Low-Field NMR in Nondestructive Quantitative Inspection of Drug Products

Abstract

Batch-to-batch inference-based quality control of drug products has historically been very effective. However, infrequent incidences of drug defects may be missed by traditional batch-to-batch testing, especially for complex drugs, e.g. biologics. Compared to small molecule drugs, complex drugs have many more factors involved their production and manufacturing, and are more prone to degrade with temperature stresses or agitation during transportation and storage. Relying on batch testing, the sole inspection method of released drug products is human visual inspection. Here we investigate the use of low-field NMR (23 MHz) to inspect four types of drug products, each addressing a different potential quality control problem: 1. Novolog FlexPen® (wrong dosage), 2. Ferrlecit® vs. generic (false equivalence), 3. Alhydrogel® (uneven filling of alum adjuvant), 4. Daptacel®, Engerix-B®, and Vaqta® vaccines (freeze/thaw stress). In every case, during our experiments the product (vial or pen) remained sealed without any tampering; low-field NMR as a method for drug product inspection is non-destructive. The water proton transverse relaxation rate, R2(1H2O), was found to be sensitive to concentration changes in aluminum hydroxide adjuvants, and insulin protein. Furthermore, differences in brand name and generic drug products were detected by the R2(1H2O), where properties measured by other analytical methods failed to detect differences. These findings suggest that low-field 1H2O NMR could serve as a non-destructive inspection method for drug products, such as insulin pens and vaccines.