrations are printed on the inside of the uid/liquid for up to an hour, or more. cases needle size can be reduced further to lid. The three simple patient steps for drug The ability to bring drug mixing and 30g or beyond with obvious advantages with transfer are shown in Figure 3a-c. reconstitution into the home self-admin- respect to patient comfort. If the drug needs to be stored in the istration setting in this way brings with it Very small, ergonomic, low-profile wear- refrigerator, the vial can be refrigerated as manifold advantages. Patient convenience able devices capable of delivering volumes normal and inserted into the transfer sys- is a key benefit but, in addition, errors due of from 1 to 10 ml or from 1 through to tem straight from the fridge. During trans- to user mixing are eliminated. Furthermore, 20 ml (Figure 1) become possible because of fer from the vial to the injector, which takes treatment and facility cost-savings are likely Enable’s proprietary S.E.T. Drive (details of just a few seconds, the system automati- and, earlier up the line, the ability to release which are available under a confidentiality cally warms the drug to room temperature, lyophilised formulations earlier brings with agreement only). meaning that instead of waiting the usual it potentially huge commercial advantages. 30 minutes between taking a drug vial out Once the transfer process is complete, PATIENTS FRONT & CENTRE FROM of the fridge and using it, the dose is ready the red retaining tab clicks back to release THE BEGINNING to inject immediately upon completion of the loaded injector device and the patient drug transfer. follows the three steps outlined in Figure 5. Human Factors Engineering (HFE) has The Enable Injection device can be con- of course been at the heart of every aspect of figured in a dual-vial format too, providing PATIENT-OPERATED TRANSFER the development of Enable’s device and the automated mixing of two vials of up to DEVICE: BENEFITS company has put intense efforts into Human 10 ml each (see Figure 4). The patient is Factors studies from the very outset. To date Central to the commercial/development 16 studies have been conducted in different advantages that Enable’s system brings is user demographics, following accepted HFE that it requires no change to the primary and Usability Engineering standards including: drug container and, further, that any standard vial or cartridge can be combined • ANSI/AAMI HE74:2001 Human factors with the Enable device at any point in the design process for medical devices supply chain, the long-term container and • IEC 60601-1-6, Ed1, Usability closure material compatibility testing hav- • US FDA Draft Guidance issued June ing already been completed with the origi- 22, 2011: Applying Human Factors and nal container. In fact the device uses only Usability standard IV materials in the entire drug path • Engineering to Optimise Medical Device meaning that any drug already approved for Design. IV administration would be exposed to the same materials, thus minimising short-term MINIMAL INTERACTION material compatibility testing too. Figure 4: The Enable Injector in Up against a preloaded device, the The HFE studies conducted during the dual-vial configuration requires no patient-loaded device gains several addi- development of the Enable device revealed additional patient steps. tional wins. In a preloaded wearable bolus clearly that users want minimal interaction

the box after drug transfer. Even the orien- tation of the finger gaps either side of the device “front-back” rather than “left-right” as it sits in the packaging has been chosen because Enable found that with this orienta- tion the user intuitively picks up the device with the correct grip to allow them to place it straight onto their skin without further fiddling around.

A B C CONCLUSION Place on Body Remove Tab Press Button Figure 5: Initiating the injection: three simple patient steps. The Enable Injection Device is not only a wearable bolus injector honed for maxi- with an injection device. In the context of doesn’t take up room in the refrigerator”, mum user comfort and satisfaction, for the current trend for numerous programma- “The vial is childproof, an injector isn’t”, optimal compliance and adherence, but also ble devices being brought forward, which “Once I start something, I want to finish it”, a unique, highly customisable drug delivery provide the user with various functions, and “If I have to leave it out, I might forget device-offering to the industry featuring: indicators, buttons and alarms, it is maybe about it.” Also, users wanted a device that initially counterintuitive to discover that is ready when they are. • Adjustable Volume users prefer not to have to make decisions The user studies also drove Enable - 1-10 ml – Standard Device on programming or about which buttons towards a clear objective of creating the - 1-20 ml – High-Volume Device to press or how many times to press them. smallest, flattest, quietest, most unobtru- - Up to 50 cc – Very High-Volume Device Steered by its user study results, Enable’s sive possible device. The word “discreet” • Adjustable Flow Rate device requires that the patient does one came up repeatedly throughout the Human - From 0.1 cc/min to 100 cc/min thing after placing the device on their skin Factors studies. We have already mentioned • Adjustable Needle Size – press the central button. On pressing the that the Enable device delivers the highest - 27-33g button the needle is inserted to the right possible volume from the smallest possible • Unlimited Viscosity depth and controlled drug flow begins. device. Additionally, when dosing is com- - 100 cP of 10 ml volume through 29g In a similar way to the question of “pro- pleted there is no audible buzzer or alarm needle at 1 ml/min grammability versus no programmability”, ringing out for all to hear like an unwanted • Automated Mixing user studies gave some unequivocal yet mobile phone call. Enable’s device makes - Vials of up to 2 x 10 ml volume possibly unexpected results in the context a subtle click on completion of dosing that - Liquid/Liquid or Lyophilised/Liquid. of refrigerated drugs (i.e. the vast majority only the user can feel and hear, since it is of biologics) on the question of “preloaded only the user who needs to know. Once To conclude, a message direct from versus patient loaded”. Specifically, every aware that the device has finished, the user Enable for formulations teams who are patient surveyed preferred the patient-load- can then make the decision as to when and spending millions of dollars and pounds ed system. Digging down into some of where they want to remove and dispose of and euros striving to adjust concentrations the most common reasons given reveals the device. to make biologics injectable or otherwise that their preference for the patient-loaded The Human Factors studies helped deliverable: “There’s no longer a need device shouldn’t be viewed as unexpected at Enable to make additional subtle (yet to to worry about that. The Enable Device all, but entirely natural. users incredibly important) design deci- can mix and deliver the drugs as for- As mentioned, whilst allowing for the sions – the clear one-word instructions mulated, with potential cost-savings and storage of only the vials in the fridge (i.e. being printed on the inside of the lid, for quicker time to market. IV is no longer the not requiring the entire wearable device example. Another example is that Enable only alternative!” to be refrigerated), Enable’s device also observed how users with impaired vision or From the stellar line-up of board mem- eliminates the need to wait for 30 minutes dexterity had difficulty peeling the cover off bers to the attention to every fine detail of for the drug to come up to temperature by the adhesive backing with one hand whilst numerous rigorous HFE and user studies, warming it during the short period of drug holding an injection device in the other every aspect of the Enable Injections wear- transfer process. Among the reasons given hand. With the Enable Injector, the cover able device has been defined with people by patients for their strong preference for is peeled off the adhesive backing automati- front and centre, from the very earliest the patient-loaded device were: “The vial cally when the user takes the device out of stages and throughout. IN WHICH EDITION COULD YOUR COMPANY APPEAR? www.ondrugdelivery.com

SAFE & RELIABLE PRIMARY DRUG CONTAINER MANUFACTURING

All wearable bolus injection devices must use a primary drug container at some stage. Some are used in conjunction with standard primary drug containers, from which the patient transfers the drug into the device at the point of use. Other wearable bolus injectors incorporate prefilled primary drug containers – standard or customised – into the device body itself. Here, Gerresheimer, a global leader in the manufacture of parenteral drug delivery systems and primary packaging, including standard and customised glass vials, ampoules and cartridges, provides a brief overview of the manufacturing process.

In vertical manufacturing, the glass tubes are positioned vertically into chucks of the forming machine. Unlike the conveyor belt in the horizontal process, the forming machine has a rotary design like a carousel. The end of the glass tube is heated and the shoulder, neck and lip are formed by using forming tools. Then, the glass tube is heated and pulled apart. To finalise the conversion of the new vial from the short section, the other end is heated to Figure 2: Traditionally vials are the form the bottom. During the process, glass storage container for parenteral tubes and sections are located in a vertical drugs that are ultimately transferred position, hence the name of the procedure. into a syringe at the point of use but After the converting process, each vial increasingly vials are used to transfer is precisely measured. If even one measure- parenteral formulations into new- generation self-injection devices. ment is outside the defined tolerance limits, the vial is rejected. Then the vials go into the annealing oven to eliminate any stress in Gerresheimer ensures that the vials make Figure 1: Vials are inspected for the glass caused by the converting process. safe packaging and that the medications cosmetic defects. This is particularly important because stress arrive intact at the pharmacy, doctor’s office, Like syringes, ampoules and cartridges, in the glass can cause cracks at a later time hospital and ultimately at the patient. Whilst vials are made of glass tubing. Vertical or and render the content of the vial unusable. traditionally vials have been used as the stor- horizontal production technology is used to When the vials have come out of the age container for parenteral drugs that would make them, depending on whether the glass annealing oven they are inspected for cos- ultimately be transferred into a syringe by a tubes are positioned vertically or horizon- metic defects (Figure 1). These include cracks medical professional at the point of use tally in the machine. and scratches, as well as impurities or bub- (as shown in Figure 2), increasingly vials On a horizontal forming machine, a bles. After an initial camera inspection they are used to transfer parenteral formulations thermal-shock process is used to cut the are also inspected visually by a member of into new-generation injection devices such glass tube to the required length when it has staff. Defective vials are rejected. The good as wearable bolus injectors. Similarly, drug been fed into the machine. One length of cut vials are sealed in shrink wrap and stacked cartridges commonly used in pens and auto- tube is then used to make two vials. Tiny onto pallets. Geometric and cosmetic inspec- injectors are now also being incorporated glass splinters or dust are sometimes created tions of each individual vial are also per- into wearable injection devices. Whatever the when the tube is cut, which are immediately formed in process (100% inline control), as intended end-use, patient safety is the highest removed with pressurised air. After the tube well as additional random quality checks. priority in every single stage of the primary cutter, the tube sections are transported on Polarised light is used to show whether all container production process. a conveyor belt along flames where both the stress has been eliminated from the glass. ends of the tube are heated and converted Chemical tests are used to assess the to create the shoulder, neck and lip in the glass’s hydrolytic resistance and at times Gerresheimer AG Klaus-Bungert-Strasse 4 required geometry. a pressure test is used to measure the 40468 Dusseldorf In the next step, the tube is heated at the vial’s mechanical resistance. All these qual- Germany centre, pulled apart, and the two ends are ity inspections are very important to ensure formed to create the bottom. During the that the vials don’t interact with the medica- T: +49 211 61 81-00 entire converting process, the tube sections tion, that they don’t cause any problems on E: [email protected] are transported horizontally orientated, our customers’ machines and that they don’t hence the name of the procedure. break during transportation. www.gerresheimer.com

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