In situ determination of alum filling evenness and sedimentation in pharmaceutical products using water proton NMR
A method of using the transverse relaxation rate (R 2 ) of solvent NMR signal to noninvasively assess alum-containing products such as vaccines. This technique can be used for quality control in vaccine manufacturing (e.g., fill-finish step) to determine the evenness of alum filling level as well as extent of alum particle sedimentation in filled and sealed products.
1. A method of determining alum particle filling level evenness and/or an extent of alum particle sedimentation in an alum-containing product, said method comprising:
measuring a transverse relaxation rate of solvent R 2,m in the alum-containing product; and
determining the alum particle filling level evenness and/or the extent of alum particle sedimentation in the alum-containing product by comparing the measured R 2,m to a reference transverse relaxation rate of solvent R 2,r , wherein the reference R 2,r represents an acceptable range of evenly distributed aluminum particles or suspended aluminum particles,
wherein when the measured R 2,m is inside the reference R 2,r range, the evenness of the alum particle filling levels and/or the extent of alum particle sedimentation is acceptable.
2. The method of claim 1 , wherein R 2,m is measured using nuclear magnetic resonance (NMR).
3. The method of claim 1 , wherein the alum-containing product is contained in a vial, and wherein no additives or probes are added to the vial prior to measurement of the transverse relaxation rate of solvent R 2,m .
4. The method of claim 3 , wherein R 2,m is measured without opening the vial or withdrawing the contents of the vial containing the alum-containing product.
5. The method of claim 1 , wherein the solvent is water.
6. The method of claim 1 , wherein the alum-containing product comprises particles in a range from 1 nanometer and 50 microns in diameter.
7. The method of claim 1 , wherein the alum-containing product comprises aluminum-containing salts selected from the group consisting of aluminum hydroxide, aluminum phosphate, alum (KAl(SO 4 ).12H 2 O), aluminum hydroxyphosphate sulfate, and any combination thereof.
8. The method of claim 1 , wherein the alum-containing product is a vaccine comprising alum adjuvants or a pharmaceutical product comprising aluminum particles.
9. The method of claim 1 , wherein acceptable alum particle filling levels and/or acceptable alum particle sedimentation indicates that the alum-containing product is useable or distributable as intended.
10. The method of claim 1 , wherein the alum-containing product comprises particles in a range from 1000 nm to 10000 nm.
11. The method of claim 1 , wherein R 2,m and R 2,r are measured at a substantially similar temperature.
12. A method of determining alum particle filling level evenness and/or an extent of alum particle sedimentation in an alum-containing product, said method comprising:
measuring a transverse relaxation time of solvent T 2,m in the alum-containing product; and
determining alum particle filling level evenness and/or the extent of alum particle sedimentation in the alum-containing product by comparing the measured T 2,m to a reference transverse relaxation time of solvent T 2,r , wherein the reference T 2,r represents an acceptable range of evenly distributed aluminum particles or suspended aluminum particles,
wherein when the measured T 2,m is inside the reference T 2,r range, the evenness of the alum particle filling levels and/or the extent of alum particle sedimentation is acceptable.
13. The method of claim 12 , wherein T 2,m is measured using nuclear magnetic resonance (NMR).
14. The method of claim 13 , wherein the NMR is portable.
15. The method of claim 12 , wherein the alum-containing product is contained in a vial, and wherein no additives or probes are added to the vial prior to measurement of the transverse relaxation time of solvent T 2,m .
16. The method of claim 15 , wherein T 2,m is measured without opening the vial or withdrawing the contents of the vial containing the alum-containing product.
17. The method of claim 12 , wherein the solvent is water.
18. The method of claim 12 , wherein the alum-containing product comprises aluminum-containing salts selected from the group consisting of aluminum hydroxide, aluminum phosphate, alum (KAl(SO 4 ).12H 2 O), aluminum hydroxyphosphate sulfate, and any combination thereof.
19. The method of claim 12 , wherein the alum-containing product is a vaccine comprising alum adjuvants or a pharmaceutical product comprising aluminum particles.
20. The method of claim 12 , wherein acceptable alum particle filling levels and/or acceptable alum particle sedimentation indicates that the alum-containing product is useable or distributable as intended.