Elemental Impurities in Pediatric Calcium Carbonate Preparations-High Throughput Quantification and Risk Assessment.

Calcium carbonate which is extracted from the Earth in combination with other mineral impurities, is largely used in preparations for pediatric supplements. Elemental impurities in drug products pose toxicological concerns without therapeutic benefits. Thus, it is very urgent to assess the safety of chronic exposure to elements that may be present in trace amounts. In the present study, we developed high throughput ICP-MS method for the quantitative determination of 62 elemental impurities in high matric calcium carbonate samples and validated according to USP 233. Calcium carbonate preparations which state clearly used for child (including neonates, infants, toddlers and children) from 9 manufactures and two types of raw materials (light calcium carbonate and ground calcium carbonate) were investigated in terms of the content and variability of 62 elemental impurities. According to the results, ground calcium carbonate was more suitable to be used in pediatric preparations concerning elemental impurities. Parts of elemental impurities in CaCO3 preparations which are derived from the raw materials and the preparation process, may cause potential risks for children. These results indicate that it is necessary to establish a modern instrumental analysis method to evaluate and control elemental impurities in CaCO3 raw materials and preparations.

Guidelines and strategy of the International Conference of Harmonization (ICH) and its member states to overcome existing impurity control problems for antibiotics in China.

In the present report, we review the technical guidelines and principles on impurity research and control for antibiotics established by various agencies, including the International Conference of Harmonization (ICH), the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) and the China Food and Drug Administration (CFDA). Progresses with the US Pharmacopoeia (USP), the European Pharmacopoeia (EP) and the Chinese Pharmacopoeia (ChP) to control impurities in antibiotics are also presented. Next, our discussion is focused on analyzing the CFDA's requirements on impurity research and control for antibiotics, and the implementation of ICH, FDA and other technical guidelines for generic drugs impurity control in China. Existing problems are further reviewed, in order to improve the overall process for the control of antibiotic purity.

Rapid identification of illegal synthetic adulterants in herbal anti-diabetic medicines using near infrared spectroscopy.

We created a rapid detection procedure for identifying herbal medicines illegally adulterated with synthetic drugs using near infrared spectroscopy. This procedure includes a reverse correlation coefficient method (RCCM) and comparison of characteristic peaks. Moreover, we made improvements to the RCCM based on new strategies for threshold settings. Any tested herbal medicine must meet two criteria to be identified with our procedure as adulterated. First, the correlation coefficient between the tested sample and the reference must be greater than the RCCM threshold. Next, the NIR spectrum of the tested sample must contain the same characteristic peaks as the reference. In this study, four pure synthetic anti-diabetic drugs (i.e., metformin, gliclazide, glibenclamide and glimepiride), 174 batches of laboratory samples and 127 batches of herbal anti-diabetic medicines were used to construct and validate the procedure. The accuracy of this procedure was greater than 80%. Our data suggest that this protocol is a rapid screening tool to identify synthetic drug adulterants in herbal medicines on the market.

[The compatibility between packing material and ipratropium bromide aerosol].

With the establishment of HPLC and LC-MS methods to determine the related substances and the content of active pharmaceutical ingredient (API) in ipratropium bromide aerosol products, several packing material-related impurities were identified, including antioxygen BHT and antioxygen 2246. Results showed that these leachable additives from the packing materials may present at a relative high level in the drug solution, and the low content of API in the drug products is usually due to the adsorption of the packing material as well as the leaking of contents. The current available assay methods for the control of ipratropium bromide aerosol products are often lack of specificity and unable to assure the drug quality effectively. To meet the increasing attention on the regulations of drug packing materials, our research would be a pilot study, indicating that the inappropriate packing materials could cause the migration and adsorption of the active ingredients, and the importance to have compatibility studies between packing materials and drugs.

[Determination of the allergic impurities in the parenteral injection of Chinese traditional medicines containing Salvia miltiorrhiza].

The residual protein mixture (the content is 4%, approximately), called Salvia miltiorrhiza antigen, was extracted from the Salvia miltiorrhiza cruel materials by mimicking the alcohol-deposit extracts process. Both rabbits and guinea pigs sensitized by Salvia miltiorrhiza could produce specified antibodies. Large molecular antigenic impurities were extracted from the Danshen injection and Xiangdan injection using the centrifugal filtering method. The test results of active systemic anaphylaxis (ASA) and passive cutaneous anaphylaxis (PCA) in guinea pigs confirmed that the extracted antigenic impurities could induce the anaphylaxis reaction in the animals which were sensitized by the Salvia miltiorrhiza antigen. Using the specified antibody produced from rabbits which were sensitiyed by Salvia miltiorrhiza, ELISA test method was developed to test the residual Salvia miltiorrhiza antigenic materials contained in the parenteral Chinese traditional medicines. Calculated as residual protein, the linear range was 0.08-5.12 microg x mL(-1) (r2 = 0.9906), the detection limit and quantization limit are 0.08 microg x mL(-1) and 0.4 microg x mL(-1), respectively. 308 batches of parenteral Chinese traditional medicines containing water-soluable components of Salvia miltiorrhiza were tested, and the Salvia miltiorrhiza antigenic impurities were spotted in 35 (11.4%) batches of samples. The test results show that the extracting process currently used can not remove the Salvia miltiorrhiza antigenic impurities completely, and this may be one of the reasons for anaphylactic reaction in clinics. The proposed ELISA method can be used for improving the manufacture process and for routine quality control of drug products.

Development of a method for the detection of beta-lactamases in milk samples.

With the rapid growth of the dairy industry and the establishment of strict antimicrobial residue limits in the People's Republic of China's (PRC) milk supply, a beta-lactamase product known as "antimicrobial destroyer" was introduced into dairy production without regulatory review. We developed a method for detecting this product in milk samples based on a modified cylinder plate method. The presence of beta-lactamase is defined as a difference between the inhibitory zones of the test samples (supplemented with 25 microg/mL sulbactam plus 0.5 microg/mL penicillin G) and control samples (supplemented only with 0.5 microg/mL penicillin G) > or = 3 mm. Using this method, 77 individually packaged milk samples were randomly collected from 5 retail stores in 3 cities over a 4-month period (May to August 2006). Of the 77 samples, 49 were found to be beta-lactamase-positive. In 2 undiluted milk samples showing extremely high beta-lactamase activity, 25 microg/mL sulbactam could not inhibit penicillin G activity. Because there is a lack of safety data on beta-lactamases in milk products, these data indicated a potentially serious safety concern for the dairy industry in the PRC.