The production of pharmaceuticals is tightly regulated. US and European Pharmacopeia lay down the law: Raw products, intermediates and final pharmaceutical products must be analyzed for Organic Volatile Impurities (OVIs), the technique mainly used is Headspace GC.
The conventional GC method used for the European pharmacopoeia analysis typically requires a 35 minute GC run time. When the Pfizer R&D Dept. in Sandwich, U.K. started looking into whether the analysis could be accelerated, they turned to the Research Institute for Chromatography (RIC) of Professor Pat Sandra. The result of the cooperation has now been published and it shows that the method can be accelerated significantly.

For the OVI determination, Pfizer was using a GC 6890 from Agilent Technologies equipped with a split/splitless inlet and a Flame Ionization Detector (FID). The column used was a DB 624, 30 meters long, 320 µm i.d. with 1 µm film thickness. This column meets the requirements of the EU- and US Pharmacopoeia, enabling good separation of all listed polar and non-polar solvents. The separation takes around 35 minutes, not counting the cool down time which in turn adds between 5 and 10 minutes depending on the ambient temperature in the laboratory.

The aim was to shorten the GC cycle time, improving throughput and productivity, without changing the basic method. The RIC added a Modular Accelerated Column Heater (MACH) from GERSTEL to the GC 6890. MACH enables mounting of up to 4 column modules with standard capillaries on the GC. MACH can be programmed to heat the column at rates of up to 1800 °C/min. Cool-down of the column from 240 auf 40 °C is achieved in 30 to 60 seconds depending on the column length.

MACH is based on Low Thermal Mass (LTM) technology. Unlike standard GC ovens, MACH column modules provide freedom from insulation materials, freedom from metal plates and freedom from large volumes of air, all of which need to be heated and/or cooled over the course of a temperature programmed analysis cycle. MACH enables significantly shorter GC cycles and higher throughput. MACH is controlled from Agilent Technologies’ ChemStation software.

Upgrade your GC in less than 30 minutes.

The GC 6890 was upgraded by replacing the standard oven door with a MACH system that can hold up to four modules. After about 30 minutes, MACH had been installed and the GC reconfigured and ready to run. Column modules were mounted on the outside of the GC using an opening in the MACH GC oven door. During then run, the GC oven is kept isothermally at high temperature. This means that no special accessories or connectors are required to keep the column ends and connectors heated, minimizing system complexity. Not having to cycle the GC oven temperature provides energy savings. No heating energy is expended to repeatedly heat the oven to high temperatures. This in turn means that less heat is released to the lab environment and subsequently that less energy is required for Air Conditioning in the summer.

For the task at hand, the RIC chose a MACH module with a column that was shorter and with smaller internal diameter than the one originally used by Pfizer: 25 meters long, 180 µm I.D. and a DB 624 stationary phase with film thickness 1 µm. This column provides more efficiency per unit length of column as well as enhanced speed of separation. The improvement was significant: Separation of a 20 solvent mixture was achieved in approximately 2.7 minutes – with good sensitivity, reproducibility, and linearity over a wide concentration range. Thanks to the ultra-short cool-down, the cycle time was reduced to 4 minutes.

Click to enlarge Separation of a 20 component solvent mixture in 2.7 minutes – including high-boiling solvent DMAC. Using MACH, the cycle time could be reduced to 4 minutes.		Click to enlarge Enlarged view: Separation of a 20 component solvent mixture

List of solvents with retention times (min), standard deviations (min) and relative standard deviations (%) of the retention times. Additionally, relative standard deviations are listed for the peak areas obtained using a System Suitability Test mix (6 µg/mL test mix in DMAC, n=6, RSD% for the raw peak areas). Limits of Detection (% w/w) are listed based on S/N=3 in addition to the linearity achieved (r²) for a three point calibration curve spanning concentrations 6, 25 und 100 µg/mL.

Source: J. Sep. Sci. 2006, 29, 695 – 698 / GERSTEL GmbH & Co. KG

Lam, Guidelines of the International Conference on Harmonisation, document Q3C (Impurities: Guidelines for Residual Solvents),
www.ich.org/cache/compo/276-254-1.html

United States Pharmacopoeia, Organic Volatile Impurities <467>, Methods I, IV and V, 2002.

European Pharmacopoeia, Section V.3.3.9-2, Residual Solvents, System A, 2002.
P. Sandra, F. David and R. Szücs, Trends in Analytical Chemistry (TraC), 21 (2002) 662-671.

F. David, D. R. Gere, F. Scanlan and P. Sandra, J. Chromatogr. A 842 (1999) 309.

Method Translation Software, can be obtained as freeware from Agilent Technologies, Santa Clara, USA,
www.chem.agilent.com/cag/main.html#mxlator

E. B. Overton and K. R. Carney, Trends in Analytical Chemistry (TrAC), 13 (1994) 258-262.
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J. C. Luong, R. L. Gras, H. J. Cortes and R. M. Mustacich,Lecture presented at 27th International Symposium on Capillary Chromatography, May 31-June 4, 2004, Riva del Garda, Italy, plenary lecture 11.

R. M. Mustacich, J. F. Everson, J. P. Richards, R. L. Gras, and J. C. Luong, Poster presented at 27th International Symposium on Capillary Chromatography, May 31-June 4, 2004, Riva del Garda, Italy, Poster I 19.