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Addressing the Challenges of Developing Large Volume Drug/Device Combination Products for Parenteral SC Delivery

SC administration has been increasing over recent years, especially for frequent and long-term applications to treat chronical diseases.

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Released By ten23 health

PD Dr. Andrea Allmendinger, CSO (Chief Scientific Officer)
Prof. Dr. Hanns-Christian Mahler, CEO (Chief Enablement Officer)
Dipl.-Ing. (FH) Helge Leibfritz, MBA, Director of Drug Product Design

The increasing need for large volume delivery devices

Biologics are typically applied parenterally, for example by intravenous (IV) or subcutaneous (SC) injection. SC administration has been increasing over recent years, especially for frequent and long-term applications to treat chronical diseases such as diabetes, rheumatoid arthritis, cancer and autoimmune diseases. There are many reasons for this including:

  • Potential therapeutic (medical) advantages, e.g. allowing longer dosing intervals compared to IV, and reaching specific physiologic targets better than IV
  • Enabling self-administration by the patient, or administration by caregivers or healthcare professionals (HCPs), for example in a home or office setting
  • Reduced need for hospital visits, leading to significant cost savings, increased flexibility in appointment scheduling, and fewer capacity bottlenecks
  • Lower treatment burden and greater flexibility and convenience, which results in improved adherence
Whilst IV administration has a (defined) bioavailability of 100%, the bioavailability after SC administration is usually lower; for monoclonal antibodies (MABs), it is typically around 60-80%. As a result, the required effective dose is typically higher for SC delivery than for IV delivery, and large volumes are needed for SC delivery because of the high effective doses of many therapeutic ingredients such as MABs.

Traditionally, SC injection volume has been considered as limited to volumes <1 mL. However, knowledge and experience in the clinical setting is increasing with regard to tolerability and usability, and SC administration has recently been facilitated by the development of highly concentrated formulations at injection volumes up to 1, 2, or sometimes 3 mL. In addition, administering even higher volumes of between 3 and 20 mL (Badkar et al., 2021; Bittner et al. 2018, Roberts et al., 2022; Mathaes et al., 2016) is also attempted. The use of innovative SC delivery devices (e.g., on-body injectors, OBIs) may facilitate such larger volume SC delivery. When transiently modifying the SC space (see Section 2.2), the injectability of such larger volumes may also be facilitated.

Selection of the appropriate device and associated challenges

Ready-to-use delivery devices such as pre-filled syringes, autoinjectors, pens, and large volume injection devices are designed to facilitate administration for the end-user, in particular to allow self-administration. Administration of large volumes to the SC space may also be achieved manually, without any further additives or delivery devices, however this is not ideal from a patient’s or HCP’s perspective as it is less convenient. Products in vials require aseptic preparation including formulation withdrawal into an administration syringe, and – in the case of highly potent compounds – may need sophisticated syringe-to-vial adapter devices, so called closed system transfer devices (CSTDs). Aseptic preparation is difficult to achieve, and ready-to-use configurations are generally preferred as they have fewer safety concerns, reducing the risk of error, incorrect use, incorrect dosing and needle injuries.

A variety of large volume injection devices is commercially available off-the-shelf, each with a different mechanism, including mechanical, electromechanical, and pressure/collapsible container-based systems (Badkar et al., 2021). The appropriate choice for a specific drug will depend on a range of factors which are discussed below.

User/patient need perspective

The suitability for the intended user population as demonstrated in human factor studies, as well as the usability for the patient, are the most important points to consider when selecting the appropriate container system. Both the device and secondary packaging should be easy and intuitive to handle. Ideally, the device is provided pre-filled and ready-to-use in order that there is no requirement to assemble the drug reservoir and device. To a large extent, single-dose devices are fully disposable. Fortunately, however, reusable devices are becoming more popular in order to improve sustainability (Roberts et al., 2022).

Due to the longer injection time for large injection volumes, the user Interface will be more complex. This means that adequate safety precautions must be taken such as:

  • Activation: the ability to recognize that the device is ready to inject when attached to the skin.
  • Automatic insertion and retraction of the needle at the start and end of the injection process. A needle shield after injection is needed to prevent needle injuries.
  • Audible and visual signals during and after completed injection. The device should communicate via clear audio and visual signals with the patient before, during and after the injection.
Patient usability and comfort are crucial issues. On-body delivery systems (OBDS) should be portable/wearable and, ideally, directly attached to the skin. They should allow easy adherence to the skin during injection and be easy to remove after injection. For non-attached devices, such as autoinjectors, the ability of patients to hold the device in place during administration is key. In many cases, 10 to 15 seconds was considered the most acceptable.

To allow convenient self-administration, the products should preferably be delivered in a ready-to-use injection device with a fixed dose, which is not bodyweight-adjusted (Bittner et al., 2018). The current trend is for complex dosing regimens to be further simplified using subcutaneous fixed-dose combinations that contain two or more active molecules co-formulated within the same formulation. An example is the recently approved PHESGO® fixed dose combination.

In order to improve patient adherence, there is also a trend towards smart/connected devices. Such therapeutic drug delivery systems are able to collect device usage information and incorporate software that analyzes the data and reports remotely. Devices can be equipped with electronic dosing reminders and/or adherence trackers and usually have a wireless connection to allow patient monitoring (Bittner et al., 2019).

Drug Product development perspective

Large volume injections are typically developed as high concentration formulations or may be co-formulated or co-injected with permeation enhancers such as hyaluronidase. This is an enzyme that transiently and locally modifies the SC space, to minimize lower tissue backpressure and hence facilitate SC injection.

From a drug product development perspective, there are four major challenges for SC high concentration formulations in general:

Challenge number 1: Product compatibility

It is essential to test compatibility and stability with the primary packaging material. Thorough investigations are warranted particularly if non-established primary packaging containers such as large volume cartridges exceeding 10 mL are chosen or in the case of relatively novel containers (novel materials, coatings or use). In such cases, characterization of the primary packaging should include Container Closure Integrity and extractables/ leachables testing to name only two examples. Stability testing of product filled into the primary containers would include a panel of biochemical and pharmacopeial endpoints that cover critical quality attributes (CQAs) including content and purity, and obligatory CQAs including (sub-visible and visible) particulates. Notably, CQAs can be impacted not only by the drug substance, or filling process, but also device assembly, storage and transport, as well as administration by the caregiver, patient or HCP.

Challenge number 2: Product viscosity and device design

The main challenge besides stability considerations is the exponential increase in viscosity with increasing protein concentration. This is associated with an increase in injection forces required to administer the product. These injection forces need to be mitigated to ensure functionality and adequate injection time in order to maintain patient usability. Product design must ensure that functionality upon stress, stability, and transport testing is guaranteed, including adequate break-loose and gliding forces.

Product design should therefore consider:

  • Choice of suitable formulation parameters, such as excipients to minimize viscosity
  • Selection and engineering of adequate needle diameter to allow injection of concentrated solutions
  • Definition of acceptance criteria and ranges, e.g. differences in needle inner diameter and ranges of concentration of the active ingredient, that will translate (exponentially) into variations of viscosity
  • Control of injection speed over injection time to ensure suitable delivery duration
  • Definition of adequate tissue pressure and adequate hold times to minimize leakage from the injection site

Challenge number 3: Manufacturability of final drug product

The drug product manufacturing capabilities must be aligned with the requirements of the device partner and primary packaging supplier to ensure that the drug product will adhere to agreed parameters. This may be achieved through the use of established primary packaging at the manufacturing facility but in some cases, qualification/validation of innovative primary packaging is required.

The drug product manufacturer needs to be capable of reliably and consistently filling the related primary packaging containers (e.g., larger volume cartridges, syringes or special containers). They ideally offer ready-to-use containers in nest/tub configuration, bubble free plunger setting if required (minimal headspace offers benefits for clinical administration handling), control of the plunger stopper position, and stoppering under vacuum to allow reduced plunger compression (e.g. for silicone-free container closure systems). They must provide qualified container closure systems which maintain the integrity of their microbial barrier and hence the sterility of the drug product.

The manufacturer should be able to handle a highly viscous product from the processing side, e.g. choosing between different pumps, and between weight or volume fill. Overfills must be minimized as this is likely to result in significant cost savings.

These challenges imply a close connection between pharmaceutical product design and device design at an appropriate manufacturing facility. Joint development and commercialization are essential in order to transfer product knowledge, and will facilitate trouble shooting activities if problems occur during manufacture.

Challenge number 4: Regulatory aspects 

Combination products are defined as therapeutic and diagnostic products that combine drugs, devices, and/or biological products, and are highly regulated. In cases where a medical device is associated with a specific treatment, regulatory requirements also consider approval of the accompanying active substance, and are typically supported by drug product technical development.

The regulatory strategy depends on product configuration and target country. Medical devices are classified into categories based on the function, patient risk, and the manufacturer’s intended use of the device. Design control requirements need to be applied for the development and industrialization of medical devices. 

To market a medical device in the US, manufacturers require the submission of a Premarket Notification 510(k) prior to commercial distribution, and the FDA issues a “letter of substantial equivalence” confirming that the device is considered substantially equivalent to one legally in commercial distribution in the US. Similarly, in the EU, medical device commercialization requires a Conformité Européenne (CE) mark that indicates compliance with specific EU regulations covering standards of performance, quality, safety, and efficacy. Where a CE mark has not been issued for the device component on its own, a Notified Body Opinion (NBOp) regarding the conformity of the medical device with the relevant Medical Device Regulation (MDR) is required and needs to be submitted for marketing authorization applications.

As an integral part of drug treatment and patient monitoring, connected devices and related health apps can meet the definition of a medical device (Bittner et al., 2019).

Switching from vial to a medical device

The benefit to the patient when switching from a vial to a pre-filled combination device configuration is clear, as discussed in the previous sections. Switching to a medical device puts the patient at the center of development, with the design focused on patient needs. Furthermore, devices may offer additional product differentiation and/or market exclusivity for the pharmaceutical company (Allmendinger et al., 2021).

The primary packaging configuration should initially be chosen to cover a range of fill volumes and viscosities and provide a reproducible injection time per drug to allow some flexibility during product development. Vials are often preferred for early-stage (preclinical and) clinical development as they allow:

  • More flexible dosing (dose by volume), with one or multiple containers in use to cover the broad range of EIH doses to Phase 1 and possibly Phase 2 dosing.
  • Use of platform knowledge and hence gate development investments.
  • More time to gain knowledge on the selection of an appropriate commercial configuration, including the device.
The timing of this change is case-by-case, but typically, the launch configuration is expected to be used for pivotal clinical studies, i.e., typically for Phase 3. The introduction of the commercial primary packaging (e.g., syringe in autoinjector) may also occur during a phase 3 study as a specific study group. In some cases, it may make sense to switch from the vial to a device (and related primary packaging) post-launch.

Switching configurations adds a high degree of complexity to the drug product development, however it is unlikely that the primary packaging will remain the same from early-stage clinical development to the launch. If the original configuration can be kept and the DP filling stays same, many stability studies and characterization and validation studies can be leveraged. Device testing such as functionality and the influence of the assembly process should also be considered. However, in the majority of cases, the primary packaging material needs to be changed, for example to a prefilled syringe or large volume cartridge.

How to succeed – selecting the right partners

In addition to the the need to increase knowledge about patient preference and overall acceptance of large volume injection devices, choosing right partners for integrated development is key. Partners should be selected according to their capabilities – the interplay and joint development between product development and manufacturer is essential to transfer product knowledge and facilitate trouble shooting activities.

Selection of the right device and primary packaging (product and supplier) for a specific product must consider the pros and cons of new device development versus established containers. Ideally, the primary packaging container supplier, medical device manufacturer, drug product filling and assembly facility, and product developer (including the pharmaceutical developer) should hold discussions from the beginning of the process, working hand in hand and agreeing mutual goals. The strategy and project timelines must be synchronized and specifications and test methods aligned; troubleshooting can be approached holistically to save time, costs, resources and, most importantly, to avoid errors. Communication is key throughout the project.

A CDMO like ten23 health is appropriately positioned to overcome the challenges of large volume injection devices. We offer integrated development of formulation services, analytical development. and product characterization, device selection and testing, drug product process design and characterization. We also provide fill and finish manufacturing of complex and high precision containers at our swissfillon facility in Visp, Switzerland.

Learn more at www.ten23.health

References

1. Badkar AV, Gandhi RB, Davis SP, LaBarre MJ. Subcutaneous Delivery of High-Dose/Volume Biologics: Current Status and Prospect for Future Advancements. Drug Des Devel Ther 2021;15:159-170.

2. Bittner B, Richter W, Schmidt J. Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities. BioDrugs 2018;32(5): 425–440.

3. Roberts BC, Rini C, Klug R, Sherman DB, Morel D, Pettis RJ. Novel cannula design improves large volume auto-injection rates for high viscosity solutions.  Drug Deliv 2022;29(1):43-51.

4. Mathaes R, Koulov A, Joerg S, Mahler HC. Subcutaneous Injection Volume of Biopharmaceuticals-Pushing the Boundaries. J Pharm Sci 2016;105(8):2255-9.

5. Bittner B, Schmit Chiesi C, Kharawala S, Kaur G, Schmidt J. Connected drug delivery devices to complement drug treatments: potential to facilitate disease management in home setting. Med Devices (Auckl) 2019; 12: 101–127.

6. Allmendinger A. Opportunities in an Evolving Pharmaceutical Development Landscape: Product Differentiation of Biopharmaceutical Drug Products.  Pharm Res 2021;38(5):739-757.

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