Abstract
The quality of therapeutic proteins such as hormones, subunit and conjugate vaccines, and antibodies is critical to the safety and efficacy of modern medicine. Identifying malformed proteins at the point-of-care can prevent adverse immune reactions in patients; this is of special concern when there is an insecure supply chain resulting in the delivery of degraded, or even counterfeit, drug product. Identification of degraded protein, for example human growth hormone, is demonstrated by applying automated anomaly detection algorithms. Detection of the degraded protein differs from previous applications of machine-learning and classification to spectral analysis: only example spectra of genuine, high-quality drug products are used to construct the classifier. The algorithm is tested on Raman spectra acquired on protein dilutions typical of formulated drug product and at sample volumes of 25 µL, below the typical overfill (waste) volumes present in vials of injectable drug product. The algorithm is demonstrated to correctly classify anomalous recombinant human growth hormone (rhGH) with 92% sensitivity and 98% specificity even when the algorithm has only previously encountered high-quality drug product.
Highlights
The use of therapeutic proteins has become common practice in medicine and their success has stimulated significant investment towards the discovery and manufacture of a wide range of biopharmaceuticals
We present a Raman instrument capable of measuring proteins in solution at dose relevant concentrations and with a sample volume small enough that it could be taken from the overfill volume used in vial packing of drug products[12], and demonstrate a classification technique that is capable of identifying degraded material based on changes in the scattered Raman spectrum
Point-of-care applications benefit from the small sample volumes (25 μL) utilized for these experiments, which is small enough that it could be taken from the “overfill volume” used to ensure that a syringe can withdraw a full dose from a vial[12]
Summary
The use of therapeutic proteins has become common practice in medicine and their success has stimulated significant investment towards the discovery and manufacture of a wide range of biopharmaceuticals. We present a Raman instrument capable of measuring proteins in solution at dose relevant concentrations and with a sample volume small enough that it could be taken from the overfill volume used in vial packing of drug products[12], and demonstrate a classification technique that is capable of identifying degraded material based on changes in the scattered Raman spectrum. This technique requires a consumable substrate with a limited shelf life[24,25]. These complications can be avoided as several therapeutic proteins are provided in formulation at concentrations high enough that the signal enhancement from SERS is not needed. This sample volume is smaller than the U.S Pharmacopeia recommended excess volume (overfill) of 100 μL for injections supplied in vial form with a label size of 0.5 mL and larger, so it would be possible to operate the system using the overfill volume present in these products[12]
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