ROJA ANANDAKUMAR, CHINMAY BAKSHI, WINNIE LEE, MARIANA N. DIMITROVA
MedImmune, Formulation Sciences Department, Gaithersburg, MD 20878, USA
Purpose:
To optimize the formulation of a high concentration monoclonal antibody (mAb) to minimize sub-visible
particles (SVP) and prevent visible particle formation during the course of shelf life.
Methods:
Sub-visible particle (SVP) analyses were performed using Micro Flow Imaging (MFI). Appearance testing to detect visible particles was performed using Black and White light box. Soluble aggregation and fragmentation were quantified using HP-SEC and RP-HPLC respectively.
Results:
A high-concentration mAb was found to have an increased propensity to form proteinaceous visible particles (particles ≥ 125 μm) within 2-4 weeks at 2-8°C and 25°C/60%RH. Formation of visible particles coincided with a significant increase in SVP (particles size range 2μm - 125μm). Formulation optimization studies were performed to evaluate the effect of surfactant and other excipients on various product quality attributes including visible and SVP formation. It was observed that addition of surfactant (≥0.02%) or preferentially excluded excipient (≥234mM) prevented the formation of visible particles and decreased SVP significantly. Preferentially excluded excipient, when combined with surfactant seemed to have a synergistic effect in decreasing SVP count, especially in the 2-10μm size range. Effect of shear induced by dilution, filtration and agitation on visible and SVP counts were also evaluated. The results suggested that surfactant and preferentially excluded excipient stabilize high-concentration mAb and minimize SVP and prevent visible particle formation.
Conclusion:
Visible particle formation posed a major challenge in the formulation development of high-concentration mAb. Studies performed demonstrated that formulation optimization can help minimize SVP and prevent visible particle formation. Sub-visible particle analysis using MFI proved to be a valuable technique to monitor the kinetics of formation and quantification of particles in various size ranges.
PRESENTED AT:
2010 AAPS Annual Meeting/FIP Pharmaceutical Sciences World Congress, New Orleans LA, USA
2010 AAPS_MedImmune_Formulation optimization to minimize sbVP using MFI.pdf
2010 AAPS MedImmune Formulation optimization