(M1530-09-62) Quantitation of Ethylene Oxide and Nitrosamines in Excipients and Pharmaceutical Products Using SIFT-MS

Purpose: Ethylene oxide (EtO), a toxic and carcinogenic impurity in polyethylene glycol, is found at high concentrations in pharmaceutical excipients. Similarly, nitrosamines are mutagenic impurities found in certain pharmaceutical products. Limits on the presence of these toxic VOCs are in place, and ultimately limiting their presence, is of utmost importance and urgency. Real-time mass spectrometry provides an attractive option for rapid testing of consumer and pharmaceutical products for extractables, leachables, impurities, contaminants, and residual solvents. Alternative methods for USP < 228 > and Polysorbate Monograph 80 for EtO analysis and USP GC < 1469 > for nitrosamine impurities are in development, using Selected-Ion Flow Tube Mass Spectrometry (SIFT-MS) coupled to a headspace autosampler, which are 10-20 fold faster than the traditional methods.

Methods: This work utilizes a Syft Technologies Voice200ultra SIFT-MS instrument operating on helium carrier gas, coupled with a GERSTEL MPS Robotic Pro autosampler. A SIFT-MS headspace method was developed, monitoring ethylene oxide, 1,4-dioxane, and acetaldehyde directly from Polysorbate 80. An EtO standard was dissolved in water and 1mL was placed in a 20mL headspace vial at 100ng/mL. 5, 10, 25, 50 and 100mg of Polysorbate 80, was then weighed into 20mL headspace vials and brought up to 1mL with water. Samples were incubated at 60°C for 10 min, prior to sampling of 2.5mL of headspace and subsequent injection into the SIFT-MS instrument. Method development for measurement of 5-8 common nitrosamines is underway from crushed tablets, using multiple headspace extraction (MHE) SIFT-MS.

Results: The measurement of ethylene oxide from excipients used in the pharmaceutical industry requires a lengthy matrix match step to isolate polyethylene glycol (PEG) from the product in question. The method also requires the use of 1g of polysorbate excipient due to the low sensitivity of traditional methodologies (GC-FID) for EtO. SIFT-MS was able to detect ethylene oxide from as little as 5mg of Tween 80. A single point external calibration of the 25mg Polysorbate 80 sample against a 100 ng/mL standard revealed the presence of 18 ng/mL EtO in 25mg of Polysorbate 80. When dissolved in 1mL or more of water, this method eliminates the need for a matched matrix, as the matrix contribution is negligible. The use of SIFT-MS for EtO measurement takes a typically two-day protocol for sample preparation and analysis and provides the same quantitative result in under two hours, including system suitability and QC checks. Experiments are ongoing to validate this procedure as an alternative method for USP < 228 >. MHE analysis of a crushed valsartan tablet demonstrated excellent comparability across a total of three quantification and qualification ions that were simultaneously acquired to ensure specific analysis of NDMA. By using a conventional area-under-the-curve quantitation approach for MHE, followed by applying the NDMA calibration, 213 ng of NDMA was found in the valsartan tablet, over double the accepted daily threshold.

Conclusion: SIFT-MS provides a faster, easier and robust option for routine quantitation of residual solvents and pharmaceutical impurities, including ethylene oxide and nitrosamines.