The majority of protein therapeutics are formulated for injectable or infusible applications, explains Vadim Klyushnichenko, Ph.D., vp for preclinical services and process development at Paragon Bioservices.
“Since alternative delivery methods like transdermal, oral, and inhalable are limited by protein size, stability, and bioavailability, and many biotech drugs are administered at high dose, formulations must accommodate very high drug concentrations.”
Formulation developers need to navigate the thin line between concentration and aggregation or precipitation, both of which are common with monoclonal antibodies. High-dose therapeutic proteins can also cause side effects, for example infusion reactions.
Paragon originally focused on development and manufacturing for therapeutic proteins, monoclonal antibodies, viruses, and virus-like particles. Formulation development was part of these services.
When their clients began asking for full biologics development, including formulation development of drug substance and drug product, short- and long-term stability studies, and fill/finish, the company doubled the size of its facilities to more than 50,000 square feet. The new space, which includes new formulation labs, stability chamber area, and cGMP fill/finish, is expected to come online next month.
From Paragon’s perspective, approaches for achieving stable, high, and effective concentrations for protein drugs lie in sustained-release technologies such as micro- and nanoparticles, liposomal complexes, or biodegradable matrices for implantable depot delivery.
“Development of such systems for targeted delivery of therapeutic proteins is the goal of formulation groups across the biopharmaceutical industry,” Dr. Klyushnichenko adds.
Formulation development should be initiated as early as possible, he says, if only through preliminary preformulation studies or protein characterization, analytical development, degradation studies, short-term stability studies, and development of a preliminary drug substance formulation.
According to this model, developers will investigate several “preformulations” for each potential formulation type and delivery mechanism. Based on data derived from actual formulation, long-term stability studies, and preclinical data, the number of candidate formulations is reduced by the time the product enters Phase I studies.
But Dr. Klyushnichenko warns companies to avoid a common catch-22. “If you do not know the properties of the protein, you cannot define the formulation and calculate accurately the quantity of drug substance required for preclinical or early clinical trials.”
This will lead to a “simple and reliable” formulation for Phase I, and perhaps Phase II as well, he says. The formulation changes subsequently as data from human studies become available.
Formulation development continues through the entire development period and, in many cases, throughout the drug’s entire lifecycle. Ideally the same protein could be formulated to cover several drug forms, administration routes, or indications. Each additional formulation provides extra IP protection and market coverage.
“There is always room for improvement in terms of additional patient safety and stable revenue for the company,” Dr. Klyushnichenko adds.