Consistency of Product Quality for SB5, an Adalimumab Biosimilar

Biologics have become a substantial component of pharmaceutical expenditure owing to their efficacy across numerous therapeutic areas including immunology and oncology [1,2,3,4]. Biologics spending has considerably increased over recent years. In the United States (US), the spending on biologics has increased from US$84 billion in 2014 to US$126 billion in 2018 [4, 5]. In 2019, biologics represented 43% of total US medicine spending [5, 6], and yet biologics spending is projected to grow even further, with immunology being one of the leading therapeutic areas of growth [7, 8]. Successful biosimilar uptake is therefore essential as biosimilars are expected to reduce the health care cost through price competition and to expand patient access to these effective biologic treatments.

SB5 is a biosimilar developed by Samsung Bioepis referencing adalimumab (Humira, AbbVie Inc.), one of world’s leading medicines in terms of pharmaceutical spending. Biosimilars are biological products that are highly similar to an existing reference biologic, and they undergo a thorough regulatory approval process to demonstrate that there are no clinically meaningful differences from the reference biologic in terms of safety and efficacy. Such demonstration of biosimilarity involves rigorous analytical, nonclinical, and clinical evaluations [9,10,11]. As of September 2022, SB5 has been approved by 14 regulatory authorities including the European Commission (EC) (August 2017, brand name Imraldi™) and the US Food and Drug Administration (FDA) (July 2019, brand name Hadlima™) [12, 13]. Based on a robust data package including extensive analytical characterization on the physicochemical and functional level using state-of-the-art analytical techniques and comparative phase I and phase III clinical studies, SB5 has demonstrated that it is highly similar to the reference adalimumab [14,15,16,17]. Since its release in various markets, over 5 million doses of SB5 have been prescribed to patients globally [18] and the real-world evidence has demonstrated that SB5 is as safe and effective as its reference product over the areas of rheumatology, gastroenterology, and dermatology [19].

Biologics, both the reference and biosimilars, are large and complex molecules produced from living systems using a multi-step manufacturing process. Due to their size, complexity, and the manufacturing process involved, heterogeneity is a common feature of biologics [20,21,22]. Most biologics are mixtures of protein isoforms arising from a variety of post-translational modifications [21,22,23,24]. These modifications can be introduced by an intracellular or extracellular process during manufacturing or storage, and the resulting heterogeneity in the key physicochemical or biological characteristics of the biologic, known as the critical quality attributes, may impact the safety and efficacy of the drug.

A drift or ‘evolution’ [25] in the critical quality attributes of marketed biologics has been reported in a number of studies [20, 26, 27]. A drift in the product quality profile can be a result of natural variability of biologics or unintended variation owing to uncontrolled variables in the manufacturing process. Moreover, manufacturers are often motivated to make intentional changes to the process for a wide variety of reasons including process improvements, scale ups or site transfers. Some changes may be minor, but others may be major in terms of their impact and can lead to an evolution, or a sudden shift, in the quality profile [25, 28, 29]. In order to maintain consistent quality and thus consistent clinical performance of a biologic, it is important for a manufacturer to carefully control the manufacturing process and closely monitor the critical quality attributes of the drug.

Despite the frequent necessity for manufacturing process changes, robust quality systems and regulatory frameworks can ensure that the quality and clinical performance of a biologic is maintained over its lifecycle [25, 29]. In particular, equivalent safety and efficacy of a biologic before and after a process change is established based on a comparability exercise. The comparability exercise is normally based on a comprehensive analytical characterization which ensures that the pre- and post-change quality attributes are highly comparable and that any difference in the quality attributes has no adverse impact on the safety or efficacy of the drug [30,31,32].

Likewise, SB5 has undergone multiple process changes, some of which were minor while others were considered major, such as transfer of manufacturing sites and introduction of a new formulation. SB5, initially available only in a low concentration (40 mg/0.8 mL), has been developed for a high-concentration, citrate-free formulation (40 mg/0.4 mL). The high-concentration citrate-free formulation has been approved by the EC and the US FDA, providing added convenience for patients. Despite such process changes, the critical quality attributes of SB5 have been tightly managed through robust quality systems and rigorous comparability exercises between the pre- and post-change products in line with the regulatory guidelines. In this report, we demonstrate the consistency of product quality for 93 batches of SB5 manufactured between 2013 and 2022.

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