In situ determination of acceptable resuspension in pharmaceutical products using water proton NMR

Inventors

YU, YIHUA (BRUCE) • Taraban, Marc • Fox, Christopher

Assignees

University of Maryland Baltimore • University of Baltimore • Access to Advanced Health Institute

Abstract

A method of using the transverse relaxation rate (R2) of solvent NMR signal to noninvasively assess if an alum-containing product, such as a vaccine, has been acceptably resuspended for use following transport and/or storage. This technique allows for the manufacturer and/or distributor and/or end user to monitor for unexpected stressors associated with transport and/or storage including, but not limited to, temperature fluctuations, pH changes, vigorous shaking during transportation, exposure to sunlight, and freezing.

Core Innovation

The invention provides a noninvasive solvent water proton NMR method for alum-containing pharmaceutical products to assess whether alum particle-containing product were acceptably resuspended following transport and/or storage. The method measures a transverse relaxation rate R2,m, or transverse relaxation time T2,m, of the solvent in the alum-containing product contained in a vial after transport and/or storage, without opening the vial and without withdrawing its contents prior to measurement. The measured value is compared to a reference transverse relaxation rate R2,r, or reference transverse relaxation time T2,r, that represents an acceptable range of evenly distributed aluminum particles or suspended aluminum particles.

The method is directed to detecting uneven alum filling and insufficient resuspension after transport and storage, by using solvent NMR sensitivity to the alum particle state. When the measured R2,m, or T2,m, is inside the reference range, the alum-containing product is determined to be acceptably resuspended; when it is outside the reference range, the product is determined not to have been acceptably resuspended. The reference range is defined to represent evenly distributed aluminum particles or suspended aluminum particles in the alum-containing product.

The invention specifies that no additives or probes are added to the vial prior to measurement of the transverse relaxation rate of the solvent R2,m, or the transverse relaxation time of the solvent T2,m. The alum-containing product includes aluminum particles and may include aluminum hydroxide, aluminum phosphate, alum, or aluminum hydroxyphosphate sulfate, including combinations. The alum-containing product is characterized as containing single particles with a diameter from 1 nm to 50 µm, and may be a vaccine with alum adjuvants or a pharmaceutical product with aluminum particles.

Claims Coverage

The document includes two independent claims that cover acceptably resuspended alum-containing products by in-vial solvent NMR measurement and comparison to a manufacturer-provided reference relaxation value, using either transverse relaxation rate R2 or transverse relaxation time T2. Across the independent claims, inventive features include the resuspension determination via measured solvent transverse relaxation parameter, comparison to a reference range representing evenly distributed or suspended aluminum particles, and constraints that the product is contained in a vial with no additives or probes added prior to measurement.

Claim coverage centers on noninvasive in-vial solvent NMR acceptability determinations of alum particle resuspension after transport and/or storage by comparing a measured solvent transverse relaxation parameter (R2,m or T2,m) to a reference range (R2,r or T2,r) that corresponds to evenly distributed or suspended aluminum particles, with acceptability concluded based on whether the measured value falls within the reference range and with no additives or probes added to the vial prior to measurement.

Stated Advantages

Documented Applications