6 Packaging And Delivery Challenges For Biologic Therapies

By Fran DeGrazio, Senior Industry & Technical Advisor, Drug Delivery Leader

Biologics-based drugs and therapies are redefining what modern medicine can achieve. From programmable mRNA therapeutics, through ADCs (antibody-drug conjugates), to tri-specific antibody formulations, these advances offer the promise of life-changing therapies more effectively than ever before.

In providing benefits to patients, many of these innovative therapies use formulation enhancers to improve stability, provide targeted release with enhanced bioavailability, and enable alternative routes of administration. Those routes can, for some biologics-based therapies, include oral delivery. However, the vast majority will, ultimately, need to be delivered into the body by way of a device, often as a combination product.

More so than for traditional chemically constructed small molecule drugs, designing effective delivery systems for biologics can bring significant challenges. These include challenges that go beyond typical compatibility or stability issues, each with direct implications for the package or device. Some challenges, such as increasing delivery volumes to patients, are well discussed while others receive less attention.

For those reasons, thorough understanding of a therapy's characteristics and technical requirements is essential for evaluating, selecting, and/or engineering the proper device to be used in a combination product. Meeting these criteria, along with addressing safety and user needs, constitutes the primary goals of product development.

As I often do (and recently did in an article similarly focused on drug delivery advances), below I offer my thoughts and recommendations on six key packaging and delivery challenges to address, resolve, or overcome in the development of biologics-based therapies.

Challenge #1: Chemical Compatibility May Not Ensure Deliverability

In the biopharmaceutical industry, compatibility is typically associated with the chemical or biological stability of the drug within its container. Many recently introduced biologics do demonstrate increased sensitivity to their packaging environment.

However, to illustrate distinctive challenges in delivering biologics, it’s helpful to consider compatibility from a different angle: that is, its influence on the functional performance of the delivery device. Two real-world examples I have experienced are particularly relevant to this issue, though I acknowledge that other cases also exist.

Increased Potential For Syringe System Clogging

The first example of a compatibility concern is the potential for clogging of the cannula used for a staked needle syringe system.¹ This phenomenon can potentially interfere with accurate drug delivery to patients. Two common mechanisms have been discussed by those in industry as potential root causes of this issue.

One is for zinc ions to leach from the rubber needle shield used to cap the staked needle. These elastomeric materials often include zinc oxide as an activator in the formulation, making zinc a likely extractable constituent. In certain cases, zinc ion release has been seen, leading to interactions with biologic drugs stored in prefilled syringe systems. Such interactions may result in drug gelation.

Another mechanism that has been discussed as a contributor to clogging is an increase in the concentration of the aqueous solution resident in the cannula due to moisture vapor transmission through the needle shield.²

Compromised Performance From Excipient And Syringe Interaction

The second example of a functional performance concern is the possible interaction between drug excipients and glass syringes, which can result in compromised device performance. Research shows that certain surfactants may interact with both the glass syringe and its silicone oil lubricant.³ Over time, this interaction may lead to the removal of the silicone oil, exposing the bare glass surface. Such changes affect the glide force needed for plunger movement within the syringe.

Increased break loose and extrusion force (BLE) poses a particular challenge when employing autoinjectors, as these devices apply consistent force to the plunger. Variability in BLE over time can adversely influence accurate drug delivery to patients.

It is critical that, as newer therapeutic technologies are developed, there is an understanding of these types of interactions, which may influence packaging and delivery device choices.

Challenge #2: Long-Acting Injectables Bring A Long List Of Variables

One recent trend is the development of long-acting injectables (LAIs). Moving towards LAIs brings the benefits of fewer injections, potentially improved compliance, and less waste from single-use devices; therefore, reducing the burden on patients.

The goal now is to take a biologic drug and formulate it for a monthly or even less frequent injection regimen. There is growing recognition within the industry that extending dosing intervals can differentiate products in the marketplace, leading to ongoing advancements in formulation technologies for these therapeutics.

Historically, long-acting injectables were often used for contraception, antipsychotic treatments, and other applications involving chemically derived medications. Nowadays, most of the biologic LAI drugs that have been successfully brought to market are peptides. More complex biologics — such as antibodies — present greater challenges.

Addressing the associated challenges, which include manufacturing scale-up, commercialization, and concerns such as sterilization, remains essential. Many of these protein-based therapies are inherently complex and fragile, particularly during scale-up, yet a variety of long-acting biologics are currently progressing through clinical trials. These developments are facilitated by a range of enabling technologies, including microspheres, nanoparticles, in-situ forming gels, oily solutions, and suspensions.

Managing Suspensions And Mixing

Suspensions are a common way of developing these LAIs, but currently there is no prefillable syringe system designed specifically to address the challenges of these types of products. For instance, needle-clogging is quite common. Understanding flow, viscosity, needle design, and other factors, and providing a syringe that can help to address these issues is an opportunity.

There is clearly a need for advanced delivery devices capable of administering challenging suspensions or mixing solutions immediately before patient administration. Historically, vials have been used in a highly manual process of preparation, mixing, and injection.

As an alternative, a bypass prefilled syringe has been used. This type of syringe is dual-chambered and used for mixing two liquids or a lyophilized drug and diluent. A major challenge with this type of syringe is the uniqueness of the glass, which is designed with a bulge to allow for fluid to flow past the middle plunger stopper, thus allowing the separate solutions or ingredients to mix. The placement of the middle plunger stopper during fill/finish can also present challenges.

Recently, we have seen the introduction of autoinjectors that can mix and deliver a solution in a more precise way. Several advancements have emerged regarding glass syringes and alternative autoinjector devices that help address certain limitations of earlier technologies; however, there is still room for further innovation in this area.

Challenge #3: Product Stability May Require Lyophilization

As these newer modalities, such as ADC’s and bi- and tri-specific antibodies, are developed, they are formulated as lyophilized powders to increase their stability. As an example, ADCs are composed of three elements: 1) the monoclonal antibody, 2) the cytotoxic drug payload, and 3) the linker which connects the two. All three pieces must be evaluated and understood from a stability standpoint.

Quite often, new technologies begin as lyophilized powders to get to market as quickly as possible with the goal of eventually developing a liquid version that is stable in room temperature as part of product lifecycle management. Advancements in understanding aspects such linker-payload development will help to overcome the need for lyophilization in the future.

The standard way to lyophilize is in a glass vial. The freeze-dried product is reconstituted immediately prior to use via a suitable diluent. Over time, to minimize some of the challenges of this type of process, especially for a patient self-administered product, vial adapters and other devices have been used to minimize the potential of needle sticks or other challenges.

As mentioned above, there are techniques and systems that allow for lyophilization in a syringe system. However, this process is rather specialized in practice. To accelerate development and commercialization, it may be beneficial to work with CDMOs that have experience with this practice.

Challenge #4: Special Storage Requirements May Emerge

If the biological drug product is not lyophilized for stability, then quite often it may need to be held in refrigerated conditions. Vaccines and some specialized products are often held in frozen or ultra-cold conditions during shipping and storage to achieve stability throughout shelf-life. Because these types of products are sensitive to temperature changes, cold-storage methods are employed to prevent degradation, ensure structural integrity, and inhibit bacterial growth.

These conditions carry the potential of affecting the materials that compose the primary package or the device constituent part. Historically, it has been quite common to see products shipped on dry ice. I have seen products in vials be impacted by pH shifts due to the ingress of carbon dioxide in transit. This result indicates inadequate container closure integrity. If the correct materials are not chosen and are not assembled and sealed adequately, then the shrinkage that occurs under the extreme environmental conditions will allow gaseous ingress from the environment to occur.

This is just a simple example of how environmental conditions can be a major risk consideration in biologics product development.

Challenge #5: Primary Packaging And Device Integration May Evolve

An often-overlooked aspect of lifecycle management for biologics delivery is the interface between primary packaging and the delivery device. It is essential to carefully consider the compatibility between the primary packaging and the device it will connect with.

And over the product lifecycle, that packaging/device relationship can evolve. Consider, for example, a prefilled syringe. In some combination products, for example, the prefilled syringe serves as both the primary packaging and the delivery device. In other cases, it is combined with a handheld autoinjector to facilitate self-administration.

The Long-Term Role Of A Prefilled Syringe

In any of those scenarios, selecting a prefilled syringe without accounting for the long-term plan may necessitate additional development and risk-mitigation efforts to achieve successful regulatory review and market introduction. If the lifecycle strategy involves transitioning to an autoinjector for a future combination product, it is important to consider whether the PFS was designed with this goal in mind.

For example, has dimensional variability of the syringe been evaluated? Additionally, are the mechanics of securing the syringe within the autoinjector — whether by the finger flange or the needle hub — fully understood? Neglecting such considerations when developing solely for manual injection can result in complications such as glass breakage or system leakage once integrated into an autoinjector.

A thorough grasp of factors such as plunger and glass barrel lubrication, including process consistency and control measures, underscores the importance of specialized knowledge. Addressing these aspects is crucial throughout the development process for this category of product.

Challenge #6: High Volumes, High Concentrations Push Injection Limits

As the value proposition of delivery via subcutaneous (sub-Q) injection continues to grow, so do the challenges involved with delivering biologics via this route of administration. Especially as organizations look to move delivery from the clinic to home administration, it’s obvious that delivery of larger volumes of biologics will be needed. A key driver of these advances is the goal of transitioning the delivery format from intravenous (IV) biologics, typically given in a hospital or clinic, to sub-Q versions.

Subcutaneous drug delivery via autoinjectors has historically handled volumes of 2 mL or less. In intravenous administration settings, volumes delivered are much greater over a longer period of time. Therefore, to compensate in a sub-Q formulation, significantly higher protein concentrations have been required to minimize IV volumes. These increases in concentration subsequently result in elevated solution viscosity.

Managing Increased Viscosity

Delivering these higher viscosities for biologics presents added challenge for the packaging and delivery system. Newer autoinjectors have been introduced that can help enable these types of biologics. They have been developed using inert gas-powered cylinders or other innovative drive systems that can enable delivery of higher viscosities.

Naturally, sub-Q formulations differ from IV versions. They present clear challenges, including reduced bioavailability and the need for formulation enhancers to temporarily improve absorption and boost bioavailability. Greater concentration also brings greater challenges in manufacturing.

Alternatively, on-body delivery systems (OBDS) can help to deliver higher viscosity or higher volume biologics using systems that allow more time for the injection to occur when compared to the typical autoinjector. Introducing a product in an OBDS may mean fewer changes to an IV biologic formulation when moving to sub-Q injections.

Advanced Therapies Drive Delivery Innovation

Innovative drug delivery device platforms address some of the challenges identified for biologics-based therapy administration. Technical requirements and patient needs inform the selection of suitable packaging and delivery systems. These highlighted challenges underscore the essential function of packaging and delivery solutions in bringing new therapeutic innovations to market, while also identifying opportunities for advancements that benefit both industry stakeholders and patients.

References:

1. De Bardi, M.; Müller, R.; Grünzweig, C.; Mannes, D.; Boillat, P.; Rigollet, M.; Bamberg, F.; Jung, T. A.; Yang, K. On the needle clogging of staked-in-needle pre-filled syringes: Mechanism of liquid entering the needle and solidification process. European Journal of Pharmaceutics and Biopharmaceutics 2018, 128 (May), 272-281. DOI: 10.1016/j.ejpb.2018.05.006
2. De Bardi, M.; Müller, R.; Grünzweig, C.; Mannes, D.; Rigollet, M.; Bamberg, F.; Jung, T. A.; Yang, K. Clogging in staked-in needle pre-filled syringes (SIN-PFS): Influence of water vapor transmission through the needle shield. European Journal of Pharmaceutics and Biopharmaceutics 2018, 127 (October 2017), 104-111. DOI: 10.1016/j.ejpb.2018.02.016
3. Physicochemical Excipient-Container Interactions in Prefilled Syringes and Their Impact on Syringe Functionality Liang Fang, Coralie AdÈle Richard, Galen Huaiqiu Shi, Xia Dong, Marissa Rase and Tingting Wang. PDA Journal of Pharmaceutical Science and Technology July 2021, 75 (4) 317-331; DOI: https://doi.org/10.5731/pdajpst.2020.012278