Formulation into the drug product – advances
Formulation development is a critical aspect as the degradation of a mAb product can affect its stability and efficacy. Throughout the drug development phases, different formulations are required, and decisions on the final mAb formulation are made at later stages of clinical development, typically in the frame of Phase 2b or Phase 3 studies. In early clinical development, IV administration is often the preferred RoA, especially when dose-ranging clinical studies are carried out. During early stages, the target dose is unknown, thus putting emphasis on allowing dose-flexibility by IV administration ensuring 100% bioavailability, and allowing comprehensive PK studies in humans during these critical early phase clinical trials (Li & Easton, 2018)
Depending on the administration, different formulations will be favoured to increase product stability and ensure product quality. For IV administration, a lyophilized powder for reconstitution and further dilution is typically prepared for increased product stability. During the drying process however, this technology leads to physical stress, potentially inducing instability and degradation, leading to decreased efficacy. Today, lyophilized formulations are not preferred as they are expensive to manufacture, and it requires further dilution prior to administration. SC and injectable administrations are prepared and stored as liquid formulations in self-administration devices. The pitfall of liquid formulations however, is an increased susceptibility to physicochemical degradation and lower stability, which can impact shelf-life and product quality (Sifniotis, Cruz, Eroglu, & Kayser, 2019). With injections being the primary delivery method for antibody products, different products exist: traditional vial and syringe (VS), pre-filled syringes (PFS), pre-filled pens, or auto-injectors (AI). While the use of PFS brings advantages such as user-friendly design and both patient and economic benefits, formulation issues arise due to solubility, aggregation and viscosity complications. The requirement for high protein concentrations of up to 200 mg/ml to achieve a therapeutic dose are thus limited by development difficulties (Li & Easton, 2018).
Aggregation is thought to be a result of the hydrophobic areas on the surface amino acid sequence, representing the most common form of instability of protein drugs. As it decreases the available efficacious product during treatment and often leads to increased side effects and immunogenicity, aggregation is very much undesirable in a drug product (Cui et al., 2017; Giannos, Kraft, Zhao, Merkley, & Cai, 2018). In an effort to reduce protein degradation and aggregation from high concentration formulations, excipients are added to injectable formulations, adhering to the International Pharmaceutical Excipient Council Europe (IPEC) guidelines which describe what an excipient should look like in terms of quality (Madani, Hsein, Busignies, & Tchoreloff, 2020). Commonly used excipients include the addition of salts, amino acids or sugars to balance repulsion and attraction forces by intermediate ionic strength or by adjusting the pH of the solution (Kemter et al., 2018). Surfactants, such as polysorbates, are used in biologics as a stabilizing agent, but addition of such agents in high concentrations can denature proteins and cause adverse side effects such as injection site reactions (Sifniotis et al., 2019). Amino acid-based formulations containing single amino acids at high concentrations serve to stabilize and reduce viscosity (Awwad & Angkawinitwong, 2018; Kemter et al., 2018). Hung et al. (2018) reported the improved use of concentrated proline in mAb formulations to increase stability and viscosity at pH 6, compared to using glycine or trehalose (Hung et al., 2018). Cryoprotectants, such as sucrose or trehalose, are commonly added to improve long-term stability as a frozen liquid and to avoid aggregation and denaturation (Cui et al., 2017). Whitaker et al. (2017) screened 56 excipients and other additives to evaluate their effect on viscosity using two different mAbs. Stability studies were performed over a 6-month period and this resulted in the ability to identify candidate high-concentration formulations with an acceptable range of viscosities. The use of excipient listings, e.g. Inactive Ingredient Search for Approved Drug Products (www.accessdata.fda.gov/scripts/cder/iig/index.cfm), provides formulation scientists with approved excipients from past formulations, avoiding extensive formulation screening experiments.
Though many mAb products are formulated in high concentration solutions, IV formulations are diluted in saline for patient administration. Ranibizumab (Lucentis®), a mAb approved for the treatment of age-related macular degeneration (AMD), was prone to aggregation and loss-of-function once removed from the manufacturer’s vial and diluted to low concentrations, potentially impacting its clinical outcome (Giannos et al., 2018).
High-throughput technologies for the screening of pre-formulations has allowed for the selection of candidates which are better suited for specific formulation and delivery requirements, as well as providing valuable information to improve process design and leading to increased yields and quality (Johnson, Parupudi, Wilson, & DeLucas, 2009; Maddux, Joshi, Volkin, Ralston, & Middaugh, 2011). Further automation tools for formulation development screening methods have been described (Razinkov, Treuheit, & Becker, 2015). Further, the use of novel and developing technologies such as small-angle X-ray scattering (SAXS) together with differential scanning calorimetry (DSC), dynamic light scattering (DLS) and viscosity measurements can be used to characterize and optimize the appropriate excipient formulation for a mAb product (Xu et al., 2019). A recent review by Le Basle et al. (2020) describes further advances used to analyse the stability and physicochemical properties of mAbs. Improvements in formulation to increase the duration of action of mAbs may also be achieved through the use of hydrogels, liposomes, micelles or micro- or nanoparticles, as described in detail by Awwad & Angkawinitwong (2018).