Development pathways for subcutaneous formulations of biologics versus biosimilar development

Abstract

Introduction: Biologics are highly complex drugs and many of their characteristics are defined by the manufacturing process. In recent years, several monoclonal antibody (mAb) biologics, which were hitherto only available for intravenous (IV) administration, have been reformulated for subcutaneous (SC) administration. Reformulation involves alterations to the established manufacturing process and it has been argued that a SC formulation should therefore be considered a biosimilar version of its previously approved IV formulation. Areas covered: Developing an SC version of an approved IV mAb product requires the adaptation of its formulation and route of administration. This process is illustrated via case examples of trastuzumab and rituximab and summarize what data requirements support the regulatory approval of these new formulations. Furthermore, we discuss similarities and differences between the development of an SC product vs. the development of a biosimilar. Expert opinion: The production process of a biosimilar is independently established from the very beginning, while the development of an SC formulation affects later stages of an already established production process and builds on extensive experience with the IV formulation. Considering these fundamentally different situations, a biologic product reformulated for SC administration should not be considered a 'biosimilar' version of itself. ARTICLE HISTORY

The Automatic Substitution of Biosimilars: Definitions of Interchangeability are not Interchangeable

“…Pharmacovigilance, the practice of identifying adverse events during routine clinical use of a drug, is essential to ensuring patient safety [74,75]. It is needed not only to identify events too rare to be observed in the randomized controlled setting, but also to identify issues related to a particular batch or lot of a product (i.e., manufacturing-or storage-related issues).…”

“…Because these changes can introduce product variability, the sponsor of an agent undergoing manufacturing changes undertakes comparability assessments throughout the manufacturing process, including product intermediates, ensuring that any variability introduced by manufacturing changes falls within pre-specified limits. Since the molecule generated before and after the manufacturing change is produced by the same sponsor in the same cell line [75], with impurities, inactive ingredients, and microheterogeneity (Table 1) kept within regulatoryapproved specifications, and since any manufacturing change must be approved by health authorities, the consistency of the biologic product is maintained over time. In contrast, biosimilarity exercises for a biosimilar can occur only with the commercially available version of the innovator (i.e., the final product) [12], not with intermediates (as would occur in a singlesupply chain).…”

The Challenges of Switching Therapies in an Evolving Multiple Biosimilars Landscape: A Narrative Review of Current Evidence

“…as those programs offered by the originator product [ 80 ]. Switching patients once or multiple times between therapies can also lead to concerns related to product delivery devices and injection-site reactions because the biosimilar may not use the same delivery device, formulation, dosage, or dosing interval as the originator [ 81 – 84 ]. Differences in formulation may also influence patient satisfaction and adherence [ 81 ].…”

Monoclonal antibody and protein therapeutic formulations for subcutaneous delivery: high-concentration, low-volume vs. low-concentration, high-volume

“…Unlike small molecule drugs, administering effective doses of mAbs orally can be extremely challenging due to their physical instability, low permeability across the gastrointestinal membrane, and vulnerability to enzymatic activity. 5 , 6 Most biologic products have traditionally been formulated at low concentrations (<30 mg/mL) convenient for IV infusion to maximize biologic stability, 7 , 8 lower manufacturing costs during development by decreasing the amount of drug needed for the stability program, and reduce waste during clinical dose-escalation studies. Altogether, compared to high-concentration formulations, low-concentration biologic drug formulations are easier and less costly to develop and are more stable due to their lower concentrations.…”