ABSTRACT
Residual solvents can be de‰ned as any solvent used or produced in the manufacturing or formulation of an oligonucleotide that is not completely removed during the process. If not removed, these solvents can be present in the ‰nal formulation of a drug product and administered to a patient when undergoing medical treatment. The solvents do not provide any therapeutic value and may even pose
11.1 Introduction .......................................................................................................................... 331 11.2 Theory ................................................................................................................................... 332
11.2.1 Injection Techniques ................................................................................................. 332 11.2.1.1 Head Space................................................................................................. 332 11.2.1.2 Liquid Injections ........................................................................................ 335 11.2.1.3 Split versus Splitless Injections .................................................................. 336
11.2.2 Detectors ................................................................................................................... 337 11.2.2.1 Flame Ionization Detector ......................................................................... 337 11.2.2.2 Mass Spectrometer ..................................................................................... 337
11.2.3 The GC Column ....................................................................................................... 338 11.2.3.1 Column Length .......................................................................................... 339 11.2.3.2 Internal Diameter ....................................................................................... 339 11.2.3.3 Film Thickness ..........................................................................................340 11.2.3.4 Stationary Phase......................................................................................... 341
11.3 History of Residual Solvent Testing ..................................................................................... 341 11.4 Overview of USP General Chapter <467> ........................................................................... 342
11.4.1 Class 1 Solvents ........................................................................................................ 342 11.4.2 Class 2 Solvents: The Option Method ...................................................................... 342 11.4.3 Class 3 Solvents: Loss on Drying ............................................................................. 342 11.4.4 USP Chapter <467> Residual Solvents by Gas Chromatography ............................ 343
11.5 Residual Solvent Testing on Oligonucleotide Products ........................................................348 11.6 Summary .............................................................................................................................. 349 References ...................................................................................................................................... 349
a potential health risk to the patient, depending on the solvents toxicity and the amount ingested, so they should be removed to the extent possible. In this chapter we will review the current testing requirements for residual solvents in oligonucleotide products as well as provide detailed instruction about how to perform this testing.
