title: An Approach to Mitigate Particle Formation on the Dilution of a Monoclonal Antibody Drug Product in an IV Administration Fluid.
abstract: To support dose reduction, low dose of a monoclonal antibody (mAb) was required to be administered via IV infusion at a concentration of 0.1 mg/mL. To achieve the target protein concentration, the infusion solution was prepared by diluting the drug product containing 10-mg/mL mAb with normal saline, a 0.9% sodium chloride injection solution. However, particles were observed in the diluted solution. Particle formation must be avoided to administer the low dose using the existing drug product. To mitigate the particle formation, an unconventional compounding approach was used. With this approach, a stabilizing vehicle containing polysorbate-80 was added to saline before drug-product dilution to maintain suitable surfactant level to prevent precipitation of the mAb. In this way, use of the stabilizing vehicle to support low doses ensured suitable quality across a wider range of mAb concentrations, thereby allowing additional flexibility to the clinical trial. Such an approach may be useful for broader application in early-stage clinical trials where there is an uncertainty regarding doses or the need to revise to lower doses based on clinical observations or other drivers.
authors.affiliation: Drug Product Science and Technology, Pharmaceutical Development, Research and Development, Bristol-Myers Squibb, New Brunswick, New Jersey 08903. Electronic address: Songyan.Zheng@bms.com.
authors.forename: Songyan
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Drug Product Science and Technology, Pharmaceutical Development, Research and Development, Bristol-Myers Squibb, New Brunswick, New Jersey 08903.
authors.forename: Monica
authors.initials: M
authors.lastname: Adams
authors.affiliation: Drug Product Science and Technology, Pharmaceutical Development, Research and Development, Bristol-Myers Squibb, New Brunswick, New Jersey 08903.
authors.forename: Rao V
authors.initials: RV
authors.lastname: Mantri
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002986:Clinical Trials as Topic; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry; D007262:Infusions, Intravenous / Q000379:methods; D019999:Pharmaceutical Solutions / Q000008:administration & dosage* / Q000737:chemistry; D011136:Polysorbates / Q000737:chemistry; D013501:Surface-Active Agents / Q000737:chemistry
chemical_list: D000911:Antibodies, Monoclonal; D005079:Excipients; D019999:Pharmaceutical Solutions; D011136:Polysorbates; D013501:Surface-Active Agents
keywords: precipitation; preformulation; protein aggregation; protein formulation; protein structure