Compatibility of rubber stoppers for recombinant antitumor-antivirus protein injection by gas chromatography-mass spectrometry

Abstract

A simple, rapid, and sensitive gas chromatography-mass spectrometry (GC-MS) method was developed and validated for the simultaneous determination of two fatty acids, methyl hexadecanoate (MH) and methyl stearate (MS), to allow the evaluation of packaging-drug compatibility. The two migrants were quantified in selective ion-monitoring (SIM) mode, with limits of detection (LOD) of 0.0030 μg/mL and 0.0121 μg/mL. Linear calibration curves for MH and MS were obtained in the concentration ranges of 0.1011–5.0570 μg/mL and 0.2015–10.0740 μg/mL, respectively. The developed method was successfully applied to estimate the safety of the injection of recombinant antitumor-antivirus protein (RAAP). The results showed that the possible maximum daily intake was 3.0 ng and 12.1 ng for MH and MS, respectively. As these values were both below the permitted daily exposure, the migrants can be considered as having low safety risk and do not affect the quality of the injection.

Effect of Primary Packaging Material on the Stability Characteristics of Diazepam and Midazolam Parenteral Formulations

“…The compatibility of the injection of recombinant antitumor–antivirus protein and bromobutyl rubber stoppers has also been evaluated to assess the possible leaching of migrants from the stoppers to the injectable solutions. The leaching materials from bromobutyl stoppers were lower than the permitted daily exposure, indicating a safe profile for this type of elastomeric material [ 39 ]. The low leachable profile, along with the reduced benzodiazepine adsorption, makes bromobutyl elastomeric gaskets a good primary packing material for the preparation of benzodiazepine autoinjectors.…”

Methyl Esterification Combined with Gas Chromatography-Mass Spectrometry (GC-MS) for Determining the Contents of Lubricant to Evaluate the Compatibility of Chlorinated Butyl Rubber Stoppers with Liposome Injections

“…After the solution was shaken thoroughly for a while, the supernatant liquid was removed and washed three times with 20.0 mL of water each time. Finally, the obtained supernatant liquid was dried with anhydrous sodium sulfate and diluted 20 times with n-heptane to gain a sample solution 1 [ 23 ].…”

“…The chlorinated butyl rubber stoppers were treated by methyl esterification to detect whether the target analytes including methyl hexadecanoate and methyl stearate were contained. Referring to the recommendations of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines [ 24 ], the liposome injections used with the chlorinated butyl rubber stoppers were stored under the accelerated aging conditions (25°C ± 2°C, relative humidity 60% ± 10%) for 3 months to detect the amounts of methyl hexadecanoate and methyl stearate in the chlorinated butyl rubber stoppers into the liposome injections and investigate the compatibility of them [ 23 ].…”

Migration and Determination of Chloride in the Chlorinated Butyl Rubber Stopper for Freeze-Dried Powder Injections

“…Because of the numerous additives and complex ingredients in chlorinated butyl rubber stoppers, the moisture, toxic and harmful substances in chlorinated butyl rubber stoppers are likely to enter the drugs with the extension of time [2,3]. At present, the researches on chlorinated butyl rubber stoppers mainly reported the extraction medium, conditions, and analysis methods of antioxidant [4,5], vulcanizing agent [6,7], vulcanization accelerator [8,9], nitrosamine [10,11], fatty acids [12,13], polycyclic aromatic hydrocarbons (PAHs) [14,15], inorganic elements [16], et.al. As reported, chloride and bromide in rubber stoppers are determined by oxygen flask combustion-ion chromatography and oxygen flask combustion-chemical titration [17][18][19].…”