Relevant peer-reviewed literature on the topics of SC injection with ADL and ADL biosimilars were identified based on the experience of the authors. Furthermore, regulatory documents (e.g., Food and Drug Administration [FDA] submissions/reviews) and product labels (e.g., US prescribing information) were searched for details of product attributes for ADL products.

This article is based on previously conducted studies and other sources; it does not contain any studies with human participants or animals performed by any of the authors.

As of October 2023, nine ADL biosimilars have been approved and are available on the market in the USA (Table 2) [33,34,35,36,37,38,39,40,41,42,43]. Additionally, a biologics license application for one proposed ADL biosimilar (AVT02, Alvotech, Reykjavik, Iceland) was accepted by the US FDA with anticipated approval in February 2024 [44].

Controlling pH is necessary for the solubility and stability of SC-injected biologic drugs. Slightly acidic formulations may be preferred for drug stability, but formulations with pH < 3.0 can cause pain and inflammation [21, 22]. Basic formulations with pH > 9.0 are associated with tissue necrosis [21, 22]. pH is often controlled by adding buffer salts to a product formulation [53].

Citrate and phosphate are two of the most used buffers and have a wide buffering range (pH 2.1–6.2 and 3.0–8.0, respectively) [22, 54]. Newer monoclonal antibody formulations use histidine or acetate as the preferred buffer; however, the buffering range (pH 5.0–6.5 and 3.8–5.8, respectively) is narrower versus phosphate or citrate [22, 55]. Citrate has been used in > 100 injectable product formulations [54]. However, stabilizing pH with citrate buffers has been associated with ISP [56, 57]. In addition, glutamate has been used as an excipient for product stability, and SC injection of glutamate has been associated with ISP and injection-site reactions [21, 58].

In a prospective single-center study of 54 adult healthy volunteers, a significantly greater number of participants (38/54; 70%) injected with a citrate-containing solution reported more or much more pain immediately after injection than participants injected with a histidine-containing solution (p = 0.002) [56]. In a prospective observational registry study in patients with inflammatory bowel disease, switching from a citrate-free reference ADL to a citrate-containing ADL biosimilar was correlated with ISP (p = 0.004) [57].

The consequences of ISP can be clinically meaningful and may contribute to non-adherence and the patient’s decision to discontinue treatment [59,60,61]. For example, in an online survey of patients with rheumatoid arthritis (RA; n = 250), the injection experience, including pain, burning, or discomfort during or after administration, was reported among the primary reasons for discontinuing a TNF inhibitor (TNFi) [59]. In a real-world study of rheumatology, dermatology, and gastroenterology patients receiving ADL (n = 744), the switch failure rate was higher for patients switched from citrate-free reference ADL to a citrate-containing ADL biosimilar than for patients switched to a citrate-free ADL biosimilar [61].

Formulating reference ADL to minimize ISP has been demonstrated to reduce the sensation of pain on administration [62, 63]. For example, in a pooled analysis of two identical, Phase 2, randomized, crossover studies in patients with RA, patients given citrate-free reference ADL reported less pain immediately after injection (p < 0.001) and were more likely to rate ISP severity as mild compared with patients given citrate-containing reference ADL (86.9% vs 42.6%) [62]. Citrate-free reference ADL was found to reduce ISP and was associated with greater treatment adherence, higher treatment persistence, and better experience of self-administration [64, 65].

Product formulations of ADL biosimilars available in the USA are summarized in Table 3 [2, 33,34,35,36,37,38,39,40,41]. High-concentration reference ADL and nearly all the ADL biosimilars offer versions that are citrate-, phosphate-, and glutamate-free [2, 33,34,35,36,37,38,39,40,41]. This is an important consideration when discussing ADL treatment options as patients and hospitals may not want to use products containing excipients that contribute to ISP.

Large SC injection volumes are generally associated with pain and adverse events at the injection site. In addition, the association between injection volume and ISP may be influenced by injection site location as injections into the thigh have been reported to be more painful than those into the abdomen [22, 77, 78]. Volumes of up to 0.8 ml are not expected to increase pain [22, 77, 78], but volumes of > 1.5 ml may be associated with increased ISP [21, 22, 79]. This observation is consistent with anecdotal reports from physicians and nurses that patients receiving 80 mg/0.8 ml loading doses of citrate-free ADL have not reported greater levels of ISP compared with those who received 40 mg/0.4 ml doses, though no formal assessments were conducted.

Reference ADL is available in a standard- (50 mg/ml) and high-concentration (100 mg/ml) solution for PFS or PFP injection [2]. Among currently available ADL biosimilars in the USA (Table 3), eight offer a standard-concentration solution (50 mg/ml) for injection by PFS or PFP [33,34,35,36,37,38,39, 41], and four offer a high-concentration solution (100 mg/ml) that allows a smaller volume for PFS or PFP injection: Amjevita™ (adalimumab-atto; Amgen Inc., Thousand Oaks, CA, USA), Hadlima™ (adalimumab-bwwd; Samsung Bioepis Co., Ltd., Incheon, Republic of Korea/Organon & Co., Jersey City, NJ, USA), Hyrimoz® (adalimumab-adaz; Sandoz Inc., Princeton, NJ, USA), and Yuflyma® (adalimumab-aaty; Celltrion, Inc., Incheon, Republic of Korea) [34, 36, 38, 40].

Reference ADL and all ADL biosimilars in the USA are available for injection as a PFS or PFP (Table 3) [2, 33,34,35,36,37,38,39,40,41]. Key features of ADL products available as a PFS or PFP are summarized in Figs. 1 and 2, respectively [2, 33,34,35,36,37,38,39,40,41, 66,67,68,69,70,71,72,73,74, 80,81,82,83,84,85,86]. The ADL PFS is composed of a needle and a syringe that is pre-filled with the appropriate drug dose, which reduces the time taken for injection and the chance of a dosing error and reduces the possibility of microbiologic contamination [87]. ADL PFPs have been designed so that the injection process is automated; their features make the injection process easier, which increases patient confidence [