Developing high-concentration monoclonal antibody formulations for subcutaneous administration to improve patient treatment.

Introduction

As of 2023, the U.S. Food and Drug Administration (FDA (U.S. n.d ).) had approved a total of 168 monoclonal antibodies (mAbs) for a wide range of therapeutic areas (U.S. Food and Drug Administration (U.S. n.d. )). Approximately 43% of these approved mAbs are for oncologic indications, including solid tumors, lymphomas, multiple myelomas, and leukemia, followed by about 23% for immunologic indications, such as rheumatoid arthritis and systemic lupus erythematosus. Almost 9% of approvals are for neurologic indications. This is followed by hematology and respiratory diseases, each comprising almost 5%. Infectious diseases, ophthalmology, and gastroenterology each represent 3.5–4%. Finally, cardiology and endocrinology each represent 2% of mAb approvals.

Treatment with a mAb therapy often requires high doses to achieve therapeutic effects. Almost 60% of FDA-approved mAbs are prescribed in a minimum dose of 200 mg per administration (Fig. 1 ) and require high-concentration formulations and/or large volumes. Because 54% of FDA-approved mAbs are produced at relatively low concentrations (< 50 mg/mL) (Fig. 2 ), a high volume is required to achieve these high doses. Due to these requirements, the prevalence of lower-concentration formulations, and the need for large solution volumes, intravenous (IV) administration is often the most feasible administration route (Fig. 3 ). The IV route offers the advantage of delivering the drug directly into the systemic circulation, ensuring high bioavailability. However, the invasive nature of IV therapy (Bittner et al. 2018 ) can be associated with potential complications such as phlebitis, infiltration, extravasation, and infections (Dychter et al. 2012 ).

A notable trend emerges when comparing administered doses in immunology and oncology. Approximately 53% of mAbs in immunology require a dose of ≤ 200 mg, whereas in oncology, only about 30% are prescribed at ≤ 200 mg and 70% require a dose of ˃200 mg. This contrast presents considerable challenges due to the necessity for larger injection volumes or multiple injections to administer the required dose. Consequently, the development of high-concentration mAb products (HCmAP) is required to bridge this gap, enabling the administration of high doses in small volumes to facilitate the transition from IV to subcutaneous (SC) administration.

Switching from IV to SC administration offers multiple benefits for hospitals, patients, and health care professionals. From a medical perspective, it reduces congestion in medical facilities, allowing priority to be given to patients in need of emergency treatment, as occurred during the COVID-19 pandemic. In addition, it helps minimize adverse events associated with IV infusion. Patients also prefer a more convenient and easily administered treatment. The possibility of supervised at-home administration provides them with a flexible treatment schedule, thereby reducing travel expenses to hospitals and lowering the risk of hospital-acquired infections. Additional benefits include decreased health care costs (Jonaitis et al. 2021 ). Dychter et al. ( 2012 ) conducted an economic evaluation to assess the cost-effectiveness of IV therapy. They demonstrated that IV delivery is significantly more expensive than SC delivery of the same biologic. For example, the average cost for nursing labor to administer an SC dose of alemtuzumab was $30, whereas an IV infusion of alemtuzumab cost an average of $113.

Although SC administration offers numerous advantages, a number of potential challenges and drawbacks are associated with this route of administration. These may include lower bioavailability due to slower absorption from SC tissue. Another challenge is posed by the presence of hyaluronan and collagen fibres in the SC connective tissue, which act as barriers that impede the spread of injected fluids and hinder large-volume injections. It is important to stress that SC, although providing the basis for a more convenient form of administration, brings in new issues caused by high-concentration, namely, “non-ideality” effects through molecular crowding and/or co-exclusion effects [macromolecules blocking the free movement in solution of other macromolecules; see, e.g., Harding ( 1997 )] and elevated self-associative or aggregative interactions, all factors contributing to lower efficacy of formulations.

The focus of this review is threefold:

Assessment of HCmAP: We evaluate the necessity for the development of HCmAP to facilitate SC administration and examine the impact of the COVID-19 pandemic on the administration of immunotherapy among oncology patients.

Manufacturing, storage, and administration challenges: A detailed analysis is conducted to identify the challenges associated with the manufacturing, storage, and administration of HCmAP.

Formulation strategies: We explore potential strategies for the formulation of HCmAP, focusing on the use of various excipients to enhance their stability.

Formulation of HCmAP

The transition from IV infusion to SC administration requires the development of high-concentration formulations, defined here as injectable mAb therapies with an overall product concentration of 100–200 mg/mL. Currently, there are 45 HCmAP on the market (Table 1 ). Of these formulations, 17 are prescribed primarily in the field of immunology and only 4 are approved for oncologic indications. The dominance of HCmAP in the field of immunology is to be expected, considering the chronicity of these diseases and the need for long-term management aimed at enhancing the quality of life for patients.

To date, only four mAbs in cancer therapy have transitioned to SC administration (PharmaCircle.com (PharmaCircle.com n.d. )). These include Darzalex Faspro (daratumumab; Janssen) for multiple myeloma, Herceptin Hylecta (trastuzumab and hyaluronidase-oysk; Genentech) for human epidermal growth factor receptor 2 (HER2)–overexpressing breast cancer, Rituxan Hycela (rituximab and hyaluronidase human; Genentech) for chronic lymphocytic leukemia and non-Hodgkin lymphoma, and Phesgo (pertuzumab, trastuzumab, and hyaluronidase-zzxf; Genentech) for HER2-positive breast cancer. Merck is actively developing an SC formulation of Keytruda (pembrolizumab) (Taylor 2023 ). The four products approved by the FDA for oncology treatment have a concentration of 120 mg/mL, are administered in volumes of 5–15 mL, and are co-formulated with recombinant hyaluronidase to facilitate the delivery of large volumes. These formulations, however, depend significantly on larger administration volumes and the potential requirement for recombinant hyaluronidase.

Challenges in the development of high-concentration antibody products

The solution behavior and stability of antibody molecules rely predominantly on intermolecular interactions involving primarily the protein component, or protein–protein interactions (PPIs). These interactions are influenced by the specific sequence of amino acids and their three-dimensional folded structure, as well as the solution environment in which the protein resides. The carbohydrate component in antibodies can also contribute to interactive effects (Abu Hammad et al. 2023 ; Jefferis 2009 ). This environment comprises elements such as pH, temperature, buffer composition and the presence of specific excipients (Pindrus et al. 2015 ; Baek and Zydney 2018 ). At high concentrations, the spacing between antibody molecules decreases, which increases the likelihood of inter-molecular interactions (Raut and Kalonia 2015 ). This in turn may cause reversible self-association or even irreversible aggregation (Kollar et al. 2020 ), which can negatively affect the antibody’s activity and physical stability (Raut and Kalonia 2015 ).

Antibody aggregation can occur through either covalent bond formation, such as intermolecular disulfide linkages, or noncovalent associations involving mainly hydrophobic and/or electrostatic interactions (Baek and Zydney 2018 ). In high-concentration antibody solutions, self-association occurs mainly through interactions between fragment antigen-binding antibodies via complementary-determining regions (Fig. 4 ) (Kollar et al. 2020 ).

As the concentration of antibody in solution increases, the viscosity of the solution can greatly increase. This escalation is driven by the increasing disruption of the laminar streamline flow of the solution. Concomitant with this is a decrease in distance between antibody molecules, which can facilitate noncovalent interactions, including van der Waals forces, hydrogen bonds, dipole–dipole interactions, and hydrophobic interactions. It can also produce associations of antibody molecules, which can lead to a further increase in the viscosity, depending on the conformation of the association complexes (Zidar et al. 2020 ; Harding 1997 ; Lu et al. 2006 ).

The production of highly concentrated mAbs is often linked to difficulties in manufacturing, storage, shipping, and administration. This is primarily due to elevated viscosity and opalescence, as well as a greater propensity for aggregation resulting from intensified molecular interactions (Kollar et al. 2020 ). To address these challenges, extensive research has been conducted over the past decade to identify the most suitable formulation excipients to minimize the extent of molecular interactions. Table 2 provides a summary of the challenges, impacts, and formulation strategies (Fig. 5 ) reported in the development of high-concentration mAbs.

Manufacturing challenges

Toward the end of the manufacturing process, a step involving ultrafiltration/diafiltration (UF/DF) is included for concentrating proteins (Garidel et al. 2017 ; Baek and Zydney 2018 ), followed by a final step of sterile filtration. The increase in viscosity and also possible self-associative/aggregative effects with concentration is a problem not only for the patient but also for manufacturing (Holstein et al. 2020 ; Zhang and Liu 2017 ) and leads to various challenges. Elevated viscosity during UF/DF can lead to increased pump back-pressure and a reduction in transmembrane flux and/or filtration flow (Garidel et al. 2017 ), potentially resulting in prolonged processing time, destabilization of the drug substance, and increased manufacturing expenses (Tomar et al. 2016 ). Other process steps, such as sterile filtration, can be hindered by filter membrane clogging (Rodrigues et al. 2021 ) and filling that might also be affected by highly viscous antibody solutions (Garidel et al. 2017 ).

One of the objectives in developing successful formulations of highly concentrated mAbs is to reduce nonspecific PPIs and carbohydrate interactions by using electrostatic and hydrophobic interactions to both disrupt protein self-association and decrease viscosity (Jiskoot et al. 2022 ). Excipients for viscosity reduction include salts such as sodium chloride (NaCl), which interact with charged residues on the protein surface. NaCl lowers viscosity by providing charge shielding, which in turn reduces electrostatic interactions among protein molecules (Rodrigues et al. 2021 ). Amino acids such as glycine, lysine, proline, and histidine (Jiskoot et al. 2022 ) can decrease viscosity by influencing electrostatic and nonpolar interactions (Rodrigues et al. 2021 ). Arginine is commonly employed to reduce viscosity and aggregation and is the most frequently used additive (Srivastava et al. 2022 ). Amino acids in their salt forms, such as arginine monohydrochloride (Arg-HCl), decrease both PPI and viscosity by more complex mechanisms. As a salt, Arg-HCl can affect viscosity by charge shielding in the same way as NaCl. It can also decrease hydrophobic interactions by engaging with aromatic and charged residues of proteins (Zeng et al. 2021 ). To mitigate hydrophobic interactions, antibodies must be stabilized in their natural folded state at high concentrations through the use of osmolyte depletants such as polymers and polysaccharides, proline, glycine, and trehalose (Hung et al. 2018 ). Hung et al. ( 2018 ) have claimed that proline reduced the viscosity of a 225-mg/mL solution of mAb by up to threefold, lowering it to 25 centipoise (cP) at pH 6.0.

Formulation pH has a significant impact on the physical stability of antibodies by influencing the number and distribution of charges on the protein surface. Formulation pH plays a critical role in chemical stability by controlling various degradation pathways such as disulfide bond formation, deamidation, and fragmentation. Selecting an appropriate buffering agent can potentially achieve both pH control and antibody stabilization (Wang et al. 2007 ). Protein formulations typically use buffers such as histidine, acetate, or citrate to maintain the solution pH within a range of 3–7. Of these buffers, histidine is one of the most widely used amino acid buffers in highly concentrated formulations (Ghosh et al. 2023 ).

In the pursuit of novel excipients that are capable of enhancing the manufacturing process for highly concentrated proteins, Ke et al. ( 2018 ) explored the organic acid dipicolinic acid (DPA), focusing specifically on ethanolamine-DPA. Their results showed a significant reduction in viscosity (cP) for multiple mAbs (mAb1, mAb2, mAb3, and mAb4) of up to 22, 9, 14, and 17 cP, respectively, compared with the control, resulting in respective viscosities of 382, 98, 706, and 158 cP at a concentration of approximately 160 mg/mL. The results of this exploration highlight the potential of DPA salts in highly concentrated formulations, offering a potential alternative for formulation scientists during the selection of excipients during formulation development.

Caffeine has demonstrated promise as an excipient for reducing viscosity without compromising protein stability or potency. Zeng et al. ( 2021 ) investigated the impact of caffeine on viscosity reduction in HCmAP by using ipilimumab at a concentration of 200 mg/mL and demonstrated that caffeine is capable of decreasing viscosity in different formulation buffers. When phosphate-buffered saline was used as a buffer, the control viscosity was 76 cP; after the addition of 75 mM caffeine, the viscosity was reduced to 17 cP, a 78% decrease. Similarly, with the commercial formulation vehicle, the control viscosity was 37 cP, and the addition of 75 mM caffeine reduced it to 16 cP, which was 57% lower than the control (Zeng et al. 2021 ).

Storage and shipping challenges

Opalescence and liquid–liquid phase separation may arise in highly concentrated proteins, presenting challenges during storage, particularly at refrigerated temperatures. In addition to affecting the visual appearance of the formulation, opalescence can indicate the presence of aggregates in the solution induced by temperature, light exposure, or agitation during shipping or as a precursor to phase separation, resulting in decreased product stability. In liquid–liquid phase separation, the initially homogeneous protein solution is separated into two distinct liquid phases, resulting in a region with lower protein content and a region with higher protein content (Raut and Kalonia 2015 ; Kollar et al. 2020 ).

The addition of surfactants, mainly polysorbates, is used to lower the interfacial concentration of proteins to substantially reduce shipping-induced aggregation (Baek and Zydney 2018 ). However, polysorbates are susceptible to degradation caused by autoxidation due to factors such as temperature, light, and oxidants (including metals). They are also prone to hydrolysis, mainly through enzymatic pathways (Jiskoot et al. 2022 ). Residual host cell proteins that can co-purify with protein products, such as lipases, have been seen to increase the degradation of polysorbate 80. To mitigate lipase activity, it is possible to incorporate a metal chelator such as ethylenediaminetretraacetic acid (EDTA) into the formulation. Because lipases rely on calcium for their activity, chelating calcium may serve as an effective control strategy (Holstein et al. 2020 ).

Highly concentrated proteins encounter storage conditions that may lead to oxidation, affecting their functionality, aggregation, folding state, and solubility. Methionine is often included in therapeutic formulations as an antioxidant (Fevre et al. 2022 ). Chelators (EDTA) also play a crucial role in reducing oxidation by effectively capturing free metal ions such as copper (from raw materials as a trace contaminant) before these ions can initiate protein oxidation (Brovč et al. 2020 ).

Delivery challenges

The high viscosity of high-concentration biologics is an area of significant concern. The viscosity of a formulation significantly influences the force required for injection, an effect that becomes particularly pronounced when using narrow-gauge needles, such as commonly used 26G or 27G gauge needles (Marschall et al. 2023 ). The increased pressure required to inject the drug results in slower injection rates. In addition, tissue back-pressure is increased when a highly viscous formulation is injected into the body (Kollar et al. 2020 ) because it encounters greater resistance in the tissues.

To facilitate self-administration through a thin needle, the viscosity of an HCmAP for SC delivery should be less than 20 cP (Baek and Zydney 2018 ). The previously discussed formulation strategies to reduce viscosity play a critical role in addressing the challenges associated with drug delivery. An alternative approach to delivering large doses without concentrating the drug product is to increase the volume being administered.

Administration of large volumes in SC tissue faces challenges, however, due to the presence of hyaluronan, a polysaccharide component of the extracellular matrix that acts as a physical barrier. Hyaluronan prevents bulk fluid flow, resulting in prolonged infusion times and limiting drug dispersion and absorption (Knowles et al. 2021 ). This constraint affects not only the delivery rate of medications but also overall patient experience, often resulting in discomfort, erythema, and reduced adherence to treatment regimens (Dolton et al. 2021 ). To address this issue, recombinant human hyaluronidase, an enzyme that degrades hyaluronan in the skin, can be incorporated into the formulation with the protein solution and co-administered. By effectively reducing the viscosity of the extracellular matrix, hyaluronidase dramatically enhances tissue permeability. This allows for the rapid delivery of large dose volumes and improves patient tolerability (Connor et al. 2023 ). Table 3 compares the advantages and disadvantages of IV administration with SC administration and SC administration with hyaluronidase.

Move toward HCmAP

Assessment of treatment delays in immunotherapy during the COVID-19 pandemic

The studies analyzed revealed significant treatment delays during the COVID-19 pandemic. In China, Sha et al. ( 2020 ) highlighted a notable increase (29%) in treatment delays for lung cancer patients during the pandemic compared with the pre-pandemic period (< 5%). Similarly, a study by Zhai et al. ( 2023 ) identified increased rates (4%) of delays in immunotherapy administrations and a higher proportion of patients experiencing delays in receiving treatment from February to March 2020 (early COVID-19 period) in comparison with the period from February to March 2019 (pre-COVID). In the UK, Pala et al. ( 2020 ) found that treatment was delayed by an average of 4 weeks, ranging from 3 to 9 weeks. In a prospective cohort study in Germany and the UK, De Souza et al. ( 2023 ) identified delays in treatment for hepatocellular cancer with a median time to treatment of 1.6 months. In China, Chen et al. ( 2020 ) found an average treatment delay of 3.8 months.

Factors contributing to delays in immunotherapy and mitigation strategies

The main factors contributing to treatment delays have been categorized into three groups: provider related, patient related, and context related. Provider-related factors include the closure of cancer care facilities due to lack of personnel and shortage of personal protective equipment (Pareek et al. 2021 ), rigorous screening and admission criteria (Sha et al. 2020 ), and prioritizing the enhancement of care for COVID-19 patients (De Souza et al. 2023 ). Patient-related factors include patients’ fear of acquiring COVID-19 during hospital visits, financial issues (Pareek et al. 2021 ), limited familial support or caregivers (Sha et al. 2020 ), and fewer visits by patients with elevated risk factors such as advanced age and comorbidities (Pala et al. 2020 ). Context-related factors include quarantine and lockdown measures to control the spread of the virus, as well as lack of public transport services (Pareek et al. 2021 ).

We observed a trend in immunotherapy during the lockdown period, which was reported in three articles (Pareek et al. 2021 ; Zhai et al. 2023 ; Russell et al. 2022 ). Immunotherapy was increasingly preferred over chemotherapy, which is considered a myelosuppressive therapy. Immunotherapy was also identified as the oncology treatment with the most frequent adjustments (Sha et al. 2020 ). These adjustments involved extending the intervals between immunotherapy treatments to reduce the frequency and duration of clinical visits (Ottaviano et al. 2020 ) through the administration of higher concentrations of the drug. For example, some studies reported switching pembrolizumab administration from 200 mg every 3 weeks to 400 mg every 6 weeks (Zhai et al. 2023 ; Aguiar-Ibanez et al. 2023 ) or adjusting durvalumab administration from every 2 weeks to every 4 weeks (Joshi et al. 2021 ).

Consequences of delays in immunotherapy administration

Despite the clear increase in treatment delays during the pandemic, the disease of cancer patients was reported to be under control (Pala et al. 2020 ). A multicenter cohort study found no significant impact of delayed treatment on progression-free survival (De Souza et al. 2023 ).

Nowara et al. ( 2021 ) and Meng et al. ( 2020 ) observed that cancer patients who contracted COVID-19 exhibited a higher fatality rate than COVID-19 patients without cancer. This was also explored in a UK study by Lee et al. ( 2020 ), who evaluated and compared adult patients with cancer with and without COVID-19. It was reported that the susceptibility to COVID-19 among cancer patients differed depending on the type of tumor. Age and sex were significant factors; older patients and those with hematological malignancies faced a particularly high risk. Not all cancer patients were equally affected.

The analysis of treatment delays in immunotherapy during the COVID-19 pandemic reveals significant disruptions in the administration of cancer treatments stemming from a multitude of factors, including those associated with health care providers, patients, and contextual circumstances. The use of HCmAP presents a promising avenue in addressing these challenges. Enabling supervised administration via SC injection at home could significantly mitigate the impact of treatment delays, ensuring uninterrupted treatment even during disruptions to hospital-based health care services and leading to improved treatment experiences and patient compliance. Roche recently announced that the European Medicines Agency has issued a positive opinion recommending an update to the European Union label for Phesgo for HER2-positive breast cancer. If approved and safely established in a clinical setting, it will be possible for health care professionals to administer Phesgo outside of a clinical setting (such as in a person’s home).

Challenges to and strategies for developing HCmAP

Transitioning from IV infusion to SC injection to allow at-home administration (at-home supervised administration), using hand-held devices such as prefilled syringes or autoinjectors, necessitates the development of HCmAP. This need is primarily due to the constrained volume capacity (< 3 mL) of hand-held SC injections (Badkar et al. 2021 ). Garidel et al. ( 2017 ) determined the potential maximum concentration of mAbs by establishing a theoretical upper limit. This estimation relied on three-dimensional structures and geometric factors, considering the packing of molecules with shapes like spheres, rectangles, and truncated cones. The concentration was calculated by using the immunoglobulin G1 mAb model, and the empirical data supported a recommendation to set the limit at levels of < 500 mg/mL.

An innovative approach that may be considered in the future for delivery of high-dose biologics has recently been developed by Elektrofi, utilizing non-aqueous microparticle suspensions generated to achieve ultra-high protein concentrations (up to 500 mg/mL) (Shadbar et al. 2025 ). This method enables low-volume subcutaneous injections, deliverable in under 20 s with injection forces below 20 N, while demonstrating bioequivalence to aqueous formulations in rodent models (Shadbar et al. 2025 ).

In an alternate approach, Marschall et al. ( 2023 ) investigated protein powder suspensions in non-aqueous vehicles, prepared by using spray-dried powders, to explore their potential to lower viscosity. This approach provides an alternative that could potentially lead to lower viscosity than that of equivalent aqueous solutions, thereby addressing the challenge of formulating concentrations exceeding 200 mg/mL. When injected, these formulations exhibit a shear thinning viscosity of < 10 cP, minimizing the force required for injection. Nevertheless, multiple obstacles must be overcome before such a product is ready for the market. These challenges include a complex manufacturing process and the need for approval as a novel vehicle in biologic formulations by the FDA.

The various excipients proposed for reducing viscosity are typically incorporated during the later stages of drug development. However, finding an effective excipient strategy for highly concentrated mAb products is not always feasible. Currently emerging approaches complement excipient strategies and are implemented at an early stage during drug discovery. These methods employ computational techniques to identify antibody variants with reduced aggregation tendencies and greater colloidal stability. Molecular design also plays a pivotal role, as modifications to amino acid sequences may optimize mAb characteristics and minimize aggregation propensity (Dobson et al. 2016 ). By combining early-stage engineering of molecules with the use of formulation excipients, future endeavors may enable the manufacturing of HCmAP for immunotherapy, potentially facilitating at-home administration (supervised at-home administration).

Sustainable and cost-effective solutions: HCmAP and SC administration

The goal of sustainability in health care is to minimize waste, carbon emissions, and environmental impacts (Javaid et al. 2022 ), ultimately aiming to enhance the quality, safety and value (Sherman et al. 2020 ) of pharmaceuticals. Health care services in the UK generate approximately 5% of the nation’s total CO 2 emissions. The majority of these emissions originate from the supply chain, particularly in the form of medicines and equipment (Cussans et al. 2021 ). Similarly, the health care sector in the USA contributes to 9% of the six “criteria air pollutants” (those identified by the Environmental Protection Agency as requiring control to meet air quality standards), namely, ozone, particulate matter, carbon monoxide, lead, sulfur dioxide, nitrogen dioxide, and 9–10% of national greenhouse gas emissions (Sherman et al. 2020 ).

Upon analyzing the transition from IV to SC administration facilitated by the development of HCmAP and innovative delivery technologies, we identified numerous reported advantages. These benefits extend beyond chronic diseases to include oncology treatment, indicating potential improvements in the sustainability of future drug products (Fig. 6 ).

SC administration of HCmAP also has benefits from an economic perspective. Decreases in both direct and indirect costs have been documented. Direct costs include expenses incurred in the delivery of the drug, such as administration fees, health care workers’ salaries, and supplier costs. Indirect costs involve factors like lower patient productivity in the workforce and the need for a broader range of health care services, such as those incurred by the potential for acquiring COVID-19 infection during hospital stays or via public transportation (Heald et al. 2021 ). The costs associated with drug wastage also represent a significant financial burden (Tjalma et al. 2018 ).

Anderson et al. ( 2019 ) published evidence to evaluate the economic consequences of SC versus IV administration of approved cancer therapies. Most of the studies focusing on economic outcomes favored SC administration. The noteworthy reduction in the time required for preparation, administration, and post-administration care is reported to have a significant impact on costs. McCloskey et al. ( 2023 ) reported that the direct costs for SC administration were roughly 1–6% less than those linked to IV administration.

The most effective approach to mitigate the presence of pharmaceuticals in the environment is to reduce the quantity of unused medication (Lipkin 2012 ). Ponzetti et al. ( 2016 ) analyzed the comparative impact of SC versus IV administration of rituximab and trastuzumab in Italy. They identified potential reductions in drug wastage with SC therapy due to its fixed-dose format. Specifically, for trastuzumab, the total median annual wastage for a complete treatment was calculated as 7376 mg for IV administration and 0 mg for the SC route. The wastage of drugs impacts costs for both patients and health care systems (Lien et al. 2016 ) and also has environmental repercussions (Smale et al. 2021 ).

In addition to these benefits, SC administration can also have reduced environmental impacts because the suppliers and devices needed for IV administration are not essential for SC administration. Ponzetti et al. ( 2016 ) observed a significant (54%) reduction in materials provided by medical staff. IV devices such as fluid bags and peripheral and central catheters often contain polyvinyl chloride and are disposed of in red bags for incineration. The combustion of polyvinyl chloride leads to the formation of dioxins, which are carcinogenic and bioaccumulative (Lipkin 2012 ).

Switching to SC administration can also have cost and environmental impacts by reducing the amount of space needed for cold storage of the drug product, thereby also decreasing electricity consumption. Storage of mAb drug products is energy intensive, as they must often be stored at a temperature of 2–8 °C (Laptos and Omersel 2018 ). For example, IV daratumumab is available in two vials, 100 mg/5 mL and 400 mg/20 mL. A patient with a body weight of 70 kg would require 2.8 vials of the 400 mg/20 mL dose. In contrast, daratumumab formulated for SC administration comes in a single vial containing 1800 mg of daratumumab and 30,000 U of hyaluronidase per 15 mL. At the recommended fixed dose of 1800 mg, only one vial would be required for each patient. Over a 1-year treatment period, IV administration requires significantly more vials than the SC route. Increasing the adoption of SC administration leads to a significant reduction in the volume required for storage and shipping and therefore represents a step toward the establishment of a more sustainable supply chain.

The SC administration route can also contribute to social equity. SC administration is four times more time efficient than the IV route (Tjalma et al. 2018 ), allowing patients to spend less time in oncology day care, thereby reducing the time nurses spend per patient and expanding the opportunity to provide services to a greater number of patients (Tjalma et al. 2018 ; Tomarchio et al. 2017 ).

Conclusion

The COVID-19 pandemic has further revealed the importance of innovative strategies for the administration of cancer therapies that provide more patient-convenient alternatives. SC immunotherapy administration offers numerous advantages over the IV route, most notably, patient compliance and satisfaction if the possibility of at-home administration becomes a reality. For oncology drugs, this would require clinical supervision and/or home visits, thereby facilitating the treatment of patients who cannot travel. In many cases, however, this transition will require the development of HCmAP because of the limited volume that can be administered via SC injection. The manufacturing process for HCmAP doses poses challenges, mainly from increased viscosity and physical instability of the formulation, which can be ameliorated by the use of specific excipients. The most commonly used excipients for these purposes are salts, such as NaCl, and amino acids, such as arginine. However, there are limitations in the extent to which viscosity can be reduced while maintaining satisfactory protein stability.

Transitioning to SC administration of cancer therapies also offers a cost-effective approach, primarily through reduced preparation and administration times. SC administration benefits the environment by reducing the drug wastage and greenhouse gas emissions that are associated with fewer hospital visits. Social benefits include improved patient convenience and quality of life. Finally, SC administration of biopharmaceutical formulations can enable health care facilities to accommodate more patients, thereby promoting equitable access to care.

Author contribution

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Laura R. R. Mijangos. The first draft of the manuscript was written by Laura R. R. Mijangos and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

This study was funded by AstraZeneca.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

N.J.D. is an employee of AstraZeneca and may have stock ownership, options, and/or interests in the company.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.