The Evolution of Self-Injection Devices 

Fifty years ago, the advent of biotechnology heralded a new era of novel drugs. With complex molecules unsuitable for oral administration, injection-based systems were required to deliver the drug either directly into the bloodstream or under the skin.

The latter route, subcutaneous injection, spawned the field of self-injection devices enabling the patient to safely and conveniently take the drug him or herself.

To begin with, the majority of these devices delivered insulin and were, with designs inspired by ballpoint pens, devices using pre-filled cartridges containing the drug. With the advent of the pre-filled syringe (PFS), self-injection entered into the space of single-fixed doses, driven by the need to administer non-preserved formulations of monoclonal antibodies. At first, reusable systems prevailed and the overall need for devices was comparably low due to the long service life and limited overall demand. Back then, these devices were considered functional secondary packaging, manufactured mostly by big pharma for its own needs. Outside of this, only a limited number of specialized suppliers, like Ypsomed, offered design and manufacturing capabilities. In this phase, regulations were light, and the focus was on simple solutions that could beat the established standard of care, i.e. vial and syringes, in terms of user-friendliness and accuracy.

From Reusable Systems to Prefilled Devices

As the market evolved in the early 2000s, usability became an important design consideration, with convenient pre-filled pen injectors rolled out to serve the needs of an exploding population of insulin-dependent type 2 diabetics with second generation synthetic insulin. In the same period, the first autoinjectors for the administration of TNF-alpha inhibiting monoclonal antibodies were successfully launched and sold in increasing numbers.

This shift from reusable systems regulated as medical devices to ever growing numbers of pre-filled products that were regulated as combination or medicinal products also required new regulatory capabilities in the pharma industry. The strong growth in this period highlighted the limits and risks in the then prevailing setup of supply chains for devices that were supporting multi-billion drug franchises.

Big pharma started to either build up massive manufacturing capacity in-house or started collaborating with a growing network of contract manufacturers that would operate multiple manufacturing lines for the same product. At the same time, it became apparent that the traditional approach towards development, industrialization and manufacturing of self-injection devices, that is, the deployment of a bespoke device for each drug, was not fast enough to ensure desired time to market, was too expensive, and also too risky given the rate of attrition in drug pipelines.

The Shift to Platform-Based Development

As early as 2010, Ypsomed therefore introduced its platform approach that offers pre-developed devices ready for production using a flexible and shared manufacturing setup (Figure 1). With such platforms, the main drawbacks of the traditional approach could be mitigated, and time to clinic as well as time to market for any drug in a self-injection device could be considerably lowered at a fraction of the cost of a bespoke development. Thus, the access barrier to state-of-the-art self-injection devices was lowered, which also opened new possibilities for the rising biosimilars‘ industry. Nowadays, platforms are an established business and manufacturing model that has given rise to a networked industry of consultancies, design companies, device companies, manufacturing equipment suppliers, primary container companies and contract manufacturing organizations.

Yet challenges related to manufacturing flexibility, speed of scale-up and continuity of supply remain, calling for specific solutions at various levels. This is because at the end of the day, as has been the case ever since the approval of the first recombinant insulin by the FDA in 1982, patients need their pharmacy to have the drugs they need in stock at all times.

Addressing Flexibility and Scale-Up Challenges

In consumer goods and cars, the “batch size of one” or fully customized product, has become the holy grail and has shaped general expectations. However, manufacturing pharmaceuticals is historically a volume business driven by batch-production and high upfront investments in highly specialized facilities dedicated to a single asset.

The same applies to the manufacturing of medical devices that ask for tooling and assembly equipment with long lead-times. Both factors work against flexible manufacturing i.e. building different products or product variants in variable lot sizes on the same production line. While adjusting lot sizes is straightforward in principle, it might raise questions about economic viability if the ratio of lot sizes to output of the line are far apart.

So, the volume flexibility needed for clinical studies, e.g with low volumes of several product variants for different dose strengths, has to be supported by an equipment with suitably high flexibility and limited output. More complex to handle, however, is variant flexibility that enables manufacturing of several product variants on the same highly automated production line. This flexibility must be built into the design of the delivery device by taking into account an expected parameter space covering all potential drugs and by designing it for a broad user population with a range of properties. The device is then configured from components that are part of that product’s platform and manufactured on this flexible line.

Robust processes, and a comprehensive control strategy that is interlinked with down-stream operations, ensure that every production campaign yields the desired product variant with the correct specifications.

Speed of scale-up has been a longstanding industry concern that often could be addressed with moderate risk-taking by building up an initial capacity based on vetted market assumptions. Even if a manufacturing line for a self-injection device is a complex procurement item that takes, depending on its output, between 1.5 and 3 years to get up and running, staggering the scale-up over time as demand evolves has worked comparably well in the past. However, as the dynamic growth driven by mass adoption of obesity treatments has shown, this is no longer fast enough. Scale-up needs to take place much more rapidly, asking for a bolder approach, i.e. earlier and more massive capital layout even in light of uncertain market uptake of the drug.

At Ypsomed, the thinking recently has gone towards challenging the assumption that fast-running assembly lines have to be “one trick ponies” geared to manufacturing a single product variant, in favor of a more flexible setup that allows the retooling of fast-running lines in acceptable timeframes for other products, thus reducing the risk of building capacity for one single asset (Figure 2).

This thought process was driven by different players in the value network and highlights the need for close collaboration within the industry. This need for closer collaboration has also shaped the way Ypsomed engages with its extended manufacturing ecosystem.

Over the past decades, a strategic network of partners has emerged, including primary container manufacturers, fill-finish providers, and final assembly CMOs. These long-standing collaborations extend across North America, Europe, and Asia and support both clinical and commercial supply. By working with trusted partners that share aligned quality and performance standards, Ypsomed is able to complement its own manufacturing footprint with additional capacity and flexibility, ultimately helping to reduce timelines and manage complexity in the development and delivery of combination products (Figure 3).

Building Supply Chain Resilience in a Volatile World

While flexible designs and fast, flexible lines are necessary to address today’s supply chain needs for self-injection devices, they are by no means sufficient. The recent pandemic, the repercussion of the war in Ukraine and the surge in demand due to the obesity treatments have highlighted the need of setting up robust supply chains that can cope with rapid change in demand, temporary disruption and shortage of raw materials, components and equipment.

Setting up a resilient and efficient supply chain comes down to balancing redundancy and overcapacity against demand, and managing multiple sources of raw materials and components. It can, as a pharma company, be tempting to ask for a fully redundant, geographically distributed supply chain based on equipment from multiple vendors using materials and components from multiple sources. It goes without saying that this often goes too far and rarely will yield an economically viable solution for a self-injection device.

At Ypsomed, we rely on assembly lines with different capacities, usually from different vendors that are located at different sites. So geographic distribution and equipment diversity can be reasonably achieved while ensuring that processes can still be easily transferred, e.g. from our leading sites in Switzerland to our new operations in Germany, China and ultimately the United States (Figure 4, Figure 5).