Kimberly Duff, RN, BSN Clinical Sciences, R&D Takeda Development Center Americas, Inc. kimberly.duff@takeda.com
Stefan Holzner, PhD* Pharmaceutical Sciences, R&D Takeda Development Center Americas, Inc.
Madeleine Gibson, MSIE* Pharmaceutical Sciences, R&D Takeda Development Center Americas, Inc.
Seth Jones, BSc* Pharmaceutical Sciences, R&D Takeda Development Center Americas, Inc.
Scott Ariagno, MSc* Pharmaceutical Sciences, R&D Takeda Development Center Americas, Inc.
*Affiliation at the time of the study
Introduction
Facilitated subcutaneous immunoglobulin 10% (fSCIG 10%) is packaged as a dual-vial unit of immunoglobulin G 10% (labelled ‘IG’) and recombinant human hyaluronidase (rHuPH20; labelled ‘HY’) for use as a prescribed immunoglobulin treatment for patients with primary or secondary immunodeficiency and chronic inflammatory demyelinating polyradiculoneuropathy. The current infusion process involves multiple steps that need repeating for patients requiring multiple dual-vial units per infusion. We hypothesized that the infusion process could be improved using patient-centric design and modular innovation principles.
Methods
Ethnographic research was conducted to understand patient and nurse experiences of administering fSCIG 10% to identify opportunities to improve the infusion process. Device design objectives were established based on feedback from 4 patients receiving fSCIG 10% for primary immunodeficiency (at-home observations and feedback sessions) and 4 nurses providing fSCIG 10% infusion training (interviews and mock training sessions). Design objectives included: simplifying steps for fSCIG 10% preparation and infusion, standardizing equipment and infusion stages and easing patient mobility during infusions. Formative usability evaluation research was conducted with 10 patients and 4 nurses to evaluate prototypes of a vial access device; observations were used to inform the modular design of the final device.
Results
The final vial access device is a base with numbered docking stations to accommodate up to 4 dual-vial units. Tubing underneath the docks separately combines the contents of multiple HY and IG vials, with separate color-coded connectors. The HY preparation process involves removing cover(s) from dock(s), inserting dual-vial units and drawing the total rHuPH20 dose into a single syringe from the HY connector attached to the device. To prepare IG, the pump tubing is attached to the IG connector on the device and primed. Following the delivery of HY, the pump tubing is attached to the same needle set; infusion administration remains similar to the current method. A device carrier, developed to hold the vial access device and a pump, enables patient mobility during the infusion. The vial access device is intended for single use and can be disposed of safely with the dual-vial units attached. Compared with the current fSCIG 10% infusion process, the vial access device simplified preparation, required fewer components and facilitated room-to- room patient mobility during infusion.
Conclusions
Patient-centric design and modular innovation principles were used to develop a vial access device to optimize the patient experience of fSCIG 10% infusion. Further research will assess its impact on patient quality of life.
Keywords
Chronic inflammatory demyelinating polyradiculoneuropathy, device, facilitated subcutaneous immunoglobulin, primary immunodeficiency, recombinant human hyaluronidase, secondary immunodeficiency
Primary and secondary immunodeficiency (PID and SID, respectively) are heterogenous disorders characterized by immune system dysfunctions and are associated with an increased risk of frequent, severe, and/or prolonged infections.1-3 PIDs, also referred to as inborn errors of immunity, comprise over 550 genetic disorders; most are lifelong conditions.4 SID is an acquired immunodeficiency that may be caused by hematological malignancies, including chronic lymphocytic leukemia and multiple myeloma (and their treatments), transplantation, environmental factors, and the use of certain medications or immunosuppressive therapies.5,6 Worldwide, incidence of PID is estimated at 1 in 10,000 individuals,7 approximately 55% of whom have antibody deficiencies.3,8 Secondary antibody deficiencies are estimated to be 30-fold more common than primary antibody deficiencies.1,6 Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare, autoimmune disorder characterized by demyelination and axonal damage of the peripheral nerves.9,10 Crude incidence of CIDP has been reported to range between 0.15 and 0.70 cases per 100,000 person-years.11 The exact etiology of CIDP remains unknown.10
Therapeutic immunoglobulin (Ig) G may be used as replacement therapy in immunodeficiencies, with low-dose Ig serving to increase circulating antibody levels, as an immunomodulatory therapy in hematological and organ-specific autoimmune disorders, and as an anti-inflammatory therapy for rheumatic inflammatory conditions, and infectious and neurological disorders.12 Immunoglobulin replacement therapy (IgRT) is used to reduce the incidence and severity of infections in individuals with immunodeficiencies:12 it is the standard treatment in PIDs and is recommended in several national guidelines for patients with SID who have repeated infections despite prophylactic antibiotic therapy.13 IgRT is typically a lifelong treatment for patients with PIDs and, depending on the underlying cause of disease, may be temporary or lifelong for patients with SIDs. For CIDP, the European Academy of Neurology and Peripheral Nerve Society joint guidelines recommend systemic corticosteroids or intravenous immunoglobulin as first-line treatment of CIDP with disabling symptoms, both for induction treatment and maintenance of response.14
Different modalities for administration of IgRT are available: intravenous immunoglobulin (IVIG), conventional subcutaneous immunoglobulin (SCIG), or facilitated subcutaneous immunoglobulin (fSCIG). SCIG and IVIG have similar reported efficacies.15,16 IVIG is administered by a trained health care professional, typically every 3-4 weeks in the clinic or at home, whereas SCIG can be self-administered at home and is associated with fewer systemic adverse events (e.g. headache, nausea, and vomiting) than IVIG.13,17-19 Patients switching from IVIG to SCIG reported significant improvements in quality of life and treatment satisfaction.20-22 However, conventional SCIG therapies required more frequent administration (typically every 1-2 weeks), multiple infusion sites owing to infusion volume limitations, and increased incidences of local adverse events.23,24 fSCIG 10% is supplied as a dual-vial unit of immune globulin infusion 10% (human; IgG 10%) and recombinant human hyaluronidase (rHuPH20).13,15 With fSCIG treatment, the rHuPH20 component depolymerizes hyaluronan in the extracellular matrix, transiently increasing the permeability of subcutaneous tissue to facilitate dispersion and absorption of the IgG 10%.17,24 This allows for greater infusion volumes and faster infusion rates than conventional SCIG.15,17 As such, fSCIG 10% can be administered subcutaneously up to every 4 weeks at home after appropriate training or within a medical facility.24,25 rHuPH20 has a short halflife in subcutaneous tissue (<30 minutes), and skin and tissue integrity at the infusion site is fully restored within 24-48 hours.15 fSCIG 10% is approved in the European Union as IgRT for adults and children (aged 0 to 18 years) with PID or SID and as maintenance therapy after stabilization with IVIG treatment in patients of all ages with CIDP.25 fSCIG 10% is also approved in the USA for treatment of PID in adults and children aged 2 years and older and for use as maintenance treatment in adults with CIDP.24 In Japan, fSCIG 10% was first approved in December 2024 for the treatment of agammaglobulinemia and hypogammaglobulinemia in adults and pediatric patients (aged ≥2 years), and in June 2025 the approval was expanded to include use for the suppression of the progression of motor function decline in CIDP (in which, improvement in muscle weakness has been observed).26 The efficacy and safety of fSCIG 10% have been demonstrated in these therapeutic indications,27-33 and despite faster infusion rates and larger infusion volumes than with conventional SCIG, fSCIG 10% has demonstrated good local tolerability with fewer systemic adverse events than IVIG.17 Furthermore, there is increasing real-world evidence for the flexibility and convenience that is offered by fSCIG 10%.34-36
Given that IgRT is often received as long-term or lifelong therapy, its impact on patient well-being, ease of administration, user experience with the infusion process, and the burden on health care resources are important practical considerations.37-40 A simplified infusion process could reduce the number of infusion rate steps, potentially resulting in a shorter administration time depending on the total doses and infusion rate ramp-up, which facilitates the transition to self-administered, in-home fSCIG 10% infusion. Here, we describe technical aspects of a vial access device for fSCIG 10% administration, developed in combination with modular innovation principles and insights from patients and health care professionals to provide improvements to the fSCIG 10% administration experience.
For fSCIG 10%, rHuPH20 and IgG 10% vials are packaged in a dual-vial unit (DVU; HYQVIA; Takeda Pharmaceuticals USA, Inc., Cambridge, MA24; Figure 1). The prescribed dose of IgG 10% can comprise a combination of the five available DVU configurations (2.5 g, 5.0 g, 10.0 g, 20.0 g, and 30.0 g). For example, a hypothetical patient receiving 45.0 g of IgG 10% (450 mL) may require three DVUs: 1 × 5.0 g DVU and 2 × 20.0 g DVUs. DVUs ensure that patients receive the correct ratio of rHuPH20 prior to IgG 10% infusion (i.e. 1:20). rHuPH20 and IgG 10% are pooled separately and administered sequentially, beginning with the rHuPH20. The steps currently involved in the fSCIG 10% infusion process (including preparation and infusion of rHuPH20 and the prescribed amount of IgG 10%) are described in Table 1. In some countries, IgG 10% can be infused directly from individual vials or by other devices, such as from a larger syringe with an electromechanical syringe-driver device.25
Ethnographic research was conducted to gain a deeper understanding of patient and nurse experience of administering fSCIG 10% and to identify opportunities for infusion-related improvements in the process. Patients (n = 4) currently receiving fSCIG 10% for PID (dose range 50–75 g) participated in a home-based observation and feedback session, and nurses providing in-person training on infusing fSCIG 10% (n = 4) participated in an interview and a mock training session. Taking a patient-centric approach highlighted several potential improvements: (1) shorter/simplified preparation and overall infusion time; (2) easier physical manipulation of the DVU and other infusion components requiring the use of multiple needles to withdraw the rHuPH20; and (3) greater patient mobility during infusion.
The key design objectives were to reduce and simplify the steps for preparing and infusing fSCIG 10%, standardize the equipment and phases for infusion, and increase patients’ ease of mobility during infusions. Practical considerations for a new DVU design included achieving consistent vial position across all DVU configurations to facilitate repeatable docking to a base component. Moreover, a modular innovation for the vial access device allowed its use with existing peristaltic pumps and possibly other infusion devices.
Formative usability evaluation research was conducted with patients (n = 10) and nurses (n = 4) to obtain feedback on user experiences with prototype devices. The patients in this study had been preparing and administering fSCIG 10% at home (usual doses ranged from 30–75 g), whereas the nurse participants had been responsible for training patients and/or caregivers to administer fSCIG 10% (maximum doses administered ranged from 25–70 g). Observations from this study were used to improve the final device concept further and ensure a patient-centric design. A prototype constructed during the development of the vial access device informed the modular design of the final devices (HyHub and HyHub Duo; Takeda Pharmaceuticals USA, Inc. Cambridge, MA).
A vial access device was developed to improve the fSCIG 10% treatment experience. The final device is provided in sterile packaging and is intended for single use only. It comprises a base with 4 numbered DVU docking stations with hidden vented spikes (Figure 1A). A second generation DVU was designed alongside the vial access device to ensure all vial sizes are compatible with the device. To optimize residual volumes, dock covers were numbered to help patients follow the optimal order in which to dock the DVUs. Spike-entry location, insertion depth, and orientation relative to the vial stopper are tightly controlled by alignment and retention features on the device and the DVU. Spike geometry and fluid path configuration were engineered to minimize drug loss (priming IgG 10% volume is 1 mL) (Figure 1B). If the patient does not place the DVUs into the docks in numerical order (e.g. dock 1, 2, 3 then 4), the vial access device will still allow administration of the drug as intended. To ensure that the rHuPH20 and IgG are administered separately without mixing when drawing rHuPH20 into a syringe and pumping IgG 10% from the base, the device ensures that DVUs are docked in a specific orientation. Accommodating up to 4 DVUs, the vial access device has a maximum IG dose capacity of 120 g.
Administration set tubing underneath the docks connects all HY vials containing rHuPH20, and a second fluid path connects all IG vials containing IgG 10% (Figure 1B). Each fluid path for rHuPH20 (labelled ‘HY’) or IgG 10% (labelled ‘IG’) is labelled and color-coded (purple for HY and orange for IG connectors) for easy identification and has opposing Luer connections that do not allow syringes to be connected to the IG connector, helping to reduce administration errors (Figure 1A). This enabled withdrawal of the total rHuPH20 dose into a single syringe without using a needle, and withdrawal of the IgG dose into the pump tubing, eliminating the need to withdraw content separately from each DVU.
The process and equipment needed for infusion of fSCIG 10% using the vial access device are described in Table 1. Overall, the ‘Infuse fSCIG 10%’ and ‘Finish up’ phases remain similar to the current infusion process. Key differences include: the design of a device carrier to hold the vial access device and the infusion pump, facilitating patient mobility during infusions (i.e. moving from room to room); after completion of fSCIG 10% infusion and confirmation that all medication has been delivered (through visual assessment), there is an optional step to ensure that the patient receives the entire prescribed dose whereby a pre-filled syringe of normal saline or dextrose 5% in water is attached to the pump tubing and used to flush the tubing.
Depending on the number of DVUs used, the vial access device streamlined the administration process by decreasing the number of steps and equipment (e.g. needles/needleless transfer devices, pooling bag, gravity-fill set with vented spike, vented spikes used to draw from the normal saline vials, and sterile cap, and IV pole) needed to infuse fSCIG 10% (Table 1). Based on the assumptions of one infusion site, the push method to administer rHuPH20, and a generic peristaltic pump to administer IgG, there are incremental percentage reductions in the total number of steps needed with the vial access device versus the pooling bag method as more DVUs are used (Figure 2A). Using the same assumptions, these incremental reductions are even greater when comparing the number of steps requiring user dexterity (Figure 2B).
After achieving the design principles and developing the vial access device with 4 docking stations, a smaller, more compact device designed to accommodate up to 2 DVUs (60 g maximum dose capacity) was developed. As with the larger vial access device, the 2-DVU device was developed with the original design objectives in mind (i.e. to simplify steps for fSCIG 10% preparation and infusion and to standardize equipment and infusion stages) but with the additional aim of enabling customized administration of fSCIG 10% according to individual patient dosage requirements and needs. The smaller device at maximum capacity (2 DVUs) reduces the total number of steps required to administer fSCIG 10% by 9% and the number of steps requiring user dexterity by 40% versus the pooling bag method (Figure 2A and 2B).
The 2- and 4-DVU-capacity vial access devices were developed according to feedback from patients receiving fSCIG 10% and health care professionals who provide training to patients prescribed fSCIG 10%, and the key design objectives were met. Compared with the current fSCIG 10% infusion process using manual spiking and a pooling bag, the vial access device simplified and streamlined preparation, included fewer steps requiring user dexterity, required fewer components, and facilitated room-to-room patient mobility during infusions owing to the availability of a dedicated device carrier. In July 2025, the 2- and 4-vial access devices received U.S. Food and Drug Administration 510(k) premarket clearance for use by patients aged 17 years and older, allowing fSCIG 10% to be transferred from vials without using a needle, as prescribed, in a home environment or clinical setting.41,42
An advantage of the vial access device is that the integrated vented spikes in the base of the device may increase the ease of drawing the necessary doses of rHuPH20 and IgG 10% by allowing the appropriate vials to be accessed simultaneously. The vented spikes are also pre-lubricated (with a small amount of silicone) for easy insertion through rubber stoppers. The vial access device removes the need for additional components such as needles or needleless transfer devices, pooling bags, a gravity-fill set with vented spike and sterile cap, and an IV pole. This may be particularly relevant in countries where equipment availability is limited. By removing the need for handling small, individualized components, the number of sometimes-challenging tasks of opening many small packages and touch-contamination risks are reduced. Furthermore, the management of air in containers and lines is simplified. Using the vial access device has fewer steps than the current infusion process, and if multiple DVUs are required, does not require patients to repeat as many steps as the pooled bag method. Spike sheaths keep the fluid path closed and allow for the use of any dock combination. Furthermore, the differences in size and capacity for a variety of dosage configurations between the 2- and 4-DVU-capacity devices enable customized administration of fSCIG 10% according to individual patient dosage requirements and needs. A hypothetical patient requiring an IgG 10% dose of 45.0 g using 3 DVUs (1 × 5.0 g; 2 × 20.0 g) would perform 58 steps with the 4-DVU-capacity vial access device, compared with 68 steps using the manual spiking and pooling process, as described in Table 1; this equates to a 15% reduction in the number of steps overall and a 49% reduction in the number of steps requiring user dexterity. Furthermore, proportional reductions in the number of steps (especially the burdensome dexterous steps) compared with using a pooling bag increases with the number of DVUs used. For a hypothetical patient requiring an IgG 10% dose of 60.0 g using 2 DVUs (2 × 30.0g), the 2- or 4-DVU-capacity multivial access device could be used, although there is the limitation that a patient would be unable to use the smaller 2-DVU-capacity device if they were to receive 3 × 20.0 g DVUs to achieve the correct dosage.
Several safety features were added to the vial access device that may reduce the probability of errors or contamination and eliminate sharps exposure during preparation compared with the current administration process. Pillars guide DVUs to the correct orientation before engaging the spikes, and color-coded IG and HY connectors (of which, only one is compatible with a female Luer fitting) are used on each fluid path end, minimizing the risk of connection errors. Additionally, dock covers help to prevent touch contamination before spiking DVUs. These additional features also enable home self-infusion by decreasing the complexity of the administration system. This innovation may benefit patients who are newly initiating fSCIG 10% or transitioning from IVIG, and potentially inform nursing practice and patient education by streamlining the preparation process and reducing the potential for errors.
Although the design of the vial access device addresses several unmet needs identified by patients using the current infusion process, some limitations remain. As with all devices using spikes, contamination is possible if the connector tip is touched while preparing the rHuPH20 or IgG 10% components. Also, the vial access device must remain level (flat) toward the end of the infusion to prevent air from entering the system. To avoid leaks and damage to the spikes, patients should avoid rotating the vials or removing their labels during the infusion process. Given that the vial access device is intended for single use, options to decrease the ecological footprint are under investigation. Furthermore, the sample sizes for ethnographic and formative usability evaluation research were small, and since this research was conducted, the fSCIG 10% U.S. label has been updated to allow patients to administer rHuPH20 via a pump (rather than the push method). Because the preparation and administration of rHuPH20 specifically was not examined as part of the vial access device design and development process, pump administration of rHuPH20 has not been assessed for use with the vial access device system. The impact of this on current infusion practices will be assessed in future planned research.
The patient-centric and modular innovation principles of the vial access device are designed to improve access to the contents of multiple vials to facilitate infusion of the full prescribed dose, decrease the potential for contamination and exposure to sharps, and streamline the administration process compared with the manual spike and pooling method. The simplified administration experience with the vial access device may help to reduce infusion preparation time, improve the patient onboarding/training experience, and allow for transition of treatment to self-administered in-home infusion. Further studies including quantitative outcomes such as patient-reported outcomes and treatment satisfaction, and a larger sample size are warranted to determine whether the devices significantly improve the quality of life of patients receiving fSCIG 10%.
Disclosures:
Editorial assistance was funded by Takeda Development Center Americas, Inc. and Takeda Pharmaceuticals International AG. K Duff is an employee and shareholder of Takeda Development Center Americas, Inc. S Holzner, M Gibson, S Jones, and S Ariagno are former employees of Takeda Development Center Americas, Inc. S Holzner is currently affiliated with Cytiva Corporation. M Gibson is currently affiliated with Delve. S Jones is currently affiliated with Baxter. S Ariagno is currently affiliated with EdgeOne Medical.
Acknowledgments:
The authors thank the patients and nurses who participated in the development of the device. Thanks also go to all those in the Takeda device design and development team, past and present, for their valued contributions, from conceptualization through development. At the direction of the authors, Jessica Donaldson- Jones, PhD, of Oxford PharmaGenesis, Oxford, UK, provided editorial assistance.
Author Contributions:
All authors contributed to the writing of this manuscript, approved the final version for submission, and are accountable for all aspects of the work. K Duff is a clinical adviser and primary immunodeficiency patient and contributed to design of patient-centric studies. S Holzner and S Ariagno were supervisors, contributed to idea generation, and to the design of the device. M Gibson contributed to the design of the device and directed patient-centric studies. S Jones contributed to idea generation and the design of the device and led development of the device from concept through launch.
1. Duraisingham SS, Buckland M, Dempster J, et al. Primary vs. secondary antibody deficiency: clinical features and infection outcomes of immunoglobulin replacement. PloS one. 2014;9:e100324. 10.1371/journal.pone.0100324.
2. Justiz Vaillant AA, Qurie A. Immunodeficiency Treasure Island, FL: StatPearls Publishing; 2019 [Available from: https://www.ncbi.nlm.nih.gov/books/NBK500027/ accessed February 24, 2022.
3. Rezaei N, Aghamohammadi A, Notarangelo LD. Primary immunodeficiency diseases: definition, diagnosis, and management. 2nd ed. Berlin, Germany: Springer-Verlag 2017.
4. Poli MC, Aksentijevich I, Bousfiha AA, et al. Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee. Journal of Human Immunity. 2025;1:e20250003. 10.70962/jhi.20250003.
5. Chinen J, Shearer WT. Secondary immunodeficiencies, including HIV infection. Journal of Allergy and Clinical Immunology. 2010;125:S195–S203. 10.1016/j.jaci.2009.08.040.
6. Patel SY, Carbone J, Jolles S. The expanding field of secondary antibody deficiency: causes, diagnosis, and management. Frontiers in Immunology. 2019;10:33. 10.3389/fimmu.2019.00033.
7. van Zelm MC, Condino-Neto A, Barbouche M-R. Editorial: Primary immunodeficiencies worldwide. Frontiers in Immunology. 2020;10:3148. 10.3389/fimmu.2019.03148.
8. Jolles S, Chapel H, Litzman J. When to initiate immunoglobulin replacement therapy (IGRT) in antibody deficiency: a practical approach. Clinical and Experimental Immunology. 2017;188:333– 41. 10.1111/cei.12915.
9. Wolbert J, Cheng MI, Meyer zu Horste G, Su MA. Deciphering immune mechanisms in chronic inflammatory demyelinating polyneuropathies. JCI Insight. 2020;5:e132411. 10.1172/jci. insight.132411.
10. Querol L, Crabtree M, Herepath M, et al. Systematic literature review of burden of illness in chronic inflammatory demyelinating polyneuropathy (CIDP). Journal of Neurology. 2021;268:3706-16. 10.1007/s00415-020-09998-8.
11. Broers Merel C, Bunschoten C, Nieboer D, Lingsma Hester F, Jacobs Bart C. Incidence and prevalence of chronic inflammatory demyelinating polyradiculoneuropathy: a systematic review and meta-analysis. Neuroepidemiology. 2019;52:161-72. 10.1159/000494291.
12. Arumugham VB, Rayi A. Treasure Island (FL): StatPearls Publishing; Intravenous Immunoglobulin (IVIG) [Updated 2023 Jul 3]. In: StatPearls [Internet]. [Available from: https://www.ncbi.nlm.nih.gov/books/NBK554446/ accessed May 30, 2025.
13. Misbah S, Sturzenegger MH, Borte M, et al. Subcutaneous immunoglobulin: opportunities and outlook. Clinical and Experimental Immunology. 2009;158 Suppl 1:51–59. 10.1111/j.1365- 2249.2009.04027.x.
14. Van den Bergh PYK, van Doorn PA, Hadden RDM, et al. European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint Task Force—second revision. Journal of the Peripheral Nervous System. 2021;26:242-68. https://doi.org/10.1111/jns.12455.
15. Wasserman RL. Subcutaneous immunoglobulin: facilitated infusion and advances in administration. Clinical and Experimental Immunology. 2014;178 Suppl 1:75–77. 10.1111/cei.12519.
16. Chapel HM, Spickett GP, Ericson D, et al. The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy. Journal of Clinical Immunology. 2000;20:94–100
17. Wasserman RL, Melamed I, Stein MR, et al. Recombinant human hyaluronidase-facilitated subcutaneous infusion of human immunoglobulins for primary immunodeficiency. Journal of Allergy and Clinical Immunology. 2012;130:951-57. e11. 10.1016/j. jaci.2012.06.021.
18. Bonilla FA. Intravenous immunoglobulin: adverse reactions and management. Journal of Allergy and Clinical Immunology. 2008;122:1238–39. 10.1016/j.jaci.2008.08.033.
19. Jolles S. Hyaluronidase facilitated subcutaneous immunoglobulin in primary immunodeficiency. Immuno-Targets and Therapy. 2013;2:125–33. 10.2147/ITT.S31136.
20. Berger M, Murphy E, Riley P, Bergman GE, VIRTUE Trial Investigators. Improved quality of life, immunoglobulin G levels, and infection rates in patients with primary immunodeficiency diseases during self-treatment with subcutaneous immunoglobulin G. Southern Medical Journal. 2010;103:856–63. 10.1097/ SMJ.0b013e3181eba6ea.
21. Hadden RD, Marreno F. Switch from intravenous to subcutaneous immunoglobulin in CIDP and MMN: improved tolerability and patient satisfaction. Therapeutic Advances in Neurological Disorders. 2015;8:14-19. 10.1177/1756285614563056.
22. Mallick R, Solomon G, Bassett P, et al. Immunoglobulin replacement therapy in patients with immunodeficiencies: impact of infusion method on patient-reported outcomes. Allergy, Asthma & Clinical Immunology. 2022;18:110. 10.1186/s13223-022-00746-3.
23. Wasserman RL. Recombinant human hyaluronidase-facilitated subcutaneous immunoglobulin infusion in primary immunodeficiency diseases. Immunotherapy. 2017;9:1035–50. 10.2217/imt-2017-0092.
24. U.S. Food & Drug Administration. HYQVIA, immune globulin infusion 10% (human) with recombinant human hyaluronidase: product information 2025 [Available from: https://www.fda.gov/media/89844/download?attachment accessed May 30 2025.
25. European Medicines Agency. HyQvia 100 mg/mL solution for infusion for subcutaneous use: summary of product characteristics 2025 [Available from: https://www.ema.europa.eu/en/documents/product-information/hyqvia-epar-product-information_en.pdf accessed May 30, 2025.
26. Pharmaceuticals and Medical Devices Agency. Japan package insert: HyQvia 10% subcutaneous injection set 2025 [Available from: https://www.pmda.go.jp/etail/ResultDataSetPDF/400256_6343501A1025_1_02 accessed July 22, 2025.
27. Wasserman RL, Melamed I, Kobrynski L, et al. Efficacy, safety, and pharmacokinetics of a 10% liquid immune globulin preparation (GAMMAGARD LIQUID, 10%) administered subcutaneously in subjects with primary immunodeficiency disease. Journal of Clinical Immunology. 2011;31:323-31. 10.1007/s10875-011-9512-z.
28. Wasserman RL, Melamed I, Stein MR, et al. Long-term tolerability, safety, and efficacy of recombinant human hyaluronidase-facilitated subcutaneous infusion of human immunoglobulin for primary immunodeficiency. Journal of Clinical Immunology. 2016;36:571-82. 10.1007/s10875-016-0298-x.
29. Wasserman RL, Isaac M, Lisa K, et al. Recombinant human hyaluronidase facilitated subcutaneous immunoglobulin treatment in pediatric patients with primary immunodeficiencies: long-term efficacy, safety and tolerability. Immunotherapy. 2016;8:1175-86. 10.2217/imt-2016-0066.
30. Patel NC, Walter JE, Wasserman RL, et al. Efficacy, safety, tolerability, and serum IgG trough levels of hyaluronidase-facilitated subcutaneous immunoglobulin 10% in US pediatric patients with primary immunodeficiency diseases. Journal of Clinical Immunology. 2025;45:81. 10.1007/s10875-025-01862-6.
31. Dimou M, Speletas M, Milito C, et al. Insights into facilitated subcutaneous immunoglobulin use in patients with secondary immunodeficiency diseases: a FIGARO subgroup analysis. Cancers. 2023;15:4524.
32. Bril V, Hadden RDM, Brannagan III TH, et al. Hyaluronidase-facilitated subcutaneous immunoglobulin 10% as maintenance therapy for chronic inflammatory demyelinating polyradiculoneuropathy: the ADVANCE-CIDP 1 randomized controlled trial. Journal of the Peripheral Nervous System. 2023;28:436-49. https://doi.org/10.1111/jns.12573.
33. Hadden RDM, Andersen H, Bril V, et al. Long-term safety and tolerability of hyaluronidase-facilitated subcutaneous immunoglobulin 10% as maintenance therapy for chronic inflammatory demyelinating polyradiculoneuropathy: results from the ADVANCE-CIDP 3 trial. Journal of the Peripheral Nervous System. 2024;29:441-52. https://doi.org/10.1111/jns.12672.
34. van Paassen P, Pittrow D, Scheidegger C, Klotsche J, and Ellerbroek PM. Use of recombinant human hyaluronidase-facilitated subcutaneous immunoglobulin in elderly patients. Immunotherapy. 2020;12:131-39. 10.2217/imt-2019-0175.
35. Hustad NB, Degerud HM, Hjelmerud I, et al. Real-world experiences with facilitated subcutaneous immunoglobulin substitution in patients with hypogammaglobulinemia, using a three-step ramp-up schedule. Frontiers in Immunology. 2021; 12:670547. 10.3389/fimmu.2021.670547.
36. Baumann U, Maria F, Christine P, et al. Facilitated subcutaneous immunoglobulin use in pediatric patients with primary or secondary immunodeficiency diseases. Immunotherapy. 2022;14:135-43. 10.2217/imt-2021-0167.
37. Ponsford M, Carne E, Kingdon C, et al. Facilitated subcutaneous immunoglobulin (fSCIg) therapy—practical considerations. Clinical and Experimental Immunology. 2015;182:302–13. 10.1111/ cei.12694.
38. Mallick R, Jolles S, Kanegane H, Agbor-Tarh D, Rojavin M. Treatment satisfaction with subcutaneous immunoglobulin replacement therapy in patients with primary immunodeficiency: a pooled analysis of six Hizentra® studies. Journal of Clinical Immunology. 2018;38:886–97. 10.1007/s10875-018-0562-3.
39. Routes J, Costa-Carvalho BT, Grimbacher B, et al. Health-related quality of life and health resource utilization in patients with primary immunodeficiency disease prior to and following 12 months of immunoglobulin G treatment. Journal of Clinical Immunology. 2016;36:450–61. 10.1007/s10875-016-0279-0.
40. Duff K, Soresini A, Wolf N, et al. Individualized hyaluronidase-facilitated subcutaneous immunoglobulin 10% administration in chronic inflammatory demyelinating polyradiculoneuropathy: the nurse’s role. Journal of Infusion Nursing. 2025;48:166-80. 10.1097/ nan.0000000000000581.
41. Takeda Pharmaceuticals. Press release: Takeda receives FDA 510(k) clearance for HyHub™ and HyHub™ Duo devices to simplify HyQvia® administration 2025 [Available from: https://www.takeda.com/newsroom/newsreleases/2025/hyhub/ accessed 20 August 2025.
42. U.S. Food & Drug Administration. 510(k) Premarket Notification: HyHub™ and HyHub™ Duo Vial Access Devices 2025 [Available from: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K243404 accessed August 20, 2025.
