Robustness evaluation of analytical procedure for the determination of residual solvent in [11C]-PK11195 using fractional factorial design

Carbon-11 labeled (Fig.1) N-butan-2-yl-1-(2-chlorophenyl)-N-methylisoquinoline-3-carboxamide ([11C]PK11195) is used as a positron emission tomography (PET) radiopharmaceutical for neuroinflammatory imaging.1 During the production process of [11C]PK11195 organic solvents (acetone, ethanol, acetonitrile and dimethyl sulfoxide) can be used and their complete removal in the final product is practically impossible, which can cause toxic effects if above acceptable concentration limits. A quality control in radiopharmaceuticals is needed to ensure patient safety and meet regulatory expectations.2 The procedure applied to control residual solvents must be validated. Robustness is a parameter that has been evaluated in validation studies, which has been defined as the capacity of an analytical procedure to produce unbiased results in the presence of small changes in the experimental conditions.3 This work aimed to robustness evaluation of analytical procedure based on gas chromatography (GC-FID) for the determination of residual solvent in [11C]-PK11195 using 2??(6−2) fractional factorial design. Six variables were studied: carrier gas flow (mL/min), time held at initial temperature (min), temperature gradient (°C/min), injection split rate, injection type (automatic or manual) and initial temperature (°C). Four types of response were monitored: time of analysis, resolution between the ethanol and acetonitrile peaks, retention time and concentration. The 2??(6−2) fractional factorial design was an appropriate chemometric tool, because it allowed determining the significance of all main effects without confounding between them. The results indicated that the procedure presents restrictions related to the injection type; in this way, special attention should be given to this step.