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ST O DELIVERY INJECTABLE MAY 31 2021 • ISSUE N 120 P 30 A SYMBIOTIC RELATIONSHIP DEVICE DEVELOPMENT: FORMULATION &

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ONdrugDelivery Issue No 120, May 31st, 2021 How to Ensure the Future Demand for Biologics Can Still be Delivered by Injectables INJECTABLE DRUG DELIVERY Anthony Vico, Technical Customer Support & Quality Management Supervisor; and 08 -12 Enrico Barichello, Product Management Specialist for Syringes and Components This edition is one in the ONdrugDelivery series Stevanato Group of publications from Frederick Furness Publishing. From Process to Product: Optimising Process Development Each issue focuses on a specific topic within the Strategies for Variable Drug-Device Requirements field of drug delivery, and is supported by industry Markus Goldinger, Senior Director of Process Development; and 16 - 21 Erik Alexandersson, Assistant Manager of Process Development leaders in that field. SHL Medical EDITORIAL CALENDAR The Added Value of a Platform Approach: Pen Injector Case Study Radosław Romańczuk, Pen Platform Business Development Director; Jun 2021 Connecting Drug Delivery Severine Duband, Category Director, Devices; and Jul Novel Oral Delivery Systems 24 - 28 Audrey Chandra, Category Project Manager Aug Industrialising Drug Delivery Nemera Sep Wearable Injectors Formulation & Device Development: a Symbiotic Relationship Sep/Oct Drug Delivery & Environmental Sustainability 30 - 32 Caroline Zakrzewski, Drug Delivery Devices Scientist Oct Prefilled Syringes & Devices Cambridge Design Partnership Nov Pulmonary & Nasal Drug Delivery Patient-Centricity: the Importance of Human Factors in the Pandemic Era Marcus Agunloye, Senior Human Factors Engineer & Industrial Designer Dec Connecting Drug Delivery Oval Medical Technologies Jan 2022 Skin Drug Delivery: 34 - 40 Asmita Khanolkar, Senior Director, Cambridge Pharma, Dermal, Transdermal & Microneedles SMC Technical Strategy & Commercialization Feb Prefilled Syringes & Injection Devices SMC Ltd. Mar Ophthalmic Drug Delivery Towards User-Centric Specification of Mar/Apr Drug Delivery & Environmental Sustainability Technical Attributes: Insights From Empirical Work 41 - 44 Andreas Schneider, Innovation & Business Development Director Apr Pulmonary & Nasal Drug Delivery Ypsomed May Injectable Drug Delivery: How Owen Mumford Carried Out Usability Formulations & Devices Testing Under Covid-19 Restrictions Miranda Newbery, Director and Founder EDITORIAL: 46 - 48 Inspired Usability Guy Furness, Proprietor & Publisher Finola Austin, Human Factors Engineering Manager E: [email protected] Owen Mumford Pharmaceutical Services Reusable Electronic Autoinjector – Flexible Performance CREATIVE DESIGN: Bjarne Sørensen, Director, Front-End Innovation 50 - 54 Phillips-Medisize Corporation Simon Smith, Creative Director (Freelance) E: [email protected] Addressing the Challenges of Viscous Injectable Administration Andrew Donnelly, Vice-President of Innovation Bespak by Recipharm SUBSCRIPTIONS: 56 - 59 Shahid Uddin, Director of Drug Product, Formulation & Stability Audrey Furness, Marketing Executive Immunocore E: [email protected] Subcuject WBI: Low-Cost, Larger Volume, High-Viscosity Wearable Print + Digital subscription: £99/year + postage. Bolus Injector – Using Standard Glass Primary Packaging Digital Only subscription: free. 60 - 62 Claus Schmidt Moeller, Chief Technology Officer Subcuject ADVERTISING: Safe and Automatic Device to Improve Drug Preparation from Multidose Vials Guy Furness, Proprietor & Publisher Benjamin Morel, Intellectual Property Manager; and E: [email protected] 64 - 66 Claire Authesserre, R&D Fluidics Manager EVEON ONdrugDelivery is published by Ensuring Functional Performance and Regulatory Compliance Frederick Furness Publishing Ltd of Elastomer Stoppers for Multipiercing Situations Bruno Morchain, Technical Center Manager, Aptar Pharma Injectables; The Candlemakers, West Street, Lewes 70 - 73 Sébastien Cordier, Technical Product Manager, PremiumCoat®; and East Sussex, BN7 2NZ, United Kingdom Estelle Verger, Business Development Senior Manager, PremiumCoat® T: +44 1273 47 28 28 Aptar Pharma Drivers for Change in Aseptic Automation Registered in England: Company No 8348388 Dave Seaward, Projects Director; and ISSN 2049-145X print / ISSN 2049-1468 pdf 74 - 79 David Phasey, Projects Director 3P innovation Copyright © 2021 Frederick Furness Publishing Ltd Ophthalmic : Pathway to Overcome Primary Packaging All rights reserved and Drug Product Manufacturing Challenges Rainer Glöckler, Chief Technical Officer; and Carole Delauney, Director Business Development 80 - 86 Swissfillon Nicolas Eon, Senior Technology Development Manager; and Katsuyuki Takeuchi, Associate Product Manager, Pharmaceutical Solutions Terumo Europe The ONdrugDelivery logo is a registered trademark of Frederick Furness Publishing Ltd. Comparative Extractable Studies for Injectables and Medical Devices Aligned with USP <1663> and ISO 10993 Guidelines The views and opinions expressed in this issue are those of the authors. Matthias Bicker, Scientific Advisor; Due care has been used in producing this publication, but the publisher Michael Müller, Study Director; makes no claim that it is free of error. Nor does the publisher accept 88 - 97 Marc Mittermüller, Study Director; liability for the consequences of any decision or action taken (or not Daniel Haines, Head of Pharma Services North America; and taken) as a result of any information contained in this publication. Uwe Rothhaar, Director Front cover image, “Medical syringe, illustration”, credit: VICTOR SCHOTT Pharma Services HABBICK VISIONS / SCIENCE PHOTO LIBRARY.

Stevanato Group

HOW TO ENSURE THE FUTURE DEMAND FOR BIOLOGICS CAN STILL BE DELIVERED BY INJECTABLES

Here, Anthony Vico, Technical Customer Support & Quality Management Supervisor, and Enrico Barichello, Product Management Specialist for Syringes and Components, both of Stevanato Group, discuss the demands that high-viscosity biologic formulations place on prefilled syringes, and how pharmaceutical companies can make the most of this growing market segment to deliver improved quality of life for patients.

Global biologic sales are expected to grow biologics are characterised by high from a market size of US$325 billion chemical sensitivity and strong dynamic (£230 billion) in 2020 to $425 billion characteristics (i.e. viscosity), which pose (£300 billion) by 2024. That represents significant challenges to PFS technology. an estimated compound annual growth As a leading provider of primary packaging rate (CAGR) of 7%, and a significant and drug delivery systems, Stevanato opportunity for pharmaceutical companies.1 Group is consistently challenging itself to Biotech drugs, especially monoclonal deliver best-in-class, optimised solutions to antibodies (mAbs) and recombinant improve patients’ lives. proteins, have enabled the pharma industry This article reviews the current state to treat incurable critical and chronic of the PFS market and discusses the diseases, such as osteoporosis, rheumatoid challenges associated with biologic drug Anthony Vico arthritis and hypercholesterolemia, delivery, before covering a case study on Technical Customer Support & meeting previously unmet needs and how to optimise needle design to mitigate Quality Management Supervisor delivering better outcomes for pharma a patient’s discomfort perception while E: anthony.vico@ companies and patients in equal measure. guaranteeing acceptable administration stevanatogroup.com Because most biologics are primarily performance for higher viscosity . administrated parenterally, particularly via Finally, this article considers the key drivers the subcutaneous route, prefilled syringes in the choice of PFS, advocating an early- (PFSs) have gained strong acceptance as the phase, full-system approach to mitigate preferred delivery system. risk and speed time to market for these Market trends have led pharma life-enhancing therapies. companies to formulate concentrated The burden of chronic disease continues biologics that reduce the required frequency to weigh heavily on populations across of injections for those who suffer from the globe. In Europe alone, these illnesses Enrico Barichello chronic conditions. These complex are the leading cause of mortality by far, Product Management Specialist for Syringes and Components E: enrico.barichello@ “Managing a chronic condition can place a high demand on stevanatogroup.com

patients, often requiring regular visits to a clinical setting to Stevanato Group SpA receive their therapies, frequently via intravenous methods. Via Molinella 17 35017 Piombino Dese Self-administration via the subcutaneous route relieves a great Padova deal of this burden by handing greater control to the patient.” Italy www.stevanatogroup.com

8 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd Stevanato Group

accounting for 77% of the total disease burden and 86% of all deaths.2 Cross- “When dealing with biologics bringing these benefits referencing these statistics with demographic trends, such as increasing life expectancy, to the patient is not necessarily as straightforward as has further implications for the future of it sounds. The main sticking point being the healthcare provision. high viscosity of the formulations in question.” By 2100, the proportion of those aged 65 years and over is projected to increase. This is despite forecasts that the overall population across the EU will decline in this will result in the global PFS market some traditional or more conventional comparison with 2019 levels. As such, this expanding at a CAGR of 9% from 2020 to autoinjector technologies may be rendered age group will grow its share from a fifth 2025, when it will be valued at $8.6 billion.6 unfit for purpose if the force required is of the current total (20.3%) to almost a There are several trends that are driving too high. Solving this challenge typically third (31.3%),3 equating to an additional the uptake of biologic treatments delivered requires compromise on the part of the 39.7 million people who are at risk of via PFSs, one key example being patient patient, such as increasing the frequency living with some form of chronic disease, convenience. Managing a chronic condition of injections, and/or when it comes to the or even multiple chronic diseases, over the can place a high demand on patients, often PFS, such as increasing the needle gauge coming decades. requiring regular visits to a clinical setting or selecting specific low-friction plunger Given the damaging impact of these to receive their therapies, frequently via stopper components; both scenarios have conditions on citizens’ wellbeing and intravenous methods. Self-administration clear drawbacks in terms of compliance, the associated negative consequences for via the subcutaneous route relieves a great comfort and ease of use. It has been down economic health, it is understandable that deal of this burden by handing greater to innovators in the field of primary prevention and early detection of chronic control to the patient. packaging and drug delivery systems to find disease is a clear focus among policymakers, However, adherence remains an obstacle a pathway that satisfies patient expectations who are seeking to tackle the issue as close to effective treatment, particularly where from the perspective of both biologic drug to its source as possible. preparation is required using a vial and delivery and user experience. At the same time, there is a growing syringe. In comparison with vials, PFSs Stevanato Group, as a leader in this requirement to address chronic diseases deliver a ready-made, high-concentration field, has carried out a detailed analysis of from the patient’s perspective through long- dose that has been prepared to precise design developments intended to manage term management and sustained treatment tolerances. These benefits mean these issues. Its work looked closely at regimes. Pharmaceutical companies are errors and overfill waste are reduced and the morphological features of thin-walled pursuing innovative R&D programmes adherence is increased, with the potential needles, which offer the advantage of in these areas that, with supply chain for further improvements in adherence simultaneously maintaining flow rates partners, aim to uncover new treatments when used in conjunction with and reducing needle gauge. However, they and drug delivery techniques that will ease and as part of a connected combination also increase the risk of both needle-tip many of the obstacles facing patients and product platform. deformation (e.g. hooks) and coring (the healthcare professionals. formation of elastomer particles caused SOLUTIONS FOR HIGH VISCOSITY by the needle tip piercing the elastomeric THE RISE AND RISE OF BIOLOGICS needle shield). The research identified When dealing with biologics, however, that needle-tip deformation is a product Biologics are at the forefront of these bringing these benefits to the patient is of the reduced mechanical strength of developments. Between 2014 and 2018, not necessarily as straightforward as it the cross-section. In parallel, Stevanato the share of net medicine spending on sounds. The main sticking point is the Group confirmed that coring propensity is biologics grew from 30% to 42% of the high viscosity of the formulations in linked to aspects including the sharpness total. Over this same period, the Center question. This is due to the strength of the and geometry of needle-tip bevels, the for Drug Evaluation and Research (CDER) intermolecular forces at play in highly mechanical characteristics of the elastomeric within the US FDA approved the biologic complex, long-chain biologics, such needle shield, and the tribology between the licence applications for 59 novel biologics. as mAbs, combined with the fact that needle tip and the elastomeric needle shield This more than doubles the 26 approved in protein concentration is deliberately – all of which are critical to quality. the preceding five-year period.4 A further formulated very high in order to meet In a further study, Stevanato Group 10 biologics were approved in 2019, as dosing requirements. While viscosity is seen attempted to determine how varying the well as 10 biosimilars based on previously to increase moderately in low-concentration needle-tip geometry would mitigate the risk approved therapeutic biological products.5 formulations, in high concentration of deformation and coring propensity when Cancer and orphan diseases (indications formulations of greater than 100 mg/ml, moving to a thin-walled configuration. affecting 200,000 patients or fewer) are the viscosity increases exponentially.7 This involved comparing the geometries of most targeted therapeutic areas. At higher viscosities, difficulties can a five-bevel and a three-bevel needle tip. Since parenteral delivery is the typical arise for parenteral delivery mechanisms, The research investigated the mechanical , the demand for including the need for additional force performance of the two designs, examining syringes is predicted to rise in line with to be applied to the plunger rod. This their hooking propensity in the context of the growth in biologics. Forecasts suggest can mean injections take longer and the required penetration force.

Copyright © 2021 Frederick Furness Publishing Ltd www.ondrugdelivery.com 9 Stevanato Group

The five-bevel needle’s lower propensity for hooking was further underlined by subsequent experimental testing. This testing also demonstrated that the predictive models overestimated the performance gap between the needle tips (Figure 3). To analyse the penetration force, the different needle types were inserted into a specific fixing tool and moved at constant speed towards a substrate (Figure 4). The insertion force was recorded as a function of penetration depth through a calibrated load cell, with the five-bevel needle registering a slightly lower needle penetration force (median of 1.12 N) compared with the three-bevel needle (median of 1.12 N). The conformance (variance) was found to be consistent between the two needle designs.

MATCHING PFS CHARACTERISTICS WITH FORMULATION

Figure 1: Theoretical predictive model based on From a device design perspective, one of the Euler’s critical load analysis, clear takeaways from Stevanato Group’s simulating the application of research is the importance of factoring axial load on the needle tip primary container selection into the to cause hook deformation. development process for injectable drugs. The ultimate end goal is to achieve a unified The study used theoretical finite Figure 2. This finding was confirmed by the solution that incorporates all aspects of the element analysis (FEA) predictive models numerical predictive model, which indicated container closure system and device at the to determine the difference between the that the axial load required to arrive at the desired tolerances and performance levels. two needle-tip designs in terms of hooking same deformation magnitude (50 µm) would This is dependent on a range of analytical propensity. Both models were based on the be 555% higher for the five-bevel needle techniques that must be used to understand experimental test setting, with a vertical than the three-bevel needle. the interplay between the various elements, load applied to control deformation. The theoretical prediction model was based on Euler’s critical load analysis, simulating an ® ® axial load applied to the needle tip to cause “Stevanato Group’s SG Alba and SG Nexa product lines, hook deformation (Figure 1). Based on this for example, have been designed specifically to meet the model, the five-bevel needle design withstood requirements of high-value biologics, accommodating an axial load 83% higher than the three- bevel needle design before achieving the same even large-volume (2.25 mL) high-viscosity formulations.” deformation magnitude (50 µm), as shown in

(A) (B)

Figure 2: The finite element analysis confirmed a significantly lower hooked needle propensity for the five-bevel needle tip design compared with the three-bevel needle tip design. The trend (A) and external load (B) required to generate a hooked needle at 50 µm is significantly higher – approximately five times – for the five-bevel needle tip design than with the three-bevel needle tip design.

10 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd Stevanato Group

Figure 3: Comparison between numerical and experimental hooking propensity testing. which in turn provides the knowledge The need to bring specialist knowledge suite of systems, processes and services that base to optimise the choice of container to the table early in proceedings underlines guarantee medicine integrity. for the specific drug product in question. the importance of the relationship Stevanato Group’s SG Alba® and SG If considered in the early stages of a between project owners and supply chain Nexa® product lines, for example, have project, this ensures the overall process is as stakeholders. Stevanato Group understands been designed specifically to meet the streamlined as possible, avoiding potential this dynamic, and is focused on its mission requirements of high-value biologics, disruption further down the line. to provide its partners with a comprehensive accommodating even large-volume

Figure 4: A penetration force test was performed to compare the three-bevel and five-bevel needle (thin walled). The penetration test is described by ISO 7684.

Copyright © 2021 Frederick Furness Publishing Ltd www.ondrugdelivery.com 11 Stevanato Group

(2.25 mL) high-viscosity formulations. inspection, assembly and packaging Eurostat, Sept 2020. This is due to their high dimensional and machines. Stevanato Group also provides 4. de la Torre BG, Albericio F, “The geometrical accuracy, as well as enhanced analytical and testing services that study the Pharmaceutical Industry in 2019. properties relating to glideability, frictional interaction between the container and drug An Analysis of FDA Drug Approvals fluid dynamics and extractables profiles. and the integration into delivery systems, from the Perspectiveof Molecules”. In addition, both product lines can be supporting the drug development process. Molecules, 2020, Vol 25(3), p 745. easily integrated into active and passive By bringing together several skills under 5. “Biosimilar Product Information”. needle safety systems and into automatic the same umbrella, Stevanato Group is able US FDA, web page. drug delivery devices, such as spring-based to offer unique solutions to companies and 6. “Prefilled Syringes Market by Type autoinjectors. reduce time-to-market and overall cost. [Conventional (Disposable, Reusable), These qualities ensure that Stevanato Safety], Material (Glass, Plastic), Group can de-risk the development process REFERENCES Design (Single-Chamber, Dual- for its pharma partners, saving costs and Chamber, Customized), Application accelerating product time to market. 1. Stops A, Karanis Y, MacDonald D, (, Cancer, Arthritis, However, the ultimate stakeholder in this “Trends in Auto-Injectors. Early Anaphylaxis, Ophthalmology) – process is, of course, the patient. Chronic considerations for an emergency Global Forecast to 2025”. conditions affect the lives of millions of people use auto-injector development and Markets and Markets, Sept 2020. and Stevanato Group’s research serves as a manufacturing: a case study”. CPhI 7. Palm T et al, “The Importance of reminder of the need to continually evaluate webinar series, Feb 2021. the Concentration-Temperature- the injection experience with a view to 2. “Chronic Disease & Policy”. European Viscosity Relationship for the reducing the discomfort that patients must Chronic Disease Alliance, web page. Development of Biologics”. repeatedly endure over an extended period. 3. “Population projections in the EU”. BioProcess International, Mar 2015. By continually identifying ways to advance needle technology, and by presenting this in a convenient, patient-friendly proposition – ABOUT THE AUTHORS one that integrates syringe, needle closure and device – Stevanato Group will continue Anthony Vico is Technical Customer Support and Quality Management Supervisor at to help pharmaceutical partners deliver the Ompi of America, Stevanato Group. He moved to the US to support Stevanato Group’s day-to-day patient benefits that, together, growth in glass primary packaging. In his previous role he spent five years as part of add up to an enhanced quality of life. the technical and quality assurance front end team at Stevanato Group in Italy. He has a wealth of experience in glass container technology for pharmaceutical use, supporting ABOUT THE COMPANY the design, development and manufacturing of ready-to-fill glass containers (syringes, cartridges, vials and special containers). He has strong expertise in technical and quality Founded in 1949, Stevanato Group is one support, including regulatory and compliance from early-stage development to lifecycle of the world’s largest providers of integrated management, dealing with parenteral in drug delivery systems based on containment and delivery solutions for prefilled glass containers. He received both his Masters in Mechanical Engineering, the biopharmaceutical industry. From the Thermodynamics and Heat Transfer, cum laude, in 2011 and his Bachelors in Mechanical beginning, Stevanato Group has developed Engineering, cum laude, in 2009 from the University of Padua (Italy). its own glass-forming technology to ensure quality of the highest standards. Stevanato Enrico Barichello has a background in industrial engineering and a Masters in Group is home to a wide range of skills Management from the University of Padua (Italy). He has acquired a broad spectrum dedicated to serving the biopharmaceutical of skills in technical concepts and complex processes. Mr Barichello joined Stevanato and diagnostic industries. It offers glass Group in 2017 on an undergraduate internship. He has since worked on defining and containers with its historic Ompi brand, co-ordinating all the activities required to bring products to market, bridging gaps plastic components for diagnostics and between different functions within the company and aligning internal teams. He is now medical devices and contract manufacturing Product Management Specialist for Syringes, Components and Analytical Services. services for drug delivery systems, up to SUBSCRIBE TODAY! PRINT SUBSCRIPTION £99/YR + POSTAGE www.ondrugdelivery.com/subscribe

12 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd Integrated solutions for pharma & healthcare

Stevanato Group integrates products, technologies and services, providing value-added solutions to improve patients’ lives stevanatogroup.com biopharma professionals who read ONdrugDelivery Subscribe OnlineJoin Today! Online and/or In Print. 30,000

2021/22 EDITORIAL CALENDAR

Publication Month Issue Topic Materials Deadline

June Connecting Drug Delivery DEADLINE PASSED

July Novel Oral Delivery Systems Jun 17, 2021

August Industrialising Drug Delivery Jul 1, 2021

September Wearable Injectors Aug 5, 2021

September/October Drug Delivery & Environmental Sustainability Aug 19, 2021

October Prefilled Syringes & Injection Devices Sep 9, 2021

November Pulmonary & Nasal Drug Delivery Oct 7, 2021

December Connecting Drug Delivery Nov 4, 2021

January 2022 Skin Drug Delivery: Dermal, Transdermal & Microneedles Dec 9, 2021

February Prefilled Syringes & Injection Devices Jan 6, 2022

March Ophthalmic Drug Delivery Feb 3, 2022

April Pulmonary & Nasal Drug Delivery Mar 3, 2022

April/May Drug Delivery & Environmental Sustainability Mar 17, 2022

May Delivering Injectables: Devices & Formulations Apr 7, 2022

14 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd biopharma professionals who read ONdrugDelivery Join Online and/or In Print. 30,000

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BD and the BD Logo are trademarks of Becton, Dickinson and Company. © 2020 BD. All rights reserved. 1910004709 (04/20) SHL Medical

FROM PROCESS TO PRODUCT: OPTIMISING PROCESS DEVELOPMENT STRATEGIES FOR VARIABLE DRUG-DEVICE REQUIREMENTS

In this article, Markus Goldinger, Senior Director of Process Development, and Erik Alexandersson, Assistant Manager of Process Development, at SHL Medical, discuss the benefits to process development provided by SHL’s fully in-house, vertically integrated model, and how those benefits are applied throughout the process from initial design work to final assembly of the drug delivery device and primary container.

Combination product development follows are of prime consideration in its device a two-pronged approach: pharma takes development strategy: the lead in drug discovery and formulation development and device companies do the • Formulation and mapping of processes same for the drug delivery system. On • Execution of these processes the device side, process development (PD) • Ensuring the quality of the output of each takes centre stage in ensuring tangible and step-by-step event leads to the carefully intangible resources are translated into developed, final assembled device. self-injection devices that reach the hands of patients across the many disease areas Early in the planning stages of a device that require them. While changes relating project with a pharma partner, a sound Markus Goldinger to the device development process and/or PD strategy is required to ensure in-process Senior Director of its intermediary products entail myriad controls are well integrated with the intended Process Development risks, SHL Medical takes a scientific and qualifiable and quantifiable outputs in T: +886 3 217 0303 ext 2443 E: [email protected] engineering-based PD approach to safeguard the manufacturing stream. Although not the execution of all stepwise procedures commonplace, SHL believes that this should undertaken in autoinjector development. be the norm in the autoinjector industry. In the autoinjector industry, where buzzwords like “streamlined operations”, CONVENTIONAL PROCESS “end-to-end processes” and “vertically DEVELOPMENT AT A GLANCE integrated services” are common and loosely used, device companies need to In brief, PD refers to the exercise of creating be challenged to substantiate such claims. a means to manufacture a specific product in For SHL Medical, three crucial elements a given quantity, involving the selection and Erik Alexandersson Assistant Manager of Process Development T: +886 3 217 0303 ext 1788 “When the research, development and formulation of a E: [email protected] drug can take 10 or more years, a PD strategy that can adapt to the customer’s needs is crucial to meet or SHL Medical AG Gubelstrasse 22 even shorten timelines in combination product 6300 Zug development, as well as mitigate project risks.” Switzerland www.shl-medical.com

16 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd SHL Medical

Figure 1: SHL Medical’s overarching PD streams. The validation phase and final assembly are not shown in this figure. sequencing of process steps from a repertoire development, as well as mitigate project A key highlight of SHL Medical’s PD of unit operations.1,2 Conventionally, what risks. For SHL Medical, the flexibility of strategy is that it comprises both the device this means is that a device will take a highly processes is key to addressing the varying development aspect of a combination specific development stream contingent requirements of stakeholders, as well product project as well as the processes to the project requirements – a project as ensuring that the manufacturing and that directly concern its pharma partners. that requires low-volume production assembly process is fully scalable. Specifically, this means that the PD strategy will undertake a distinct manufacturing is streamlined not only for activities that process different from that which requires A SCIENTIFIC AND constitute its autoinjector development high-volume production. Likewise, the ENGINEERING-BASED PROCESS streams, but also for the processes which overarching development process for a fully DEVELOPMENT APPROACH would be undertaken by its customers, such bespoke device project will differ from a as the final assembly of the autoinjector project that leverages the technology of a The PD strategy at SHL Medical (Figure 1) sub-assemblies with the syringe. It could modular platform offering. takes a scientific and engineering-based be said that this PD strategy, which covers Interestingly, when a device project approach to ensure that the following both the upstream and downstream requires not just one but a combination critical considerations in combination processes of combination product of these factors, the dependencies and product development are taken: development, draws from SHL Medical’s interdependencies of upstream and years of experience in supporting the downstream processes exponentially multiply 1. Delineate the primary function of the regulatory approval and launch of a myriad and the complexities become increasingly device with the end-user requirements in of self-injection devices. apparent. In drug device development, mind during early design work SHL’s participation in the market launch the competencies of a device developer to 2. Establish design requirements of pharma of more than 47 combination products – address the requirements of the customer, partners, establish robust and efficient designed for a wide variety of disease areas primary container, branding or patient processes, and deploy these into the and end users – provides the company with become important to the project’s success. manufacturing streams a contextual perspective that translates to When the research, development and 3. Ensure successful design transfer and cycles of assessing, verifying and testing formulation of a drug can take 10 or more guide the execution of the penultimate devices and iterating designs of its device years, a PD strategy that can adapt to the steps for the customer to undertake in technologies. The depth and breadth of its customer’s needs is crucial to meet or even the combination product development cumulative experience have fortified SHL’s shorten timelines in combination product process (i.e. final assembly). focus on a scientific and engineering-based device development approach with the end user in mind. “SHL’s participation in the market launch of more than 47 combination products – designed for a wide MANAGING DEVELOPMENT RISKS THROUGH DFMA PRINCIPLES variety of disease areas and end users – provides the company with a contextual perspective that translates On the device side of combination product to cycles of assessing, verifying and testing devices development, the robustness of a device technology is just one side of the story. and iterating designs of its device technologies.” The other side relies on an informed system of processes and procedures. An informed

Copyright © 2021 Frederick Furness Publishing Ltd www.ondrugdelivery.com 17 SHL Medical

system means that the way the steps are undertaken downstream of the device project relies on insights from data upstream of the whole device development process. With an informed set of procedures, root causes can be identified from the upstream processes, preventing the impact of change versus the cost of change casualties. In brief, various experts are sought to ensure that the manufacturing stream is seamless. This improves device manufacturability and mitigates project risks in relation to the impact of design changes versus the costs of running a device project. Changes brought about by data gathered from simulations in the early stages of a project will impact costs less than when a device part is already produced, or when the combination product is already Figure 2: A generalised comparative graph representing the relationship between launched on the market (Figure 2).3 the impact of a change versus the cost of that change in combination product While design for manufacturing and development, with a focus on the device aspect. assembly (DFMA) concepts are not new, the PD structure at SHL Medical This framework generally serves as a material and design. This way, the functional continuously adapts its scientific and “robust anchor” that guides the development requirements for the assembly equipment engineering-based approach for DFMA. As – and prevents unintended issues – of an are defined and automation experts can a systematic solution to device projects, autoinjector project for a pharma partner. proceed with developing the right assembly engineering feasibility studies, as well as In accordance with the project and end-user equipment for small-scale studies, as well as DFMA evaluations, are carried out at the requirements, a draft design will be made by the mass-production phase. earliest practicable stages of product design. the design engineers and a feedback loop will When it comes to establishing the actual An important highlight of this system commence to evaluate the manufacturability process, scientific injection moulding is is that DFMA concepts are explicitly of that draft design, as well as ensure that, carried out to design, as well as to produce, outlined during the design proposal step in downstream of the process, such a device the right tools that conform to the design preparation for a device project’s engineering can be fully assembled with the primary specifications, based on the initial simulation phase. This ensures that tools and process container carrying the drug. results. The first iteration of the tool is flows are well co-ordinated and integrated Starting from the raw materials to be constructed and the design of experiments with mass production requirements and used, computer-aided engineering allows (DoE) is performed to test variables in the tuned to manufacturing capabilities, SHL’s subject-matter experts to understand moulding process and ultimately come up ultimately supporting the original device the injection processability of the input with a consistent approach that would design requirements. , as well as minimise warpage and not require any modifications once the An SHL device project will undergo shrinkage of the moulded parts. Injection process is set. On the other hand, assembly stringent reviews by various subject-matter moulding simulations are run to analyse process assessment testing is also carried out experts during its design phase, well before and visualise how much shrinkage and on the autoinjector prototype to support it enters the mass manufacture stage. This warpage to expect, given the current part the establishment of the requirements and would include: material, design and expected processing acceptance testing for the equipment to be conditions. The results of these simulations used in the actual assembly process. 1. A review of the input materials, such make it possible to consider a wider range For SHL, consistency in results as the plastic and metal components to of possible solutions early in the design is tantamount to ensuring a robust PD be used throughout the manufacturing phase of a project, and to come up with an strategy. This comes from understanding the process optimised combination of design, material whole combination product development 2. Injection moulding and assembly and processing parameters to produce the process and the causes of issues within its simulations by computational engineers desired part. streams, leading to an informed PD strategy 3. Moulding and assembly process reviews A keen understanding of the assembly where both simulation and actual results in accordance with historical data or of each moulded autoinjector part is also meet – indicating a robust process that prior knowledge from similar projects developed early in the device development guides the fate of the stepwise procedures 4. Toolset review of mould structure by process. Similar to injection moulding PD, along the whole device development. tooling experts computer-aided engineering is used to Figure 3A shows warpage trend 5. Review by process and automation understand and analyse the physical force simulation data for a specific part of SHL’s experts of the assembly process, as well requirements of the device assembly process, modular platform device technology, and as equipment considerations for mass such as the assembly and separation force, Figure 3B shows warpage data for its actual production. given the known parameters of the part moulded part. This indicates a highly similar

18 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd SHL Medical

automation, verification, testing, etc) to create a robust device. In a grander scheme, this presents a multitude of advantages, including an improved time to market for customer projects, as well as enabling SHL to execute various device projects in parallel to meet their independent timelines.

INTEGRATING PROCESS DEVELOPMENT AND FINAL ASSEMBLY

As a device developer with fully in-house capabilities, SHL’s insight into the processes involved in the whole combination product development is unparalleled. Early in the autoinjector development, SHL’s final assembly experts synchronise with project teams to ensure successful design transfer and execution of the final assembly of the autoinjector with the primary container. Figure 3: From simulation to actual results, a robust PD strategy ensures the This ensures synchronisation of deliverables desired output of the stepwise procedures along the whole device development. during various phases of the project’s lifecycle, where SHL ensures a successful integrated system at SHL Medical, enabling final assembly process for the pharma “In contrast to a linear various product development activities partner by guiding them through the to have parallel, overlapping timelines. process, as well as providing them with the device development For SHL, these are what truly constitute design verification master report – technical process, SHL device an end-to-end system of processes. This is documentation which is a suite of test projects are supported reflected in the establishment of PD from methods, protocols and reports detailing the planning through to the validation stages of particular device. through an array of in- a device project. There is depth and breadth in the sourced capabilities, Subsequently, this vertical integration of informed device data that SHL analyses resulting in a parallel core capabilities enables intra-organisational prior to releasing sub-assemblies to communications where information, whether customers. This level of comprehensiveness development process. technical or not, can be relayed directly is made possible by the expertise of SHL’s These in-house capabilities between different functions. Using this design verification and testing experts, ensure a vertically model, communication failure is minimised. as well as the SHL-built testing machines Likewise, this means that feedback, and in-house test method development. integrated system at SHL such as verifying or confirming the The composite of these also enables SHL Medical, enabling various information received, can be provided in to better understand and dissect the product development a timely fashion to avoid process errors. complexities of device design. At present, While various organisational models suffer SHL the flexibility in device testing options activities to have parallel, from asynchronous communications, the that extend to fully automatic device testing. overlapping timelines.” vertical integration of PD capabilities equips It was mentioned earlier that a key SHL Medical with streamlined, highly element of SHL’s PD strategy is the responsive lines of communication across integration of processes that have an impact the project. This presents a considerable not only on SHL but also on its customers. warpage trend for both the simulation and improvement in logistics management and To reduce lead time for equipment design the actual process output, validating the helps lessen lag or idle time over stepwise and procurement, SHL has the capacity to robustness of checkpoints put in place along work operations. develop the client’s device and the required the device development stream. A suitable analogy for describing PD final assembly equipment in parallel. within SHL is the relationship between This means that in the initial stage of FULLY IN-HOUSE CAPABILITIES the “spider and its web”. With most the device development, SHL’s in-house device development functions in-house PD engineers collaborate closely with the In contrast to a linear device development (representing the spiderweb), PD experts equipment engineers to provide guidance process, SHL device projects are supported are able to “spider” over all the steps in on the assembly process and acceptance through an array of in-sourced capabilities, the autoinjector development – optimising testing, ensuring that the final assembly resulting in a parallel development process. procedures and leveraging the know-how process effectively aligns with the specifics These in-house capabilities ensure a vertically of each specialist department (tooling, of the device.4

Copyright © 2021 Frederick Furness Publishing Ltd www.ondrugdelivery.com 19 SHL Medical

Figure 4: From process to the product, the Molly® modular platform technology, along with its robust PD strategy, allows for device configurations that conform to the highly specific requirements of any combination product. Device renderings only, not representative of final product.

A MODULAR PLATFORM AND A STREAMLINED PROCESS STRATEGY “Molly® is a device technology with proven successes and

It should not be forgotten that PD is always launches in the market, demonstrating its credentials as a entwined with a device technology. In 2020, platform device offering that has been optimised over the years. SHL Medical published a review of a This goes hand in hand with a robust PD strategy that ensures modular platform technology; the Molly® autoinjector device.5 quality in the combination and interaction of its input variables.” First launched in 2010, Molly® has since supported the development and regulatory approval of around 16 combination products Medical is able to leverage a wealth of that support the design, development and covering a range of disease areas. Over the resources from within its organisation, manufacture of combination products. years, the Molly® technology has matured to coming in the form of platform data, subject- With the ever-changing needs and become a modular platform that allows an matter experts per variables in the PD varying complexities in combination appreciable level of freedom for customisation stream and historical data that can be pulled product development, an end-to-end while maintaining its rotator-based mechanism. from a multitude of past device projects that process stream that includes a proven The device technology is a modular platform in have shared various common elements. For device technology enabled by a streamlined the sense that both the front and rear sub- SHL, this translates to a modular platform process that extends to the final assembly assemblies comprise five to six intricately technology that enables the Molly® device to of the device and the primary container designed parts that are configured to support draw upon years’ worth of testing platform will be crucial to maintain a continuous flexibility in both design and manufacturing. parts and sub-assemblies, as well as iterating and sustainable supply chain on both the Molly® is a device technology with designs, to ensure a robust device offering. drug and device development sides. SHL is proven successes and launches in the market, This has allowed SHL to develop a platform disrupting the norms of the medtech space demonstrating its credentials as a platform technology that allows for customisations by providing solutions that cater to the device offering that has been optimised over in the front and rear sub-assemblies of end-to-end requirements of combination the years. This goes hand in hand with a the autoinjector, supporting an autoinjector product development. robust PD strategy that ensures quality in device that can address the requirements of the combination and interaction of its input the primary container, industrial design and The authors would like to thank Kai Kiutra, variables. When it comes to autoinjectors, usability needs of the end user (Figure 4). Robin Wang and William Wang for their these input variables pertain to various contributions to this article. layers of elements that are involved in device CONCLUSION development, including the interacting parts ABOUT THE COMPANY that constitute a final assembled device and SHL believes that the key to delivering self- the network of processes involved. administrable medicines in the comfort of SHL Medical is a world-leading solutions With more than 20 years of experience one’s home is not only innovative device provider in the design, development and developing drug delivery devices, SHL technologies, but also the sound processes manufacturing of advanced delivery

20 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd SHL Medical

devices, such as autoinjectors, pen Processing: Development, Design and 4. “Final Assembly, Labelling & Packaging: injectors and wearable drug delivery Implementation of Manufacturing An Integrated Solution for a Frustration systems. It also provides final assembly, Processes” (Jagschies G et al, eds). Free Last Mile”. ONdrugDelivery labelling and packaging services for Elsevier Science, 2018, pp 1105–1136. Magazine, Issue 86 (May 2018), pp 6–8. leading pharmaceutical and biotech 3. Williams T et al, “The Effects of 5. Wild L, Fuensalida Pantig GR, companies across the globe. With locations Design Changes and Delays on “The “Customisable Platform” in Switzerland, Taiwan, Sweden and the Project Costs”. J Oper Res Soc, Paradox”. ONdrugDelivery, US, SHL has successfully built a strong 1995, 46(7), pp 809–818. Issue 113 (Oct 2020), pp 80–85. international team of experts that develops breakthrough drug delivery solutions for pharma and biotech customers. These include advanced reusable and disposable ABOUT THE AUTHORS injectors that can accommodate high- Markus Goldinger is the Senior Director of Process Development at SHL Medical located volume and high-viscosity formulations – in Taiwan. He joined SHL in 2017 as Senior Manager in Process Development, where and connected device technologies for next- he was responsible for project engineering, moulding process development and assembly generation healthcare. process development. In late 2018 he also took over component development, including metal, packaging and printing process development. Before his current role, Mr Goldinger REFERENCES took directorship of process development in early 2019. In this position, he successfully restructured and guided his team towards SHL Medical’s high-volume production strategy. 1. Clark JP “Chapter 6 - Process and equipment selection” in “Practical Erik Alexandersson is an Assistant Manager of Process Development at SHL Medical. Design, Construction and Operation He is responsible for assembly process development, a key stream in the design, development of Food Facilities” (Clark JP, ed). and manufacturing of parts and sub-assemblies that make up SHL’s autoinjector device Elsevier Science, 2008, pp 85–123. technologies. Mr Alexandersson brings a wealth of subject-matter expertise in process 2. Hejnaes KR, Ransohoff TC, development relating to medtech devices, having 15 years of experience in the medical “Chemistry, Manufacture and device industry. He holds an MSc in Embedded System Design. Control” in “Biopharmaceutical

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5-6 OCTOBER 2021 GOTHENBURG, SWEDEN PRE-CONFERENCE WORKSHOPS: 4 OCTOBER CONFERENCE & EXHIBITION: 5-6 OCTOBER TRAINING: 7-8 OCTOBER Nemera

THE ADDED VALUE OF A PLATFORM APPROACH: PEN INJECTOR CASE STUDY

In this article, Radosław Romańczuk, MD, Pen Platform Business Development Director; Severine Duband, Category Director, Devices; and Audrey Chandra, Category Project Manager, all at Nemera, discuss the development of the company’s pen-injector platforms and how they are tailored to meet the customer’s needs.

INJECTION AND PATIENT ADHERENCE Over the last decade, we have witnessed a dynamic increase in therapies that make Parenteral administration is preferred in use of biological drugs – medicines derived emergencies related to cardiac diseases from living cells or through biological or anaphylactic shock, and, in certain processes.2 therapies, it is the only possible route of Polypharmacy and dosing frequency administration (monoclonal antibodies appear to be rate-limiting factors in patient Dr Radosław Romańczuk (mAbs), , etc). In comparison with satisfaction and subsequent adherence.3 Pen Platform Business , injection has a number For self-injected drugs, the user interface Development Director of significant advantages, such as better plays an important role in the catalogue of E: [email protected] bioavailability, faster onset of effect, factors that influence patient compliance, more predictable pharmacokinetic and while reducing the complexity of the pharmacodynamic profiles and avoiding drug administration procedure has been the first-pass effect. The subcutaneous highlighted as particularly important.4 route of administration is highly preferable for many injectable drugs, such as A PLATFORM APPROACH trastuzumab, rituximab, bortezomib, TO MEET KEY USERS’ NEEDS granulocyte-colony stimulating factor (GCSF), immunoglobulins, epoetin alfa and In order to increase patients’ compliance Severine Duband heparin. For some drugs (e.g. insulin), the and adherence, as well as to accommodate Category Director, Devices choice of administration route depends on pharmaceuticals’ needs, developing a device E: [email protected] the clinical circumstances.1 platform needs to be strategically defined to ensure that it is designed for the maximum possible range of potential therapeutic areas and “In order to increase patients’ patient populations. This is to compliance and adherence, ultimately assure the device as well as to accommodate effectiveness. With this in mind, through user-evaluation studies, pharmaceuticals’ needs, a platform should be tested by developing a device platform a broad, representative range of Audrey Chandra participants that reflects the Category Project Manager needs to be strategically defined E: [email protected] diversity of potential device end- to ensure that it is designed for users. After performing this the maximum possible range of upstream work and early-stage Nemera diligence, a platform can be further 20 Avenue de la Gare potential therapeutic areas and 38290 La Verpillière examined using risk analysis to France patient populations.” mitigate negative surprises in the late-stage development process. www.nemera.net

24 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd Nemera

in early design research framework and human-factors strategy enables the company to leverage and tailor its product lines and platforms across different administration routes, including the recently acquired former Copernicus’s (Szczecin, Poland) pen platforms. Insight Innovation Centre (Chicago, IL, US) brings its experience from the earliest development phase. For example, within the US market, Insight helps navigate through the regulatory landscape to develop fitting solutions based on US FDA prerequisites (Figure 1). Furthermore, Copernicus’s proven Figure 1: Comprehensive capabilities in the design and manufacture of pen injectors track record in the design, development built through years of experience and targeted acquisitions. and manufacture of pen injectors boosts Nevertheless, a platform should go In this way, the combination of Nemera’s parenteral product portfolio and through several adjustments and a few technological solutions that ensure small series capabilities. The acquisition customisations to further translate it functional parameters are specified in strengthens the company’s proprietary into a suitable combination product for defined ranges that provide a platform for product platform offering and establishes both its target drug and the intended user the development of new products. an operations footprint in Eastern Europe. population. The goal is to leverage baseline The use of the existing platform for the Nemera’s story continues to reinforce knowledge and generated data throughout development of other pen injectors based its focus and purpose of always putting the the development of a device platform, then on technological solutions invented in the patient at the centre of everything it does tailor it into a specific combination-product course of the development of this platform by becoming the partner of choice for the to meet pharma’s needs. is associated with a number of significant design, development and production of benefits, amongst which the following devices, including pen injectors. NEMERA PEN INJECTOR PLATFORMS: deserve special attention: Acquired by Nemera in October 2020, DESIGNED FOR VARIOUS THERAPIES Copernicus has developed four product AND APPLICATIONS • Reduced development time platforms for pen development and • Lower development costs manufacturing. These include PENDURA Innovative technological solutions that • Reduced risks of developing a new pen AD®, PENONE®, PENVARIO® and offer a simple and intuitive user interface • Implementation of a user interface with PENHV®, which are designed for reusable are easily adopted by patients. This favours market-proven acceptability. and disposable devices for various therapies adherence to therapy as well as safe to meet key users’ needs (Figure 2). and reliable dose delivery. Furthermore, By fostering the platform approach, PENDURA AD® is Nemera’s product successful technology can be applied to the coupled with Nemera’s integrated end- platform, dedicated to the manufacturing development of other medical devices. to-end service programme offerings, the of market-proven, reusable pen injectors, company helps its customers accelerate their which integrates an automatic, spring- specific combination product development driven feature coupled with a side- programmes in the sprint to market. activation button. The range of products “Nemera’s long-standing Nemera’s long-standing experience in developed from the PENDURA AD® experience in the the high-scale production of tailor-made platform includes pen injectors dedicated pen injectors serves as a strong foundation to the administration of insulin and its high-scale production and legacy that steers the company to analogues, growth hormones and of tailor-made pen go the extra mile, continuing its story. PTH analogues, amongst others. injectors serves as a Thanks in large part to the two strategic In the disposable segment, PENONE® acquisitions made in the last couple of has been marketed for its multiple-use fixed- strong foundation and years, Nemera is well on its way to dosing feature, including a dose counter in legacy that steers the fulfilling its vision of becoming one of the addition to the ergonomic side-activation company to go the extra most patient-centric drug delivery device button, as well as the automatic, spring- companies worldwide. driven delivery. Thanks to the presence mile, continuing its story.” Due to the acquisition of Insight Product of a dose counter, the user of each pen Development in 2019, Nemera’s strength from the PENONE® platform has ongoing

Copyright © 2021 Frederick Furness Publishing Ltd www.ondrugdelivery.com 25 Nemera

spring-assisted, non-extendable push-button on top of the pen to facilitate seamless, low-force injection. It provides constant speed delivery for both fixed- and variable-dose pens and is highly customisable. Depending on the functional parameters defined together with the customer, a platform is selected that will be used to develop the pen injector with parameters strictly defined in the user requirement specification. Each product platform can be used to design pen injectors dedicated to both generic and innovative drugs. Having Nemera’s own design and development, own tool shop for the production of moulds, fully equipped plastic injection moulding setup and the possibility of both semi-automatic and fully automated production, means the company is able to provide a short time-to-market and cost-effective development of the pen injectors, based on its proven product platform, and to scale the production according to the actual customer needs.

Figure 2: Four pen injector platforms for various therapies to meet key user needs. control of the number of doses remaining in the pen. As a result, the PENONE® platform is regularly chosen for the development of pen injectors dedicated to various drugs with a fixed therapeutic dose. Continuing Nemera’s story within the disposable pen injector space, its standard platform, PENVARIO®, is designed to be suitable for any drug with standard manual variable dosing. It is highly customisable for a wide range of applications, to match any drug administration. Thanks to its high flexibility in scaling production, Nemera is capable of meeting its customers’ needs in both low- and “Developing a pen high-scale production. device based on existing Along with the rise of high viscous platforms facilitates drugs and larger-dose the application of such volume administration, technological solutions Nemera identified the need for low- that can significantly force spring-assisted foster patient adherence disposable pen to the therapy, hence the injectors designed for ease-of-use. Therefore, competitive positioning using its long-standing of the drug used for experience in spring- administration with a assisted pen injectors, Nemera has developed given pen.” the PENHV® platform, Figure 3: Improving patients’ adherence through which incorporates a ergonomic solutions.

26 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd Nemera

CASE STUDY: PATIENTS’ BENEFITS TRANSLATED INTO SALES INCREASE

Innovative, user-friendly technological solutions invented during the development of the product platform are used in all pen injectors from a given platform. For this reason, the customer can be more confident both in terms of development timelines and its final results. Moreover, developing a pen device based on existing platforms facilitates the application of such technological solutions that can significantly foster patient adherence to the Figure 4: The impact of introducing a pen injector from the PANDORA AD® platform therapy, hence the competitive positioning on the dynamics of drug sales. of the drug used for administration with a given pen (Figure 3). to the new platform, dedicated to the are developed based on proven technological An example is the introduction of a pen production of other types of pen injectors. solutions, and their development is carried from the PENDURA AD® platform to the For example, the use of a technological out by experts in the field of human factors European market. The manufacturer of solution that allows the ergonomic location engineering, design and production. the drug, whose domestic sales growth was of the dose-release button on the side of the Looking to the future, Nemera is three times lower than that of the market pen, allowing the user to stabilise their hold actively working on innovative platforms, leader, decided to change the pen injector on the pen by resting their hand against the by leveraging existing and discovering previously offered for use with its drug to body during dosing. novel techno-bricks. Tapping into the a pen from the PENDURA AD® platform. The positive assessment of this converging trend of digital health and Within two years after the introduction technological solution used in reusable pen connectivity, the company is currently of the pen injector from the PENDURA injectors from PENDURA AD® platform, developing advanced solutions with the AD® platform, there was a decrease in the expressed by users in several post-market ultimate purpose of improving patient official drug price, which have could have surveys, meant that the technological outcomes through offering robust and easy- significantly jeopardised the sales results solution enabling the location of the to-use solutions. of all the drug manufacturers. However, dose-release button on the side of the pen thanks to the introduction of the was also used in the PENONE® product ABOUT THE COMPANY PENDURA AD® platform pen injectors, platform dedicated to disposable fixed-dose the sales value of the drug used with this pen injectors. As a world-leading drug delivery device pen increased, while the sales value of solutions provider, Nemera’s goal of the company’s competitors significantly NEMERA: YOUR PARTNER OF putting patients first enables it to design dropped. This example shows the value CHOICE IN DESIGN, DEVELOPMENT and manufacture devices that maximise for the user of the pen injectors from the AND MANUFACTURING treatment efficacy. Nemera is a holistic PENDURA AD® platform, as well as the partner and helps its customers succeed in role of the injection devices in the choice of With the integration of Copernicus and the sprint to market with their combination the brand within a therapy area (Figure 4). Insight Product Development, Nemera products. From early device strategy to It is worth mentioning that some detailed offers the highest quality standard for its state-of-the-art manufacturing, Nemera is technological solutions can be imported customers and patients. The pen injectors committed to the highest quality standards. Weknow drug delivery www.ondrugdelivery.com/subscribe

Copyright © 2021 Frederick Furness Publishing Ltd www.ondrugdelivery.com 27 Nemera

Agile and open-minded, the company works with its customers as colleagues. ABOUT THE AUTHORS Together, they go the extra mile to fulfil its mission. Radosław Romańczuk, MD, Pen Platform Business Development Director, has over 20 years of experience in the life sciences industry. He is the author of the concept of a REFERENCES series of pen injectors, produced by Copernicus, which was acquired by Nemera in 2020. The development and usability of medical technologies is perceived by Dr Radoslaw 1. Jin J et al, “The optimal choice in three dimensions, representing his versatile experience – the perspective of a medical of medication administration doctor, the perspective of the person managing marketing and business development in a route regarding intravenous, biotechnological company, and the perspective of a person in charge of development of intramuscular, and subcutaneous pen injectors franchise within a patient-centric device manufacturing organisation. injection”. Patient Prefer Adherence, 2015, Vol 9, pp 923–942. Séverine Duband is Marketing Director for drug delivery Devices at Nemera, steering overall 2. Sengupta A, “Biological Drugs: category strategy, product portfolio and innovation development for five key delivery routes. Challenges to Access”. Third World She has been leading the parenteral segment at Nemera since 2018, focusing on proprietary Network, Penang, Malaysia, products such as safety systems, pen injectors and on-body injectors. Ms Duband graduated 2018, pp 5-15. from Emlyon Business School (Lyon, France) in 2004, and joined Nemera’s Global 3. Boccara, F et al, “Practical Marketing team in 2018 as a Global Category Manager, focusing on the parenteral segment. Considerations for the Use of Subcutaneous Treatment in the Audrey Chandra is the Category Project Manager at Nemera. She joined Nemera in 2019. Management of Dyslipidaemia”. Adv Ms Chandra graduated from the Faculty of Medicine, Atma Jaya University (Jakarta, Ther, 2017, Vol 34, pp. 1876–1896. Indonesia) and pursued her master’s degree in strategy and business development at 4. Zahn JD, “Analysis: desirable Toulouse School of Management (France). With her dual competencies, she is in charge attributes of insulin injection pens of providing strategic support for various targeted marketing projects. Additionally, that drive patient preference and Ms Chandra actively works on diverse content management along with communication compliance”. J Diabetes Sci Technol, activities co-ordination. 2011, Vol 5(5), pp. 1210–1211.

21 October 2021 - PLATFORM Congress Center Basel Register now

8th Medtech & Pharma Platform (MPP) Annual Conference: ‘Achieving agility to foster innovation and bring value to patients’ The MPP organizes the Annual Conference to provide a cross-sectoral forum to exchange knowledge, collaborate in technology and regulatory areas, as well as to promote product development and innovation. As the leading conference in Europe for products and solutions that combine medicinal product and medical device components, including devices that incorporate software, our annual event is dedicated to enhancing partnership between the pharma, medtech and tech sectors. Our audience includes experts and professionals from the pharma, medtech and tech industries as well as regulators, patients, academia and payers active in the field.

Knowledge exchange Exhibit at the platform 2021 1-on-1 partnering Prominent speakers from regulatory Showcase your company or The 1-on-1 partnering enables authorities, patients‘ organizations, organization to industry and participants to start building government institutions and industry regulatory professionals new partnerships and to foster share their insights across various by becoming an Exhibitor or a cooperation in a business-friendly session topics, providing insights into Sponsor and benefit from additional environment. It is an excellent current and future opportunities and presentation and networking opportunity to network with many challenges in the development of opportunities. high-profile industry players. innovative combined products.

About the Medtech & Pharma Platform association The MPP Association is a cross-sectoral not-for-profit industry association focusing on combined products. The Association comprises medtech, pharma and ICT companies dedicated to enhancing synergies between these industries. The Association aims to achieve a balanced regulatory framework for products combining medicinal product, medical device and software components to reduce time to market improve access to innovative products and better match patients’ needs. www.medtech-pharma.com

28 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd World-leading drug delivery device solutions provider

Holistic partner

Early device strategy to state-of-the-art manufacturing

High quality standards

www.nemera.net [email protected] +33 (0)4 74 94 06 54

ODD PENS - 05-2021_revMB-bleed.indd 1 18/05/2021 08:32:03 Cambridge Design Partnership

FORMULATION & DEVICE DEVELOPMENT: A SYMBIOTIC RELATIONSHIP

In this article, Caroline Zakrzewski, Drug Delivery Devices Scientist at Cambridge Design Partnership, considers the interaction between formulation and device development and the challenges that drive innovation in the field. Her work frequently sits in the overlap between formulation and device development, navigating the interwoven steps that lead to the sweet spot, where formulation and a device work in tandem, providing safe and effective delivery of the drug.

It’s often been said that formulation PRIMARY CONTAINER SELECTION development would be easier with the “final” device, and developing the device would be In its most basic presentation, a easier with the “final” formulation. It’s a formulation can be stored in a vial or nice idea, but it could miss the symbiotic ampoule and extracted by a syringe just effect that each can have on the other – before administration. This is easy to driving innovation in both fields (Figure 1). manufacture but does not consider all the Here we will explore some of the key needs of the end user. It was the method topics that arise when developing a drug used 100 years ago, when the first insulin and device combination product, and how injections were carried out in humans and, the iterative development of formulation whilst the fundamental mechanism remains and device can be beneficial for all the the same, the development in primary key stakeholders. containers has significantly improved.

Caroline Zakrzewski Drug Delivery Devices Scientist T: +44 1223 264428 E: caroline.zakrzewski @cambridge-design.com

Cambridge Design Partnership Ltd Figure 1: The symbiotic Church Road relationship of Toft formulation and delivery Cambridge device drives innovation. CB23 2RF United Kingdom

www.cambridge-design.com

30 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd Cambridge Design Partnership

Most primary containers used for storage administer the formulation. There is a broad dispersal, but this isn’t always possible or of small-volume injectables are made of classification in the USP that small-volume acceptable to the patient. There’s a tendency glass. The formulation’s influence on the parenterals are those which have a volume to increase the formulation concentration choice of glass primary container can be under 100 mL, but the volumes discussed to reduce the volume, which can be effective as simple as UV sensitivity, driving the here focus on the range of 0–10 mL. but goes hand in hand with an increase in use of amber ampoules or vials, or more Consider a delivery volume requirement viscosity. Increasing the viscosity affects the complex, with interactions on a molecular of a straightforward liquid formulation. force required to deliver the formulation, level seen with silicone or tungsten oxides. The most basic presentation would be particularly through thinner needles, Commonly, liquid silicone is used to coat a vial or ampoule and a syringe, where hindering the appropriate administration the inside of syringes and cartridges so that the vial (not reasonably constrained by in a manual injection and stretching the plungers can advance to administer the size) could hold several doses. But what the capabilities of many autoinjectors. dose. The silicone can form microdroplets if this isn’t suitable? As well as reducing In response to this, thin or ultra-thin walled in the formulation, providing nucleation the number of required components, PFSs needles have been developed, but there are sites and initiating agglomeration of larger reduce the number of use steps and the physical limits constraining innovation in molecules, such as biologics. Overcoming potential for use error associated with the this area. this interaction may involve moving to a vial and syringe presentation. However, If the requirement is for delivery of more primary container coated with baked-on they do bring additional challenges related than 2 mL, particularly for a subcutaneous silicone, which is chemically bonded to the to formulation stability. The requirement delivery, it’s sensible to consider whether glass surface, or to more recent silicone-free to be able to inspect the contents of the a bolus injector would be appropriate. developments such as the GORE (Newark, syringe prior to administration prevents Attached to the body for a short period of DE, US) ImproJect Plungers with Schott’s the use of amber-coloured materials, which time, these devices deliver a larger-volume (Mainz, Germany) syriQ BioPure® silicone- would have been present in the vial format injection over a set time of minutes or free syringes. There’s a similar consideration to prevent the formulation being degraded hours, and have capacities up to 10 mL, for the sensitivity of the drug to tungsten by UV light. This can be resolved either sometimes more. Examples of these types oxide residues deposited during the glass- through tertiary packaging or changes in of injector can be seen in the development forming process. Spiking the formulation the formulation – the former being easier of West Pharmaceutical Services’ (Exton, with representative residues can give an early than the latter. PA, US) SmartDose®, the Enable Injections’ warning of whether this will be an issue, and PFSs can be used on their own or (Cincinnati, OH, US) delivery device and alternative manufacturing methods can be within autoinjectors that carry out many BD’s Libertas™. In a similar class are used, although this increases cost. of the use steps required in a repeatable the ambulatory pumps which provide a The requirements for a sterile, single- and reproducible way, improving patient consistent, fixed-rate infusion of a drug use syringe to draw up from an ampoule compliance. It’s possible, as shown by into the body and are commonly used for or vial led to the development of plastic Teva (Petah Tikva, Israel) with Copaxone® insulin delivery. syringes, which are cheap to mass produce (glatiramer acetate injection), to launch and customise, and much more robust for the PFS as a stand-alone presentation DRUG CHARACTERISTICS handling and transport. Typically made prior to investing in the development of an from , these can be unsuitable autoinjector. Most autoinjectors currently So far, the consideration has been for for prefilled syringes (PFSs) because the on the market are for delivery volumes formulations that are stable as , but moisture vapour transmission rate can up to 1 mL, either subcutaneously or this isn’t always possible due to either cause concentration changes over time intramuscularly. There are systems that the nature of the active ingredients and absorption of the molecules onto the can deliver larger volumes, but these come or the time available in development. internal surfaces of the syringe can occur. with challenges; a high flow rate during The current crop of covid-19 vaccines More recently, advances in administration can cause local pain and is a good example of this latter point. technology have sought to overcome these discomfort at the injection site, and for issues. Cyclic olefin copolymer (COC) and slower flow rates it may be difficult to cyclo olefin polymer (COP) are gaining maintain the injector position for the time it traction in the pharmaceutical industry takes to inject. “The move towards more as viable alternatives to glass PFSs. As the delivered volume requirement patient-centric treatments, The tighter dimensional tolerances and more increases to 2 mL and above – particularly where the patient is not flexible customisations of these syringes give common in biologics – there’s a decision to them advantages in more complex delivery be made. With an injection of up to 2 mL constrained to having devices, with a growing body of stability completed within 15 seconds, the reaction their treatment delivered evidence behind them to address business of the injection site to the introduction in a healthcare setting risk concerns. of this volume becomes a factor in the ability to effectively deliver the formulation. or even by a healthcare DELIVERABLE VOLUME The 5 mL of professional, is driving Roche’s (Basel, Switzerland) Herceptin innovation in both For subcutaneous or , (trastuzumab) has shown that changes the delivered volume has perhaps the largest to the formulation, such as the addition formulations and devices.” influence on the type of device selected to of hyaluronidase, can help subcutaneous

Copyright © 2021 Frederick Furness Publishing Ltd www.ondrugdelivery.com 31 Cambridge Design Partnership

Lyophilisation is a well-established process HOW WILL THE DEVICE BE USED? with the drug presented to the user in a dry “Innovation in formulations form for the addition of a diluent The move towards more patient-centric to reconstitute the formulation immediately treatments, where the patient is not and their devices is far prior to administration. The knowledge and constrained by having their treatment from finished, as therapies experience of manufacturers around the delivered in a healthcare setting or even become more complex and lyophilisation in vials, as well as the capital by a healthcare professional, is driving investment needed for the infrastructure to innovation in both formulations and current markets experience support this, creates inertia in the introduction devices. This can be seen most clearly a trend towards patient- of this type of formulation. The number in the range of treatment options that centric self-administration.” of use steps required for reconstitution is exist for Type I diabetic patients. Although significantly more than for just a vial drawn the basic vial and syringe format is still up into a syringe, requiring transfer of the common, disposable and reusable injector diluent from a second container followed pens, such as Eli Lilly’s KwikPen (insulin devices that provide tangible data on patient by agitation to ensure a homogenous lispro injection) or Novo Nordisk’s compliance, and more cost-effective primary solution. This increases in significance if the NovoPen respectively, are widely available container technology to support the next resulting solution is to be administered with on-body pumps, such as Medtronic’s generation of formulations. in several small doses. The need for a MiniMed™ providing additional options. The challenges that formulators and more user-friendly administration of this The device developers have challenged device developers set for each other are type of formulation drove the development formulators to develop insulin formulations driving innovation in the field, and it is of dual-chamber systems and the devices that are stable at body temperature, to exciting to play a part in this process. that contain them. Taking inspiration support the use of ambulatory pumps. In from the PFS model, dual-chamber systems return, the formulators have challenged ABOUT THE COMPANY were developed to reduce the use steps device developers to accurately deliver single and materials required to reconstitute and doses of increasingly concentrated solutions, Cambridge Design Partnership (CDP) is administer this type of formulation. with the move from a standard U-100 to an end-to-end innovation partner focused Dual-chamber systems contain both the U-500 and even U-1000 formulations. on helping clients grow. Some of the dry powder drug and diluent in separate No discussion of devices would be world’s largest companies trust CDP to chambers during storage to maintain the complete without mentioning connectivity. design and develop their most important shelf life and stability of the drug product The recent trend towards connected devices innovations. Located in Cambridge (UK) and facilitate the integral reconstitution allows feedback to the user – normally using and Raleigh (NC, US), CDP specialises in though a simple use step prior to an app – on how well they are adhering the consumer, healthcare and industrial administration. Common systems include to their regime. This can also provide markets. Its multidisciplinary teams a glass syringe or cartridge with an external information to the monitoring physician have expert knowledge to identify bypass – a channel that allows the diluent on the suitability of the treatment format, opportunities and overcome challenges to transfer past the separating plunger and with the potential to provide in-market throughout the product development and into the dry powder chamber. Adding only trends that drive further formulation and manufacturing process. enough components needed to facilitate device innovations. the administration, devices such as Vetter’s (Ravensburg, Germany) Lyo-Ject® embody THE FUTURE the core functionality of this type of system. ABOUT THE Systems such the Credence MedSystems’ So, what is next? Innovation in formulations AUTHOR (Menlo Park, CA, US) Companion® series and their devices is far from finished, as build on this principle, linking novel internal therapies become more complex and current Caroline Zakrzewski is a Science bypass technology with the passive needle markets experience a trend towards patient- Consultant with Cambridge Design safety that is becoming a requirement in centric self-administration. We’ve seen how Partnership. Holding masters degrees many healthcare settings. previous limits of acceptable subcutaneous in Chemistry and Pharmaceutical Like the PFSs on which they are based, injection have been stretched by Roche’s 5 mL Engineering, she specialises in drug dual-chamber systems are expanding into Herceptin (trastuzumab) formulation, how delivery devices. Her career includes autoinjectors, with products such as Pfizer’s devices have assisted in the delivery of highly the co-ordination of multidisciplinary Genotropin® (somatropin) pen guiding the viscous formulations previously unable to be groups involved in the design, user through the reconstitution steps and administered by manual injection, and how development, industrialisation enabling them to dial subsequent doses for the introduction of integrated reconstitution and commercialisation of PFSs, delivery. The challenge of the current dual- has allowed patients more freedom over autoinjectors, pen injectors and a range chamber systems goes back to deliverable their treatment profile. of inhalation devices. Ms Zakrzewski volume. In the current format, the need for On the horizon are integrated systems has a keen interest in the establishment both the diluent and dry powder chambers that overcome the challenges still present in of robust processes to facilitate the to have sufficient space to contain the reconstitution by the patient, devices that technical transfer of products into deliverable volume makes the devices bulky, help to maintain a formulation manufacturing. particularly as volumes increase. over time in a bolus injector, connected

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2021-01-21 Ad Medical Magazin_final.indd 1 22.01.2021 11:26:25 Oval Medical Technologies

PATIENT-CENTRICITY: THE IMPORTANCE OF HUMAN FACTORS IN THE PANDEMIC ERA

In this article, Marcus Agunloye, Senior Human Factors Engineer & Industrial Designer at Oval Medical, and Asmita Khanolkar, Senior Director, Cambridge Pharma, SMC Technical Strategy & Commercialization, discuss how patient-centricity is at the heart of drug delivery device design and innovation, and how the global pandemic Marcus Agunloye has highlighted the importance of patient-centric development in this field. Senior Human Factors Engineer & Industrial Designer The drug delivery device T: +44 1223 736220 E: [email protected] market is expected to grow “There is a lot of work still to be done tremendously, bringing novel Oval Medical Technologies technologies and therapies to in this field to truly understand the Unit 3, Enterprise 3930 life. The key factors driving concept, process and what exactly Cambridge Research Park this innovation peak include Beach Drive the success criteria are towards a Waterbeach a trend towards moving care Cambridge out of hospitals and into patient-centric development. The United Kingdom patients' homes, adoption pandemic has opened our eyes to of smart devices, predictive the importance of human factors www.ovalmedical.com data analytics, targeted therapeutics and personalised considerations even further.” medicine. Patient focus is a common theme in all these drivers. As we begin this decade, it is clear pandemic threat of covid-19 the push for that patient-centricity is at the heart of virtual care, longer time between hospital all innovation and one of the most visits, and at-home care for chronic diseases important considerations throughout the has increased. An example is the transfer of development process. However, there is a chemotherapy treatment from hospitals to lot of work still to be done in this field homes, which has led to a requirement for Asmita Khanolkar to truly understand the concept, process subcutaneous delivery of cancer treatments Senior Director, Cambridge Pharma, and what exactly the success criteria are as opposed to intravenous delivery in a SMC Technical Strategy towards a patient-centric development. hospital setting. This trend is generating a & Commercialization T: +1 978 422 6800 The pandemic has opened our eyes to the need for devices for self-administration that E: [email protected] importance of human factors considerations can deliver large volumes of formulation even further. and drug containers that can withstand high SMC Ltd pressures in order to provide acceptable 18 Independence Drive MARKET TRENDS delivery times. Successful high-pressure Devens MA 01434 delivery device systems will determine the United States Global trends continue to move medical success of this important transition from care from hospitals to homes, with the hospital to home. www.smcltd.com

34 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd Oval Medical Technologies

current global pandemic. The three effects experience (Figure 1). Patient safety and “The three effects of the of the covid-19 pandemic, namely isolation, therapy outcomes are the first layers of virtual care and remote learning, are all consideration. Current complaints vary covid-19 pandemic, namely elements that amplify the problems of with the application and include both isolation, virtual care and self-administered devices. Under the crisis and chronic use. For life threatening remote learning, are all conditions of the pandemic, patients diseases, obviously this can be profoundly couldn't be trained in hospitals and overall serious and have serious consequences. elements that amplify access to healthcare practitioners (HCPs) For emergency-use devices, it is imperative the problems of self- was limited, yet more and more therapies that the accurate dose is injected at administered devices.” started moving towards home care. the correct depth, intramuscularly The pandemic emphasised the need for or subcutaneously. Some of the human intuitive devices that need only very minimal factors considerations in these applications training. Crisis devices are often used by a focus around patient populations. Patient Smart devices are an area of opportunity carer, a teacher or even a passer-by, and physiology is different in children compared to enhance user engagement with their again, in such cases, intuitive-to-use devices with adults, and important considerations treatment process. Using a smartphone or are needed for effective dosing. of needle-to-muscle depth accuracy other digital device can offer the patient In addition, the effect of isolation repeatability when overcoming population an expanded user interface, including and emotion on the use of the device diversity is an important factor. useful functionality such as dose tracking, requires a non-threatening, welcoming, Some of the challenges with glass reminders and training information, integrated functional approach. containers include breakage and and can also offer opportunities for the The pandemic also highlighted the effects repeatability issues due to siliconised prescriber to understand adherence when of disparity where technology may not rubber. In high-pack glass syringes, care is moved to the home. However, be universally available. Not everyone patients have experienced variability of this relies on two things from the patient – is technology savvy, and digital literacy injection times, resulting in wet injections. access to technology and their engagement may be a big factor in the correct use of In the case of biologic drugs, this can with the smart system. Whilst the adoption the device. In addition, diversity factors potentially cause immunological response of smartphones is becoming more and are more exaggerated with remote site due to wet injections. Other impurities more widespread, there are still patient limitations, spread of information and such as tungsten in needle-staked glass populations that may struggle to afford an patient involvement. It is clear that the containers can pose issues for the stability of up-to-date smartphone, so understanding one-size-fits-all approach does not work delicate drugs, such as biologics, and result patient access to technology must be a key with diverse patient populations, including in degradation of the drug and unwanted consideration in the inclusion of this type of paediatric and geriatric populations, and therapy outcomes. Finally, use errors are technology into a drug delivery device. a range of users from patient to carer to on the rise due to the pandemic and lack of Whilst adding further functionality and community pharmacist, and a variety of training, this demands intuitive devices. data information for the user through a dose regimens are required. Patient adherence and overall experience connected device may seem like an easy are the second layers of considerations and way to improve the patient experience, it ELEMENTS OF A equally important. Particularly with self- is important to understand if the patient “PATIENT-CENTRIC” MODEL administered devices, ease of use becomes a wants to engage with this. Some patient priority. Devices need to be easy to use without populations may find the steps required to set The four important areas of considerations training, or with minimal training, should up a connected device confusing or taxing, for human factors include patient safety, promote adherence, be non-intimidating and or may have a general reluctance towards patient outcomes, patient adherence or perform robustly and reliably every time for technology that might make a connected compliance, and finally, the overall patient a positive overall experience. device a barrier to adherence rather than a motivator. Overall, there may be compelling use cases for the integration of digital systems into drug delivery devices, but it is important to understand how the patient population will respond to it by exploring the area with them and considering the full range of costs and benefits associated with this type of integration before moving forward with it.

HUMAN FACTORS CONSIDERATIONS IN THE PANDEMIC

Human factors considerations are even more important than ever in identifying specific patient needs, particularly in the Figure 1: Elements of a patient-centric model.

Copyright © 2021 Frederick Furness Publishing Ltd www.ondrugdelivery.com 35 Oval Medical Technologies

“Using patient insights on cognitive and emotional needs, lifestyle, population diversity, technology access and adoption skills, reliability and sustainability can help add further benefits to the therapy.”

Long-acting injectables provide a better overall patient experience due to a reduced number of injections. However, it is important to focus on adherence and if the Figure 2: Incorporating patient needs for intuitive autoinjector designs. patient will remember to administer their injection regularly each month, and to create First and foremost, the best approach available for the patient to support a feedback loop so the prescriber knows to solve this is to make the device as themselves, such as training videos and clear that the patient is receiving their treatment. simple and intuitive to use as possible. instructions for use. Training decay can also be an issue if the This can also be supported with training A patient-centric model requires patient only uses the autoinjector once a the patient, such as having an HCP additional elements with the patient at the month – will they be able to remember how guide the patient through the first few heart of the thought process, and designing 1 to use it again a month later? injections and by having robust information around the patient. Using patient insights on cognitive and emotional needs, lifestyle, 6 population diversity, technology access and adoption skills,9 reliability and sustainability 1 can help add further benefits to the therapy. 1 Oval’s approach to device development 7 6 combines6 a deep understanding of the Key Characteriscs 1 9 patient’s needs, coupled with the technical 97 needs when developing 3patient-centric 1. Curved Top Body 6 Figure 3: Key design features with a human approach. 1 2. Tacle Waist autoinjectors that can be customised to 9 3. Cap smile 7 deliver a wide range of drug formulations, 1 6 2 Key Characteriscs 4. Cap Tacle Proudness 1 including8 fragile 8molecules for both 9 2 5. Frosted Cap 7 subcutaneous and intramuscular injection 3 1. Curved Top Body 6. Front View Symmetric6 Body with high3 viscosities and a wide range of 2. Tacle Waist 7. Crisp Edges (For smaller devices) 9 6 delivered volumes (Figure 2). 3. Cap smile 8. Tension Viewing window 5 5 5 2 4 4 4. Cap Tacle Proudness 9. Down Force Dexterity Friendly 8 8 PATIENT-CENTRIC DESIGN THINKING 5. Frosted Cap 2 9 6. Front View Symmetric Body 3 7. Crisp Edges (For smaller devices) 1 To put the user case at the heart of the 8. Tension Viewing window 5 5 5 process, the device design must satisfy 7 4 4 9. Down Force Dexterity Friendl1 y 6 functional, cognitive, aesthetic and Key Characteriscs 9 emotional balance. This requires flexibility 7 in the design space for both the inside and 3 outside of the device. Moulded primary 1. Curved Top Body 6 drug containers provide both flexibility of 2. Tacle Waist container size and shape, and control of 9 tolerances for reliability of repeated use. 3. Cap smile 2 4. Cap Tacle Proudness 8 8 The inside mechanics need to deliver the 2 therapy in optimised delivery time, depth 5. Frosted Cap and bolus size. 6. Front View Symmetric Body 3 The outside is equally important for key 7. Crisp Edges (For smaller devices) design features with a human approach, 8. Tension Viewing window Figure 4: Human 5 5 5 such as those shown in Figure 3. Figure 4 factors attributes 4 4 shows the human factors attributes applied 9. Down Force Dexterity Friendlappliedy to design. to the product design.

36 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd Oval Medical Technologies

“...with detailed device-user input, supporting materials can be developed, while the internals of the device are developed to meet the needs of the drug formulation.”

materials they were provided with by the manufacturer – and one that may not have been uncovered in a formative evaluation in the development of the autoinjector, as few users vocalised these feelings until they were directly asked how they were currently carrying their autoinjector. A range of packaging concepts were developed at the same time as the crisis autoinjector. Concepts were selected and prototyped, giving a range of materials that could be brought to an early-stage formative evaluation, provoking further conversations with users about their full Figure 5: Patient process mapping. range of needs from end to end of their treatment process, while at the same time The combination of innovative design treatment, and an understanding of issues developing an understanding of how they coupled with small footprint, quiet devices with treatment that may become barriers to were able to use the device. that provide consistent delivery performance adherence (Figure 5). This approach can be applied to both for patient safety, outcome, adherence and There are many examples of such early- platform customisation and bespoke preference is a crucial consideration. stage insights that can have a real effect device development, with early-stage user on the design approach of an autoinjector. research occurring in parallel with the PATIENT PROCESS MAPPING Chronic versus crisis applications pose drug formulation characterisation process, different requirements. Looking at a crisis providing a strong understanding of Patient process mapping is a method that autoinjector that patients must always carry both key inputs: user needs and technical outlines the process of how the autoinjector with them, Oval found users adopting a needs. From there, with detailed device- is used, such that the inputs of the three range of coping strategies for how to store user input, supporting materials can be elements that affect device use – the user, the their devices when carrying them day to day developed, while the internals of the device use environment and the user interface – are – they were using anything from pencil cases are developed to meet the needs of the drug captured in the process. Early-stage field work to zip-lock bags to Tupperware containers formulation. Depending on the identified is a must to put the patient’s needs to the in attempts to make sure that their life- patient needs, a number of design solutions forefront at each stage of autoinjector design. saving device was protected and ready in may be developed encompassing device A key focus in the early stages is getting case they needed to use it. This pointed to packaging and labelling details, with a view feedback and input from patients and users an unmet need – many users didn’t feel their to bringing one or more concepts to an as soon as possible. Through fieldwork, autoinjector was safe enough in the packaging early-stage formative evaluation. such as interviews with patients, caregivers and HCPs in their living and working environments, insight into the patient’s treatment journey can be gained. This can be “This feedback loop of design development and user used to map out each of the touchpoints the interaction allows both the development of a thorough patient interacts with during their treatment, identifying pain points and difficulties they understanding of the users’ interactions with the device may encounter along the way. From this, and use-related risk, while also continuing a conversation the patient’s needs throughout the process with the patient and user population about their needs can be identified, taking into account the basic need to receive the dose, along beyond just the delivery of their medication.” with their emotional needs related to their

Copyright © 2021 Frederick Furness Publishing Ltd www.ondrugdelivery.com 37 Oval Medical Technologies

user and patient’s voice throughout, putting focus not just on the device but on the wider environment and scenarios that affect the patient’s experience, resulting in an end product that is both safe and effective for the user, and optimised to the needs of the patient throughout their treatment journey.

PATIENT USABILITY STUDIES

Formative usability studies are an important part of the feedback loop in patient-centric development, providing insights into device handling and patient preference. The use steps of the device can be tested, with prototype variants of the device provided with packaging, labelling and instructions for use, allowing the evaluation of injection site preference, observation of use errors for safety, improvement areas for the user interface, effectiveness of training and population diversity factors. Examples of feedback Figure 6: Human factors process. measurements may include successful dose PATIENT-CENTRIC development of a thorough understanding delivery and an understanding of the visual DEVELOPMENT STRATEGY of the users’ interactions with the device and audible feedback provided by the device. and use-related risk, while also continuing The feedback from these studies can then These early-stage activities then form a a conversation with the patient and user be used to inform device design, developing crucial input for the rest of the human population about their needs beyond just a device that users can understand and feel factors process. Early concepts are the delivery of their medication (Figure 6). comfortable using. refined and narrowed down and, as the As the device reaches maturity, a Late-stage user studies can then be used autoinjector design develops, subsequent thorough understanding of the use of the to further analyse the design of the user formative evaluations can be undertaken device user interface and its associated risks interface once it has matured. Through with increasingly high-fidelity prototypes. has been developed, with mitigations applied the use of tools such as use-related risk This feedback loop of design development where necessary, ready for validation. At analysis, critical tasks can be identified, and user interaction allows both the the same time, this process maintains the and, by testing these with the intended user population, it can be determined if the device is safe and effective for use and ready “Patient input will always be key to developing the best for human factors validation. Alongside this, late-stage user studies can also be used possible autoinjector. By involving the patient in the to verify that the design decisions made in process early and often, you have the best chance of response to early-stage observations work uncovering their full range of needs and ensuring that for the patient population’s wider needs through discussion on the use of the device. what you are designing responds to them.” This approach was taken in the case study shown in Figure 7, where three user studies were conducted on early-stage device designs. The results from these studies eventually led to the design of the ArQ platform, with its user interface undergoing further refinement through another two user studies (Figure 8). Through this process, findings were made, both about how the device functions and how it fits into the patient’s daily life. In the early stages, user feedback led to the development of the key user interface elements, now found across Oval’s platforms, such as the audible and visual feedback mechanisms. The process also involved testing an autoinjector variant tailored to patient populations with low Figure 7: Design evolution through multiple user studies and patient populations. manual dexterity, the learnings from which

38 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd Oval Medical Technologies

Figure 8: Optimised user interface design elements for ArQ.

Window in cap allowing 360 window allows Indicator fully fills inspecon of drug before visibility of indicator window at end of cap removal with a range of delivery orientaons and grip techniques

Skin sensor extends and Skin sensor visible locks providing needle through translucent cap safety Figure 9: Optimised user interface design elements for ArQ-Bios high viscosity/volume.

influenced Oval’s approach to building an understanding of patient’s specific needs and customising devices to patient populations (Figure 9).

PATIENT FEEDBACK

Patient input will always be key to developing the best possible autoinjector. By involving the patient in the process early and often, you have the best chance of uncovering their full range of needs and ensuring that what you are designing responds to them. By making sure this input is implemented throughout the design process, you can reach validation with a device that is not just safe and effective to use but fits properly into the patient’s life and eases some of the issues they may have previously experienced with Figure 10: “Easy-to-use” steps for a patient-centric design. their treatment (Figure 10).

Copyright © 2021 Frederick Furness Publishing Ltd www.ondrugdelivery.com 39 Oval Medical Technologies

ABOUT THE COMPANIES provides product services from initial SMC has global GMP manufacturing sites concept through the final packaged device; in the US, UK, Costa Rica and India for Oval Medical Technologies, an SMC Ltd including programme management, design moulding, assembly and automated package company, is a drug delivery company whose and development, product manufacturing, integration. SMC's service offerings have patient-centric autoinjector platforms clinical manufacturing, electronics integration been established to ensure the company enable pharmaceutical companies to deliver and global supply chain management. offers superior value to its customers. a wide range of drug formulations for both subcutaneous and intramuscular injection. Oval’s flexible, robust drug ABOUT THE AUTHORS delivery platforms can be tailored precisely, Marcus Agunloye, Senior Human Factors Engineer & Industrial Designer, Oval Medical providing unprecedented scope for Technologies, is a human factors engineer, with experience working in industrial design pharmaceutical companies to address the and human factors in the medical device industry. He joined Oval in 2017, where his needs of current patient populations and focus has been on improving patient experience and safety through user interface design. develop and market new products. With its He graduated with a BA in industrial design and technology from Brunel University (UK). patented integrated primary drug container technology at their core, Oval’s devices Asmita Khanolkar, Senior Director, Cambridge Pharma, SMC Technical Strategy & are safe, reliable and easy to use in their Commercialization, has a master’s degree in materials science & engineering from Worcester target patient populations. The company is Polytechnic Institute in Worcester, MA, US. With over 24 years of manufacturing experience certified to ISO 13485 (2016). specialising in the medical device and pharmaceutical industry, she has managed various device projects from concept to commercial launch. Her product portfolio includes single- SMC is a global device manufacturer for use, wearable and implantable devices, and drug device/device-biologic combination the healthcare industry specialising in drug products for drug delivery, biotech and pharmaceutical applications. Ms Khanolkar has held delivery, medical devices, diagnostics and various engineering and management roles in new product development, manufacturing pharmaceutical services. With over 33 years engineering, advanced quality planning, operations, supply chain and product life cycle of experience, SMC provides an “End-to- management. Her current responsibilities include technical strategy and commercialisation End” integrated solution for clinical and of innovative technology platforms for drug delivery and fill-finished combination product. commercial product manufacturing. SMC

40 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd Ypsomed

TOWARDS USER-CENTRIC SPECIFICATION OF AUTOINJECTOR TECHNICAL ATTRIBUTES: INSIGHTS FROM EMPIRICAL WORK

Here, Andreas Schneider, PhD, Innovation & Business Development Director, of Ypsomed Delivery Systems, discusses an empirical study into both users’ ability to remove the cap from an autoinjector and the difficulty those patients perceived in doing so. Furthermore, the study builds a quantitative model relating the empirical data to patient perception.

Although user-centricity has been a guiding paradigm in the development “A great deal is known of new drug delivery devices, little is known about how technical attributes about if and how of spring-actuated prefilled autoinjectors autoinjectors can be used shape patient perceptions about the ease safely and effectively for of handling them. To shed further light on the subject, Ypsomed conducted an their intended uses and use empirical study1 that explored users’ ability conditions. However, there to remove an autoinjector’s protective cap is limited understanding and quantitatively assessed how patient characteristics, such as dexterity, age, of how user perceptions and sex, influence self-reported ease- shape the specification of of-use. In so doing, the empirical work clinically relevant technical provides much-needed insights into how clinically relevant technical attributes attributes of autoinjectors.” relate to user perceptions and, ultimately, device preferences. The study concludes with selected recommendations for new paradigm in the development of new prefilled product development and considerations autoinjectors. For example, formative and for device specification on the basis of summative usability studies have proved patient-specific needs. to be indispensable tools for effective new product development, and research has PATIENT-CENTRICITY – provided rich insights into how patients, Dr Andreas Schneider FROM WORDS TO ACTION caregivers and healthcare professionals Innovation & Business administer drugs subcutaneously with the Development Director “Putting the patient at the centre of help of innovative self-injection devices. T: +41 34 4243206 E: [email protected] everything we do” may sound like a very A great deal is known about if and bold statement, but this mindset has how autoinjectors can be used safely and nevertheless permeated throughout drug effectively for their intended uses and Ypsomed AG delivery device development, be it with use conditions. However, there is limited Brunnmattstrasse 6 3401 Burgdorf device manufacturers, pharmaceutical understanding of how user perceptions Switzerland companies or regulators. In fact, patient- shape the specification of clinically relevant centricity has become the standard guiding technical attributes of autoinjectors. www.ypsomed.com/yds

Copyright © 2021 Frederick Furness Publishing Ltd www.ondrugdelivery.com 41 Ypsomed

The lack of relevant studies is surprising, given that industry is acutely aware how clinically relevant technical attributes may shape design “Interestingly, and contrary to expectation, preferences and drive treatment choices. A misleading specification of clinically relevant technical attributes may negatively impact the the upper limit of cap-removal force perception of the device, and also limit its safe and effective use. that might prevent effective device The study discussed in this article1 puts the autoinjector cap- usage was apparently above the range removal process under the microscope – a critical step for effective device use. Specifically, the empirical work studied whether patients, included in the study. With respect to caregivers and healthcare professionals with a range of disabilities the ability to remove the cap of the were able to remove the autoinjector protective cap with target autoinjector, no differences were found removal force up to 55 N. The study also shows how the cap- removal force and participant characteristics, such as age, sex and based on patient characteristics.” dexterity impairment, shape self-reported perceived ease of cap removal, and ultimately device preferences. CAP-REMOVAL FORCES OF UP TO 55 N REMOVE THE NEEDLE CAP FROM THE AUTOINJECTOR – ENABLE EFFECTIVE DEVICE USAGE INTRODUCING THE EXPERIMENTAL DESIGN The empirical study shows that all participants were able to The single-site simulated-use study included 42 participants across effectively remove the autoinjector cap with target cap-removal five user groups: forces of up to 55 N with the YpsoMate 2.25mL autoinjector and its unique protective cap design. Interestingly, and contrary to • Adolescent patients expectation, the upper limit of cap-removal force that might prevent • Adult patients effective device usage was apparently above the range included in the • Elderly patients study. With respect to the ability to remove the cap of the autoinjector, • Non-professional caregivers no differences were found based on patient characteristics, such as • Healthcare professionals. age, professional education or dexterity impairments. Although other studies have identified use difficulties and use Participants were sampled to assess the potential effects of errors due to the cap-removal process, the results of this study user characteristics, such as dexterity, age, sex and professional were consistent with earlier anthropometric research on finger education, on the cap-removal process. All patients were diagnosed pull strength. Here, scholars observed that healthy male volunteers with at least one chronic disease for which autoinjector-based drug applied up to 98 N when pulling with one hand on a device products are being commercialised, such as rheumatoid arthritis, equipped with force sensors. Previous anthropometric work has also diabetes or multiple sclerosis. Each participant was asked to remove demonstrated the importance of a device design that accommodates the protective needle cap of four non-functional devices with cap- different types of pinch grips to maximise the pull force. The results removal forces in the range of 25–55 N. Effective task completion of the empirical study summarised here similarly underscores the and user-reported ease of cap removal were documented for each need for flexible protective needle cap geometry to allow for different cap-removal process. pinch grips during the cap-removal process. The study included non-functional mock-up devices of the prefilled YpsoMate 2.25 mL autoinjector TOWARDS A QUANTITATIVE MODEL FOR USER-CENTRED platform (Figure 1). The US FDA-approved and SPECIFICATION OF CAP-REMOVAL FORCE commercialised two-step YpsoMate 2.25 mL autoinjector is based on a push-on-skin In addition to the findings on users’ ability to remove the protective principle to initiate the injection; users cap, the empirical work also modelled the relationship between then sustain a minimum force to the cap-removal force and user-reported ease of cap removal. hold the device against the This was done as a basis for a user-centred specification of skin to complete cap-removal force. Specifically, users rated the perceived ease of the injection.

“Users whose hands were affected by rheumatoid arthritis reported higher discomfort when removing the autoinjector cap compared with other

Figure 1: The YpsoMate 2.25 mL user groups – despite the fact that autoinjector platform included in all users effectively removed the the empirical study. The device platform is marketed as a prefilled protective needle cap independent of two-step autoinjector device for dexterity impairments.” Teva’s migraine-treatment drug AJOVY® (fremanezumab).

42 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd Ypsomed

cap-removal for each cap-removal process on a five-point scale (one being very difficult and five being very easy). A linear model was then built to quantitatively relate the cap-removal force to the user- reported ease of cap removal (Figure 2). The statistical analysis not only confirms a negative relationship between cap-removal force and user-reported ease of cap removal, but also quantifies this relationship. The results show that a 1 N increase in cap removal force results in a 0.064 point lower self-reported ease of cap-removal on the five-point scale. This model is a first step towards establishing a comprehensive toolbox for device development teams to predict user perception of clinically relevant device attributes, such as the cap-removal force. Consider an illustrative example. A cap-removal force of 25 N corresponds to a mean of 4.62 on the five-point scale for user- reported ease of cap removal. If the specification of this force was increased by 9 N, for example due to the use of an alternative rigid needle shield, it would still maintain an average value of 4.0 on Figure 2: Graphical representation of the relationship between the five-point scale for ease of cap removal. cap-removal force and user-reported ease of cap removal.

USER CHARACTERISTICS MATTER – autoinjector cap and their perceived ease of cap-removal, it provides WATCH FOR DEXTERITY-IMPAIRED PATIENTS a more nuanced understanding of the autoinjector cap removal process. As such, the simulated-use study provides a measure of how The linear model also uncovered a negative effect of dexterity increasing the cap removal force reduces the user-reported ease of impairment on perceived ease of cap removal. Users whose hands cap removal. were affected by rheumatoid arthritis reported higher discomfort The resulting model is a starting point for building an advanced when removing the autoinjector cap compared with other user toolbox for predicting user perceptions based on device technical groups – despite the fact that all users effectively removed the attributes. Finally, while the study suggests that dexterity protective needle cap independent of dexterity impairments. impairment does not affect users’ ability to remove the protective These findings are critical for the design and development of drug needle cap, it reveals a negative effect of dexterity impairment on delivery devices for chronic debilitating disease states, such as users’ perceived ease of cap removal. These insights have important multiple sclerosis or rheumatoid arthritis. This patient group is implications for the design and development of new autoinjectors expected to be most sensitive to higher cap-removal forces, as this and injection devices, such as those developed by Ypsomed may have stronger effects on device perception and preference. (Figure 3), as they re-emphasise the importance of involving users In addition, cap-removal force deserves close attention as these early in new product development. disease areas are characterised by especially strong intra-class competition between treatment options. ABOUT THE STUDY

EMPIRICAL INSIGHTS TO GUIDE The empirical study summarised here was funded by Ypsomed FUTURE DEVICE DEVELOPMENT and conducted in collaboration with Design Science (Philadelphia, PA, US). As a leading developer and manufacturer of self-injection The simulated-use study provided important insights for the user- systems for subcutaneous drug delivery, Ypsomed has established a centric specification of clinically relevant technical attributes, such scientific research & communications programme with the purpose as the cap-removal force. The results show that users were able to of advancing new insights relevant to industry and academia. effectively remove the device’s cap with target forces up to 55 N. The results regularly appear in peer-reviewed scientific forums, Because the study distinguishes between users’ ability to remove the such as Expert Opinion on Drug Delivery, Patient Preference

Figure 3: Ypsomed’s leading portfolio of drug delivery device platforms to facilitate subcutaneous drug administration.

Copyright © 2021 Frederick Furness Publishing Ltd www.ondrugdelivery.com 43 Ypsomed

and Adherence, and Medical Devices: pharmaceutical customers, payers and experts on-site at each location. Ypsomed’s Evidence and Research, and are presented healthcare professionals, Ypsomed moves FDA-registered manufacturing facilities are at leading medical device and drug delivery beyond manufacturing connected sensors. regularly inspected by pharma customers conferences, such as the PDA Universe of Ypsomed’s smart device solutions strive and regulatory agencies to supply devices Prefilled Syringes and Injection Devices. to transform patients’ lives by capturing for global markets including the US, Europe, therapy-relevant parameters, processing Japan, China and India. ABOUT THE COMPANY them to facilitate self-management of chronic diseases, and integrating these REFERENCE Ypsomed’s comprehensive drug delivery insights with third-party digital ecosystems. device platforms consist of autoinjectors The company leverages its in-house 1. Schneider A et al, “User-Centric for prefilled syringes in 1 mL and capabilities in electronics, software and Approach to Specifying Technical 2.25 mL formats, disposable pens for connectivity for the development of new Attributes of Drug Delivery Devices: 3 mL and 1.5 mL cartridges, re-usable pen devices and digital product systems. Empirical Study of Autoinjector-Cap injectors, ready-to-use prefilled wearable Ypsomed is ISO 13485 certified and all Removal Forces”. Patient Prefer patch injectors and injection devices processes comply with design control and Adherence, Feb 2021, Vol 15, for drugs in dual-chamber cartridges. cGMP guidelines with operational QA/QC pp 159–168. Unique click-on needles and infusion sets complement the broad self-injection systems product portfolio. ABOUT THE AUTHOR With over 30 years of experience in the Andreas Schneider, PhD, is Innovation & Business Development Director at Ypsomed development and manufacture of innovative Delivery Systems. He leads a team that drives the definition and development of new systems, Ypsomed is well equipped delivery device platforms, such as next-generation pen and autoinjector devices, wearable to tackle digital healthcare challenges and patch injectors, connected systems and digital solutions. Dr Schneider has published has strategically invested in the development various articles and given presentations in the areas of innovation management and drug of connected solutions and therapy-agnostic delivery. He holds a PhD in innovation management and organisational sciences from digital device management services. ETH Zurich, Switzerland. Anticipating the future needs of patients,

44 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd Go for smart guidance.

Transformation without change

YpsoMate® autoinjector suitable for standard Fully connected smart product system including 1 mL long and 2.25 mL pre-filled syringes YpsoMate®, SmartPilot™ and mobile application 10213147-MSTR-en/V02 Reusable add-on transforms YpsoMate® into a smart product system.

Bluetooth®-based wireless tracking of injection date, time and success Advanced step-by-step patient guidance to avoid handling errors Identify batch number and expiry date of combination product No need to charge SmartPilot™ to improve patient convenience Access to therapy-relevant injection data via standardized interfaces Remote device management-as-a-service in place

For more information visit www.ypsomed.com/yds Ypsomed AG // Brunnmattstrasse 6 // 3401 Burgdorf // Switzerland T +41 34 424 41 11 // [email protected]

YDS_ADV_SmartServices_MSTR-en.indd 1 02.05.21 08:47 Inspired Usability/Owen Mumford

HOW OWEN MUMFORD CARRIED OUT USABILITY TESTING UNDER COVID-19 RESTRICTIONS

Miranda Newbery, Director and Founder of Inspired Usability, describes working with Owen Mumford Pharmaceutical Services on usability testing for a platform autoinjector under covid-19 restrictions.

When lockdown measures were first introduced in 2020, human factors “Cancelling the usability professionals were faced with the challenge of carrying out usability testing remotely. study was an option but There is certainly a wide range of human both companies were factors tools that can be employed without keen to see if there was any contact with end users, such as use risk assessments, expert reviews and device a solution that would get Miranda Newbery comparisons. Also, known use problems them the feedback they Director and Founder for similar or previous devices can be researched. really needed.” Inspired Usability T: +44 07855 943098 However, first-hand user feedback E: [email protected] is invaluable and usability testing is a regulatory requirement for most drug and did not cause any unforeseen problems. www.inspiredusability.com delivery devices. It is only when a potential The best way to do this was via a follow-up end user tests a prototype that it is formative usability study with potential end Contact: possible to truly understand issues with users. Cancelling the usability study was an the device, and to make important design option but both companies were keen to see decisions. For medical device development if there was a solution that would get them to continue, usability studies needed to be the feedback they really needed. reimagined as we entered into the “new The work began with an assessment of normal”. Any new solution still needed the requirements of an effective usability to fulfil the required standards for human study to be able to prepare a study design: factors studies, to satisfactorily demonstrate device safety and usability. • Representative participants: to ensure that participants were representative of Finola Austin SUCCESS FACTORS end users, it was important to brief Human Factors Engineering Manager recruiters thoroughly. As well as the type E: [email protected] Owen Mumford Pharmaceutical Services of device being researched, they had to Owen Mumford was in the latter stages of working on have a good understanding of what is Pharmaceutical Services a platform autoinjector when lockdown involved in human factors studies and Brook Hill measures were introduced. Inspired Usability how they differ from market research. Woodstock had conducted a large-scale formative study For their part, participants also needed Oxfordshire OX20 1TU in January 2020 and Owen Mumford to be briefed fully about what the study United Kingdom wanted to confirm that the subsequent would entail so that they could give design changes had improved the design informed consent. www.ompharmaservices.com

46 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd Inspired Usability/Owen Mumford

ADAPTING TO COVID-19 “It was important to be “The prototypes were all For platform devices, it is important to able to see elements of be as inclusive as possible during testing packed at least three the autoinjector up close, to cover as many usability problems as days in advance of the and to be able to hear possible. In this example, the aim was to study by engineers test the most challenging cases. The cohort feedback clearly at the start included children, older adults, people with wearing PPE – and were and end of an injection.” musculoskeletal conditions, people with kept sealed until needed.” neurological conditions, people with visual and hearing impairments and healthcare professionals, all with and without injection • Clear protocol and study design: a clear experience. To increase participation, the even included gathering anthropometric data protocol and discussion guide would chosen venue was in a suburban area with to inform the design input requirements, so make it easier to repeat the study parking, and participants were encouraged to the moderator described to participants multiple times, allowing user actions and walk or drive rather than use public transport. how to use the equipment. Since needlestick behaviours to be compared. The aim was In terms of the practical considerations, injury was a risk during the study, the to ensure that the study itself was not too extra time was needed for each session to allow moderator was highly vigilant when complicated, and to focus on evaluating for cleaning and for the room to be ventilated. participants handled the prototypes and key parts of the device design. There was also additional preparatory work, there were no incidents. • A comfortable environment: although as the prototypes were all packed at least three Despite social distancing measures, rapport the setting had to simulate where the days in advance of the study by engineers seemed easy to build as participants appeared device would be used, participants wearing PPE – and remained sealed until to enjoy being out of their homes – and enjoyed needed to feel relaxed and not under needed. Rather than being handed prototypes the process of testing the device and providing pressure. Building up a rapport between for different parts of the study, each participant feedback. To allow for observation of the participants and moderators running the was allocated a set of trays that contained all testing process, a local video company was study would put participants at ease so the devices they would need (in this case, recruited to help with live video streaming. that they felt free to interact with the 15 autoinjectors). The prototypes were There were production-equivalent cameras device as if they were at home (or in their numbered and placed in colour-coded sections that could transmit high-definition video feeds place of work) and to express their views. of the trays so that the moderator could easily simultaneously. The picture-in-picture facility • First-hand observation: the moderator, direct participants during the session. showed a close-up view of the autoinjector observer and client had to be able to see Although the general flow of the study going into the injection pad, and a wide and hear first-hand what was occurring remained the same, there were some view of the participants and their interaction during the usability sessions. It was noticeable changes. The moderator had with the device. High-quality microphones important to be able to see elements to describe actions that would normally captured audible feedback and participant of the autoinjector up close, and to be done for them, such as handing out responses. Inspired Usability used Microsoft be able to hear feedback clearly at the prototypes. Both working and non-working Teams to stream the content so that the start and end of an injection. This also prototypes may be used during a study, Owen Mumford team could ask the needed to be recorded on video at a high so it is critical that the correct one is moderator questions about participant quality to allow for thorough review used at each stage. This particular study behaviour during the sessions. after the study. • Device safety: the safety of participants and moderators had to be ensured during the sessions by completing a “Despite social distancing measures, rapport seemed risk assessment beforehand and putting easy to build as participants appeared to enjoy being risk mitigations in place. This was out of their homes – and enjoyed the process of especially important for handling the autoinjector as needles and injectable testing the device and providing feedback.” liquids were involved.

IN 2021 WE’RE BRINGING YOU... BETTER CONTENT THAN EVER!

Copyright © 2021 Frederick Furness Publishing Ltd www.ondrugdelivery.com 47 Inspired Usability/Owen Mumford

CONCLUSION that some of these restrictions will stay in The company combines knowledge of place for some time – particularly guidelines product development and human factors Overall, the study was a success. It allowed on hygiene and infection control, which will regulations with a sensitive and creative the Owen Mumford team to move to the become best practice – so the lessons learned approach. The team is inspired by the design freeze stage, ready for product over the past year may continue to be useful users and the complex, ever-changing world launch in 2021. The restrictions and for future testing. around us. Using a range of human factors changes did not seem to impact the flow methods, Inspired Usability can apply insight of the study, participant recruitment or ABOUT THE COMPANIES and rigour to inform the design process and how the participants interacted with the create medical devices and submission files autoinjectors. The restrictions imposed by Inspired Usability was founded by Miranda that are fully compliant with regulations covid-19 were a concern at first – but the Newbery to support the medical device and and that delight the people using them. measures in place soon became second pharmaceutical industry as it reaches beyond The company has experience with a range nature, showing people’s ability to quickly the regulatory human factors requirements of drug delivery devices, hospital-based adapt to the change in conditions. It is likely to create effective and inspirational products. medical devices, surgical equipment, smart devices, apps, wearables and consumer health products. ABOUT THE AUTHOR Owen Mumford is a major healthcare Miranda Newbery is a creative human factors and user research consultant with over company and device manufacturer that 10 years’ product development experience. She firmly believes in putting the user at the commercialises pioneering medical products heart of the design process and combines her expertise in medical devices, human factors in its own brand and custom device solutions regulations, design and user research to creatively identify unmet needs. Ms Newbery for the world’s major pharmaceutical and has a wealth of experience in combination drug delivery devices. She originally studied diagnostic companies. Owen Mumford’s Mechanical Engineering at Cambridge University (UK) and Industrial Design at the Royal goal is to enhance access to diagnostics, College of Art (London, UK). She is a chartered ergonomist with the CIEHF and founded encourage adherence to treatment and Inspired Usability in 2016. reduce healthcare costs, making a world of difference to a world of people.

48 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd 1mL & 2.25mL Spring-free passive safety devices for pre-filled syringes

The benefits of spring-free are:

• There is no risk of pre-activation in transit, manufacturing and removal from packaging prior to use • User confidence with an unobscured syringe for full drug visibility • Intuitive to use, same injection technique as a pre-filled syringe • Simplified assembly and manufacturing processes • It supports sustainability and reduces cost • UniSafe® 1mL and 2.25mL have an on market shelf life of 3 years

Fully industrialised and ready to supply

To find out more visitompharmaservices.com or email [email protected]

OMPS/odd/ad/ob/0521/7

OB3825 - 1ml and 2.25ml OMPS Ad Set up - OnDrug Delivery - 210 x 297mm 2.indd 1 29/03/2021 15:12 Phillips-Medisize

REUSABLE ELECTRONIC AUTOINJECTOR – FLEXIBLE PERFORMANCE

In this article, Bjarne Sørensen, Director, Front-End Innovation at Phillips-Medisize, discusses the ability of electronically driven injection devices to cater for a broad range of liquid drug properties within a single device platform.

In a previous ONdrugDelivery article, platform devices that can be reused across Phillips-Medisize argued that there are multiple drug formulations with widely several changes in the market that might varying properties. This article focuses on accelerate a transition from disposable this aspect of electronically driven injection mechanical to electronic reusable devices; the ability to cater for a broad autoinjectors. Beyond megatrends around range of liquid drug properties within a sustainability, connectivity and self- single platform device. Data from a administrationFlexibility of drugs, at pharmaceutical its core mathematical model will be presented to companies continue to pursue broad range support this hypothesis.

SmartBasic SmartAdvanced

Reusable device with Reusable device with simple LED user a screen-based user interface for standard interface providing injection sequence more features to

patient protocols

1 mL Bjarne Sørensen staked needle Director, Front-End Innovation PFS E: [email protected] SmartCassette or Single-use cassette compatible across Phillips-Medisize Corporation Phillips-Medisize 1201 Hanley Road 2.25 mL smart autoinjectors Hudson staked needle WI 54016 PFS United States

Figure 1: Key elements of the Phillips-Medisize smart autoinjector. www.phillipsmedisize.com

50 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd Phillips-Medisize

Phillips-Medisize has been developing into cassettes in a controlled environment, a new smart autoinjector that is small and including serialisation, if desired. “The injection sequence easy to use for patients and provides a The cassette label can include a powerful and flexible platform for radio frequency identification (RFID) also provides for a pharmaceutical companies. This new tag, readable from the device, and configurable dwell time development presents a very different selected data can be submitted to a with a specific force on take on the challenges with injection devices connected system. that follow new agendas like connectivity the stopper to minimise and sustainability, but it also presents Device dead volume before the a powerful approach to addressing the The reusable device includes an end-of-dose signal is challenges and compromises coming electronically controlled drive train, from autoinjectors with spring-driven powered by a rechargeable battery, with indicated to the user.” drive trains. Bluetooth Low Energy (BLE) connectivity options. RFID reading of cassettes is an KEY ELEMENTS OF THE option as well. A key advantage of the motor drive is SMART AUTOINJECTOR The device is available in two versions: that high forces can be applied in a fully controlled manner, so it is possible to As shown in Figure 1, the device consists 1. The SmartBasic device with LEDs and optimise delivery of even highly viscous of a single-use, disposable cassette that audible support, which is similar to drugs and still minimise the needle size. contains the prefilled syringe and an typical disposable autoinjectors but with The algorithm prioritises the target electronic reusable device that contains an extended user interface. injection time, varying the force as all the electronics and offers product 2. The SmartAdvanced device with a required to achieve this time (up to customisation through different versions of graphical user interface and a menu- the configured maximum force). The the user interface, including the possibility driven operation, also including audible injection sequence also provides for a of a full graphical display. support. It is possible to have a custom- configurable dwell time with a specific designed user interface, including force on the stopper to minimise dead Cassette buttons and further functionality, with volume before the end-of-dose signal The disposable cassette, which incorporates this version. is indicated to the user. needle safety features, can include either The configuration of the device during a 1.0 mL (all flange types) or 2.25 mL Both device versions have the manufacturing will include the following (small round flange) syringe. The cassette connectivity option embedded and can parameters: is discarded in a sharps container after convey selected information to an app and use, as usual. It is compatible with a a secure backend platform. Phillips-Medisize • Target injection time range of standard prefilled syringes and offers a complete connected health solution • Maximum force applied components, according to ISO 11040. or customers can connect the devices to • Target dwell time and plunger force. This is a true platform opportunity for the other systems. pharmaceutical industry, as the same In the advanced device, the target cassette can be used to deliver a wide range Drive Train Description injection time and other settings can of drug products with different injection The drive system is microprocessor optionally be adjusted by the patient. volumes and viscosities. controlled and features a brushless DC The battery in the reusable device is a The cassette is made of plastic and lacks motor that, via gearing, drives a threaded rechargeable lithium-ion cell which can be metal springs. It is significantly smaller spindle. There is an encoder embedded in charged from a USB port. and lighter than current disposable devices. the motor, so the position and speed of During transport and storage, the cassette is the plunger is known by the processor. DIFFERENCES BETWEEN not under any load, allowing for a minimal Furthermore, the processor can tightly ELECTRONIC DRIVE TRAIN AND approach to packaging. control the applied force on the syringe, SPRING-DRIVEN DRIVE TRAIN The cassette can be loaded with a syringe so all aspects of the plunger movement by axial insertion, and with automated are controllable from parameter settings Electromechanical drive trains offer locking in the cassette. Phillips-Medisize in the firmware of the device and can be several potential benefits when compared can supply cassettes in bulk or handle configured to the specific requirements of with spring-driven systems. Configuration the complete process of fitting syringes the drug and therapy. of the latter requires a delicate balance between several, sometimes counteracting, aspects whereas the important parameters of an electronically driven system can be “A key advantage of the motor drive is that high forces configured to consistently deliver the target can be applied in a fully controlled manner, requirements, with headroom available so it is possible to optimise delivery of even highly to account for real-world variation encountered via the full system interactions, viscous drugs and still minimise the needle size.” including primary container, drug, needle and injection site.

Copyright © 2021 Frederick Furness Publishing Ltd www.ondrugdelivery.com 51 Phillips-Medisize

Function Electronic drive train Spring driven

1.0 mL and 2.25 mL The device and cassette accommodate both 1.0 mL Different devices are usually required due to the compatibility and 2.25 mL syringes, so it is a true platform, with increased power (approximately 4 x force if all sufficient power to drive both syringe sizes. other factors, such as needle gauge and injection time remain equal) and hence size required.

Engagement with The plunger moves at a constant injection speed, and At the start of an injection, the plunger is released the stopper thus engages with the stopper in a controlled manner, with the full force of the compressed spring, quickly gradually building up the required force on the plunger accelerating towards the stopper. At impact, the to achieve and maintain the target injection speed. plunger strikes the stopper with a considerable impulse force that creates a shock wave in the drug and stresses within the prefilled syringe.

Partially filled As above, the plunger moves at a constant injection In a partially filled syringe, the additional flight syringes speed, regardless of syringe fill volume, and distance between plunger rod and plunger therefore the stopper engagement is controlled stopper generally occurs over the highest force and gentle across all syringe fill volumes. profile of a compressed spring, increasing the impact and shock forces on the syringe assembly.

Break-loose force The electronic drive system has a large and controlled Spring-driven systems are generally sized to overcome power reserve, meaning it can overcome the break- the break-loose force but have little ability to loose force while still controlling the rate of injection control the rate of injection once stopper movement immediately after stopper movement commences. commences. At this point, injection rate is driven by spring-force decay versus the resistive forces of the syringe barrel and liquid flow through the needle bore.

Variations in The electronic control maintains a constant As the majority of spring-driven devices use siliconisation injection speed, adjusting motor current and hence compression springs, the available force tends plunger force to deliver a consistent injection time. to decrease over the stroke length. Springs need Because the full force is available throughout the to be sized to overcome potential resistive forces entire stroke, the electronic system is able encountered throughout the stroke, such as to accommodate changes in resistive forces siliconisation. Variations in these resistive forces tend from sources such as siliconisation variations. to impact injection time as it is the parameter that can’t easily be controlled in spring-driven devices.

Different drug The electronic drive and motor system has the Spring-driven systems for high viscosity drug viscosity ranges power to cope with very high viscosities, which delivery can require large, powerful springs to be can allow a thinner needle to be used in some maintained in a compressed, or energised, state until applications. The same device can work with both activation. This places a constant high load on the low and high viscosities without any changes as the plastic device body throughout transport and storage. drive algorithm will adjust the force output to maintain the programmed injection time.

Dead volume in syringe Configurable force on plunger at end of stroke, to Dependent on remaining at end of stroke compress stopper as required, minimising dead volume. force from spring at end of stroke.

End-of-dose The end-of-dose indication is software controlled, Typically, end-of-dose indication is provided indication encompassing full stroke travel, stopper compression by a mechanical sound initiated by the plunger followed by a programmable dwell time. Therefore, movement nearing the end of its stroke. This typically the audio-visual end of dose indication provides direct happens slightly before the injection is complete, user feedback that it is safe to remove the injection requiring an instruction for the user to “hold” device without a separate “hold” time. This should the injector in place for a period of time before have the added effect of reducing “wet” injections removing. Removal before the end of this time caused by users removing the device too soon. period may result in a “wet” injection.

Table 1: Functional differences between electronic drive train and spring-driven drive train.

In Table 1, some of the key functional Zhong X et al (2020).1 The model assumes: In Figure 2, we show different key differences are described. parameters for a 50 cP, 2.0 mL drug, 27GTW • A flight distance between the plunger needle with a targeted injection time of 15 s, SIMULATIONS PERFORMED ON rod and plunger stopper for the and for both drive train types. A spring rate THE SMART AUTOINJECTOR mechanical autoinjector of 3 mm of 1050 N/m for the spring-driven system AND SPRING-DRIVEN SYSTEMS • An air bubble of 5 mm between the was defined to suit these requirements. plunger stopper and the liquid in the As can be seen in Figure 2a (plunger To simulate the performance of mechanical prefilled syringe rod force), the electronic autoinjector can and electromechanical autoinjectors, • Injection into air (so no back pressure) deliver a soft controlled engagement with Phillips-Medisize developed a complete • The algorithm as embedded in the smart the stopper, and a constant force on the dynamic model like that published by autoinjector. plunger throughout the injection. During

52 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd Phillips-Medisize

Figure 2: Spring-driven autoinjector versus smart autoinjector 50 cP.

Figure 3: Spring-driven autoinjector versus smart autoinjector 4.5 cP. the configurable dwell time, the force on (needle-flow velocity) shows the constant during the actual injection. It is these the stopper can be optimised to minimise flow in the fluid path of the electronic drive higher forces that are likely to limit the the dead volume – shown here as 35 N. train, and the declining flow rate of the performance of the drive train to deliver It is also evident that the force available spring-driven version. the drug without risk of damaging the from the spring-driven system is significantly As shown in Figures 2d, 2e and 2f, for prefilled syringe. For the electronic drive, different at the start and end of the stroke. the initial phase of the injection, the forces the nominal force on the plunger stopper Figure 2b (plunger rod velocity) shows from the spring-driven plunger on impact after the free flight gradually increases as the the constant plunger speed of the smart with the plunger stopper, after the free flight air bubble is compressed and then remains autoinjector, and the declining plunger distance, are approximately three to four constant as the plunger stopper is driven speed for the spring-driven one. Figure 2c times the nominal plunger force calculated along the barrel.

Copyright © 2021 Frederick Furness Publishing Ltd www.ondrugdelivery.com 53 Phillips-Medisize

The additional force headroom for parameters and settings unchanged, showing The motor control algorithm, as developed the electronic drive train enables a the superior flexibility of the electronic for the smart autoinjector firmware, enables potentially shorter injection time in this platform. The same settings in the smart swift configuration of the system to the example and increases the ability to work autoinjector can be used for 1.0 mL syringes selected parameters such as injection time with higher viscosities. Furthermore, it is and 2.25 mL syringes. and maximum applied force on the plunger. more straightforward to optimise the set- Given the very different delivery The smart autoinjector provides a powerful up for the required target injection time requirements, the spring-driven drive train platform device featuring a very high degree with the minimum possible needle size. will require different spring rates of 1050 of flexibility on critical parameters, and wide The maximum force applied to the syringe N/m and 172 N/m respectively, resulting suitability as the system can be used for both can be configured to accommodate the in further development work to determine 1.0 mL and 2.25 mL syringes. specification of the actual syringe assembly and verify the functionality for different which, in most cases, determines the overall drug properties and parameters such as ABOUT THE COMPANY limitations of the system. Given the large break-loose force, changes in siliconisation, headroom, there are none of the typical mechanical stability of the device and all Phillips-Medisize, a Molex company, is issues with potentially excessive break-loose other relevant design considerations an end-to-end provider of innovation, force or stalling plungers due to differences developmentand manufacturing solutions in siliconisation. SUMMARY to the pharmaceutical, diagnostics and Figure 3 shows the same curves but for a medical device market segments. Backed 4.5 cP, 2.0 mL drug with 8 s injection time, Beyond the sustainability and connectivity by the combined global resources of Molex and again for both drive train types. A spring benefits offered by the smart autoinjector, and its parent company Koch Industries, rate of 172 N/m for the spring-driven system it is evident from the simulations presented Phillips-Medisize’s core advantage is the was defined to suit these requirements. here that the electronic drive train offers knowledge of its people to integrate design, The only difference to the electronic performance and platform benefits for the moulding, electronics and automation, drive train used for the 50 cP liquid and the delivery of injectable drugs. The approach providing innovative, high-quality 4.5 cP is that the target injection time offers a wider range of flexibility and manufacturing solutions. was set to 8.5 s, with the other device suitability compared with traditional spring-driven autoinjectors, which are REFERENCES likely to be more sensitive to changes in drug delivery parameters, and thus also 1. Zhong X et al, “An experimentally “Beyond the sustainability require more development efforts and validated dynamic model for spring- and connectivity benefits fine-tuning to optimise the design for each driven autoinjectors”. Int J Pharm, offered by the smart new application. 2020, 594:120008. autoinjector, it is evident from the simulations ABOUT THE AUTHOR presented here that the Bjarne Sørensen, Bsc, ME, is a Director of Front-End Innovation at Phillips-Medisize, based in the company’s Development Centre in Denmark. With more than 35 years of electronic drive train offers experience within Product, Strategy and Business Development, Mr Sørensen has a very performance and platform visible track record within different business areas. At Phillips-Medisize he participates benefits for the delivery of in customer programmes, typically involving electronic injectors and connected health systems. He is also deeply involved in new electronic platform programmes, especially on injectable drugs.” conceptual, technical and sustainability aspects.

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54 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd Leading the Way in Medical Devices and Connected Health

Phillips-Medisize, a Molex company, is committed to serving pharmaceutical, diagnostics and medical device customers by creating technology and products to improve people’s lives.

We operate innovation centers in North America, Europe and Asia, and manufacturing sites at 26 locations in 10 countries.

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ADDRESSING THE CHALLENGES OF VISCOUS INJECTABLE ADMINISTRATION

Andrew Donnelly, PhD, Vice-President of Innovation, at Bespak by Recipharm, and Shahid Uddin, PhD, Director of Drug Product, Formulation & Stability, at Immunocore, look at the challenges of self-administration of injectable viscous formulations and the technology that is helping to overcome these issues.

To date, one of the key issues holding Liquid drug formulations can have back the widespread adoption of self- different viscosities, depending on the nature administration for injectable formulations of their APIs, the solvents used or the release is that many of the available devices are not profile they have been designed to achieve. able to deliver the drug through a needle The more viscous drug formulations in fine enough to be acceptable to the patient, common use include: particularly for viscous formulations. A wide-diameter needle is perceived as • Formulations containing high uncomfortable or even painful, to use, concentrations of large molecules. making many patients reluctant to use them. Biologics, including monoclonal This reluctance can all too easily translate antibodies (mAbs), are a key example into non-compliance, with repercussions for of formulations containing large, long- the medicine’s efficacy and, ultimately, the chain molecules. The nature of these patient’s health. therapies means that they often need to be With this in mind, it is clear that there is delivered by injection. The impracticalities Dr Andrew Donnelly a pressing need to create more user-friendly of intravenous administration mean that Vice-President of Innovation T: 07551170796 devices, even when the formulation is viscous. subcutaneous routes are more desirable E: [email protected] To achieve this, significant challenges must when it comes to developing biologic be overcome during drug development to treatments for self-administration. Bespak by Recipharm improve ease of administration, and steps However, the volume of formulation that Bergen Way must be taken to create devices that can can be delivered in a single dose with a King’s Lynn Norfolk cater for more challenging formulations. syringe or autoinjector is limited to 2 mL PE30 2JJ or less. The need for higher doses is driving United Kingdom WHAT MAKES A LIQUID VISCOUS? the need for higher concentrations of the drug, especially when it comes to mAbs. www.bespak.com A liquid with high internal resistance to This increase in concentration generally flow is described as having high viscosity. leads to formulations with much higher This internal resistance is created when viscosities in the range of 20–100 cP. the molecules move past one another, for example when the liquid is poured out of a container. Liquids made up of small, “The intrinsic nature of relatively simple molecules tend to have low viscosity, whereas liquids with larger, many high-viscosity more complex long-chain molecules have formulations means that a much higher viscosity. This is because only so much can be done Dr Shahid Uddin the molecular chains get tangled up in each Director of Drug Product, other as the liquid moves. to optimise them for use Formulation & Stability Viscosity is also governed by the strength in standard autoinjectors. E: [email protected] of a liquid’s intermolecular forces, especially This is driving the need Immunocore the shapes of its molecules. Liquids with 92 Park Drive molecules that can form bonds with each for alternative devices Milton Park other are usually more viscous. Honey, that can offer a viable Abingdon which mostly comprises of relatively small Oxon alternative when reducing OX14 4RY glucose and fructose molecules, is a good United Kingdom example of a liquid that owes its viscosity viscosity is not an option.” to internal bonding. www.immunocore.com

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• Formulations designed to provide sustained or controlled release. For many therapeutics that are rapidly cleared from the body, it is desirable to control the rate of release of the active agent from the site of injection, thus reducing the need for multiple doses. However, many of these controlled-release formulations include polymers with a high molecular weight, which render the formulations extremely viscous. The viscosity of these formulations can be more than 1000 cP. • Non-aqueous formulations. For some Figure 1: Representation of diafiltration setting.2 (Source: WikipediaDorian). formulations, the solvent itself is highly viscous. Oil-based formulations, for However, diafiltration can pose concentration operations. Using a membrane example, may be needed to generate challenges when it comes to manufacturing with a low molecular weight cut-off may controlled-release characteristics or as a formulation, particularly with regard reduce protein loss during filtration.4 solvents for drugs that are poorly water to stability and aggregation, as protein- Furthermore, the high mechanical stress soluble. The viscosity of these formulations protein interactions become more likely experienced during diafiltration can cause is similar to the viscosity of the oil – for when concentration increases. Ordinarily, irreversible protein aggregation. This is a example, the viscosity of castor oil is in instability and aggregation occur because phenomenon that sees protein molecules excess of 2000 cP. diafiltration is a dynamic operation in which group together into insoluble masses, protein concentration increases by volume negatively impacting their effectiveness That said, it is clear that there are reduction and buffer matrix changes.1 This in the finished formulation, as well as limitations on how much drug formulations, instability can have significant repercussions potentially increasing viscosity further. particularly those for biologic treatments, in terms of product quality and shelf life. To enable successful development of can be improved to reduce their viscosity. As such, the diafiltration process requires high-concentration biologics, a number of The intrinsic nature of many high-viscosity extensive expertise and should be highly excipients can be added to formulations formulations means that only so much can controlled to ensure product quality is not to stabilise proteins by suppressing be done to optimise them for use in standard impacted (Figure 1). aggregation and surface adsorption. In autoinjectors. This is driving the need for Manufacturing scalability is also a key liquid formulations, buffers with phosphate alternative devices that can offer a viable concern with diafiltration. It is not a simple or histidine and a small amount of detergent alternative when reducing viscosity is not case of expanding the filter membrane can be useful. Excipients for lyophilised an option. surface area as the proportion of protein formulations include sucrose, trehalose, being processed is increased. The high mannitol and glycine, among others. THE COMPLEXITIES OF viscosity of high protein concentrations However, these add complexity and cost MANUFACTURING HIGHLY increases operating pressure in diafiltration.3 to the formulation development process, VISCOUS FORMULATIONS This can reduce the protein-loading capacity further impacting on manufacturing of the filter, which means that the protein efficiency (Figure 2). Increasing the concentration, and thus load ratio must be decreased to achieve the On top of challenges when producing the viscosity, of biologic formulations has same performance at higher scale. stable, high-concentration biologic ramifications for the manufacturing process In addition to these scalability issues, formulations, viscosity can cause and the product’s storage requirements, as viscous biologics can lead to costly material complications during processing. The well as how it is ultimately administered waste during the filtration process, leaving transfer of viscous solutions via pumping to patients. One example is the biologic behind unused but viable protein in the can be challenging and can generate high therapies used to treat immunological filters. Although this problem may be back pressures during the filtration process. and genetically related diseases. prevented by oversizing the membrane, a The physical stresses that these processes As previously mentioned, these are setup that uses low-concentration operations apply to the solution can also create stability often delivered subcutaneously, which necessitates changes that promote high- issues. Clogging of the filling needle can means the formulations must contain high concentrations of drug substance to overcome the limited volume of drug that can be administered in a single dose. “Despite the development and manufacturing challenges To achieve these high concentrations within a formulation, diafiltration is used – a posed by the viscosity of biologic drug formulations, process that separates out different-sized they remain an exciting area for drug innovation. Steps protein molecules within a preformulation can be taken not only to overcome manufacturing via micro-molecule permeable filters in order to concentrate quantities of the efficiency issues, but also useability issues for patients.” desired protein.

Copyright © 2021 Frederick Furness Publishing Ltd www.ondrugdelivery.com 57 Expert View

“By taking the patient experience into account from the beginning of the parenteral drug development stage, we can ensure that we do our part to create easier-to-use injectable drugs.”

breaking, the device stalling or causing undue discomfort for the patient. As a result, they can eliminate the need for unpleasant wide-diameter needles. One final hurdle that needs to be overcome is the design of the primary formulation container. Many standard autoinjector devices utilise glass prefilled syringes, which can be susceptible to cracking when high pressures are applied to deliver a viscous drug formulation. Improvements to container design in recent years have significantly reduced the likelihood of this happening, but there is still a risk. An option to overcome this issue is Figure 2: Protein aggregates.5 (Source: Ciryam P, Antalek M, Cid F, et al, to use polymeric primary containers, such “A metastable subproteome underlies inclusion formation in muscle as those based on cyclic olefin polymer proteinopathies”. Acta Neuropathol Commun, 2019, Vol 7(197)). and copolymer (COP/COC). These can better withstand the pressures experienced occur as solute is deposited in the needle creating a better experience for patients, during the administration of viscous drugs. with high drying rates, if temperature and with or without changes to the formulation. However, there are concerns with stability humidity are not controlled.6 Furthermore, Viscous formulations need to be and leachables for some products, which the process-yield issues that this creates lead delivered with relative ease and cause means they are not yet a universal solution to significant economic losses. limited pain, which is a challenge using to the problem of drug container breakage. These issues can be daunting for drug standard devices. Many traditional syringes companies, creating a false perception that are only able to deliver viscous formulations TIME TO ACT: CREATING A the overall profitability of parenteral drug by using a needle with a wider diameter, as BETTER USER EXPERIENCE products using viscous drug formulations this can significantly reduce the pressure may be lower than desirable. It may also required to administer the drug. These The growth of viscous formulations on lead them to believe wrongly that their wider needles can cause unpleasantness the market shows no sign of slowing options are limited when it comes to for patients, particularly if they are self- down, with many new treatments in designing more patient-friendly parenteral administering, since they are not trained development. Consequently, the need to drug products for self-administration, to manage the potential discomfort in the keep patient-centricity front of mind grows impacting on the adoption of autoinjectors. same way as healthcare professionals. This ever more pressing, especially if we are can lead to a poor patient experience, with to continue to develop drugs designed for ACHIEVING DRUG DELIVERY SUCCESS potential negative consequences for patient self-administration. By taking the patient adherence. experience into account from the beginning Despite the development and manufacturing However, advances in technology can of the parenteral drug development stage, challenges posed by the viscosity of biologic overcome this issue, to the benefit of the we can ensure that we do our part to drug formulations, they remain an exciting patients self-administering the drug. One create easier-to-use injectable drugs. There area for drug innovation. Steps can be such innovation involves devices that use a may be limitations in terms of how far we taken not only to overcome manufacturing liquefied , rather than a spring, to push can improve the formulations of drugs to efficiency issues, but also useability issues the formulation through the needle. This reduce their viscosity, but there are many for patients. Enhancing the effectiveness can allow greater pressure to be exerted opportunities to enhance the design of the of the delivery device used for viscous to push the drug through a fine needle, devices that deliver the finished formulations. can go a long way towards while minimising the risk of the needle There are third-party device experts

58 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd Expert View

available who can support drug companies the potential to create new treatments and A review”. Biotechnol Bioeng, 2020, in developing more useable, patient- opportunities across the globe, as well as Vol 117(11), pp 3591–3606. friendly injectable treatments. By working accelerating routes to market. 4. Sahin E, Deshmukh S, “Challenges with outsourced partners that specialise in and Considerations in Development the creation of high-quality autoinjector REFERENCES and Manufacturing of High devices, drug companies can ensure that Concentration Biologics Drug they have the help and guidance they 1. Arunkumar A et al, “Effect of Products”. J Pharm Innov, 2019, need to overcome the administration channel-induced shear on biologics Vol 15(1), pp 1–13. and manufacturing challenges of viscous during ultrafiltration/ diafiltration 5. Ciryam P, et al, “A metastable injectable drug formulations. (UF/DF)”. J Membr Sci, 2016, subproteome underlies inclusion By working with such partners, Vol 514, pp 671–683. formation in muscle proteinopathies”. companies can ensure that even viscous 2. Kovács Z, Discacciati M, “Modelling Acta Neuropathol Commun, 2019, drugs are easy for patients to administer of Multi-Step Microfiltration Process Vol 7(197), pp 1–14. themselves with minimal discomfort, for Solvent Exchange”. Hung J Ind 6. Haslip S, “Challenges in filling High allowing them to truly harness the benefits Chem, 2008, Vol 36(1–2), pp 65–69. Concentration, High Viscosity Drug of self-administration in the parenteral 3. Holstein M et al, “Strategies for Product Formulations”. PDA, 2017 space. These will offer greater patient high‐concentration drug substance Universe of Pre-filled Syringes and convenience and the liberation of healthcare manufacturing to facilitate Injection Devices 2017. professionals from the time-consuming need subcutaneous administration: to administer injections on their patients’ behalf. As such, better delivery devices have the potential to optimise patient adherence, ABOUT THE AUTHORS transforming their health, while enhancing Andrew Donnelly, PhD, is Vice-President of Innovation at Bespak by Recipharm. efficiency for resource-constrained public With 25 years of experience in the pharmaceutical industry and a PhD in drug delivery, healthcare systems. Dr Donnelly is responsible for leading the Bespak by Recipharm innovation team of engineers and scientists, and working to identify needs for new technologies. As part of ABOUT THE COMPANY his role, Dr Donnelly is also responsible for creating and identifying new solutions, as well as working with the biopharmaceutical industry to develop combination products. Bespak by Recipharm delivers market- leading design, development and Shahid Uddin, PhD, is currently Director of Drug Product, Formulation & Stability manufacture of drug delivery devices to within the Chemistry, Manufacturing and Controls department at Immunocore. the global pharmaceutical market. This Dr Uddin is responsible for commercialisation and bringing research candidates includes inhalers, nasal technologies and into the clinic. Prior to this, Dr Uddin held the position of Head of Formulation at autoinjectors, as well as development and MedImmune (AstraZeneca), where he supported the biologics portfolio covering manufacturing services. Recipharm is at mAbs, peptides, bispecifics and other proteins. He has extensive experience in the leading edge of drug delivery device preformulation/formulation, forced degradation and delivery of biologics both for innovation. Driven by customer and patient early- and late-stage programmes. demand, the company’s innovations have

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SUBCUJECT WBI: LOW-COST, LARGER VOLUME, HIGH-VISCOSITY WEARABLE BOLUS INJECTOR – USING STANDARD GLASS PRIMARY PACKAGING

Here, Claus Schmidt Moeller, Chief Technology Officer of Subcuject, introduces the company’s wearable bolus injector for single use and discusses the advantages of the device.

HIGHER VOLUME DELIVERY OPTIONS “Subcuject has developed Subcutaneous injection of volumes above 2 mL is becoming a reality. To administer a purely mechanical this, a pharmaceutical company can choose wearable injector for single one or more prefilled syringes, more than use, using forward osmosis one autoinjector or a wearable injector. The use of more than one device for as the drive mechanism a single injection sequence increases the and using a standard risk of incorrect use by the user. Hence, glass primary container. a single injection device in the form of a wearable bolus injector may be preferable. This achieves significant However, several of the wearable injectors economic advantage, with in development are either expensive to the device cost expected manufacture, use primary packaging materials that are not covered in standard to be in the range of a stability documentation or involve single-use autoinjector.” additional user steps – such as assembly of parts. Furthermore, a number of wearable injectors in development are quite big in size significant economic advantage, with the due to the need to accommodate motors, device cost expected to be in the range gears and batteries or a large spring as the of a single-use autoinjector. Subcuject drive mechanism. is currently collaborating with Phillips- Subcuject has developed a purely Medisize to bring the wearable bolus mechanical wearable injector for single injector (WBI) to market. use (Figure 1), using forward osmosis as the drive mechanism and using Claus Schmidt Moeller a standard glass Chief Technology Officer primary container. T: +45 2773 6420 E: [email protected] This achieves

Subcuject ApS Nordre Strandvej 119, F1 DK-3150 Hellebaek Figure 1: Denmark The Subcuject WBI (5 mL). www.subcuject.com

60 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd Subcuject

Water molecule Excess properties of the membrane. As the salt molecules bind a high water number of water molecules, the concentration of free water Ion molecules is lowered, resulting in a spontaneous net flow of water Net water ow molecules from the freshwater side to the saltwater side of the membrane. The attraction between the ions and the water molecules further increases the net flow of water molecules through the membrane (Figure 2). In the Subcuject WBI, the osmotic agent is released to a “pressure chamber” when the activation button is pushed. A few seconds after activation, the osmotic process starts and water is driven through the membrane to the pressure chamber. The excess water flow builds up a pressure and moves the plunger in a drug-filled cartridge, pushing the content of the cartridge out through the connected needle mechanism. The speed at which the plunger is driven is determined by several factors such as Flexible Pressure membrane characteristic/permeability and area, osmotic agent and chamber chamber concentration. A patented design ensures that the flow is constant over the entire injection and independent of the device orientation.

ADVANTAGES OF USING AN OSMOTIC-DRIVE MECHANISM Osmotic membrane From a user’s perspective there are several advantages associated with using an osmotic/hydraulic-driven device. One of the most Figure 2: Schematic representation of the osmotic process in the Subcuject wearable injector. apparent advantages is the size of the device. As the drive mechanism is hydraulic, there is no need for a mechanical plunger rod, which SUBCUJECT WBI WORKING PRINCIPLE is often a primary factor for defining the size of an injection device. A 5 mL version of the WBI has approximate dimensions of The driving mechanism main elements are freshwater, salt and 84 x 48 x 18.5 mm, while a 10 mL version of the device is two semi-permeable forward osmosis membranes. Osmosis is a anticipated to have dimensions around 93 x 51 x 20 mm – which is spontaneous process, where water molecules move around randomly expected to be significantly smaller than most competitive wearable and cross the membrane in both directions without spending any injectors in development. external energy (Brownian The absence of mechanically moving parts has the added movements). When a advantage that no sounds are made during injection and, except for salt (osmotic agent) is “click” sounds during activation of the device and at retraction of the dissolved in the water on “As pressure needs needle, the device is completely soundless. Furthermore, as pressure one side of the membrane, to be built up before needs to be built up before the plunger starts moving, there is a soft each ion of a dissolved salt the plunger starts injection start for increased patient comfort and minimised risk of crystal attracts and binds impact damage in the primary container. several water molecules. moving, there is a As the device contains only a small number of parts, a non-toxic The permeability of these soft injection start for salt and no electronic parts, the device is as acceptable for disposal hydrated ions through the increased patient as a single-use autoinjector. membrane is much lower From the perspective of a pharmaceutical company, the use of than for the free water comfort and inexpensive elements and the fact that no electronical components molecules, and they stay on minimised risk of need to be handled during development, assembly, storage and one side of the membrane impact damage in the disposal of the device is advantageous. As previously noted, the cost due to a combination of of the WBI is expected to be comparable with an autoinjector and, their size and the complex primary container.” therefore, offers a considerably more cost-effective solution than hydrophilic/hydrophobic most competitive prefilled wearable injectors. IN WHICH ISSUE SHOULD YOUR COMPANY APPEAR? www.ondrugdelivery.com/participate

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Figure 3: Delivered dose 1 cP and 100 cP examples.

standard rubber compounds during early stability testing and, “An injection device is all about as such, selecting a device using such preferred components and materials poses a low risk of experiencing drug stability issues. delivering a pharmaceutical product, The Subcuject WBI is based on a glass cartridge and a plunger made often biologic, and this must be stable of a standard rubber compound. in the device during the shelf life of the In manufacturing, the drug-filled cartridge is assembled as the last part and can be added to the device by the pharma company or product. Therefore, primary packaging CMO (Figure 4). is generally a major concern for pharmaceutical companies.” OUTLOOK

Subcuject has previously demonstrated a 3 mL wearable injector and is now working with Phillips-Medisize on a 5 mL device that will be Osmotic processes can be very strong and easily create a pressure ready for demonstration during 2021. The forward osmosis principle above 40 bars under the right conditions. The Subcuject WBI used in the Subcuject WBI is not limited to injection of certain operates within an approximate pressure range of 0.2–1 bar, volumes, and larger volume devices are planned for development. depending on the viscosity of the drug, and as this is in the lower Phillips-Medisize and Subcuject are ready for engagement into drug- pressure range of the osmotic process, the flow rate is relatively specific development programmes with pharmaceutical companies modestly affected by high viscosity. The flow rate when injecting a drug with a viscosity of 100 cP is just 25–30% lower than for a drug ABOUT THE COMPANY with a viscosity of 1 cP. Accumulated volume injection from the 3 mL device is shown in Figure 3 with typical examples of 1 cP and Subcuject is a privately held company, developing an innovative 100 cP fluids. and proprietary device platform for wearable bolus injection. An injection device is all about delivering a pharmaceutical The management team and board of directors have decades product, often biologic, and this must be stable in the device during of experience and a track record in medical devices, the shelf life of the product. Therefore, primary packaging pharma and drug delivery. Subcuject collaborates with is generally a major concern for Phillips-Medisize on development, commercialisation pharmaceutical companies. and manufacturing of the Subcuject WBI. Most drugs are tested in glass and with ABOUT THE AUTHOR Claus Schmidt Moeller, Founder of Subcuject and inventor of the Subcuject device concept, has 25 years’ experience in innovation of drug delivery devices. He is the inventor of the mechanical concept of Novo Nordisk’s Novopen 4, 5 and 6, and co-inventor of the company’s Flexpen and Flextouch insulin pens. Additionally, he has developed and licensed several injection device concepts for major pharma and device companies, and Figure 4: is named as inventor or co-inventor on more than 60 patent Final assembly step – families. Mr Moeller holds a BSc in Mechanical Engineering. cartridge insertion.

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SMi Group Proudly Present... CONFERENCE: Medical Wearables 25TH - 26TH WORKSHOPS: 27TH for Biosensors OCT Exploring therapeutic applications of connected on-body devices 2021 OFFICIAL MEDIA PARTNER Sheraton Boston Hotel, Boston, USA Virtual Attendance Option Available

PLUS TWO INTERACTIVE POST CONFERENCE WORKSHOPS HIGHLIGHTS FOR 2021: WEDNESDAY 27TH OCTOBER 2021, SHERATON BOSTON HOTEL, BOSTON, USA • Engage in case studies from leading experts on wearable devices for A: Digital Integration within Clinical Trials remote diagnostics and patient monitoring Workshop Leaders: • Delve into the evolving research into smart vaccines for COVID-19 Gary McNamara, Senior Delivery Manager, Aparito and the developing wearable technology being used in the response Daniel Lewi, Head of Business Development, Aparito against the pandemic 8.30 - 12.30 • Uncover how medical wearables and digital health technologies are B: Energy Harvesting Systems for Body-Worn Sensors advancing the potential of clinical trials Workshop Leaders: • Explore a future outlook of the industry with insights from leading start-ups Veena Misra, Distinguished Professor, Director, NSF Center for Advanced and thought leaders on novel developments in digital medicine Self-Powered Systems of Integrated Sensors and Technologies (ASSIST) 13.00 - 17.00

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SMi Group Proudly Present the 2nd Annual Conference… CONFERENCE: Wearable Injectors 18TH - 19TH and Connected WORKSHOPS: 20TH Devices Conference OCT Copthorne Tara Hotel, Kensington, London, UK 2021 Virtual Attendance Option Available Sponsored by: The latest innovations in digital health and on-body drug delivery for the pharmaceutical industry

PLUS TWO INTERACTIVE HALF DAY POST CONFERENCE WORKSHOPS HIGHLIGHTS FOR 2021: WEDNESDAY 20TH OCTOER 2021, COPTHORNE TARA HOTEL, KENSINGTON, LONDON, UK • Gain insight into developments in wearable devices in clinical trials and adapting to decentralised trials during the pandemic A: Cross company collaboration to develop • Explore design strategies for connectivity and digital health with digital therapeutic solutions using connected devices sessions from Novartis and Bayer Workshop Leader: Digby Harris, Global Procurement Lead • Hear key regulatory updates from regulatory and notifi ed bodies – Digital Therapeutics, AstraZeneca including TÜV SÜD 8.30 - 12.00 • Discover advances in device design for large volume delivery via on-body injectors B: Optimising Patient Engagement and Creating • Explore and benchmark against industry developments through Novel Company Value through Digital Technologies case studies and real world examples in device development for Workshop Leaders: Alex Gilbert, Digital Medicine, Huma on-body injectors 13.00 - 17.00

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Copyright © 2021 Frederick Furness Publishing Ltd www.ondrugdelivery.com 63 EVEON

SAFE AND AUTOMATIC DEVICE TO IMPROVE DRUG PREPARATION FROM MULTIDOSE VIALS

In this article, Benjamin Morel, Intellectual Property Manager, and Claire Authesserre, PhD, R&D Fluidics Manager, both of EVEON, discuss the challenges and opportunities presented by multidose vials.

The use of multidose vials (MDVs) versus of the covid-19 vaccination race, MDVs single-dose vials (SDVs) has been the have been at the forefront. Worldwide subject of a 40-year debate. Yet the industry demand for glass vials, as well as the glass has been slow to implement alternative technicity required for vaccine stability, and formats to SDVs, even though alternatives the low number of vials providers, led to are being developed and can challenge the situation of potential shortage if only existing practices.1,2 SDVs were used.12 To illustrate this point, In 1983, it was already outlined by a few weeks ago the US FDA approved two Sheth et al3 that MDVs could be used with new MDVs, enabling a shift from six to relatively low risk of bacterial contamination. 11-dose and 15-dose vials to overcome this More recent studies demonstrate that situation.14 This measure is another step using MDVs as packaging presentation for toward avoiding a vial shortage, but also a vaccines does not affect immunogenicity.4,5 proven efficient measure to reduce what is However, this type of packaging is considered “inevitable waste”.15 associated with some clinical outbreaks.6,7,8 Indeed, the covid-19 crisis pushes forward The resulting manual handling can induce the use of MDVs – but it is important to dosing mistakes and increase the risks of consider the beneficial aspect observed on the Benjamin Morel drug contamination and needle-stick injury. vaccination value chain and our ecosystem Intellectual Property Manager Therefore, MDVs require more training and to use them for more general purposes. E: [email protected] and more stringent practices to ensure We learnt from vaccination campaigns in patient safety.9,10 low- and middle-income countries that Furthermore, this type of packaging MDVs enable a 40% packaging waste presentation has often been questioned reduction16 and a 47% storage volume from an economical point of view. The use reduction in vaccination centres and storage of MDVs brings an additional challenge rooms.16 Those benefits are key when you of increased dose wastage if opened with consider the waste management crisis, which lack of planification during a vaccination has already started on a global scale. campaign,9,11 and is inevitable, according to That is why it would be of interest to experts.12 In addition, studies have revealed see how to improve the use of MDVs and Dr Claire Authesserre that, during the H1N1 pandemic, MDVs to challenge the current paradigm of SDVs. R&D Fluidics Manager E: [email protected] were not as economic as expected due to This global vaccination campaign is the the additional cost of time spent on manual right time to think out of the box, push handling and administrative processes.13 innovations and overcome the drawbacks EVEON Today, more than 10 years after the of MDVs. Identifying key learnings helps 305 rue Aristide Bergès 38330 Montbonnot-Saint-Martin H1N1 pandemic, MDVs are at the centre to further improve practices and bring France of the global strategic plan to overcome the new solutions for future local, regional or current global crisis. Since the beginning global vaccination campaigns. www.eveon.eu

64 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd EVEON

Expelled dose Dose Dose accuracy standard deviation n “EVEON’s technologies (mL) (%) dedicated to automated (mL) drug preparation and 3 0.1 3 n=6

injection demonstrate key 1 0.01 1 n=6 advantages to overcome 0.3 0.005 2 n=30 cost efficiency, healthcare worker usability and 0.02 0.0005 3 n=5 patient safety challenges.” Table 1: Examples of doses expelled from EVEON devices for several targeted injected doses (3 mL, 1 mL, 300 µL and 20 µL) Errors bars correspond to standard deviations; n is the number of expelled doses used for standard deviation calculations.

One way to improve is to standardise EVEON devices, using the company’s The use of medical devices also enables the manual work performed by healthcare proprietary micropump, can deliver doses control and reduction of dead volumes workers (HCWs) to get a repeatable, from 20 µL up to several millilitres with a to maximise drug retrieval within the consistent, secure and cost-efficient high accuracy (<3%). The Intuity® Ject device vial. EVEON devices are developed to be vaccination process for each injection. This has been used for several applications with adapted to standard pharmaceutical can be achieved through HCW training different targeted injected doses. Table 1 shows containers. The design of the fluid path in best practice. Since manual work still the dose accuracy for four expelled doses. and the fluidic process is optimised to remains user dependent, a medical device For example, a 1 mL bolus has been injected reduce dead volume and drug loss in both approach would enable the standardisation with ± 0.01 mL, leading to 1% accuracy the containers and the device fluid path. of preparation and injection steps by getting (n-6), and a 300 µL dose has been injected EVEON’s development within its Intuity® rid of inter-user variability and greatly with ± 5 μL, leading to <2% accuracy (n=30). Mix platform (Figure 1) demonstrates a limiting the number of manipulations. Such levels of dose accuracy with highly 56–66% reduction in drug wastage within One of EVEON’s goals is to address the reproducible results allow optimisation of the vial, compared with other products on challenge raised by drug preparation and the filling of the drug container. In the case the market. injection. How can medical devices bring of MDVs, the extraction and delivery of an As HCW time is precious, especially answers to questions raised around patient accurate dose allows for the same number in the context of a pandemic, EVEON safety and cost efficiency? How can medical of doses to be delivered every time, without devices are also designed to minimise the devices be part of the solution for reducing requiring precise handling or losing time number of manipulations and the process product wastage and improving usability during the process. In the context of vaccine time required for use. For example, for physicians? dose shortages, it also avoids the possibility the Intuity® Ject device (Figure 2) is EVEON’s technologies of an HCW wasting a dose because of a capable of injecting a 300 µL dose in less dedicated to automated wrong move. than three seconds. drug preparation and injection demonstrate key Figure 1: The Intuity® advantages to overcome Ject device. cost efficiency, HCW usability and patient safety challenges. By developing electromechanical devices, EVEON enables the automation of drug preparation and/or delivery. All parameters – such as the injected dose, the injection flow rate and the process time – are highly controlled, leading to a very reproducible preparation or delivery and a standard process, thus avoiding user- dependent variability, manipulation risks Figure 2: The Intuity® and dosing mistakes. Mix platform.

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10. Tabatabaei SM et al, “A Study “An appropriate medical device, coupled with on Bacterial Contamination of Multidose Vaccine Vials in best-practice training, can fill the economic and Southeast of Iran”. Int J Infect, patient-safety gap between MDCs and SDVs.” 2017, Vol 4(4), e62887. 11. Usuf E et al, “Vaccine wastage in The Gambia: a prospective observational study”. BMC Public Usability is also an important factor 4. Panda B et al, “Safety evaluation Health 18, 2018, article number 864. for time efficiency and device acceptability following immunization of 12. Ojeda J et al, “Immunogenicity and on the part of the user. That is why pentavalent vaccine (multi-dose vial): safety of a multi-dose quadrivalent EVEON works in close collaboration with experiences and comparative study”. inactivated influenza vaccine in HCWs to understand users’ needs and the Int J Contemp Pediatr, 2021, individuals aged 6 months to 17 environment and use conditions of the Vol 8(2), pp 243–247. years: a randomized phase III trial”. device. EVEON is used to working with 5. “Vaccine wastage is one of the Hum Vaccin Immunother, 2020, ergonomists and designers to take human many challenges authorities balance Vol 16(6), pp 1380–1384. factors into account, right from the first during historic rollout”. ABC News, 13. Pereira C et al, “Vaccine presentation steps of device design, to be sure to design April 2, 2021. in the USA : economics of an appropriate and easy-to-use device. 6. Miller D et al, “The safe use of prefilled syringes versus multidose An appropriate medical device, coupled multi-dose and single-dose vials”. vials for influenza vaccination”. with best-practice training, can fill the SIS FactFinder, 2018. Expert Rev Vaccines, 2010, economic and patient-safety gap between 7. Chung Y-Seok et al, “A Large Vol 9(11), pp 1343–1349. MDVs and SDVs. EVEON can bring easy- Healthcare-Associated Outbreak 14. “Moderna COVID-19 Vaccine: to-use and robust medical innovation to of C Virus Genotype 1a New Multidose Vial; Updated Storage standardise dose preparation (dilution) in a Clinic in Korea”. J Clinical Conditions”. MPR, April 2, 2021. and injection – and turn MDVs into an Virol, 2018. 15. “The looming waste crisis that will attractive and competitive solution. 8. Roseira CE et al, “Injectable follow COVID-19 vaccinations”. medications: self-reported practices Devex, April 18, 2021. ABOUT THE COMPANY of nursing professionals”. Rev Esc 16. Kaucley L et al, “Decision making Enferm USP, 2020, Vol 54. process, programmatic and logistic EVEON is an ISO 13485-certified company 9. Kasi SG et al, “Prefilled syringes impact of the transition from a single- that designs and manufactures safe, versus vials: Impact on vaccination dose vial to a multi-dose vial of the connected, automatic medical devices for efficiency and patient safety in Indian 13-valent pneumococcal vaccine in the preparation and delivery of therapeutic private market”. Pediatr Infect Dis J, Benin”. Vaccine, 2020, Vol 38(43), treatments to improve patient quality of 2013, Vol 5(4), pp 181–186. pp 6807–6813. life. EVEON places the needs of patients and care professionals at the heart of its development by designing simple, intuitive ABOUT THE AUTHORS devices to improve therapeutic performance, compliance and the conditions of at-home Benjamin Morel holds a master’s degree in Bioengineering, specialised in applied care. The company’s expertise has been molecular and cellular biology, and an advanced master’s degree in Biotechnology recognised by Forbes magazine, which Management from Grenoble Ecole de Management (France). After working as a ranked EVEON as the third most inventive consultant in intellectual property strategy and business intelligence for the life science company in France in the category of industry, he joined EVEON as Intellectual Property Manager in 2019. Part of his medical technology in 2019. mission is to assist the R&D team by using tangible information to stimulate the process of innovation. This interdisciplinary role involves integrating multiple business-related REFERENCES aspects from the early stage of product development to generate solutions with strong potential to answer technical needs. 1. Sedita J et al, “Cost of goods sold and total cost of delivery for oral Claire Authesserre, PhD, is an engineer who graduated from ESPCI Paris, a major and parenteral vaccine packaging French institution of higher education that combines multidisciplinary scientific formats”. Vaccine, 2018, Vol 36(12), courses in physics, chemistry and biology. She is also a graduate of Imperial College pp 1700–1709. London (UK), where she obtained an MSc degree in Biomedical Engineering in 2013. 2. Pagliusi S et al, “Vaccines, inspiring She then completed a PhD in Microfluidics at CEA Leti Grenoble (France). innovation in health”. Vaccine, 2018, Since 2017, Dr Authesserre has been R&D Fluidics Manager at EVEON, leading a Vol 36(48), pp 7430–7437. team of fluidics engineers and technician. Placed at the heart of EVEON’s development, 3. Sheth N et al, “Multidose vials the R&D fluidics team works very closely with both the mechanical & and versus signle-dose vials: a study in digital teams to design medical devices with optimised performance to fit with sterility and cost-effectiveness”. customer and patient needs. J Clin Microbiol, 1983, pp 377–379.

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ENSURING FUNCTIONAL PERFORMANCE AND REGULATORY COMPLIANCE OF ELASTOMER STOPPERS FOR MULTIPIERCING SITUATIONS Bruno Morchain Technical Center Manager, Aptar Pharma Injectables In this article, Bruno Morchain, Technical Center Manager, Aptar Pharma Injectables, T: +33 1 4863 5686 E: [email protected] Sébastien Cordier, Technical Product Manager, PremiumCoat®, and Estelle Verger, Business Development Senior Manager, PremiumCoat®, all of Aptar Pharma, discuss a series of experiments conducted on Aptar Pharma’s PremiumCoat® vial stoppers to demonstrate their compliance with EU and US Pharmacopeia standards and their excellent performance in multipiercing situations.

When developing a drug product, be it plays a critical role in facilitating easy a new drug, a generic or repurposing an and safe collection of the drug product by existing drug, specifying the appropriate healthcare practitioners. primary packaging is an essential step. In the majority of cases, elastomeric Sébastien Cordier Because it is in direct contact with the stoppers are not removed from the vial Technical Product Manager, drug product, the primary container plays in order to preserve the integrity of the PremiumCoat® a critical role in preserving the drug’s drug product. Instead, a needle is inserted T: +33 6 3170 5278 integrity throughout its lifecycle, from through the stopper to access the drug. E: [email protected] the initial point of production, through However, this piercing action can lead packaging, distribution, short- or long- to critical incidents, making the stopper’s term storage, up to the moment when it functional performance key in protecting is administered to the patient. As such, both the drug and the patient. any failure associated with the primary In the first instance, the needle must container has the potential to result in pierce through the elastomer. Although the serious adverse effects for the patient or the design of the needle contributes to reducing healthcare practitioner, which, aside from the insertion force required, the stopper the potential significant human impact, can material also plays an important role in Estelle Verger also result in financial implications for the easing the act of insertion. Furthermore, Business Development Senior drug manufacturer. the use of hard rubber may bend the tip of Manager, PremiumCoat® Primary drug packaging for injectables the needle and increase patient discomfort T: +33 6 4263 1821 is typically comprised of two parts: a glass during the injection. E: [email protected] container for holding the solution and an An additional risk to patient safety is elastomeric component. In applications through coring (tearing off small fragments Aptar Pharma using vials, further to requirements that the of the elastomer when the needle pierces Bâtiment Le Raspail container can be closed easily during the the rubber), which leads to contamination 45 Rue des 3 Sœurs Hall A 93420 Villepinte filling process and that container closure of the drug solution. Furthermore, since France integrity be maintained throughout the glass vials can be used to package multiple product’s lifecycle, the elastomeric stopper doses, often the stopper must be pierced www.aptar.com/pharma

70 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd Aptar Pharma

several times while maintaining a seal (A) (B) after the delivery of each dose. Elastomeric solutions providers, therefore, need to ensure that the self-sealing capabilities of their components continue to preserve the drug’s integrity over time, avoiding the potential for contamination and oxidation that would be detrimental to patient safety. This is particularly true in the current covid-19 context, where the need to mass-vaccinate large populations has led pharma companies to choose multidose vials as their favoured type of vaccine container. Over the course of 50 years of collaboration with pharma and biotech Figure 1: Measurement of needle insertion force. A) Representation of the experimental partners, Aptar Pharma has developed setup. B) Representation of the maximum insertion force and average insertion force expertise to address such drug delivery measured for steam- and gamma-sterilised PremiumCoat® 20 mm stoppers. The data challenges, working with vaccines, biotech were collected after two years of ageing and using 21G 3-bevel needles. drugs and small molecules. Aptar Pharma’s latest innovation is PremiumCoat®, needle designs that which combines start-of-the-art elastomer minimise patient “Sharpness may become problematic formulation with market-proven ethylene discomfort during tetrafluoroethylene (ETFE) film-coating an injection. This is when the needle punctures the elastomeric technology. Under testing, the functional usually achieved by vial stopper as it may tear off fragments, performance of PremiumCoat® stoppers using thinner needles which will end up in the drug solution was shown to be fully compliant with or by increasing the the quality controls specified by EU sharpness of the tip. and may compromise patient safety.” Pharmacopoeia (EP) 3.2.9, demonstrating However, sharper tips excellent properties for protecting drugs and thinner needles and patients, and facilitating the drug are inevitably more fragile and therefore to pierce PremiumCoat® stoppers remains development process. more likely to bend if excessive force well within EP 3.2.9 and US Pharmacopeia is applied when piercing the elastomer. (USP) <381> recommendations. It was PREMIUMCOAT®: The discomfort and pain associated with a shown that PremiumCoat® stoppers are REDUCING PIERCING FORCES bent needle can be avoided by improving easy to pierce, facilitating ease of the the mechanical properties of the vial’s injection process and potentially helping When working with vial containers, stopper to help reduce the needle insertion to reduce perceived pain among patients healthcare practitioners need to pierce force required. during the injection by preserving the needle the elastomeric closure components to Aptar Pharma’s experts have evaluated tip’s integrity. access the drug. The force required to the insertion force required to pierce insert the needle depends on factors such PremiumCoat® stoppers using a 21-gauge PREMIUMCOAT®: as needle diameter and tip design, but needle, comparing stoppers that were PROTECTING THE PATIENT AGAINST also on the mechanical properties of the sterilised using steam or gamma radiation FRAGMENT CONTAMINATION elastomer. While this force is usually not a processes after two years of ageing limiting factor for the health practitioner’s (Figure 1). The insertion force was Sharpness is an essential quality for activity, it may affect the integrity of the measured using a dynamometer at an needles, allowing them not only to needle tip. Over the decades, injectables insertion speed of 200 mm/min, with penetrate effectively through the rubber companies have worked to develop recordings taken of the maximum force stopper but, most importantly, to limit the registered during the insertion. EP 3.2.9 sets patient’s discomfort during an injection. the maximum acceptable force at 10 N. However, this sharpness may become Results showed that, regardless of the problematic when the needle punctures the “The need to mass- sterilisation method used with PremiumCoat® elastomeric vial stopper as it may tear vaccinate large populations stoppers, the needle insertion force is off fragments, which will end up in the significantly below the limit imposed by EP drug solution and may compromise patient has led pharma companies 3.2.9. The average insertion force reached safety. Therefore, manufacturers must to choose multidose vials 2.4 N (maximum at 2.8 N) for steam- ensure elastomer formulations are less as their favoured type of sterilised stoppers, and 2.8 N (maximum at prone to fragmentation to help limit the risk 3.4 N) for gamma-sterilised stoppers. of coring without the need to compromise vaccine container.” These results confirm that, despite the on the increased patient comfort provided presence of an ETFE film, the force required by sharper needles.

Copyright © 2021 Frederick Furness Publishing Ltd www.ondrugdelivery.com 71 Aptar Pharma

(A) (B) piercing events). In the case of gamma- sterilised stoppers, either zero, one or two fragments were counted after 48 piercings. After conducting the experiment three times, an average of one fragment was observed per 48 piercings. The results demonstrate that the risk of rubber fragmentation is very low with PremiumCoat® stoppers and fully in accordance with EP 3.2.9 and USP <381> guidelines. PremiumCoat® stoppers reduce the risk associated with elastomer fragment contamination of drug products, contributing to improved patient safety and safe drug injections.

PREMIUMCOAT®: MAINTAINING OPTIMAL SEALING AFTER MULTIPIERCING Figure 2: Evaluation of PremiumCoat® 20 mm stoppers piercing fragmentation. A) Representation of the experimental design: each stopper is pierced four Multidose primary drug packaging is times successively at a different spot and the vial’s content filtrated to look for visible fragments. B) Representation of the fragmentation results: the data are commonly used in the injectables market, represented as the number of fragments per 48 piercing events. Three sets of especially in the case of vaccination 12 steam-sterilised and three sets of 12 gamma-sterilised stoppers were each campaigns or in settings that focus on waste pierced four times with 21G needles. limitation and cost savings. In principle, the stopper of a multidose vial will be pierced Aptar Pharma’s technical team evaluated This experiment revealed that, regardless several times, and each piercing increases the the performance of PremiumCoat® stoppers of the sterilisation method, the number risk of compromising the sealing properties in terms of the risk of coring (Figure 2), of fragments recorded over 48 piercing of the stopper. Due to their elastic properties, referring to the limits set out in EP 3.2.9. events for the PremiumCoat® stopper was elastomers demonstrate a level of resilience A total of 12 stoppers were manually very clearly within the acceptance level of that allows them to reseal after being pierced four times, each time at a different EP 3.2.9 and USP <381>. For the steam- breached, and rubber-component providers site. The EP 3.2.9 acceptance limit is set at sterilised stopper, no fragments were counted have been working on specific formulations five fragments over the 12 stoppers and 48 after performing the experiment three times that ensure long-lasting protection for drugs piercing events. (a total of 36 stoppers tested with 144 in multipiercing applications.

Figure 3: Evaluation of the self-sealing ability of PremiumCoat® 20 mm stoppers. Each stopper was pierced 10 times at a different site with a 21G needle then immersed in a coloured solution while reducing ambient pressure by 27 kPa in a vacuum chamber. Atmospheric pressure was then restored and the inside of the vials were monitored for evidence of potential leaks of the coloured solution. The arrow represents the pressure gradient. A total of 30 observations were performed for both steam-sterilised and gamma-sterilised stoppers.

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closure integrity. PremiumCoat® stoppers, BOX 1: APTAR PHARMA’S therefore, provide an optimal solution ® for preserving the drug product – even PREMIUMCOAT in multidose applications – and ensuring patients receive safe injections (Box 1). The function of ETFE films is to form is a reliable solution that ensures the a barrier to protect the drug from success of Aptar’s pharma partners by: All data referenced in this article are from extractable and leachable chemicals. Aptar Pharma’s internal report #TR20-0206, However, the presence of a film must • Facilitating easier injections and conducted in 2020 in Villepinte, France. not negatively affect the other key potentially reducing perceived pain properties of stoppers. The results of among patients by protecting the ABOUT THE COMPANY the tests performed by Aptar Pharma’s needle tip. expert teams show that PremiumCoat® • Helping to protect the drug and patients For pharma customers worldwide, Aptar stoppers are fully compliant with the EP against particulate contaminations, Pharma is the go-to drug delivery expert, 3.2.9 recommendations. Regardless of the even in a multipiercing context. providing innovative drug delivery systems, sterilisation method chosen and even in • Safeguarding the drug’s integrity components and active packaging solutions straining circumstances, such as the mass throughout its lifecycle, even for across the widest range of delivery routes vaccinations for covid-19, PremiumCoat® multidose applications. including nasal, pulmonary, ophthalmic, dermal and injectables. Aptar Pharma’s experts evaluated the The experiment clearly demonstrated Aptar Pharma Services provides early- ability of PremiumCoat® stoppers to preserve the self-sealing performance of stage to commercialisation support to the seal closure in conditions that simulate PremiumCoat® stoppers, with the seal accelerate and derisk the development multipiercing applications (Figure 3). closure maintained even after 10 successive journey. With a strong focus on The stoppers were pierced 10 times with the piercings. No leakage was observed among innovation, Aptar Pharma is leading the same needle before the vial was submerged the 60 stoppers tested, and the sterilisation way in developing connected devices into a coloured solution. The system was method did not affect the performance of to deliver digital medicines. With a placed in a vacuum and the pressure the stoppers. global manufacturing footprint of 14 reduced. Upon restoring atmospheric These results highlight how, even in an manufacturing sites, Aptar Pharma provides pressure, any failures in sealing properties extreme case where the rubber is pierced security of supply and local support would be highlighted by a colouration of the 10 times, the self-sealing capabilities of to customers. Aptar Pharma is part of contents within the vial. PremiumCoat® stoppers maintain container AptarGroup, Inc (NYSE:ATR).

ABOUT THE AUTHORS

Bruno Morchain is Manager of the Technical Center in Villepinte (France) for Aptar Pharma’s Injectables division. A graduate in mechanical engineering from the University of Technology of Compiègne (France), Mr Morchain has over 18 years’ experience in the pharmaceutical industry. He joined Aptar Pharma in 2012 as a Technical Support Engineer, where he was in charge of supporting customers with elastomeric primary packaging selection, validation, filing and use during the product lifecycle. In 2018, he became Technical Center Manager, where he leads a technical team involved in developing new products, evaluating their performance and conducting studies to support customers and their projects.

Sébastien Cordier is the Technical Product Manager for PremiumCoat® projects at Aptar Pharma’s Injectables division. A graduate of MINES ParisTech and EDHEC Business School in France, Mr Cordier first spent over 15 years in the automotive industry, where he developed a strong expertise in plastics and elastomers, before joining Aptar Pharma in 2020. In his current role as Technical Product Manager at Aptar Pharma, Mr Cordier is responsible for the PremiumCoat® platform of vial stoppers and syringe plungers, and is dedicated to supporting customer development projects involving coated elastomeric solutions.

Estelle Verger is the Business Development Senior Manager for PremiumCoat® coated solutions for Aptar Pharma’s Injectables division, and is responsible for the growth of the PremiumCoat® platform in the global injectable market. A graduate from ESSEC Business School (Cergy, France) and Fachhochschule Dortmund (Germany), with a masters degree in International Business Management, she joined Aptar Pharma in 2011 as a Sales Manager, Injectables. Ms Verger then moved to Aptar Pharma’s Consumer Healthcare division as a Product Manager, where she was responsible for airless dispensing solutions for pharmaceutical applications for a number of years, before returning to the Aptar Pharma Injectables division in 2020.

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DRIVERS FOR CHANGE IN ASEPTIC AUTOMATION

Here, Dave Seaward, Projects Director, and David Phasey, Projects Director, both of 3P innovation, discuss the factors that have led to recent growth in aseptic automation within the pharmaceutical industry.

MACRO TRENDS “A rise in insoluble small The last few years have seen a significant shift in focus by aseptic machinery vendors molecules and biologics as they respond to their clients’ demands. [is] driving more parenteral This is merely a reflection of structural applications. In turn, this is changes within the pharmaceutical industry. Parenteral drug delivery remains an area of leading to growth in significant growth, with the trend towards aseptic automation home healthcare and self-administration of dominated by fill-finish.” injectables (to reduce administration costs and improve the “patient journey”). Dr Dave Seaward Overlaid upon this, is a rise in insoluble Projects Director small molecules and biologics driving more Manufacturing facilities are having to T: +44 1926 408933 parenteral applications. In turn, this is adapt to ever-smaller batch commercial E: [email protected] leading to growth in aseptic automation manufacturing. Vendors are developing dominated by fill-finish. flexible automation systems to serve the The rise of biologics and, more recently, growth of biologics, orphan drug products some of the cell and gene therapies – also and personalised medicines. known as advanced therapy medicinal This has led to the need for flexible products (ATMPs) – has driven machinery capable of smaller batch sizes much of this change within (see Figures 1 and 2), the rise of robotics and aseptic machinery vendors. the need for custom

David Phasey Projects Director T: +44 1926 408933 E: [email protected]

3P innovation Ltd Tournament Fields Business Park Bosworth Avenue Warwick Warwickshire CV34 6UQ United Kingdom

Figure 1: Ultra-low scale fill-finish (3P’s F2V). www.3Pinnovation.com

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machinery to assemble novel administration Industrial robotics are seeing a boom devices. While some products still require across many industrial sectors. This high-speed, high-volume and relatively is driven by a need for improved inflexible fill-finish machinery, vendors product quality, greater assembly are increasingly offering smaller footprint precision and greater automation flexible machines filled with reconfigurable flexibility. In previous decades, robotic processing. the cost of robots often precluded The borosilicate glass vial remains the their implementation. However, go-to primary drug container for many ever lower cost robots can now of these medicaments, especially during lead to very rapid paybacks. clinical trials and initial commercial Notwithstanding the desire for manufacture. There is, however, a continued more consistent process aseptic trend towards prefilled syringes (PFSs) and processing, robots enable a cartridges that typically are then used within reduction in particulates. Numerous autoinjectors, dual chamber/reconstitution articles have demonstrated that applications and wearable devices. human operators are the main This trend can be traced back to the early contamination risk in cleanrooms, 1980s, when Sanofi and Rhône Poulenc- particularly through the shedding Rorer (now Sanofi-Aventis) successfully of particles from personal clothing introduced them as the primary drug Figure 2: Low-scale fill-finish (even undergarments) and skin, container for heparins. Prior to this, PFSs (3P’s F2V-W-N-S). exacerbated by movement. A typical were very much a niche market product. person sheds around one billion skin cells The use of plastics and, in particular, every day and 10% of them have micro- cyclic olefin copolymer (COC), is opening “Industrial robotics are organisms on them.1 Meanwhile, every up many new primary drug container seeing a boom across minute, microorganism-loaded liquid opportunities – this material can enable many industrial sectors. droplets are released from the mouth the elimination of silicone oil lubricants and nose (10 million/g of saliva or nasal that interact with some drugs (~10% of the This is driven by a need for fluid).1 Hence, manual aseptic tasks are biologic pipeline drugs are ultra-sensitive improved product quality, increasingly being converted to non- to silicone), it is more robust at cryogenic greater assembly precision shedding robotic tasks typically within an temperatures, and injection moulding isolator.2 To paraphrase another machinery provides for the addition of features to be and greater automation company, “if it can be automated, it will moulded onto the primary drug container. flexibility. In previous be automated!” The ability to add features via injection decades, the cost of moulding to the primary drug container THE TREND TOWARDS enables the medical device designer to get robots often precluded CUSTOM AUTOMATION really creative – in particular, this is leading their implementation. to more compact devices. However, ever lower cost The previous paragraphs refer to the The trend towards PFSs from vials is macro trends that all aseptic automation likely to continue as they enable easier and robots can now lead to companies are observing. As experts in safer injections. Since the drug is already very rapid paybacks.” custom aseptic automation, 3P has some filled in the container in its exact dose, unique insights into many of the niche this prevents the risk of dosing error and applications – in many cases, these have reduces overfill during the production of a re-nesting) tubs of primary drug containers. been under development for several years potentially very costly drug. Simple changes to the robot end effector and they are now starting to appear on Many of these drugs are high value and also enable the same line to process vials, the market. These applications require low volume. As such, the space and capital cartridges, PFSs and novel primary drug assembly and fill-finish equipment that equipment cost required to depyrogenate/ containers when packages are in ISO- simply did not exist before 3P “invented” it. sterilise primary drug containers ahead of a standard tubs. To minimise development, Aseptic processing equipment and fill-finish line is falling out of favour for all many vendors of aseptic automation automation has to be developed from first but the largest volume production facilities. have elected to use “standard” robots, principles for these applications. In its place are the use of presterilised tubs albeit to cleanroom/sterilisable standards The trend of self-administering injectable containing nests of primary drug containers (3P uses a Stäubli (Freienbach, Switzerland) drugs and the goal to reduce injection (according to ISO11040-7:2015[en]). This integrator). Typically, these six-axis or frequency has driven the development of has led to smaller fill-finish production SCARA robots are relatively large for wearable/large volume injectors. These are equipment focused on the rapid sanitisation the application, leading to larger-than- designed for administering injectable drugs of the outside of the tubs prior to removal necessary isolators. More recently, vendors in large volume, typically more than 2 mL, of the Tyvek™ (DuPont, Wilmington, DE, have begun to introduce their own compact and/or injection over an extended time. US) lids and the fill-finish process. Robots robots (3P has recently introduced the Many of these devices use conventional are the natural solution to de-nesting (and “Crabot” tub-handling robot). cartridge-based primary drug containers.

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The growth is very reminiscent “In connection with the trend towards COC, there are a of the not-so-distant biologics boom in monoclonal antibodies. By way of example, number of novel devices in development taking advantage in 2017 there were reported to be ~2,600 of the flexibility of injection mouldings to create patient ATMP trials across 38 countries4 and benefits. Some of these unique features are driving the need market surveys suggest over 30% annual growth between 2020 and 2027 from for custom automation and custom fill-finish solutions.” around US$2.5 billion (£1.8 billion) to $25 billion (£18 billion).5 In 2020, there were 154 reported trials within the UK In connection with the trend towards COC soluble materials). The reconstitution within alone.6 The technology is moving rapidly previously mentioned, there are a number vials is a complicated multistep process from the lab to patients, and that hints of novel devices in development taking for caregivers, which can lead to errors. at some of the challenges. Poorly defined advantage of the flexibility of injection Numerous reconstitution “twin chamber” semi-automatic and manual processes mouldings to create patient benefits. systems are under development with some developed by academics in university Some of these unique features are driving form of bypass/valve between the chambers. laboratories are currently being the need for custom automation and custom These enable liquid/liquid or powder/liquid industrialised, scaled and validated. fill-finish solutions. As the drug substances reconstitution just prior to administration. The pharmaceutical sector is a highly are denatured by terminal sterilisation, This trend has given rise to the need regulated environment used to high-volume the custom automation and fill-finish need for precise aseptic powder dispensing. production, with formal procedures for to be accomplished aseptically. In addition, the physical properties the simplest of tasks. Knowledge and the Linked to desire of reduced injection required for solubility tend to go hand in guidance are having to be developed for frequency, some daily injections are moving hand with a sensitivity to humidity and these novel ATMP treatments. Meanwhile to “depot”-based sustained-release products. poor flow characteristics, meaning these the rapid expansion of the sector has led The drug is mixed with a polymer, which tend to be a challenge to dispense to a skills shortage drawing in staff from biodegrades safely to release the drug over from bulk into a primary drug container traditional high-volume manufacture. many days or weeks. These technologies such as a twin chamber cartridge or Manufacturing costs and complexity of are typically based around poly lactic-co- novel device. manufacturing tend to be high in a nascent glycolic acid (PLGA), which is now used in Another area that has grown in interest industry launching products made with many US FDA-approved devices owing to is the generation of small diameter extruded an innovative technology. For the ATMP its predictable and tuneable biodegradability depots. In these applications, a small depot companies, working through the scale-out/ and biocompatibility (safety profile).3 similar in size to a grain of rice is first scale-up challenge is a priority. Such technologies have the ability to deliver extruded into a continuous length prior For autologous treatments the batch size small molecules and biologics, including to drying and cutting operations. Such is one. Cells are harvested from a patient, proteins, vaccines, DNA, RNA and peptides. devices are clearly limited in the size of modified and expanded and then returned Typically, these devices rely upon some the payload. They are typically injected to the patient, typically intravenously. form of reconstitution between a powder under the skin to deliver sustained-release As discussed, laboratory processes can be (often freeze or spray dried) and a diluent to hormones or vaccines. As above, these very manual and there is currently no form a subcutaneous sustained-release gel drug substances are typically denatured scale. As such, the introductory price for following injection. by terminal sterilisation, such that these ATMPs can range from $18,950 (£13,650) The recent success of covid-19-related novel processes must be produced in an to $1.2 million (£869,256) per patient.7 vaccines has brought into sharp focus aseptic manner. There is a real and present need to reduce the challenges of cold chain logistics. the cost of production by a factor of 10–20. It is well recorded that cold chain logistics THE RISE OF CELL AND GENE (ATMP) The situation is reminiscent of bespoke car can be challenging, especially in hot and production before Henry Ford introduced developing nations. Even within developed One cannot discuss trends within parenteral the production line in 1913. nations the “last-mile” is a recognised administration without discussing what The jury is currently “out” on what problem leading to cold chain breaches. tends to be called “cell and gene” in the the equivalent efficient production system Drug substances tend to be significantly US and ATMPs in Europe. These therapies is for ATMPs. Some believe the future lies more shelf-stable at ambient conditions as a encompass a wide range of treatments in closed single-use ecosystems designed powder rather than as a liquid and, clearly, including genetic editing techniques and to only run upon dedicated processing parenteral injections are predominantly chimeric antigen receptor (CAR) T-cell machines. This is an Apple business model, liquids delivered through a needle. therapies. They use engineered cells to boost whereby all items of the ecosystem need to This has led to the rise in reconstitution a patient’s own immune system to fight be procured from a single source. Others are devices, which mix a shelf-stable powder diseases such as cancer. These intravenous investigating robotic processing within an with a diluent just prior to administration. therapies are currently seeing an explosion aseptic isolator, agnostic to the consumable These are dominated by lyophilisation in activity with billion-dollar acquisitions, vendors: think open-source Android. What within vials or cartridges. Some applications IPOs and investments. It is only a few is clear, is the future will require significant use spray drying as a means of improving years (2017) since the FDA made its first amounts of automation technology. The the speed of reconstitution (for poorly approval of a gene therapy. goal is to create a repeatable manufacturing

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Figure 3: Drivers for change in aseptic automation and 3P’s response. platform for ATMPs that many companies ONE COMPANY’S RESPONSE focus on low-particulate generation and can replicate. Aseptic equipment class-leading precision. Hence, the company manufacturers have their part to play in As a custom automation house, 3P is, and has a range of modules to de-lid tubs, to responding to this new market need with has been, well placed to respond to the manipulate tubs, to de-nest and to re-nest innovative solutions. above trends and challenges. A significant devices into tubs. 3P has a range of pumps proportion of the company’s work remains and lift/rotate modules to enable aseptic A SUMMARY OF ASEPTIC the development of highly engineered custom liquid dispensing (and some unique powder AUTOMATION TRENDS solutions for its clients. These systems are dispensing technology – see Figure 4). developed to enable clients to scale-out There are stopper feed bowls and The parenteral market for aseptic and/or scale-up, depending upon need. stoppering modules (including vacuum). automation is changing, as shown pictorially The automation is developed specifically Finally, the company has low-particulate in Figure 3; this is being driven by a number for the needs of the client’s product. generating crimping modules. Systems can of factors. As described, this is partly due Some recent custom examples include: then be “glued together” by its robotic to the trend of new medicaments being solutions and placed into an isolator from higher value but lower volume. Tubs are • Aseptic ram-die and aseptic twin screw a range of isolator vendors with a range of now available from numerous vendors to extrusion of depots sterilisation methods (iHP/vHP/HPV etc). hold arrays of primary drug containers. • Aseptic cutting of depots To this end, 3P has focused on aseptic The introduction of COC primary drug • Manufacture of COC-based primary drug robotic solutions from a particular vendor; containers and large-volume (on-body) containers (for terminal sterilisation) the company’s default is to use the Stäubli devices is requiring custom automation • Helium leak testing of primary drug TX2 range of aseptic six-axis collaborative solutions. Depot-based and reconstitution- containers robots, so called “cobots”. The cobot based technologies also require custom • Aseptic liquid and powder filling of feature enables the safe integration with automation solutions, and often, this standard and custom primary drug manual operations and enables the guard also includes the need for aseptic powder containers: line to be within the reach of the robot (to dispensing. The current explosion of ATMP – Including device assembly minimise the size of any isolator). These application is also driving the need for • Aseptic cell processing are also sealed against hydrogen peroxide automation innovation – this is particularly • Vision inspection systems of the product sanitisation and have an exterior that is the case for autologous applications in Grade A. a specialist non-shedding white coating. where the batch size is one. Overlaid on For some space-constrained tub-based top of these device-driven trends is the Like many automation houses, 3P has solutions, 3P has developed its own compact need to minimise the number of manual a range of “standard” aseptic modules “crabot” robot. This system has a small operations to reduce particulates and that can be employed as required, each an footprint and can remove devices from an product-to-product variability. evolution in known technologies with a ISO-tub filled with devices.

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With the need for flexible tub-based fill-finish systems, 3P repackaged some of its “standard” fill-finish modules described above, into a flexible multi- format robotic powder or liquid-filling system with integrated stoppering/capping and crimping – the F2/F5 range of fill- finish equipment (Figure 5). By creating a configurable platform comprising state- of-the-art technologies, these systems address the aforementioned need to provide solutions for new products/devices, such as an aseptic spray-dried powder into a dual chamber syringe, in a way not yet seen by the industry. This filling platform is then encapsulated within an isolator with tub loading via NTT (Neweco, Warsaw, Poland) or a decontamination chamber to Figure 4: Mid-scale robotic fill-finish suit the product and operator protection (3P’s custom R1000). requirements. While these could be gloveless systems, clients still prefer the 3P’s award-winning Fill2Weight powder or clean in place (CIP). Expertise has been insurance that gloves provide, in case a rare dispensing technology (originally developed developed to ensure powder is not released, intervention is required. for inhaled applications), has been used in even within low-humidity environments and To address the very low-volume ATMP aseptic processing applications for over 10 under unidirectional air flow. 3P’s patented requirements, the “standard” modules years. The narrow form factor is ideal to aseptic gravimetric powder dispensing is described previously have been repackaged maintain unidirectional air flow within an one of the company’s unique offerings to as stand-alone pieces of semi-automatic isolator and it is fully sealed for sanitisation the market. machinery. These can be single stations or integrated with a small indexing carousel to increase throughput. They are designed to “By creating a configurable platform comprising be very compact for integration into small isolators and to be operated via glove ports. state-of-the-art technologies, these systems address the need to provide solutions for new products/devices, CONCLUSION AND OUTLOOK such as an aseptic spray-dried powder into a dual It is clear that it is an exciting time for chamber syringe, in a way not yet seen by the industry.” the aseptic automation sector. Automation vendors need to embrace the changes brought about by a wide range of factors:

• New and innovative injectable devices taking advantage of the trend for home administration and caregiver convenience. • A move from glass to plastic (COC) primary drug containers. This is partially led by robustness against cryogenic temperatures, advances in polymers, market acceptance and also because they enable additional features to be moulded onto the primary drug container. • A reduction in batch sizes taken advantage of by tub-based supply of primary drug containers. This, in turn, leads to a requirement for more compact fill-finish lines to reduce the size of very costly aseptic clean room facilities. • A reduction in human variability (and Figure 5: Commercial-scale robotic fill-finish. error) by automating manual processes. The drive to robotics and automation

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is also driven by a desire to reduce fill-finish automation platform technologies. the design, manufacture and support of operators and gloves to reduce particulate These platform technologies can be production equipment. Based in a purpose- generation. configured for benchtop solutions for built facility in Warwick, UK, this award- • A desire to avoid cold chain is leading to clinical and ATMP applications. Similarly, winning business employs over 70 people investment in engineered particles such they can be integrated within a higher and services a multinational customer as those produced by spray drying, bulk volume robotic solution, typically with a base with machines installed worldwide. freeze drying and cryo-milling. This, in tub-based infeed. Aseptic liquid and powder 3P’s specialisms include aseptic processing turn, is leading to a growth in precision dispensing can be added to these fill-finish machines, powder- and liquid-filling aseptic powder-filling technology. lines as required. Finally, custom modules technologies, custom device manufacture, • Huge investments are being made in can be developed as required to deal with assembly and test. cell and gene therapies (ATMPs), which innovative injectable devices. have only recently emerged from the lab. What is clear is the outlook for aseptic REFERENCES The commercialisation of these ultra-low automation companies is one of innovation volume and ultra-high value products is and change. Fun times ahead! 1. Sandle T, “People in Cleanrooms: being hampered by the lack of “open- Understanding and Monitoring the source” (think the Apple ecosystem) ABOUT THE COMPANY Personnel Factor”. Journal of GxP automation solutions. Compliance, 2014, Vol 18, pp 1–5. 3P innovation is a life sciences engineering 2. Keller M et al, “Optimized All the above has led to an explosion of and custom automation company. It Robot Systems for Future Aseptic innovative aseptic automation solutions, works collaboratively with pharmaceutical Personalized Mass Production”. of which 3P innovation is at the forefront and medical device customers to develop Procedia CIRP, 2018, Vol 72, with a wide range of liquid and powder and industrialise new products through pp 303–309. 3. Makadia HK, Siegel SJ, “Poly Lactic-co-Glycolic Acid (PLGA) ABOUT THE AUTHORS as Biodegradable Controlled Drug Delivery Carrier”. Polymers (Basel), Dave Seaward, PhD, is a chartered engineer and 3P innovation’s founding director. 2011, Vol 3(3), pp 1377–1397. He has a first degree in electrical and mechanical engineering and a control theory PhD 4. Ginn SL et al, “Gene therapy (applying servo motors to automation). Dr Seaward’s 35-year career has focused on clinical trials worldwide to 2017: developing custom automation for numerous industries, including the pharmaceutical An update”. The J Gene Med, 2018, and MedTech sectors. He is named inventor on over 20 patents including Unilever’s Vol 20:e3015. pyramid teabag patent, which is included in the UK Patent Office book “Inventing 5. “Global Cell and Gene Therapy the 20th Century”. Many of Dr Seaward’s projects have included powder or liquid Market”. Research Report, dispensing, and recently he worked on numerous dry powder inhalers, drug eluting and BIS Research, 2021. injectable drug delivery projects. 6. “Cell and Gene Therapy Catapult ATMP Clinical Trials Database David Phasey joined 3P innovation in 2010 as a project development engineer to help 2020”. Company Web Page, develop automation for a novel healthcare device. In the subsequent 10 years, Mr Phasey Cell and Gene Therapy Catapult has risen to Projects Director, delivering projects across a spectrum of industries, each (Accessed April 26, 2021). of which has contributed to the development of 3P’s range of platform of technologies. 7. Seoane‐Vazquez E, Shukla V, This breadth of experience has enabled Mr Phasey to develop a valuable set of capabilities Rodriguez‐Monguio R, “Innovation across manufacturing processes, such novel vaccine delivery and ATMPs, with a specialist and competition in advanced therapy knowledge of sterile manufacturing. medicinal products”. EMBO Mol Med, 2019, Vol 11(3):e9992. SUBSCRIBE TODAY! PRINT SUBSCRIPTION £99/YR + POSTAGE www.ondrugdelivery.com/subscribe

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OPHTHALMIC DRUGS: PATHWAY TO OVERCOME PRIMARY PACKAGING AND DRUG PRODUCT MANUFACTURING CHALLENGES

In the second in a series of two articles, Rainer Glöckler, Chief Technical Officer, swissfillon, Carole Delauney, Director Business Development, swissfillon, Nicolas Eon, Senior Technology Development Manager, Terumo Pharmaceutical Solutions, and Katsuyuki Takeuchi, Associate Product Manager, Terumo Pharmaceutical Solutions, discuss the myriad complexities of developing drug products for intravitreal injection, and how the partnership between swissfillon and Terumo can ease and accelerate these products to market. The first article, published in April, covered how swissfillon’s state- of-the-art filling line meets the complex requirements of ophthalmic drug products. Rainer Glöckler With the trend towards personalised OVERVIEW OF THE OPHTHALMIC Chief Technical Officer medicines, there is a growing demand MARKET FOR RETINAL DISORDERS T: +41 27 948 90 90 E: [email protected] for highly complex drugs to treat a wide variety of diseases, each with a relatively The ophthalmic drug market can be Carole Delauney small number of patients. In the case of broken down into segments based on Director Business Development injectables, highly flexible production filling therapeutic area. The largest sector in T: +41 79 905 36 91 lines are needed for different categories of terms of market share is retinal disorders, E: [email protected] drugs which will be ultimately presented in which are responsible for some of the combination with tailored primary packaging. most common causes of blindness in the Swissfillon AG This could include vials, prefilled syringes world, including: Rottenstrasse 7 and cartridges, which may then be assembled 3930 Visp Switzerland into medical devices such as pens, wearable • Diabetic retinopathy – the most common devices or autoinjectors. These drug products cause of blindness in the working-age www.swissfillon.com (DPs) require a high level of process know- population of industrialised countries how and state-of-the-art technologies. • Age-related macular degeneration Dr Nicolas Eon Advanced DPs with a small to mid-size (AMD) – the third most common cause Senior Technology annual demand (fewer than 500,000 units) of blindness in the world Development Manager and innovative containers and devices pose • Retinopathy of prematurity – a notable T: +33 6 49 59 62 96 a major challenge to existing manufacturing cause of blindness in children in middle- E: [email protected] business models based on large throughputs. income countries Katsuyuki Takeuchi The regulatory requirements for the DP • Retinal vein occlusion. Associate Product Manager, in combination with the medical device Pharmaceutical Solutions are particularly stringent in the case of Retinal disorders are caused partly by T: +32 16 38 15 49 ophthalmic products, and must be fully over-production of a protein called vascular E: katsuyuki.takeuchi @terumo-europe.com understood before a product can be endothelial growth factor (VEGF) and are brought to market. By working together, treated with anti-VEGF drugs, which are swissfillon and Terumo Pharmaceutical administered by intravitreal injection into Terumo Europe NV Solutions are exceptionally well positioned the back of the eye. AMD may recur Interleuvenlaan 40 3001 Leuven to provide innovative DP manufacturing after anti-VEGF treatment, and require Belgium solutions to satisfy previously unmet market multiple rounds of treatment (once every and patient needs. two months). www.terumopharmaceuticalsolutions.com

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(USP) 789 relates to particulate matter “The use of ophthalmic injections is increasing, but it is in ophthalmic solutions and describes tests for enumerating extraneous particles extremely challenging to develop the necessary very low within specific size ranges. The ophthalmic dose syringes which are silicone-oil free, and which need solution is first tested by the light to be filled to an extremely high level of precision, while obscuration procedure and, if it fails to meet the prescribed limits, it must pass a minimising the presence of particles and bubbles.” microscopic procedure. Sampling plans need to be based on consideration of product volume, particle numbers historically found The global ophthalmic drug market is biosimilars, not only in Western Europe to be present in comparison with limits, the forecasted to grow from US$28.4 billion and the US, but also in Eastern Europe and size distribution of particles present and (£20.5 billion) in 2020 to $36.2 billion in Asia. At the same time, a number of pharma variability of particle counts between units. 2025, and to reach $47.6 billion by 2030. companies are working on next-generation The US FDA has issued a Guidance In 2020, retinal disorder drugs accounted ophthalmic formulations. for Industry2 which specifies recommended for the largest share of the market, with The R&D pipeline for drugs to treat endotoxin levels for intraocular ophthalmic sales of $13.1 billion and 46% market retinal disorders also includes new classes devices. The recommendations specify a share.1 Growth in the market will be driven of therapeutic agents. It is likely that the limit of no more than 0.2 endotoxin units by the rapidly ageing global population, dominance of blockbuster products will per millilitre (EU/mL) for all ophthalmic the increasing prevalence of diabetes and diminish as medicines become more focused, viscosurgical devices. ocular diseases, unmet clinical needs in and the potential growth in ophthalmic Visible and subvisible particulates may many disease areas and economic growth drugs will be driven by innovative products be present in the drug formulation or may resulting in increased demand in developing developed by biopharma companies. arise from the primary packaging or during countries, particularly in Asia. At present, the filling process. If the formulation is not North America and Europe together make SPECIFIC REQUIREMENTS AND stable, particulates may develop over time. up 68% of the global market. COMPLEXITY IN OPHTHALMIC The primary packaging manufacturer and The most common drugs for retinal DRUG PRODUCT MANUFACTURING the contract development and manufacturing disorders are Regeneron’s Eylea (aflibercept) organisation (CDMO) must guarantee and Genentech’s Lucentis (ranibizumab) and The use of ophthalmic injections is increasing, that their products are in accordance with Avastin (bevacizumab). Eylea accounted for but it is extremely challenging to develop the the relevant standards, and a great deal 62% of the retinal disorder drugs market in necessary very low dose syringes which are of experience and expertise is needed to 2020, replacing Lucentis as the ophthalmic silicone-oil free, and which need to be filled minimise all possible risks. Subvisible pharmaceutical product with the greatest to an extremely high level of precision, while particle testing using the light obscuration revenue. OSI Pharmaceuticals’ Macugen minimising the presence of particles and method is one of the pre-release tests carried (pegaptanib) and Bausch & Lomb’s bubbles. The following sections discuss the out by Terumo for its ready-to-fill syringes. Visudyne (verteporfin) also continue to be key considerations for primary packaging and used to a lesser extent. The patent for DP manufacturing in ophthalmic projects. Use of Silicone-Oil Free Syringes to Lucentis will expire in 2022, and Eylea’s Avoid Floaters and Subvisible Particles patent will expire in 2025 in Europe. Regulatory Requirements and Silicone oil has traditionally been used as The opening up of the market to biosimilar Recommendations on Subvisible a lubricant for syringes so that the plunger drugs once patents expire represents a Particles and Endotoxins can move smoothly in the syringe barrel. major opportunity for new players wishing Ophthalmic solutions should be essentially However, in the case of ophthalmics, it is to enter the sector. There is already interest free from particles that can be observed known that silicone oil would be deposited from biotech companies in producing on visual inspection. US Pharmacopeia in the eye’s vitreous body after repeated

’s expertise

Small scale clinical to commercial Sterile Drug Product manufacturing Handling innovative containers and devices Processing complex formulations

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injections and cannot be evacuated.3 Silicone-oil droplets which remain in the “A speciality of swissfillon is that its filling line transports eye are called “floaters” and avoiding them is one of the unmet needs in ophthalmic through syringe by syringe. This allows every syringe to be injection treatments. There are recent weighed using the tare and gross weigh installed on the studies which recommend the use of silicone machine, and the volume in each syringe to be calculated.” oil-free syringes for intravitreal injections to address this concern.4 In addition, silicone-oil droplets may react with the DP in the syringe and suitable for drugs that are extremely volume is usually in the range of 100–200 µL, create subvisible particles. Studies show sensitive to silicone oil, and in such cases and filling syringes with such small volumes that silicone oil plays a role in both the a silicone oil-free system is the only requires high-precision systems. denaturation of proteins, and the initiation option. During the development of new A speciality of swissfillon is that its of aggregation processes in proteins.5,6 formulations, it is impossible to tell in filling line transports through syringe As soon as the protein is denatured or the advance whether or not the drug will be by syringe. This allows every syringe configuration is changed, the efficacy of sensitive to silicone oil. Pre-stability studies to be weighed using the tare and gross the treatment will be reduced, or it may no could be carried out, but the safest option is weigh installed on the machine, and the longer work at all. Any increase in the level to use a silicone oil-free solution so that the volume in each syringe to be calculated. of subvisible particles will also increase the question does not arise. Depending on the gap between the target risk of failing to comply with USP 789. These considerations are a major driver and actual weight of the syringes, a feedback Technologies such as crosslinked silicone in deciding the most suitable system for loop corrects the pump automatically. oil, baked-on silicone oil, or plasma treated ophthalmic projects. The PLAJEX™ 0.5ml In practice, an average of three to five silicone oil have been developed by the Luer lock syringe is supplied silicone-oil syringe weights is used to smooth the curve, industry to minimise free silicone oil in free, with Terumo’s proprietary i-coating™ rather than correcting for each syringe. drug solutions. But experience lubricant on the plunger stopper (Figure 1). This approach means that swissfillon shows that even these silicone- can achieve exceptionally high accuracy oil layers using plasma or Use of Next-Generation Syringes to during filling, despite such low fill other treatments are not Ensure Safe and Easy Ophthalmic Injection volumes, and typically has an accuracy well As ophthalmic injections are directly within ±2%. administered to the eye, it is vital This monitoring of individual syringes is Figure 1: Terumo’s to minimise the potential risks around very unusual. Most CDMOs carry out nest PLAJEX™ 0.5 mL the injection process. With the trend of filling, for which such a tight specification Luer lock silicone injectable drug development towards more on fill accuracy is not possible. With nest oil-free, ready-to-fill syringe system viscous formulations, and with thin needles filling, there is usually a 2% fully automatic with i-coating™ (for example, 30 or 31 gauge) being used in-process-control (IPC) weigh calculation, stopper.6,7 for ophthalmic injections, it may be necessary so only two out of every 100 syringes are to apply high pressure to the syringe. One checked. This means that any overfill or of the major advantages of using a polymer underfill will result in 50 syringes being syringe is that the Luer lock and the syringe rejected, rather than a single syringe on the barrel are a single moulded component, swissfillon filling line. known as an integrated Luer lock, such as PLAJEX™ Luer lock syringes. In the case of a glass syringe, a polycarbonate Luer lock adaptor is assembled onto the syringe, “Wastage due to overfilling known as an assembled Luer lock, and there is extremely costly for is a risk that the Luer lock adaptor pops off from the syringe barrel when high pressure pharmaceutical companies is applied to the syringe, such as during the in the case of both injection of viscous formulations. ophthalmic drugs and Another advantage of a polymer syringe is the wider design flexibility, other very expensive DPs. so it is possible to design syringes By working together, that are easier to handle by adjusting the syringe manufacturer the inner diameter, outer diameter and length of the syringe as required for the and filling company can intended use. reduce overfill and thereby achieve significant savings Ensuring Accurate, Low-Volume Doses Very low fill volumes are required for for the client.” ophthalmic injections. The range of the fill

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Filling accuracy is driven by the pump, the syringe manufacturer and filling Similarly, the sterilisation process of the the tubing and the filling needle. The pump company can reduce overfill and thereby syringe surface placed into a blister closed is one of the most critical considerations in achieve significant savings for the client. with a lid is most commonly carried out the filling process. A peristaltic pump has The primary packaging has an important with ethylene oxide (EO), and a vacuum a press release mechanism and, over time, role to play because overfill is necessary is applied outside the syringe during the particulates may occur due to damage to not only to compensate for any variation sterilisation process. The difference the pump tubing. This must be considered of the filling process, but also to allow in pressure results in bubble expansion, when deciding how long a filling process for any variation in the dimensions of the with large bubbles expanding much more can run, as the particulates enter the system primary packaging. than small bubbles, potentially inducing after the filter. The process uses very specific stopper movement. This means that a final high-quality silicone tubing, but with the Bubble-Free Filling sterilisation which involves vacuum can pump running at around 500 revs per Bubble-free filling, the stoppering process be designed more easily if the headspace minute in order to guarantee that syringes and minimised overfill are all closely is smaller. can be filled within two seconds, each fast connected. For medical devices which At present, although the bubble may be start/fast stop causes extreme stress to the require an exact injection volume, reduced in the syringe, air will generally tubing. For this reason, the tubing must the precision will be higher if bubbles remain in the syringe Luer bore. Air in the be checked and changed if necessary after are minimised, however, in the case of Luer bore could be avoided by applying a 8–10 hours’ run time. ophthalmics, marketed products are known strong vacuum to the empty syringe prior An accuracy of ±5% is usually to present quite a large bubble (i.e. head to filling. Vaccum filling is now being guaranteed because fill accuracy depends space air). Any air in the syringe must implemented by swissfillon, which allows to some extent on the product solution. be expelled before the injection can be the residual air in the system to be reduced For critical, higher risk solutions, there administered, and this will result in loss or removed. This will help to reduce loss of needs to be very well-defined accuracy. of the drug substance. Even if there are no the DP and will be particularly valuable in If required, improved levels of accuracy bubbles in the syringe, very small amounts the case of -sensitive products. could be achieved by changing from a of residual air may remain in the Luer peristaltic pump to a rotary piston pump. bore and in the needle. If bubbles can be Stoppering Stainless steel or ceramic rotary piston completely avoided, there will be no air to One of the challenges of using very small pumps offer exceptional accuracy and be removed so the overfill can be reduced, stoppers, which are necessary for 0.5 mL remove the risk of particulates as no tubing and less of the DP will be needed. syringes, is that the stoppers must be is placed under stress. In order to achieve bubble-free filling, correctly positioned and oriented during the stoppering process has to be adapted, the transport and stoppering process on Minimising Overfill and the plunger stopper must be set under the manufacturing line in order to be Minimising overfill in ophthalmic prefilled quite a high level of vacuum. The stoppering correctly inserted into the syringes. The syringes is a challenge. Given the very small process is driven by the product solution sorting of the stoppers in the bowl is very volumes which are filled and administered, itself. If the solution is compatible with a important, and therefore a high level of even a reduction in the filling volume of high level of vacuum, the stopper setting precision in the design of the bowl is needed 10–20 µL will have a significant impact in is reasonably straightforward. It is always to guarantee that the system runs well percentage terms. important to apply the vacuum, but this throughout the process. If there is a stopper Typically, only a third of the filled may be achieved with non-compressional which is not correctly aligned in the filling DP is injected into the eye – in other stoppering or with a very short insertion system, syringes can be lost or damaged. words, syringes are overfilled by a factor tube. This means that wrongly positioned of three in order to guarantee the expected Bubble-free filling may be crucial to stoppers must be removed at the start of the administration volume. Two-thirds of the reduce the risk of protein degradation in transport system to the stoppering position DP is wasted due to the hold-up volume certain drugs. Denaturation of a protein- (as they enter the swinger). (dead space) of needles and syringes, the based product could start at the fluid-air With small stoppers, the ratio between priming process for expelling air bubbles interface, and the formation of aggregates diameter and length means that the stoppers from the syringe and overfilling to address must be avoided so that there is no risk of will be relatively longer than other stoppers. variation in the filling process. For example, aggregates entering into the eye. This, in turn, means that the centre of in the case of Lucentis, syringes are prefilled A further consideration is that during gravity of the stopper is usually higher than with 165 µL but only 50 µL are injected. transportation, the syringe can be exposed normal. The sorting board uses the position Some wastage is unavoidable – even with to variations in pressure. Even with road of the centre of gravity of the component to extremely thin needles, there will be residual transportation, changes in altitude during sort and orientate the stoppers, and to feed drug inside the needle, needle hub, and the journey cause changes in pressure the stoppers into the machine, which can be syringe Luer bore – but it is important to (particularly in mountainous regions) and much harder to achieve in this context. ensure that residual drug in the needle and this can result in lower pressure outside The other challenge is that silicone syringe is minimised. the syringe than inside the syringe. If this oil-free stoppers are preferred for the Wastage due to overfilling is extremely happens, and the headspace or the bubble ophthalmic market, in order to avoid costly for pharmaceutical companies in the is too big, it may induce stopper movement subvisible particles and floaters in the eye, case of both ophthalmic drugs and other during transportation, and result in loss of which means that silicone oil cannot be very expensive DPs. By working together, sterility of the product. used on any of the filling machine

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components. With standard plunger bioburden at the end of the compounding do all they can to respond to customers’ stoppers, there is “transport” silicone oil, process is too high, it will result in a requirements as quickly and effectively and nearly all stoppers on the market have higher level of endotoxins due to cells as possible. By forming relationships and been covered with a very small quantity killed during compounding releasing a working with machine makers, they are able of silicone oil to avoid stickiness during large number of endotoxins. This must to pre-validate or pre-design solutions, so processing. In the absence of silicone oil, be kept under control as only bioburden they can be ready when a customer chooses the movement of the stopper in the bowl (not endotoxins) is removed by sterile to implement their technology. is very different, and the stoppers are not filters, so there is a risk that endotoxins will Having multi-use and flexible filling synchronised. The nature of these stopper be found in the syringe. equipment allows swissfillon to handle complexities in DP manufacturing requires complex implementations. However, one of a high level of expertise and experience ADVANTAGES THAT SWISSFILLON/ the most critical steps is the time taken to from the CDMO. TERUMO CAN OFFER TO MEET establish a process on the filling machine. YOUR REQUIREMENTS This requires discussions on the best way Sterilisation to work together with the customer in order The final sterilisation of the surface of the Taking into consideration the many to have the solution on the machine in the drug-filled syringe is very important for complexities and specific requirements shortest possible period of time. ophthalmic drugs. There are a number for ophthalmic DPs discussed thus far, a Ideally, swissfillon would like customers of options: drug manufacturer can minimise risks by to get in contact eight months before the working with experts who have a proven filling is due to start, and Terumo should • Steam sterilisation is commonly used if track record and who are able to offer the also be included in these initial discussions the product is stable enough to be heated, latest technology. This will provide a much in order to consider the compatibility of but this is rarely the case for ophthalmic more streamlined solution than attempting the packaging that can be supplied. This DPs as thermal sterilisation will destroy to achieve each stage of the process would allow for the optimisation of process biologically derived substances. in isolation. parts at the outset and set up of the initial • EO may be suitable in some applications, Very few companies offer silicone oil-free templates, including the stoppering process. but any contamination with EO passing systems, but such coating is one of Terumo’s The discussions should consider how through the packaging may damage or core technologies, and it has developed and the rubber components will be supplied, destroy the product inside. applied a proprietary i-coating™ on the

• Nitrogen dioxide (NO2) is a relatively plunger stopper that allows for a consistent new technology that may be suitable in and predictable gliding force of the syringe.

these applications, as NO2 is known to Terumo is confident that its advanced be less aggressive than other sterilisation technologies can add value to its clients’ and the process can be carried out ophthalmic projects. in relatively low temperature. A state-of-the-art filling environment has been developed by swissfillon that Although the final sterilisation ensures maximum safety for ophthalmic is not part of swissfillon’s process, the applications. This was achieved by working fact that sterilisation will subsequently from the outset with Optima (Schwäbisch be carried out has an impact on the DP Hall, Germany), a highly respected manufacturing requirements, including the filling line manufacturer, in order to need for bubble-free filling and avoiding achieve exceptionally high specifications. the use of silicone oil. The swissfillon technology involves a 100% It is very important that swissfillon automated filling process in which every fully understands the final sterilisation glove intervention is documented, 100% tare requirements for a product, as this will and gross weighing to deliver high accuracy affect the release testing and storage. on extremely low filling volumes, and If there is too much bioburden on a syringe 100% stopper setting control to minimise when it is introduced into the steriliser, bubbles. A speciality of swissfillon is that the system may not be able to achieve its filling line transports through syringe by effective sterilisation. For this reason, the syringe, providing exceptional accuracy and final inspection is performed in an ISO 7 efficiency in the fill process. The company’s cleanroom, in order to guarantee a class D aim is to become the global market leader minimum release environment. in high-precision DP manufacturing, Another specific requirement for filling complex pharmaceuticals into next- ophthalmics relates to endotoxins. As generation containers and devices. mentioned prior, FDA guidance recommends that there should be no more than Implementing the Technology 0.2 EU/mL for ophthalmic viscosurgical The key principle of the swissfillon/ devices. This has an impact on the DP Terumo collaboration is readiness. Figure 2: swissfillon’s rapid transfer port manufacturing process because if the Working together, the companies will used for ophthalmic fill & finish.

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for example in a transfer bag solution, strengths is that it can accept components in advance in order to assess whether it or a double sterile bag solution. It is also in either a 110 mm port bag or 190 mm port is necessary to customise either the filling necessary to consider whether the rapid bag (Figure 2). 190 mm systems allow bags machine or the packaging of the primary transfer ports (RTPs) be 110 mm or 190 mm to be hooked up and disconnected several container. If the manufacturer’s preferred in port diameter. One of swissfillon’s times. These points have to be agreed well solution isn’t immediately available, it may take some time to develop and validate.

CONCLUSION swissfillon/Terumo • Streamlined communication between partners is key is the right DP The close collaboration between swissfillon • Time is critical from your and Terumo has allowed the companies manufactacturing first inquiry to delivery to tackle and solve the specific challenges related to ophthalmics and add value to partner for you if: • Maximum quality and customer projects. security and minimal There is a tendency for the industry to product loss are must-have work in silos, which can slow down the requirements manufacturing processes. However, once it can be demonstrated that a tiny detail in the • Bubble-free filling and precise design of a syringe can have a huge impact plunger setting are crucial on the finish, then it becomes possible to • optimise the overall value chain. Innovative silicone oil-free Time to market is often a key factor syringes could reduce the risks in the success of start-up companies of your drug development developing biosimilars or entering the market with new DPs – and minimising Figure 3: Together, swissfillon and Terumo offer a best-in-class solution for time to market is one of the strengths of ophthalmic projects. the swissfillon/Terumo collaboration. Early

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discussions and collaboration between the JAMA Ophthalmol, 2017, Pharmaceuticals Proteins”. J Pharm drug manufacturer, the primary package Vol 135(7), pp 800–803. Sci, 2015, Vol 104(2), pp 527–535. manufacturer and the specialist CDMO is 4. Olea JL et al, “Silicone Oil Droplets 6. Yoshino K et al, “Functional vital to support a project’s timeline. in Repackaged Anti–Vascular Evaluation and Characterization of The companies are confident that the Endothelial Growth Factors for a Newly Developed Silicone Oil-Free combination of Terumo and swissfillon will Intravitreal Injections: In Search of Prefillable Syringe System”. J Pharm offer a best-in-class solution for ophthalmic the Main Source of Contamination”. Sci, 2014, Vol 103(5), pp 1520–1528. projects (Figure 3). Their combined expertise Eur J Ophtalmol, 2020, Vol 30(4), 7. Kiminami H et al, “Impact of and experience of using the technologies pp 774–779. Sterilization Method on Protein needed for this complex area enables them 5. Krayukhina E et al, “Effects of Aggregation and Particle Formation to provide support for other biologics Syringe Material and Silicone Oil in Polymer-Based Syringes”. J Pharm entering the market, and offer reliable and Lubrication on the Stability of Sci, 2017, Vol 106(4), pp 1001–1007. stable solutions suitable for each product’s specific requirements. ABOUT THE AUTHORS ABOUT THE COMPANIES Rainer Glöckler is Chief Technical Officer of swissfillon and swissfillon is a CDMO for complex holds a degree in microbiology. As CTO, he is responsible for injectables, providing aseptic DP innovation, technology and production. Mr Glöckler has over manufacturing (filling) services to 20 years of professional experience in pharmaceutical pharmaceutical and biotech companies. It production. He was plant manager for large-scale pharmaceutical ensures the highest quality, security and production at Lonza AG before moving to swissfillon. fully cGMP compliant services for high value, complex and difficult to fill products. With its innovative, fully automated and Carole Delauney is Director Business Development at highly flexible filling line, swissfillon swissfillon. She has 18 years’ expertise in the field of provides manufacturing capacity for vials, CDMOs, during which she held highly technically skilled syringes and cartridges for 1–200 L batch commercial positions looking for specific solutions adapted to sizes, when the product is too complex for the outsourcing needs of pharmaceutical and biotechnology small (manual) DP manufacturing or when companies with a focus on sterile drug product manufacturing. the larger manufacturers are fully utilised She holds a five-year degree in Biochemistry. for large quantities.

Terumo Pharmaceutical Solutions is a Nicolas Eon is Senior Technology Development Manager at global company which offers comprehensive Terumo. He graduated from the University of Nancy and product design and development services, Nantes (France) and holds a Fluid Mechanics & Energy Science as well as a portfolio of injection, infusion, Engineering degree, a master’s degree in Energetics and Heat and primary packaging solutions. Terumo Transfer and a PhD in Biomechanics. Dr Eon worked for 10 is trusted for quality and precision and years in the automotive safety industry where he led the system has decades of experience collaborating engineering department of a leading global company. Dr Eon with pharmaceutical companies from the started to build his expertise in the field of pharmaceutical earliest phases of drug development to the primary containers 15 years ago. He held several managing latest stages of product commercialisation positions, from product development to strategic marketing, to optimise critical aspects of parenteral in leading global companies that covered the full range of drug delivery. primary packaging, where he launched successful products on the market and built sustainable long-term strategies. Dr Eon REFERENCES joined Terumo Pharmaceutical Solutions in 2020. Since 2010, he has been an active expert on ISO technical committees as 1. “Global Ophthalmic Devices part of the French and Swiss delegation. Market 2020-2030”. Visiongain, March 2020. 2. “Guidance Document: Endotoxin Katsuyuki Takeuchi is an Associate Product Manager at Testing Recommendations for Terumo Pharmaceutical Solutions. With extensive knowledge Single-Use Intraocular Ophthalmic in pharmaceutical science, he has worked in research and Devices”. US FDA, Aug 2015. development for injectable drug products, such as IV solution 3. Khurana RN, Chang LK, Porco bags and prefilled syringes, and contributed to launch TC, “Incidence of Presumed Silicone various products onto the market. Using his experience, Oil Droplets in the Vitreous Cavity Mr Takeuchi currently has product management responsibilities After Intravitreal Bevacizumab for Terumo’s polymer-based prefillable syringes platform. Injection with Insulin Syringes”.

86 www.ondrugdelivery.com Copyright © 2021 Frederick Furness Publishing Ltd Technology for today and tomorrow. Think Terumo.

Our PLAJEXTM primary packaging solutions offer the functionality and compatibility needed to deliver today’s most challenging biologics and parenteral drug products. PM-04656

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COMPARATIVE EXTRACTABLE STUDIES FOR INJECTABLES AND MEDICAL DEVICES ALIGNED WITH USP <1663> AND ISO 10993 GUIDELINES

Here, Matthias Bicker, PhD, Scientific Advisor, Michael Müller, Study Director, Marc Mittermüller, Study Director, Daniel Haines, PhD, Head of Pharma Services North America, and Uwe Rothhaar, PhD, Director, all of SCHOTT Pharma Services, discuss the regulatory requirements that need to be considered when designing an extractables and leachables study for a drug product or medical device. To illustrate the subject further, the authors provide two example studies, each following a different set of regulatory guidelines.

In order to conduct best practices for the revised guideline is the identification and safety assessment of materials used for quantification of the chemical constituents pharmaceutical drug product packaging and of medical devices in a stepwise approach, medical devices, the most recent regulatory including an estimation of the potential guidance needs to be considered. For of the medical device to release chemical chemical characterisation of components substances (extractables) and a measurement Dr Matthias Bicker and materials, different regulatory guidelines of released chemical substances (leachables). Scientific Advisor T: +49 6131 667334 focused on extractables have been established. The new ISO 10993-18 revision emphasises E: [email protected] United States Pharmacopeia (USP) <1663> a greater integration and harmonisation provides a framework for an extractables with ISO 10993-1 (a general framework assessment of pharmaceutical packaging for planning of biological evaluation and Michael Müller Study Director and drug delivery systems.1 The principles testing within a risk management process), of this framework are recommended for ISO 10993-12 (recommendations for pharmaceutical development, manufacturing sample preparation and specific extraction Marc Mittermüller Study Director applications and medical device components conditions) and ISO 10993-17 (allowable related to combination products. USP <1663> limits for leachable substances).3–5 comprises scientific principles and best Further frameworks have been Dr Daniel Haines practices recommended for the manufacturer established by the Product Quality Research Head of Pharma Services North America of drug substances and drug products as well Institute (PQRI)6,7 with general and specific as manufacturers of pharmaceutical and recommendations for extractables and medical device packaging. leachables (E&L), by the EMA with a Dr Uwe Rothhaar Director ISO 10993 addresses the evaluation guideline focused on “plastic immediate of medical devices with respect to their packaging materials” addressing the need biological safety. An important part of this for testing of the compatibility of the plastic SCHOTT Pharma Services framework is the new revision of ISO 10993- material with the medicinal product by Hattenbergstraße 10 55122 Mainz 18,2 focused on chemical characterisation performing extraction studies,8 and by USP Germany of medical device materials within a risk <661>9 among others. USP <661> is a management process. The scope of this new further standard for plastics used to package www.schott.com

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medical devices, which will be substituted and drug contact, such as labels, need to be expanded upon by USP <661.1> for plastic “Secondary packaging taken into account as potential sources materials of construction and USP <661.2> of chemical compounds that can migrate for plastic packaging for pharmaceutical use. components and into the drug product. Typical applications In addition to the implemented ICH Q3D components with indirect for extractables characterisation are standard for elemental impurities,10 a new drug contact, such as primary packaging components made chapter for organic impurities, “ICH Q3E: of polymer, glass or elastomer (rubber Assessment and Control of Extractables labels, need to be taken into material), or secondary packaging materials, and Leachables for Pharmaceuticals and account as potential sources labels on polymer packaging and other Biologics”, is currently under development.11 of chemical compounds manufacturing components used by the Different levels of identification have been pharmaceutical industry. suggested for extractables studies, including that can migrate into the Components that need to be considered “partial”, “tentative”, “confident” and drug product.” include: “confirmed”, with increasing certainty that the identification is correct.12 • Primary packaging components of SCHOTT Pharma Services offers – PQRI7,18 container closure systems, such as: analytical services for extractables and – ISO 10993-18 or 10993-12,2,4 – Polymer syringe: plunger (rubber leachables testing and related chemical including exhaustive extraction or stopper), tip cap characterisation of primary packaging simulated extraction conditions. – Glass syringe: plunger (rubber and medical device components and 6. Simulated in-use study (e.g. leachables stopper), needle shield materials.13,14 These services are aligned with from processing components) following – Glass cartridge: plunger (rubber the requirements presented by customers current ISO 10993-18 recommendations.2 stopper), rubber cap and the most recent regulatory guidelines. 7. Accelerated leachables studies or – Glass vial: rubber closure To address the demands of E&L bridging studies to fill the gap between – Coated primary packaging characterisation, this article covers the extractables and leachables. components, such as siliconised importance of the following systematic steps 8. Collaboration with a toxicologist for components. for conducting an effective extractables study. alignment of organic and inorganic • Labels with glue and ink (particularly target compounds for a subsequent required for polymeric primary PROCEDURE – HOW TO GATHER leachables study. packaging). THE RIGHT INFORMATION TO SET • Secondary packaging materials, such as: UP AN EXTRACTABLES STUDY The results of such an extractables – Nest study together with the toxicological – Tub The overall procedure to collect the assessment are the basis for the target list of – Cover sheet underlying information for extractable substances to be considered in a subsequent – Bag studies typically comprises some or all of leachables study. – Tray the following steps: – Secondary packaging components COMPONENTS – WHAT NEEDS of medical devices, for example the 1. Clarification of the customer’s request, TO BE CHARACTERISED WITHIN polymer adapter or plunger rod. product application (drug or medical AN EXTRACTABLES STUDY? • Manufacturing components, such as: product and associated packaging or – Silicone tubing device) and related requirements Extractables data need to be generated – Filters supported by scientific consulting. for all materials with direct or indirect – Carboys. 2. Scientific advice concerning any relevant drug contact, and should be separately regulatory guidelines. generated for each individual component. As an example, different components 3. Support for analytical evaluation Additionally, secondary packaging of a sterile nest/tub packaging solution for threshold (AET) calculation based on components and components with indirect glass vials are shown in Figure 1. ICH M7,15 USP <1663>,1 ISO 10993-182 or PQRI16 recommendations. 4. Recommendation of appropriate study Nest design for drug product application, including a detailed study protocol and suitable extraction method (e.g. sealed vessel extraction with shaking incubation, reflux or Soxhlet extraction). Tub 5. Extractables study, according to the recommendations from one or more of: Vial – USP <1663>,1 including exaggerated or simulated extraction conditions – ICH Q3D10 – USP <232>17 Figure 1: Components of a sterile ready-to-use packaging solution.

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• Liquid chromatography – (LC-MS) and ultraviolet detection (LC-UV) – Used for determination and screening of extractable and leachable non- volatile organic compounds (NVOCs) – Allows for the identification and quantification of organic compounds with high polarity and medium to high Figure 2: Polymer syringe system. molecular weight compounds, such as antioxidants (Figure 3), fatty acids The next section presents an example when the components of a packaging system from polymer and rubber component of a comparative extractable study for are exposed to suitable solvents, which are manufacturing and non-volatile injectables and medical devices aligned recommended by the regulatory guidance. plasticisers and processing agents. with USP <1663> and ISO 10993 guidelines. The analytical methods used are: • High-resolution inductive coupled The study is focused on a polymer syringe plasma mass spectrometry (HR-ICP-MS) system consisting of a polymer barrel, • Gas chromatography – mass spectrometry – Used to quantify the amounts of polymer tip cap and elastomeric plunger (GC-MS) extractable and leachable elemental (Figure 2). An example with polymer and – Used for determination and screening impurities elastomer components was chosen for this of semi-volatile organic compounds – Allows for the identification and comparison because specific extraction (SVOCs) qualification of elements of ICH Q3D conditions were recommended in both – Allows for the identification and classes 1–3 (summarised in Table 6).10 guidelines that should be applied for quantification of low to medium • Ion chromatography (IC) these materials. molecular weight compounds, such – Used to quantify the amounts of as additives, catalysts, residual extractable and leachable target anions. STUDY DESIGN – A SUITABLE monomers and oligomers of polymers • Gravimetric non-volatile residue (NVR) ANALYTICAL PROCEDURE FOR and rubbers, as well as semi-volatile analysis AN EXTRACTABLES STUDY plasticisers and processing agents. – Used to determine the amount of non- • Headspace gas chromatography – mass volatile residue of solvent solution The design used for an extractables study spectrometry (HS-GC-MS) after extraction should be appropriate to identify organic – Used for determination and screening – Allows for an assessment concerning and inorganic substances that are extracted of volatile organic compounds (VOCs) the maximum total amount of non- – Allows for the identification and volatile extractables and whether the (A) quantification of low molecular extraction was exhaustive according weight leachables, such as residual to ISO 10993-12.4 monomers of polymers or elastomers, residual solvents19,20 from component Two examples of appropriate study manufacturing and volatile oxidation designs for extractables studies conducted and degradation products. for polymer syringe components are illustrated in Table 1 and Table 2. The study design shown in Table 1 is aligned with current USP <1663> recommendations1 and the one in Table 2 is aligned with (B) current ISO 10993-18 and 10993-12 (C) recommendations.2,4 The studies also each use different extraction techniques and methods. Study protocol A is based on a reflux extraction technique, while study protocol B is based on a sealed vessel extraction technique and an exhaustive extraction method. Results from a practical example of this study are shown in Box 1.

Analysis of VOCs by HS-GC-MS • Incubation of neat sample material at (D) 150°C for 45 minutes in sealed vessels • Qualitative and semi-quantitative screening analysis of an aliquot of the Figure 3: Typical antioxidants used as polymer addatives. (A) BHT, (B) Irgafos 168, respective gas phases for VOCs by (C) Irganox 1010 and (D) Irganox 1076. HS-GC-MS

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Analysis of NVOCs by LC-MS and/or LC-UV Solvent • Liquid-liquid extraction of aqueous extracts Analytical Neat with dichloromethane (DCM) at different method material (*) IPA: Water Water Water (50:50) (pH 5.2) (pH 9.5) pH values and subsequent pooling of organic phases, followed by concentration Headspace X – – – of extracts and reconstitution in isopropyl GC-MS (VOCs) alcohol if necessary GC-MS (SVOCs) – X X X • Target screening for typical polymer additives, and qualitative and semi- LC-MS and/or – X X X quantitative screening analysis of LC-UV (NVOCs) prepared extracts for NVOCs by LC-MS HR-ICP-MS and/or LC-UV – – X – (elemental impurities) • Identification and semi-quantitative evaluation of substance signals by using IC (anions) – – – X high-resolution, time-of-flight MS, internal databases and suitable internal Table 1: Tests to be performed during study design A (aligned with USP <1663>). (*) – direct analysis of neat sample material during thermal extraction. standards.

Extraction of Inorganic Elemental Solvent Impurities and Anions Analytical Neat Study protocol A: method material (*) Ultrapure n-Hexane IPA Water • Samples for HR-ICP-MS analysis reflux Headspace extracted in water (pH 5.2) X – – – GC-MS (VOCs) • Samples for IC analysis reflux extracted in water (pH 9.5). NVR – X X X

GC-MS (SVOCs) – X X X Study protocol B:

LC-MS and/or – X X X • Pooling of extracts from relevant LC-UV (NVOCs) extraction cycles using ultrapure water HR-ICP-MS for both HR-ICP-MS and IC analysis. – – – X (elemental impurities) Analysis of Inorganic Elemental IC (anions) – – – X Impurities and Anions Table 2: Tests to be performed during study design B (aligned with ISO 10933). • Analyses of resulting extracts by (*) – direct analysis of neat sample material during thermal extraction. HR-ICP-MS for elemental impurities and reporting of up to 40 elemental • Identification and semi-quantitative extraction cycles for subsequent GC impurities including all class 1–3 evaluation of substance signals using and LC analyses. elements outlined in ICH Q3D and USP commercial and internal databases and • Exhaustive extraction of samples in <232> guidelines.10,17 suitable internal standards. ultrapure water, IPA and n-hexane • Analyses of resulting extracts by IC • Multiple extraction cycles (incubation for the following target anions: acetate, Extraction of SVOCs and NVOCs condition: 50°C, 72 hours, under formate, bromide, chloride, fluoride, Study protocol A: agitation) performed, depending on the nitrate, phosphate and sulfate. results of individual NVR determinations. • Reflux extraction of samples in 50:50 RATIONALE BEHIND isopropyl alcohol (IPA) and water, water Analysis of SVOCs by GC-MS THE STUDY PROTOCOLS (pH 5.2) and water (pH 9.5). • Liquid-liquid extraction of aqueous extracts with dichloromethane (DCM) Study Design A – USP <1663> Study protocol B: at different pH values and subsequent Study design A and the respective extraction pooling of organic phases, followed by conditions are aligned with the USP <1663> • Exhaustive extraction conditions based concentration of extracts if necessary guideline for “assessment of extractables on determination of NVR: • Qualitative and semi-quantitative associated with pharmaceutical packaging/ – Evaporation of extract solutions from screening analysis of prepared extracts delivery systems”,1 where the general each extraction cycle to dryness for SVOCs by GC-MS framework of scientific principles and aliquots of each extract • Identification and semi-quantitative best practices for extractables studies is – Determination of NVR by gravimetric evaluation of substance signals by using described. According to USP <1663>, analysis of dry residue commercial and internal MS databases extractable studies are required due to the – Pooling of extracts from relevant and suitable internal standards. [Continued on Page 93...]

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BOX 1: TEST RESULTS OF EXTRACTABLES STUDIES

A set of extractables studies for a commercial polymer syringe system were conducted using study protocols A and B. The syringe system under investigation comprises of a barrel made of polymer material and halobutyl rubber components (plunger, tip cap). Some selected results for antioxidants (polymer additives), non-volatile residues and concentrations of elemental impurities and anions in the following section are shown here (note: the peaks labelled with “IS” in the chromatograms belong to internal standard reference material for analysis – they were deliberately added and are not a syringe constituent). HS-GC-MS

Figure 4: HS-GC-MS chromatogram of polymer syringe Figure 5: HS-GC-MS chromatogram of rubber stopper barrel component after incubation at 150 °C for 45 minutes. component after incubation at 150 °C for 45 minutes.

GC-MS

Figure 6: GC-MS chromatogram of polymer syringe barrel Figure 7: GC-MS chromatogram of polymer syringe barrel after extraction in water (pH 5.2). after extraction in water (pH 9.5).

Figure 8: GC-MS Chromatogram of polymer syringe barrel after extraction in IPA/water (1:1).

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BOX 1: TEST RESULTS OF EXTRACTABLES STUDIES, CONT’D

LC-MS and LC-UV

Polymer syringe barrel Halobutyl rubber tip cap Halobutyl rubber stopper (Irradiation sterilised) (irradiation sterilised) (irradiation sterilised) Antioxidant / degradation product Water Water IPA: Water Water Water IPA: Water Water Water IPA: Water pH 5.2 pH 9.5 (50:50) pH 5.2 pH 9.5 (50:50) pH 5.2 pH 9.5 (50:50)

BHT < RL < RL < RL < RL < RL 5.4 < RL < RL 5.7

BHT aldehyde < RL < RL < RL < RL < RL < RL < RL 0.08 0.35

Irganox 1010 < RL < RL < RL < RL < RL < RL < RL < RL < RL

Irganox 1076 < RL < RL < RL < RL < RL < RL < RL < RL < RL

Irgafos 168 < RL < RL < RL < RL < RL < RL < RL < RL < RL

Irgafos 168 oxidised < RL < RL < RL < RL < RL < RL < RL < RL < RL

All amounts in (µg/unit)

Table 3: LC-MS results of quantities of antioxidants found in components of a prefillable syringe system after extraction with aqueous and mixed solvents aligned with USP <1663>.1 Reporting limit (RL) was within the range 0.05–1.0 µg/unit.

Polymer syringe barrel Halobutyl rubber tip cap Halobutyl rubber stopper Antioxidant / (Irradiation sterilised) (irradiation sterilised) (irradiation sterilised) degradation Ultra pure Ultra pure Ultra pure product IPA Hexane IPA Hexane IPA Hexane water water water

BHT < RL < RL < RL < RL 14 47 < RL 19 19

BHT aldehyde < RL < RL 19 0.06 0.49 1.5 0.06 0.67 1.2

Irganox 1010 < RL < RL 393 < RL < RL 0.22 < RL < RL < RL

Irganox 1076 < RL < RL < RL < RL < RL 0.09 < RL 0.03 0.04

Irgafos 168 < RL < RL < RL < RL < RL < RL < RL < RL < RL

Irgafos 168 oxidised < RL < RL < RL < RL < RL 0.34 < RL < RL 0.08

All amounts in (µg/unit)

Table 4: LC-MS results of amounts of antioxidants found in components of a prefillable syringe system after extraction with polar and non-polar solvents according to ISO 10993-18 and 10993-12. Reporting limit (RL) was within the range 0.02–1.2 µg/unit. NVR

Polymer syringe barrel Halobutyl rubber tip cap Halobutyl rubber stopper Extraction cycle (Irradiation sterilised) (irradiation sterilised) (irradiation sterilised) no. IPA Hexane IPA Hexane IPA Hexane

1 < 0.35 16 1.2 20 0.7 8.0

2 < 0.35 8.4 0.7 4.4 0.4 1.1

3 – 5.2 0.4 1.2 0.2 0.3

4 – 4.0 0.2 – 0.2 –

All amounts in (µg/unit)

Table 5: Results of gravimetric determination of NVR shown for up to four extraction loops. Extraction was conducted at 50 °C for 72 hours, in accordance with ISO 10993-12.4

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BOX 1: TEST RESULTS OF EXTRACTABLES STUDIES, CONT’D

HR-IDP-MS

Classification Classification Elements Tested Elements Tested ICH Q3D ICH Q3D Class 1 As, Cd, Hg, Pb Class 4 Ba, Cr, Cu, Li, Mo, Sb, Sn

Class 2 Co, Ni, V Other elements Al, B, Ca, Fe, K, Mg, Mn, Na, W, Zn

Class 3 Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se, Tl Additional Si, Bi, Ce, Hf, P, S, Ti, Zr

Table 6: Overview of elemental impurities listed in ICH Q3D and USP <232> by their classification10,17 and additional elements tested for.

Polymer syringe barrel Halobutyl rubber tip cap Halobutyl rubber stopper Classification (Irradiation sterilised) (irradiation sterilised) (irradiation sterilised) Elements according to ICH Q3D Water Ultrapure Water Ultrapure Water Ultrapure pH 5.2 water pH 5.2 water pH 5.2 water

As, Cd, Hg, Pb class 1 < RL for all class 1 elements for all extracts of all components

Co, Ni, V class 2A < RL for all class 2A elements for all extracts of all components Ag, Au, Ir, Os, Pd, class 2B < RL for all class 2B elements for all extracts of all components Pt, Rh, Ru, Se, Tl Ba, Cr, Cu, Li, class 3 < RL for all class 3 elements for all extracts of all components Mo, Sb, Sn Ca – < RL < RL 1.4 1.5 0.26 0.41

Mg < RL < RL 18 17 2.6 2.1 Al, B, Fe, K, Mn, elements < RL for respective “other elements“ for all extracts of all components Na, W, Zn

Si Additional < RL < RL < RL 6.6 < RL < RL Bi, Ce, Hf, (not classified < RL for respective additional elements for all extracts of all components P, S, Ti, Zr in ICH Q3D) All amounts in (µg/unit)

Table 7: Results of HR ICP-MS analyses for elemental impurities after extraction in water (pH 5.2) or in ultrapure water. Reporting limit (RL) for class 1–3 elements in the range of 0.003–0.33 µg/unit, for “other elements” of ICH Q3D in the range of 0.063–12 µg/unit and for additional elements in the range of 0.003–25 µg/unit.

IC

Polymer syringe barrel Halobutyl rubber tip cap Halobutyl rubber stopper Extraction (Irradiation sterilised) (irradiation sterilised) (irradiation sterilised) cycle no. Water pH 9.5 Ultrapure water Water pH 9.5 Ultrapure water Water pH 9.5 Ultrapure water

- Acetate (CH3COO ) < RL < RL 2.8 4.1 < RL < RL Bromide (Br-) < RL < RL 6.5 6.2 2.4 2.6

Chloride (Cl-) < RL < RL < RL 0.43 < RL < RL

Fluoride (F-) < RL < RL < RL < RL < RL < RL

Formate (HCOO-) < RL 2.3 32 34 < RL 0.47

- Nitrate (NO3 ) < RL < RL 3.8 3.5 0.78 < RL

3- Phosphate (PO4 ) < RL < RL < RL < RL < RL < RL

2- Sulfate (SO4 ) < RL < RL < RL < RL < RL < RL All amounts in (µg/unit)

Table 8: Results of IC analyses for target anions after extraction in water (pH 9.5) or in ultrapure water.

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[...Continued from Page 89] potential exposure of patients to leachable “For material and extractables characterisation of substances that could migrate from the pharmaceutical packaging or delivery polymeric components, all guidelines have many system into the drug product, therefor it aspects in common. However, as can be seen by is important to assess the safety risk to the the approaches taken by study designs A and B, patient and any other potential issues posed by leachables. the guidelines partially differ in details of the procedures For a leachables assessment, it is required and extraction conditions they recommended.” to “know the identities and the levels to which leachables will accumulate in the finished drug product over its shelf life”. Since the primary ISO 10993-12. According to this guideline, polymers should be determined based on an and secondary packaging components are the the quantities of low molecular weight exhaustive extraction method applied with “primary sources of potential leachables”, compounds (LMWCs) of polymers, such both polar and non-polar solvents.4 The performing an extractables study on these as additives, catalysts, residual monomers strong focus on this exhaustive extraction components is justified. and oligomers, that can potentially migrate method for polymer medical device Depending on the chemical nature into the drug or medical product (and components is only found in this guideline. of the drug formulation and its route subsequently into the ) should A hint for different concepts and of administration, specific examples are be determined, and an exhaustive extraction recommendations depending on the applied given in USP <1663>. For a small-volume using both polar and non-polar solvents regulatory guideline is also briefly mentioned parenteral drug product application based should be applied. in the new ISO 10993-18 guideline,2 on an aqueous formulation (e.g. a drug An extraction is defined as exhaustive including a short statement that exaggerated product dissolved in a formulation with if the residues extracted by a subsequent conditions might be requested by some legal a pH value of 6.5), extractions of rubber extraction are below 10% of the amounts authorities like the US FDA as credible components with three different solvents found after the first extraction. In the case alternatives to the ISO recommendation of are recommended “to reflect the chemical of polymer components used in medical exhaustive extraction. For medical device nature of the formulation”: devices, it needs to be confirmed within the applications, this topic is also addressed by extractables study that the extraction was the FDA,22 which states that “a chemical • Aqueous acidic (pH 5.2) exhaustive. For this purpose, a gravimetric analysis of the materials used in a device in • Aqueous alkaline (pH 9.5) method is recommended. In study design B, its final finished form can be informative”, • Mixed aqueous and organic – IPA and the NVR is determined using a gravimetric “can be used to assess the toxicological risk water (50:50). method for confirmation that the extraction of the chemicals that elute from devices” was exhaustive. Study protocol B has been and “chemical analysis using techniques Study design A has been shown to established to fulfil the requirements of both per ISO 10993-12 can also be helpful be well suited for following all relevant ISO 10993-18 and ISO 10993-12. to evaluate long-exhaustive extraction USP <1663> guideline recommendations in term toxicity endpoints, such as potential numerous studies SCHOTT has conducted DIFFERENCES BETWEEN ISO carcinogens”. On the other hand “chemical for its customers. AND USP GUIDANCE AND analysis is usually insufficient to identify all PQRI RECOMMENDATIONS of the risks of the device in its final finished Study Design B – ISO 10993-18 form, because it will not consider aspects of and ISO 10993-12 For material and extractables the finished device such as surface properties Study design B is primarily based on the characterisation of polymeric components, or device geometry that could affect the recommendations of the new ISO 10993-18 all guidelines have many aspects in biological response in certain scenarios.” guideline, which outlines a chemical common. However, as can be seen by the Furthermore, “extraction solvents should be characterisation of medical device materials approaches taken by study designs A and selected to optimise compatibility with the within a risk management process. B, the guidelines partially differ in details device materials and provide information on A framework is specified in this guideline of the procedures and extraction conditions the types of chemicals that are likely to be for “the identification and, if necessary, they recommended. extracted in clinical use.” quantification of constituents of a medical USP <1663> has a special focus on As shown by the results data for LC-MS device, allowing the identification of the chemical properties of the drug (Tables 3 and 4), the two study designs biological hazards and the estimation and formulation (e.g. “many drug products found significantly differing quantities control of biological risks from material are compositionally intermediate between of antioxidants (polymer and elastomer constituents”.2 polar and non-polar”) and on the route of additives), which can be explained by the For extractable studies, ISO 10993-18 administration. For example, for simulation different extraction conditions and solvents. is focused on the chemical characterisation of a worst-case leachable profile, solvents It is plausible that higher quantities of procedure. Related to extraction conditions, should be applied for extraction that have a antioxidants were found in the non- ISO 10993-18 integrates and refers to similar or greater propensity for extraction polar hexane extracts, whereas very low ISO 10993-12.4 For chemical characterisation of substances than the drug formulation.1 quantities, sometimes even below the of polymer components, an exhaustive As another example, according to reporting limit, were found in the aqueous extraction concept is recommended in ISO 10993-12, the quantities of LMWCs of extracts due to their higher polarities.

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more or less comparable. These results Relevant regulatory guidelines for “It is a mandatory indicate that similar quantities of the cations leachable studies are: and anions were released for the aqueous precondition for an solvents with different pH values and • USP <1664>21 appropriate extractables extraction conditions. • USP <232>17 study design to review the As a further example, according to • USP <233>23 PQRI recommendations for parenteral and • ISO 10993-182 drug product or medical ophthalmic drug products, extractables • ISO 10993-17.5 device application and the studies should be conducted with aqueous route of administration in solvent solutions covering a very broad pH CONCLUSION range between 2.5 and 9.5.18 This is based detail in order to align with on the rationale that most aqueous drug A deep understanding of the most recent the relevant regulatory product applications will be covered within regulatory guidelines, in particular requirements, which this broad pH range because only a few the USP <1663> guideline and the new therapeutic products have pH values outside ISO 10993-18 international standard,1,2 is can vary by region, and of this pH range. very important to give drug product-specific to obtain a common As a consequence, it is a mandatory recommendations for an appropriate understanding of the precondition for an appropriate extractables study design for extractables studies for study design to review the drug product or pharmaceutical packaging, drug delivery purpose of the study.” medical device application and the route of systems and medical devices. Two different administration in detail in order to align appropriate study designs, each primarily with the relevant regulatory requirements, focused on one regulatory standard, and Nevertheless, the main purpose of an which can vary by region, and to obtain a the applied analytical methods, have been extractables study is the identification of common understanding of the purpose of described in detail, and example study results potential leachables and both study designs the study. The identification of potential have been shown (Box 1) and the differences met this goal, based on their respective leachables within a customised extractables between them have been discussed. regulatory frameworks. study can provide the basis for a subsequent SCHOTT Pharma Services provides Furthermore, the data for the HR-ICP-MS toxicological assessment. Based on the analytical services, including extractables (Table 7) analyses showed comparable toxicological assessment of the extractable testing related to chemical characterisation amounts of Ca and Mg found for the rubber profiles, the target compounds for the of primary packaging and medical device components, even though aqueous solvents subsequent leachables study can be specified. components and materials. Such studies are with different pH values and extraction For leachables studies, method designed with both customer requirements conditions were used. Also, the data for development and validation is required and the most recent regulatory guidelines IC analyses (Table 8) indicated that, for before determination of leachables in mind. Furthermore, SCHOTT provides most anions, the extractable quantities were in order to meet the required AET. leachables testing, including method

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development and method validation, Quality, Washington DC, March 2017. 16. Ball DJ, “Derivation of the Parenteral following ICH Q2 (R1) recommendations24 7. Paskiet D et al, “The Product Quality Safety Concern Threshold (SCT)”. and leachables characterisation based on Research Institute (PQRI) Leachables and PQRI PODP Extractables & USP <1664>, USP <232>, USP <233>, ICH Extractables Working Group Initiatives Leachables Workshop, Apr 2018. Q3D and/or ISO 10993-18 and 10993-17 for Parenteral and Ophthalmic Drug 17. “USP<232> Elemental Impurities guideline recommendations. Product (PODP)”. PDA J Pharm Sci – Limits”. US Pharmacopeial SCHOTT Pharma Services’ laboratories Technol, 2013, Vol 67(5), pp 430–447. Convention, 2020. are ISO/IEC 17025 accredited and FDA 8. “Guideline on plastic immediate 18. “Experimental Protocol for registered. SCHOTT Pharma Services has packaging materials”. EMA, Qualitative Controlled Extraction more than 40 years’ experience in analytical published 2005. Studies on Material Test Articles testing of pharmaceutical packaging 9. “USP<661> Plastic packaging systems Representative of Prefilled Syringe containers. All quality relevant documents and their materials of construction”. (PFS) and Small Volume Parenteral are electronically available, ensuring a US Pharmacopeial Convention, 2020. (SVP) Container Closure Systems”. hassle-free audit process. 10. “ICH guideline Q3D (R1) on elemental PQRI, Published 2011. impurities”. EMA, published 2019. 19. “USP<467> residual solvents”. ABOUT THE COMPANY 11. “ICH Q3E: Guideline for US Pharmacopeial Convention, 2020. Extractables and Leachables (E&L)”. 20. “ICH Q3C (R6) Residual solvents”. SCHOTT Pharma Services provides ICH, published 2020. EMA, published 2019. pharmaceutical analytical testing, focusing 12. Jenke D, “Identification and 21. “USP<1664> Assessment of drug on drug formulation/container interaction Quantitation Classifications for product leachables associated with studies (E&L, glass delamination), glass Extractables and Leachables”. pharmaceutical packaging”. US breakage root cause analysis (fractography), PDA J Pharm Sci Technol, 2020, Pharmacopeial Convention, 2020. container reliability/suitability (strength Vol 74(2), pp 275–285. 22. “Guidance for Industry: Use of testing), compendial verification testing 13. Sögding T et al, “How Sterilisation International Standard ISO 10993-1 according to USP/EP/JP/YBB/ISO/ASTM, and of Primary Packaging Influences the – Biological evaluation of medical material identification testing. Composed of Results of E&L Studies”. Contract devices - Part 1: Evaluation and a seasoned team of chemists and physicists, Pharma, June 2015. testing within a risk management SCHOTT Pharma Services offers insight and 14. “Pharma Analytics”. SCHOTT process”. US FDA, Sept 2020. support for all development and commercial Pharma Services, web page. 23. “USP<233> Elemental Impurities parenteral packaging challenges. 15. “ICH M7 Assessment and control – Procedures”. US Pharmacopeial of DNA reactive (mutagenic) Convention, 2018. REFERENCES impurities in pharmaceuticals to 24. “ICH Q2 (R1) Validation of limit potential carcinogenic risk”. analytical procedures: text and 1. “USP<1663> Assessment of EMA, published 2017. methodology”. EMA, published 1996. extractables associated with pharmaceutical packaging/delivery systems”. US Pharmacopeial ABOUT THE AUTHORS Convention, 2020. 2. “ISO 10993-18: Biological evaluation Matthias Bicker, PhD, is a Scientific Advisor at SCHOTT Pharma Services and is an of medical devices – Part 18: Chemical experienced expert in customised test designs, including alignment with the most recent characterisation of medical device regulatory guideline recommendations. Dr Bicker holds a PhD in physics in the field of materials within a risk management nanostructures in thin film coatings. process”. ISO, published 2020. 3. “ISO 10993-1: Biological evaluation Michael Müller is Study Director at SCHOTT Pharma Services. He holds a diploma in of medical devices – Part 1: Evaluation biotechnology and manages the laboratory focused on the characterisation of organic and testing within a risk management extractables & leachables. process”. ISO, published 2020. 4. “ISO 10993-12: Biological evaluation Marc Mittermüller is Study Director at SCHOTT Pharma Services, holding responsibility of medical devices – Part 12: Sample for co-ordinating study activities. He is a chemist with extensive experience in the preparation and reference materials”. analyses of inorganic leachables and elemental impurities. ISO, published 2021. 5. “ISO 10993-17: Biological evaluation Daniel Haines, PhD, is Head of Pharma Services North America at SCHOTT Pharma of medical devices — Part 17: Services, with responisbility for laboratory activities and customer relations in North Establishment of allowable limits America. He holds a PhD in inorganic chemistry and has over 20 years’ experience in the for leachable substances”. field of drug/container interactions. ISO, published 2002. 6. Paskiet D et al, “Thresholds and Uwe Rothhaar, PhD, is Director at SCHOTT Pharma Services. He earned his PhD in Best Practices for Extractable physics in the field of surface and thin film characterisation and has remained connected and Leachables”. 3rd PQRI/FDA to analytics in various positions he has held during his career. Conference on Advancing Product

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