The Interface Between Prefilled Syringe and Autoinjector – a Development Framework

Expert View

THE INTERFACE BETWEEN PREFILLED SYRINGE AND AUTOINJECTOR – A DEVELOPMENT FRAMEWORK

In this article, Jeffrey Philippson, PhD, Drug Delivery Test and Evaluation Specialist, and Tom Kemp, PhD, Drug Delivery Design and Optimisation Specialist, both of PA Consulting, outline the challenges for autoinjector developers at the interface between the device and the prefilled syringe – and describe a framework to formalise analysis of the interface.

The prefilled syringe (PFS) has widely published benefits over “Formed glass barrel meets the traditional syringe and vial,1 leading to an increasing share precision-moulded parts, stopper of the drug delivery market glide force meets dynamic device in recent years.2 The addition spring-load, and syringe robustness of an autoinjector to deliver a PFS can enhance safety and the meets plunger impact load.” patient experience,3 opening up new opportunities for home- and self-administration.4 Finally, we extend the interface concept The typical starting point for beyond purely functional considerations development of an autoinjector solution, to include organisational challenges – whether a novel development or application dysfunction at the interfaces within and of a market-ready device, is an existing between organisations involved in selection PFS used in clinical trials – but this leaves and development of autoinjectors can mirror little opportunity for syringe selection challenges within the device. The benefits or modification. Many of the technical of getting it right are far-reaching and challenges facing device developers stem include rapid and effective evaluation of Dr Jeffrey Philippson from dysfunction at the interface between new PFS-autoinjector pairings, improved Drug Delivery Test and Evaluation Specialist the device and the primary container and device performance and reliability, and T: +44 1763 267 030 nowhere is this more evident than at the accelerated development timelines. E: jeffrey.philippson@ interface between PFS and autoinjector: paconsulting.com formed glass barrel meets precision-moulded CRITICAL DIMENSIONS AT parts, stopper glide force meets dynamic THE GEOMETRIC INTERFACE device spring-load, and syringe robustness meets plunger impact load. The most obvious point of contact at the This article outlines the key features of interface is the axial mounting of the PFS the interface between device and syringe, within the device. Early autoinjectors addressing the functional dependencies and mounted the PFS at the flange, which has the challenges that can arise. A framework the natural perpendicular geometry is then described to formalise the analysis to resolve the axial load during syringe of these features through the introduction emptying. Unfortunately, the geometry Dr Tom Kemp Drug Delivery Design and of an interface specification that brings that makes it so apparently suitable for Optimisation Specialist together overlapping requirements of the mounting also makes it a key weak point T: +44 7866 549 536 two subsystems to ensure compatibility and that is vulnerable to fracture under load. E: [email protected] drive the development of test methods that Unacceptably high rates of breakage on directly address critical interdependencies. firing were attributed to stresses on the PA Consulting Global Innovation and Technology Centre “The choice of mounting location and geometry defines Back Lane Melbourn many aspects of the final assembled device, including Hertfordshire critical requirements such as injection depth.” United Kingdom www.paconsulting.com

Figure 1: Diagram showing dimensions for manufacturing control and those critical to device functionality. A red cross indicates dimension typically not provided; a green tick indicates dimension typically provided. The details can vary from one manufacturer to another. The datum is the point on the syringe shoulder in contact with the device. flange, leading to recalls in extreme as the shoulder-to-needle-tip distance. cases.5 Something had to change. “In the new world of biologics, Figure 1 shows the critical measurements Most autoinjectors currently on from the points of view of manufacturing the market mount the PFS at the with higher spring loads required and device functionality. shoulder, where the needle meets to accommodate increased The story of in-use syringe breakages the glass body, which is the only volumes and viscosities, we as an may have further twists in store. In the other suitable surface. This change new world of biologics, with higher spring was adopted to reduce stress on the industry must remain vigilant.” loads required to accommodate increased flange.6 However, the impacts of volumes and viscosities, we as an industry that decision went far beyond the must remain vigilant and ensure the limits initial drivers that motivated it. mitigated by post-forming inspection. to syringe robustness are well understood. The choice of mounting location and To make matters worse, although all geometry defines many aspects of the manufacturers comply with the ISO- FORCE BALANCE final assembled device, including critical specified dimensions, varying processes can AT THE INTERFACE requirements such as injection depth. still result in different nominal geometries. The syringe shoulder is created by forming Needle placement during manufacture In addition to the geometric interface, semi-molten glass over a tungsten pin, and stoppering during fill and finish are the balance of forces between PFS and in a process that inevitably results in a usually referenced to the flange, resulting autoinjector is also critical to device variable geometry, although this can be in unpredictable offsets that appear as performance (Figure 2). The spring rate variability in critical dimensions such and precompression must be sufficient to overcome the stopper break-loose force to initiate syringe emptying, exceed the glide force to prevent stalling and achieve the required injection time. At the upper limit, spring load is limited by available space and the maximum impact force to avoid damage to the syringe and material creep in moulded parts. Although long springs with a low spring rate can seem like an ideal solution, with almost constant spring load, equilibrium spring length is limited Figure 2: A force diagram showing a by the challenge posed prefilled syringe being emptied under the by compressing very device spring load, showing the spring load long springs as part (Fs), stopper friction (Fk), fluid inertia (Fi), of an automated viscous drag (Fμ) and the resultant force (Fr). Arrows not to scale. assembly process.

The standard force characteristics measured by manufacturers and users “A critical task when integrating a PFS with an of PFSs in characterisation and quality control studies include the break-loose autoinjector is a detailed characterisation of the primary force and glide force at constant velocity. container, matching up measured characteristics of the Glide force is generally reported as a syringe with their counterparts in the device.” mean value at a given velocity, whereas design for a specified injection time must take account of the dynamic force profile of the combined drive system and load. materials or mechanical construction. characterisation tests to assess compatibility Consider that the spring load is constantly The choices of spring rate and between autoinjector and PFS. The decreasing as the spring expands, while precompression influence the observed development of the specification and the the stopper friction varies with both breakage force, necessitating a stepped associated tests is a crucial learning step velocity and lubrication. Siliconisation approach with multiple impacts at increasing that should be integral to the device reduces stopper friction but lubricant forces to produce a conservative estimate of development process. It further comes into mobility during stopper travel can add the threshold breakage force. Statistical its own when the inevitable question is further variability.7 analysis of the results must be undertaken asked: “Can the device deliver a different A critical characteristic that can be with care; breakage processes tend to be PFS?” Whether it is a new drug product, extremely challenging to quantify is the non-normal, with long high tails that can a new syringe or both, the interface threshold force for impact breakage. On lead to misinterpretation of results. specification provides a clear process and release, the plunger accelerates towards Cap removal force is an important unambiguous answers to critical questions the stopper under the applied spring characteristic of autoinjectors and, for of compatibility. load, generating a large transient force drugs indicated for acute conditions, can In an ideal world, the syringe on impact. Designers attempt to minimise be an essential performance requirement. requirements would simply be taken the initial gap between the plunger and Although a modest additional friction from the manufacturer drawings and stopper but the gap must be sufficient to component is added by the device, cap other specifications. However, life is avoid contact before firing, accounting for removal force is dominated by the force to rarely so simple. Dimensions specified by dimensional tolerances. Impact forces can remove the needle shield. Such high forces manufacturers relate to the manufacturing be modelled or measured relatively easily are required to accommodate the variable process rather than to optimal seating but the corresponding threshold for syringe seating geometry, while maintaining within an autoinjector, having been breakage is more of a challenge. container closure integrity. The standard developed for manual administration. The Simply replicating the conditions inside claimed upper limit on needle shield mass-produced glass prefillable syringe an autoinjector is not expected to yield removal force is 35 N, constraining the has existed for 65 years11 and is highly observed breakages for any reasonable test design window for cap removal force and optimised as a low-cost, sterile, high-barrier sample size. A nonparametric tolerance leading to usability problems.3 Although primary container and drug delivery system, limit can be placed on breakage rate most fall well below this limit, forces over manufactured in enormous volumes. based on observed incidence of non- 25 N are not uncommon, particularly at low breakages but demonstrating an acceptably temperature. Many syringe manufacturers THE INTERFACE WITHIN AND low breakage rate would again require are now filing IP for needle shield removal BETWEEN ORGANISATIONS unrealistic sample sizes. tools for manual administration8,9 and some For example, demonstrating a breakage device developers are adding mechanisms to Beyond purely functional considerations, rate below one part-per-million with 95% assist with cap removal.10 challenges extend to the organisational confidence would require observation interface between primary container and of 2,995,731 firings with no breakages. A FRAMEWORK FOR ADDRESSING medical device teams. Pharmaceutical Alternatively, a parametric approach can OVERLAPPING REQUIREMENTS companies have long had dedicated teams be used, measuring the force at which AT THE INTERFACE focused on evaluation and selection of breakage does occur by using much higher primary containers, including syringes, loads than those applied during device A critical task when integrating a PFS which play critical roles protecting the firing. In principle, the distribution of with an autoinjector is a detailed drug product, maintaining sterility breakage forces can be compared with the characterisation of the primary container, and achieving the required shelf- measured device impact force distribution, matching up measured characteristics of life. More recently, dedicated medical with the overlap integral between the two the syringe with their counterparts in the device teams have appeared, focused on representing the expected breakage rate and device. A useful framework for this is evaluation and selection of devices such the difference between the tolerance limits the concept of an interface specification, as autoinjectors. on the two distributions representing a with requirements defined in terms of The relatively recent appearance and conservative safety margin. functionality and referenced to both the generally low profile of medical device There are limitations to this approach: design input requirements of the device and teams can lead to a disconnect between a test apparatus that can reliably a specification for the PFS. them and the wider organisation, with achieve syringe breakage cannot be fully A clearly defined interface specification limited communication and a lack of joined- representative of device spring load, can be used to define a matched set of up decision making. This mirrors the siloed

mentality that has traditionally existed come to that. We have a vision of prefilled errors”. AAPS Open, 2018, between the chemistry, manufacturing syringe and autoinjector working together Vol 4(7), pp 1–14. and control (CMC) and research and in harmony and, with good communication 4. Bernstein D et al, “Usability of development (R&D) divisions. within and between partner organisations, mepolizumab single-use prefilled Overcoming this divide has the potential we as an industry can make it happen. autoinjector for patient self- to pay significant dividends through sharing administration”. J Asthma, 2019, of expertise, strategic decision making and ABOUT THE COMPANY Vol 56, pp 1532–4303. early consideration of opportunities for drug 5. DeGrazio F, Paskiet D, “Glass delivery devices when selecting a primary PA Consulting is an innovation and breakage, delamination and container for clinical trials. Typically, transformation consultancy with more compatibility with biologics have primary container selection is locked down than 2,800 specialists working in a number boosted interest in novel materials long before any consideration is given of key industries globally. It has over in pharma packaging”. to medical device options and there is a 40 years’ experience in the design, ContractPharma.com, 2012. natural reluctance to change the container development, characterisation and 6. Nemera.net, “Safelia® 1 ml and selection when proceeding to device evaluation of drug delivery devices. PA has 2.25 ml Autoinjectors Designed selection or development. a dedicated parenteral drug delivery team, to be Patient Friendly”. The concept of the organisational covering everything from prefilled syringes Product leaflet, 2014. interface can be extended to address the and reconstitution kits to autoinjectors, 7. 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Weinhold T et al, “Improving the Generation in Glass Prefillable have been slow to adopt polymer syringes: safety of disposable autoinjection Syringes”. Drug Dev Del, 2014, the excellent barrier properties of glass; devices: a systematic review of use Vol 14(1), pp 55–61. sensible risk aversion, a “go with what you know” attitude; and some inevitable inertia. Japan is a notable exception, having fully ABOUT THE AUTHORS transitioned to moulded polymer syringes, cartridges and vials, partly due to the risk of Jeffrey Philippson is a specialist in testing and evaluation of parenteral drug delivery glass breakage during earthquakes. devices with PA Consulting in Cambridge, UK, and leads the PA injection science Polymer syringes would certainly address team. He applies statistics and data analysis to the development and evaluation concerns around dimensional tolerances of drug delivery devices, with a particular focus on autoinjectors, pen injectors and the Japanese example demonstrates the and infusion pumps. Dr Philippson is an expert in design input creation, effective and scalable nature of this solution. test method development and validation, and design verification processes. He holds a Market shifts point to a steady increase in PhD in Experimental Physics from Queen’s University (Kingston, ON, Canada). the use of polymer syringes and that is one way to address complexities at the interface Tom Kemp is a specialist in the design and optimisation of parenteral drug with drug delivery devices. delivery devices with PA Consulting in Cambridge, UK and leads the PA injectable drug delivery engineering team. A mechanical engineer by training, he has deep experience CONCLUSION in the design and development of injectable drug delivery systems, having led a range of autoinjector, large-volume-device and pen-injector programmes, evidenced by 50+ Dysfunction at the interface between injector patents. Dr Kemp supports companies to manage the drug-device interface prefilled syringe and autoinjector? With a successfully and continually seeks to enhance the device offering to patients. He holds a clear view of the critical inter-dependencies PhD in MEMS Technology. and a well-characterised syringe, it need not