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).