Risk Assessment Of Environment Pollution In The Productive Process Of Bulk Drugs Of Highly Sensitizing

The quality risk assessment of the manufacturing process of APIs is at the initial stage in China, with the lack of specific guidance documents and scientific methods. In recent years, many typical drug injuries have appeared in some enterprises due to the lack of the awareness of quality risk, fully illustrating the necessity of risk assessment.The workshops of APIs are generally composed of semi-closed synthesis areas and closed clean areas. The workshops are equipped with air supply and exhaust systems. Fresh air, collected by air inlets, is supplied to each operation room after filtration. The operation rooms are equipped with air outlets, and total exhaust air is evacuated to the outside through the air outlet of HVAC system. Because the highly sensitizing materials have the characteristic of easily leading to allergies, domestic and foreign GMP explicitly requires that the dedicated production areas, which can include facilities, air handling equipment and/or process equipment, should be employed in the production of highly sensitizing materials, and the air outlets of the facilities should keep away from the air inlets of HVAC system for other products, so as to prevent cross-contamination. Taking the highly sensitizing drug cephalexin and the nearest product caffeine in the same chemical industrial area an example, assess the production quality of API caffeine to lay the foundation for the quality risk assessment of manufacturing process of APIs.The environment pollution risk of highly sensitizing material cephalexin and the main raw material—7-ADCA in the production process was assessed in this subject. The analytical method was established and the environmental pollution was effectively controlled to improve the safety of the drug. The research mainly includes establishment of analytical method of cephalexin and7-ADCA in the air; establishment of analytical method of cephalexin and7-ADCA in the caffeine; the choice of the sampling location, the capture device and time; study of the risk assessment cases; assessment summary and corrective measures.1. Establishment of analytical method of cephalexin and7-ADCA in airHPLC method was established for the determination of cephalexin and7-ADCA content in the air and the methodology was validated. The results indicated that in the specified chromatographic conditions, the cephalexin peak, the7-ADCA peak and other impurities peak possessed a good separation. The blank solution doesn’t interfere with the determination. In the range of6.432～0.064μg/ml and61.5～0.615μg/ml, the peak area and concentration of cephalexin and7-ADCA showed a good linear relationship, respectively. The RSD in the precision test were less than2%, and the recovery was in the range of98.0%and102.0%(RSD%<1%). The test solution prepared within8hours was stable. So the established method was available for the determination.2. Establishment of analytical method of cephalexin and7-ADCA in caffeineHPLC method was established for the determination of cephalexin and7-ADCA residues in caffeine. The results showed that the peaks of caffeine, cephalexin,7-ADCA and other impurity had a good separation via injection of the caffeine solution and7-ADCA solution prepared by saturated cephalexin solution into HPLC, and the blank solution doesn’t interfere with the determination. In the range of0.061μg/ml-6.06μg/ml and0.64μg/ml-64.14μg/ml, the peak area and concentration of cephalexin and7-ADCA showed a good linear relationship, respectively, The RSD in the precision test were less than2%, the recovery rate was in the range of98.0%and102.0%(RSD%<1%). The test solution prepared within8hours was stable. So the established method was available for the determination.3. Choice of sampling location, collecting sample equipment and collecting sample timeAccording to the characteristics of cephalexin and caffeine manufacturing processes, the centrifugation area of sodium theophylline, the centrifugation area of the crude caffeine, the fresh air inlet of clean area, the exhaust outlet of cephalexin and the exhaust outlet of7-ADCA were determined as the optimal sampling points. By comparative analysis of data from different sampling instrument, Leibo2030Intelligent Integrated Atmospheric sampler was used to gather cephalexin and7-ADCA in the air for2h. The recovery validation indicated that the whole process included sample collection and dissolution, assay by HPLC were valid.4. Study of the risk assessment casesSamples were collected on critical control point by Leibo2030Intelligent Integrated Atmospheric sampler and the content of cephalexin and7-ADCA was determined by HPLC The result showed that the corresponding pollutants are evacuated in the exhaust outlet of the cephalexin and7-ADCA, which were monitored throughout the year to further confirm the risk of contamination. The maximum dust output in cephalexin workshop was deduced according to the test data. And through experiments, we could analyze and assess the cephalexin in caffeine. The results showed that the production of cephalexin didn’t cause pollution to caffeine, but the sensitizing material was detected in cephalexin exhaust outlet. Therefore cephalexin production can still brings potential risks to the environment and other products of the chemical area. So the effective measures should be taken to control evacuation of cephalexin and7-ADCA.5.The summary to evolution and measures to correctionTo avoid contamination to other products, cephalexin dust production step had been improved.7-ADCA was feed by automatic operation instead of manual operation, the closed feeding was implemented. And water spray device was installed in the feeding process, which could effectively prevent the spread of dust. The material transferring system in the finished product room was changed from the original cart to closed pipe conveying, a fully closed feeding manner is implemented during the whole manufacturing process, which could avoid dust dispersion to the utmost extent. After improvement, the samples in exhaust outlet of cephalexin and7-ADCA were collected and the tested, the results showed that no cephalexin or7-ADCA was detected in the exhaust outlet of cephalexin and7-ADCA, which demonstrated the corrective measures were effective and successful.