EXECUTIVE INTERVIEW - BD Integrated Systems: From Innovation to Integration

The growing complexity and regulatory rigor of combination products has called for increasingly innovative delivery devices. To learn more about the advantages of using an integrated system for these drug-device combination products, Drug Development & Delivery recently interviewed Theresa Bankston, PhD, Director of the Technical Services group for BD Medical – Pharmaceutical Systems, who is responsible for providing technical support, solutions and services around delivery systems for injectable drug therapies.

Q: Can you begin by describing what an “integrated system” is, and why it is necessary?

A: The number of biological therapies in development to treat chronic diseases has risen steadily throughout the years. The fact that many of these therapies are designed for home delivery by patients or caregivers via subcutaneous injection, combined with the increasing complexity of longer acting formulations, larger injection volumes, and longer injection durations, has raised the bar for seamless injection delivery technology. Patients today receive these drugs inside prefilled injection devices, known as combination products.

To bring a drug-device combination product to market, pharmaceutical companies must select and assemble multiple components that work together effectively to deliver the drug formulation safely and effectively. These components include a primary container consisting of a syringe barrel, stopper, plunger rod, and backstop; a secondary delivery system, such as an autoinjector or wearable injector; and an add-on needlestick safety guard. These components are available from a variety of suppliers, but pharmaceutical companies who purchase components separately take on additional risks that can be significantly reduced by selecting an integrated system.

Q: What background and specific experience does BD bring to this field?

A: Across BD, we have extensive experience in multiple areas impacting combination products: the drug-container interface, the container-device interface, and the patient-device interface. The latter comes through extensive work developing standards in injection technique across various care settings and preclinical and clinical capabilities in injection science. Specifically, with our long history and expertise in combination products, BD’s integrated systems offer a means to incorporate already existing world-class technologies with novel secondary delivery mechanisms to provide a seamless solution.

BD is a leading provider of primary containers globally. We also offer secondary delivery systems, which are designed to integrate with the well-established primary containers already used by most pharmaceutical manufacturers, for a complete combination product solution. This increases convenience, but also enables more flexibility in device selection before manufacturers make downstream decisions about device features and functionality.

BD has developed and currently provides billions of prefillable syringes and components to the pharmaceutical industry every year, meaning that we have the analytical tools and lab test capabilities to optimize the components of combination products to operate cohesively.

Our experience in designing and integrating components into systems, and extensive collaboration with drug developers has led to the development of a range of end-to-end services. These will help pharmaceutical companies in three main ways: first to choose the correct components and system for their application, second, to assess and offer solutions to any potential challenges or sensitivities, and finally to produce the data packages needed to demonstrate the safety and performance of the integrated combination product.

Q: What are the drawbacks and risks of using separate components?

A: Broadly, the risks include the delivery system not functioning as intended, such as primary container breakage, inconsistent system performance, and incompatibility with key container components. These risks may include increases in cost, project management complexity and time, potential delays to launch, and unforeseen problems post-launch. Moreover, such problems may not be revealed until late in development, or possibly after commercialization, when the combination product has already been manufactured in large quantities, and reached patients. The consequences can range from high scrap rates and waste during the filling or assembly process to the loss of costly drugs and therapy delays in the care setting.

Q: And how does BD address these risks?

A: For combination products to perform most effectively, special attention must be paid to component interfaces throughout the product development and delivery process, from the early design phases to manufacturing strategy and execution. At the interface between the drug and primary container, BD leverages its expertise and capabilities in glide force testing to ensure the drug is in the appropriate primary container to meet the manufacturer’s needs. Then, between the primary container and the device, BD provides statistical tolerance analysis to specify interface requirements that minimize the risk of system failures. Finally, between the drug and secondary delivery system, BD employs injection time modelling to improve overall device performance.

A well-integrated system anticipates and mitigates performance risks early in development. BD performs system validation and design verification testing on established reference systems, challenging system performance at the limits of process capability. The outputs of this process are provided in summary report documentation.

Q: How does this impact savings for pharmaceutical companies?

A: In terms of time and cost, the most significant savings come from avoiding potentially delayed launch timelines. BD’s integrated approach is focused on ensuring that every system component functions cohesively. This approach is intended to develop a seamless delivery system that meets the rigorous regulatory requirements for safety, effectiveness, functionality, and usability.

For example, BD’s leading primary container technology designed for biologic drugs, BD Neopak^TM, ensures a fit with many secondary systems, including BD handheld autoinjectors, wearable injectors, and passive safety devices. This enhanced fit supports greater choice and flexibility for pharmaceutical companies to serve diverse patient groups, therapeutic areas, and markets, minimizing the costs associated with managing multiple component interfaces and suppliers.

Q: What processes are in place to optimize product development?

A: In terms of risk mitigation, because BD produces both primary and secondary systems, we have a unique appreciation of nuances in meeting ISO standards that can help customers. Visibility across secondary system platforms results in product designs that ensure system integration between BD prefillable syringes and secondary systems, both during development and after manufacturing scale-up through commercialization. Internal experts share learnings from implementation across project teams. Moreover, quality commitment is maintained at component and system (including primary container) level, which forces tighter specifications and reduced variability in system performance. This creates a high degree of accountability for BD, as the single party responsible for the performance of the total delivery system.

Finally, BD conducts human factors engineering testing on its most advanced products across a range of representative users to confirm that the integrated devices are safe and user friendly. While pharmaceutical companies will conduct their own testing with the actual formulation, this early testing increases confidence in usability and reduces the risk of unforeseen issues. Testing for performance feasibility may include in vivo testing, demonstrating that various injection volumes or flow rates are feasible. Combination product support occurs throughout the development process, from matching the right set of components with the formulation in Phases I and II, to validation testing of the system in Phases II and III.

For example, BD integrates its best-in-class BD Hypak^TM, BD Neopak^TM, and cannula technologies into our self-injection systems, providing multi-platform flexibility across a range of dose volumes. BD’s wearable injector, BD Libertas^TM, is the leading model of BD systems integration, designed from the bottom up, with an array of proven BD components, including BD Neopak^TM technology and cannula.

BD also offers a leading brand of passive needle guards through its BD UltraSafe Passive^TM and BD Plus^TM Needle Guards. Unlike most add-on safety devices, BD UltraSafe Passive^TM and BD Plus^TM Passive Needle Guards are designed to work with BD prefillable syringes. Because BD develops both components, we can test compatibility long before a pharmaceutical customer can test the components together with a specific drug.

Q: Can you give specific examples of the most common issues that are solved with integrated systems?

A: First, let’s look at cap removal malfunction and wasted drugs. When patients remove the cap from an auto-injector, the rigid needle shield (RNS) may not always be pulled from the needle. The result could be damage to the needle and the drug delivery device, rendering the device unusable. For the pharmaceutical company, this issue may produce complaints, drug wastage, and negative quality perception.

With BD’s integrated auto-injectors, the caps are designed to integrate with and remove the RNS so that the needle is not damaged. Knowing that even minor changes, such as tool replacement, can affect RNS dimensions, BD routinely and proactively assesses design and manufacturing updates. Another issue is that needle extension (depth) is not always well controlled or understood when the auto-injectors and prefillable syringes are combined. The range of specifications for each component can result in an unexpectedly wide variation when the tolerances are stacked. As a result, unexpected clinical outcomes may occur when bridging from syringe injection to auto-injection, which can lead to pharmaceutical companies needing to repeat clinical studies or perhaps even re-design the auto-injector or prefillable syringe. Either case could result in product launch delays.

And finally, let’s look at primary container defects. Like needle extension, component dimensional variability (eg, prefillable syringe variability) is not always well accounted for in the design of the auto-injector assembly. This can lead to higher reject rates and possible primary container breakage.

Q: And in what ways do your key products address these integration issues?

A: I’ll focus on just two core products to answer your question: BD Physioject^TM and BD Intevia^TM. Let’s start with the BD Physioject^TM: a disposable auto-injector that fully integrates with the BD Neopak^TM 1-mL glass prefillable syringe or the BD Hypak^TM for biotech 1-mL glass prefillable syringe. With BD’s clear vision on detailed, proprietary prefillable syringe component specifications, critical dimensions that incorporate both BD Physioject^TM and prefillable syringes are factored in within the assembly process design.

In an ISO 11608 drop test (1 meter drop) study comparing BD Physioject^TM with one of the most commonly marketed disposable auto-injectors, BD Physioject^TM outperformed the comparator auto-injector in terms of prefilled syringe breakages and successful complete injections. Clinical studies conducted by BD show how injections with BD Physioject^TM (compared to injection with a syringe alone) provide evidence of more predictable clinical outcomes with BD’s integrated system.

And then there’s the BD Intevia^TM: an auto-injector platform technology specifically designed for high-viscosity drug delivery. It supports biotech’s evolving needs for high dosages, while offering integration with BD Neopak^TM technology and BD Hypak^TM for biotech, and providing manufacturers with the flexibility to accommodate formulation changes.

The team went a step further to optimize the system by setting out to eliminate the variability of requiring a skin pinch upon injection, simplifying the process for the patient. BD’s ability to tightly control variability of components enables consistent targeting of the subcutaneous space. Preclinical studies have demonstrated that, without the use of a skin pinch, BD can reliably control injection depth, greatly improving the injection experience all round.

Q: How would you summarize BD’s solutions in a nutshell?

A: Combined with BD’s continuous process and service improvements, BD integrated solutions are designed to mitigate system performance risks, facilitate cost savings, and prevent launch timeline delays to help pharmaceutical companies succeed in bringing their drug-device combination products to market and achieve commercial success.

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