Detection of pharmaceutical product freezing history using water proton NMR
Inventors
Yu, Yihua Bruce • TARABAN, Marc B. • BRIGGS, Katharine T.
Assignees
University of Maryland Baltimore
Publication Number
US-12203882-B2
Publication Date
2025-01-21
Expiration Date
2040-03-11
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Abstract
A method of using the relaxation rate (R1 and/or R2) of solvent NMR signal to invasively or noninvasively assess whether vaccines and other aqueous-based pharmaceutical products have been frozen during transport and/or storage.
Core Innovation
The invention provides a method to determine if vaccines or other aqueous-based pharmaceutical products have experienced freeze-induced damage during transport and storage using the nuclear magnetic resonance (NMR) relaxation rates of solvent—specifically, the transverse relaxation rate constant R2 and/or the longitudinal relaxation rate constant R1 of water. By measuring these relaxation rates in the sealed container (vial) of the product and comparing them to reference values established by the manufacturer for non-frozen products, it is possible to detect prior freezing without opening, altering, or removing the label from the vial.
This technology addresses the problem of inadequate, slow, or destructive current methods for freeze detection, such as visual ice inspection and the WHO Shake Test, which are subjective, labor intensive, require vial destruction or alteration, and may not accurately identify all vials that experienced freeze-induced damage. The inability to efficiently, reliably, and non-invasively identify freeze-damaged pharmaceutical products has resulted in either unnecessary product wastage or inadvertent usage of damaged products, risking reduced potency or patient harm.
The presented method enables both invasive and non-invasive measurement, including the use of benchtop or handheld NMR devices. It is applicable to a wide range of pharmaceutical products, particularly those with aluminum adjuvants and aqueous media, and can be used for quality control during manufacturing, shipment, distribution, or immediately prior to administration. The detection is quantitative, rapid, does not require highly trained personnel, and allows for the individual assessment of each vial, reducing unnecessary wastage and enhancing patient safety.
Claims Coverage
There are two independent inventive features described in the patent claims.
Determination of freeze-induced damage in pharmaceutical products using solvent transverse relaxation rate (R2)
A method for determining if a vaccine or aqueous-based pharmaceutical product containing an aluminum adjuvant has experienced freeze-induced damage by: 1. Measuring the transverse relaxation rate of solvent (R2,m), preferably water, in the product vial without opening or adding additives or probes. 2. Comparing the measured R2,m to a manufacturer-provided reference range (R2,r) representing acceptable values for non-frozen products, at substantially similar temperature and magnetic field strength. 3. Using the result of this comparison to determine if freeze-induced damage has occurred. Specifically, if R2,m is less than the reference R2,r range, the product is deemed not to have experienced freeze-induced damage.
Determination of freeze-induced damage using solvent transverse relaxation time (T2)
A method for determining if a vaccine or aqueous-based pharmaceutical product containing an aluminum adjuvant has experienced freeze-induced damage by: 1. Measuring the transverse relaxation time of solvent (T2,m), preferably water, in the product vial without adding additives or probes or opening the container. 2. Comparing the measured T2,m to a manufacturer-provided reference range (T2,r) representing the acceptable range for non-frozen products, at substantially similar temperature and magnetic field strength. 3. Determining from this comparison if freeze-induced damage has occurred, whereby T2,m less than the reference T2,r range indicates freeze-induced damage.
In summary, the inventive features broadly cover methods for the non-invasive determination of freeze history in aluminum-adjuvanted pharmaceutical products by measuring solvent NMR transverse relaxation properties, compared to reference values.
Stated Advantages
The method is easy to use and can be performed noninvasively without opening the vial or removing labels.
Results are obtained rapidly, typically within less than one minute, enabling fast decision making.
The method is highly sensitive and quantitative, improving the accuracy in detecting freeze-induced damage compared to subjective methods.
No destruction or alteration of the vial or product is necessary, supporting non-destructive quality control.
It allows for the individual testing of every vial in a batch, minimizing unnecessary wastage and maximizing product potency.
Minimal technical expertise is required; the process can be automated and is not dependent on highly trained human observers.
The technique is low-cost, making use of benchtop or handheld NMR devices.
Applicable to both biologic and small molecule aqueous-based pharmaceutical products, including anti-bacterial and anti-viral vaccines and emulsions.
Documented Applications
Non-invasive quality control in the supply chain of vaccines and aqueous-based pharmaceutical products to determine if individual vials have experienced freeze-induced damage and should be removed from distribution.
Assessment of freeze-induced damage in vaccines comprising aluminum adjuvants, such as DAPTACEL, ENGERIX-B, and VAQTA, during transportation and storage.
Detection of freeze-induced damage in aqueous-based emulsion drugs such as DIPRIVAN and PROPOFOL.
Screening of pharmaceutical products before administration to ensure viability and potency by assessing freeze history.
Application to continuous-flow manufacturing processes for pharmaceutical quality control.
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