Stuart R. Gallant, MD, PhD

In today’s post, some important aspects of development and manufacture of combination products with pharmaceutical autoinjectors are considered.  Pharmaceutical autoinjectors provide three key advantages over individual vial and syringe delivery of intramuscular and subcutaneous parenteral drugs:

• Ensuring the same injection force, needle gauge, needle insertion depth, injection time, and accuracy of dose in each injection.
• They allow administration by patients and caregivers with minimal training.  This facilities administration at home and on the battlefield.
• By shielding the needle before and after administration, they prevent both anxiety about the needle and risk of needle stick injury.

These advantages go a long way to explaining the size of the $60B autoinjector market and its growth at 16% CAGR expended in the coming years.

Rise of Platform Injectors

Autoinjectors have been available for decades with early applications including military autoinjectors to counter nerve gas exposures and epinephrine EpiPens to treat life threatening allergic reactions.  Early autoinjectors were custom designed devices—not unlike tailored suits—and while tailored suits fit the wearer precisely, they are more expensive than off-the-rack clothing.

In the last decade, “platform” injectors have become available—the delivery device equivalent of the off-the-rack suit.  Platform autoinjectors such as SHL’s Molly, Ypsomed’s Ypsomate, and Gerresheimer’s Gx Inbeneo offer a package of important features at reasonable per-unit prices.  The reasonable price is possible because development and manufacturing costs of the autoinjector are spread across many pharmaceutical firms who all adopt the platform design.  Features of platform autoinjectors include:

• Patented Engineering Design to ensure freedom to operate for the device in the marketplace.
• Compatibility with Common Primary Containers such as prefilled syringes and cartridges.
• Technical Support to test the concept of the device and implement device assembly and regulatory support to facilitate licensure.
• Customizable Outer Appearance (color, label, and shape) to allow a unique autoinjector appearance to support brand strategy and customizable operating parameters to allow products of varying injection volume and viscosity.
• Safety Features such as:  pre- and post-use needle shielding, validated ergonomics, operational verifications (e.g., clear windows into the device which allow injection to be monitored and audible clicks for the start and end of an injection).
• Established Supply Chain including:  1) a device manufacturer which delivers partially assembled autoinjectors to the packaging and labeling site and 2) packaging and labeling partners capable assembling prefilled syringes or cartridges into combination devices.

This approach a proven path to market, with SHL’s Molly having been first used in a combination product licensure in 2016 and Ypsomed’s Ypsomate having been first used in a combination product in 2018.

Diversity of Approaches

Currently, a plethora of autoinjector designs compete within the packaging marketplace.  Here are a sampling of currently available autoinjectors:

• Standard Platform Autoinjectors:  For injections from a fraction of 1 mL up to 2.25 mL, SHL’s Molly, Yposmed’s Ypsomate, and the new entry Gerresheimer’s Gx Inbeneo, as well as others are great choices.  Autoinjectors with primary containers consisting of prefilled syringes and cartridges are both available.
• High Viscosity:  Required injection force increases as the viscosity of the drug product increase.  With protein solutions regularly reaching 100 mg/ml—and at times, 200 mg/ml—as pharmaceutical companies attempt to cram more drug into a smaller volume, viscosities have increased significantly.  Since the relationship of viscosity to concentration in protein solutions is nonlinear, the demands placed on an autoinjector for a high concentration injection can be significant.  Some high viscosity autoinjectors include:  SHL’s Maggie and Bertha and Gerresheimer’s Gx Inbeneo.  Gx Inbeneo offers springs with 30 N and 70 N force.  (To put that in perspective, 40 N is the maximum force typically expected in a manual syringe injection, and 80 N is the maximum force most people are capable of delivering manually.)
• Large Volume Injection:  In the recent past, large volume “wearable” autoinjectors have become an important category of combination product.  Becton Dickinson Libertas, Ypsomed YpsoDose, Nemera Simbioze, and others can deliver 10 or 20 mL of often high viscosity drug product subcutaneously in a controlled manner (by bolus or by slow infusion).  These devices are a significant advance over decades old syringe pump technology which has long been used to deliver large volume injections.
• Lyophilized Drug Products:  Drug products (particularly proteins and some small molecules) may require storage as a lyophilized cake followed by reconstitution with sterile water or another solution.  The vial offers optimal conditions for lyophilization and reconstitution, based on its relatively low ratio of height to diameter and its relatively large head space.  Autoinjectors for lyophilized products support lyophilized products either by containing two cartridges and mixing between the cartridges (for example, Windgap’s ANDIPen) or a single cartridge containing both lyophilized drug product and diluent separated by a rubber stopper (for example, Ypsomed’s LyoTwist).  In either case, a premium is placed on a drug product which is easily and reproducibly reconstituted—an important consideration as formulation studies are performed during pre-clinical development.

Timeline and Cost

In developing a timeline for launch of an autoinjector, the first step is developing a supply chain which includes:  autoinjector supplier, drug product filling site, and assembly-packaging-labeling site.  As with all supply chain relationships, best practice is to have serious and detailed discussions with more than one vendor to ensure the service (in this case, development, testing, filling, and assembly of the autoinjector) is an optimal fit for the product.

The stages of development for a parenteral drug include:

1. Discovery
2. Pre-formulation, early stability, and animal tox material production
3. Clinical Phase 1 and Phase 2:  By this time, the formulation is locked in place; however, the dose is not decided.  Use of vial/syringe for delivery makes the most sense.  Introduction of autoinjector (in small numbers) to Phase 2B can produce useful supporting data, but as will be seen below, this can be challenging in timeline.
4. Phase 3:  In Phase 3, the formulation and the dose are locked in place.  Two options exist for timing of the autoinjector.  1) If time and resources are limited, the product may be launched using a vial/syringe or prefilled syringe with safety housing format.  If this is the case, bridging data to the autoinjector may be collected later, following Phase 3.  2) If development of the autoinjector has moved quickly, then the autoinjector may be included in the Phase 3.

A sample timeline for the initial phase of development of a platform autoinjector could look like this:

One year from contract signing to availability of clinical supplies in small numbers is reasonable.  At that point, stability studies of the combination product and clinical testing of the device are possible.  The subsequent elements of the timeline include:  1) application to register the combination product (follows completion of stability and clinical testing), 2) technology transfer to the device manufacturing and device assembly sites (follows design verification), and 3) manufacture of lot(s) to support commercial launch.

Cost of combination product development and manufacture for a platform autoinjector is highly variable.  Some goals to consider are:

• Development costs:  less than $1M
• Purchasing costs:  $2 to $10 per device (volume dependent)
• Assembly, packaging, and labeling costs:  less than $5 per device

Add drug substance and drug product manufacturing costs to the costs listed above.

Conclusions

There are a vast number of companies offering autoinjectors (Becton Dickinson, SHL, Ypsomed, Gerresheimer, Recipharm, Owen Mumford, Dali, Kaleo, Nemera, Windgap, Oval, Aktiv, Haselmeier, and others).  Becton Dickinson and some others have adopted the approach of offering a small number of configurations—presumably this allows the most attractive pricing, by virtue of only supporting a few products.  Some others, such as SHL, have wider product offerings—presumably allowing a broader range of autoinjector properties, allowing greater customization of performance.  It is reasonable to expect that there will be some shake out in this sector with some autoinjector products rising to the top while others are discontinued.

Disclaimer:  PharmaTopo^TM provides commentary on topics related to drugs.  The content on this website does not constitute technical, medical, legal, or financial advice.  Consult an appropriately skilled professional, such as an engineer, doctor, lawyer, or investment counselor, prior to undertaking any action related to the topics discussed on PharmaTopo.com.