Mass spectrometry and GC / MS

Analytical testing is a critical part in every step of drug development and manufacturing. The qualitative and quantitative results generated from validated analytical testing provide first-hand information to control and ensure the quality and safety of raw materials, intermediates, and finished products. Like many other CMC (chemical, manufacturing and control) activities, analytical testing is also frequently outsourced. Many factors are attributed to this rapid market growth, including continuous outsourcing from pharmaceutical companies, growing pipelines for biological candidates, and increasing demand for more analytical details on drugs and process development by regulatory agencies. In response to the changing market dynamics, service providers are striving to provide analytical testing with quality, accuracy, and robustness all within tight timelines. As the contract research organizations (CROs) have become more integrated, small analytical labs need to establish their niche to succeed. Global contract analytical Laboratories provide QC laboratory analysis, method development, validation and expert advice for both finished products and raw materials for pharmaceutical and biopharmaceutical companies. Quality Compliance testing is done a wide variety of raw material and finished product forms including High Potent Active Pharmaceutical Ingredients (APIs), Raw Materials and Excipients, Powders - Capsules/Semi-solids, Oils - Oral Solutions and Syrups, Liquids, Vitamins, Minerals, and Nutritional, Natural Health Products (NHPs) – Powders, Herbals – Suspensions, Finished Pharmaceutical Products (Tablets, Capsules/Semi-solids, Oral Solutions and Syrups, Gels, Creams and Ointments, Powders, Suspensions, Transdermals etc. Blend uniformity is a function of both the formulation and mixing action. Once the formulation is optimized from a theoretical process standpoint, blend uniformity must be validated during piloting and scale-up. From a manufacturer’s perspective; poor uniformity generates unacceptable amounts of discarded products, resulting in significant loss of revenue. However, no method currently exists that detects uniformity during the blending process, and as a result the true optimum endpoint is realized rarely. CGMP (21 CFR.211.110) for testing homogeneity and uniformity requires an in-process testing of powder blends to demonstrate adequacy of mixing, but it does not state that the blend has to be directly assessed for uniformity. It was on this premise that the original draft stratified sampling guidance document allowed the use of in-process dosage unit data as a surrogate to demonstrate dosage unit uniformity during routine manufacture. Blend uniformity should be assessed during process design (Stage 1 Validation) and process qualification (Stage 2 Validation). Defaulting directly to the testing of in-process dosage units is discouraged, the exception being when blend sampling presents severe risks to the operators taking the samples (which should be discussed and accepted by regulators). Gas Chromatography Mass Spectrometry (GC-MS) combines two powerful techniques to provide the identification of compounds with low detection limits and the potential for quantitative analysis. GC-MS analyses can work on liquid, gaseous and solid samples, but is primarily restricted to volatile and semi-volatile compounds. In Gas Chromatography (GC), a sample is volatilized and carried by an inert gas through a coated glass capillary column. The “stationary phase” is bonded to the interior of the column. The time it takes a specific compound to pass through the column to a detector is called its “retention time”, which can be used for identification when compared to a reference. In the usual Mass Spectrometry (MS) step of GC-MS, compounds leaving the GC column are fragmented by electron impact. The charged fragments are detected, and the subsequent spectrum obtained can be used to identify the molecule. Fragmentation patterns are reproducible, and can be used to produce quantitative measurements. Gas Chromatography Mass Spectrometry analysis can be performed on liquids, gases or solids. For liquids and gases the sample is commonly directly injected into the GC. For solids, the analysis is carried out by solvent extraction, outgassing (desorption) or pyrolysis. Desorption experiments are performed under helium flow at a controlled temperature between 40-300 ºC, with analytes being collected on a cryogenic trap during desorption. The sample chamber is a 1.25”x4” cylinder. GC-MS is a great technique for analysis of trace level impurities such as residual monomers because of its excellent sensitivity and specificity. Gas Chromatography Mass Spectrometry (GC-MS) combines two powerful techniques to provide the identification of compounds with low detection limits and the potential for quantitative analysis. Mass spectrometry expertise and techniques include Mass Spectrometry (MS), High Resolution Mass Spectrometry (HR/MS), Gas Chromatography Mass Spectrometry (GC/MS), Inductively Coupled Plasma Mass Spectrometry (ICP/MS, GC/ICP/MS), Liquid Chromatography Mass Spectrometry (LC/MS), Tandem Mass Spectrometry (MS/MS), HRMS with EI, CI, DEI and DCI, Field Desorption Mass Spectrometry (DCI/MS), Liquid Secondary Ion Mass Spectrometry (LSI/MS), Secondary Ion Mass Spectrometry (TOF-SIMS), MALDI, MALDI-TOF Spectrometry, Thermal desorption (TD) GC-MS, Headspace GC-MS, Pyrolysis GC-MS, Gel-permeation chromatography (GPC-MS) and Accelerator Mass Spectrometry (AMS).