Rapid Depressurization Based Controlled Ice Nucleation in Pharmaceutical Freeze-drying: The Roles of the Ballast Gas and the Vial.

Controlled ice nucleation offers several key benefits to the pharmaceutical lyophilization process, including reducing lyophilization cycle time, control of ice crystal morphology, and increased consistency of lyophilized product quality attributes. The rapid depressurization based controlled ice nucleation technique is one of the several demonstrated controlled ice nucleation technologies and relies on the rapid discharge of an inert pressurized gas to induce ice nucleation. In this work, a series of custom wireless gas pressure and temperature sensors were developed and applied to this process to better understand the mechanism of controlled ice nucleation by depressurization. The devices capture highly transient conditions both in the chamber near the vial and within the vial headspace throughout the entire process. The effects of ballast gas composition, initial charge pressure, and vial size on gas pressure and headspace/chamber temperature are explored individually. We model the depressurization as an isentropic process, allowing the influence of these parameters to be evaluated quantitatively. It is demonstrated that monatomic gases (e.g. argon) with low thermal conductivity produce the most favorable conditions for ice nucleation at the end of depressurization, based on temperature drop in the vial headspace. Experimental data also reveal a correlation between initial charge pressure and vial size with the temperature drop within the vial headspace, during depressurization. These findings ultimately provide deeper insight into the rapid depressurization based controlled ice nucleation process and help lay the foundation for a more robust process development and control.

Strategies to Reduce Reconstitution Time of Lyophilized Biotherapeutics.

Lyophilized biotherapeutics with high protein concentration may have long reconstitution times, which pose an inconvenience to the end user. This report describes 2 approaches that lead to reduction of reconstitution time: (1) incorporation of tert-butyl alcohol (TBA) in the prelyophilization formulation and (2) decreased headspace pressure in the final lyophilized vial. Cakes made from prelyophilization formulations containing a range of TBA concentrations were physically characterized. The stability of antibodies with TBA in the liquid and lyophilized states was evaluated under stress conditions. Reconstitution time was minimized (>50% reduction) at a TBA concentration of 5% w/v. Reduced headspace pressure in the lyophilized vial demonstrated greater than 50% reduction in reconstitution time at headspace pressures of less than 50 Torr.

High shear rheology and anisotropy in concentrated solutions of monoclonal antibodies.

The high shear rheology of three concentrated solutions of immunoglobulin G1 monoclonal antibodies (mAb1, mAb2, and mAb3), differing only in their complementarity determining regions, was characterized using rotary and capillary rheometry. The more viscous solutions (mAb1 and mAb3) showed non-Newtonian behavior at high shear rates exhibiting both shear thinning and appreciable normal stress differences (NSDs) in the shear rate range γ = 10 to 10(4) s(-1) . The rheograms were retraced after γ is increased and decreased, suggesting reversible self-associations under shear. In contrast, mAb2 solutions showed Newtonian behavior up to γ = 6 × 10(4) s(-1) . The critical shear stress τc , corresponding to the onset of the reduction in the viscosity η, is a measure of mAb equilibrium cluster strength and increased rapidly with concentration for the high viscosity mAb solutions above 100 mg/mL. In addition, decreasing the temperature from 20°C to 5°C increased η at low γ, but shear-thinning was enhanced and its onset occurred at a lower γc . Using an Arrhenius model η = A exp(Ea /kT), the activation energy for viscous flow Ea was found to decrease for mAb1 solutions as γ was increased from 10 to 10(4) s(-1) , suggesting mAb cluster disruption or rearrangement under shear. In contrast, for mAb2, this Ea remained constant in the γ range. Finally, mAb1 and mAb3 solutions showed appreciable NSDs, with their N1 > 0 scaling linearly with γ in the range 10(3) to 10(4) s(-1) , whereas their |N2 /N1 | was less than 0.25 in this region. These suggest anisotropy and deformation of their solution microstructure toward the extensional quadrant of the flow at high γ. In contrast, the NSDs for mAb2 were close to zero indicating that the solution microstructure under shear is practically isotropic.

A new roadmap for biopharmaceutical drug product development: Integrating development, validation, and quality by design.

Quality by design (QbD) is a science- and risk-based approach to drug product development. Although pharmaceutical companies have historically used many of the same principles during development, this knowledge was not always formally captured or proactively submitted to regulators. In recent years, the US Food and Drug Administration has also recognized the need for more controls in the drug manufacturing processes, especially for biological therapeutics, and it has recently launched an initiative for Pharmaceutical Quality for the 21st Century to modernize pharmaceutical manufacturing and improve product quality. In the biopharmaceutical world, the QbD efforts have been mainly focused on active pharmaceutical ingredient processes with little emphasis on drug product development. We present a systematic approach to biopharmaceutical drug product development using a monoclonal antibody as an example. The approach presented herein leverages scientific understanding of products and processes, risk assessments, and rational experimental design to deliver processes that are consistent with QbD philosophy without excessive incremental effort. Data generated using these approaches will not only strengthen data packages to support specifications and manufacturing ranges but hopefully simplify implementation of postapproval changes. We anticipate that this approach will positively impact cost for companies, regulatory agencies, and patients, alike.