Toxicological overview of impurities in pharmaceutical products

While the use of pharmaceuticals is always a balance of risks and benefits, the same is not true for impurities in pharmaceuticals; impurities convey only risk. A number of international guidelines and regional guidances instruct drug developers and regulatory agencies on how to evaluate and control impurities in drug substances and drug products. While impurities should always be reduced to the lowest levels that are reasonably practical, it is acknowledged that impurities cannot be reduced to zero and specifications for impurities need to be established. This chapter discusses practical and theoretical methods for qualification of different classes of impurities.     

创新性化学药物杂质研究目的、思路与技术要求

权衡杂质风险和水平一直是创新药物关注的重点,国内外相应指导原则对创新药物的杂质都有相关指导原则予以阐述.众所周知,杂质不可能完全消除,只能在实际生产和技术审评中,将杂质控制在尽可能低的水平,以保证药品的安全性.本文结合杂质研究指导原则,对创新药物杂质研究的思路和技术要求进行了探讨.     

The determination of chlorpromazine, related impurities and degradation products in pharmaceutical dosage forms

The literature relating to the determination of chlorpromazine, related impurities and degradation products in pharmaceutical preparations is reviewed. Related impurities and degradation products are defined and official methods of analysis are described. Analytical methods including gravimetric, titrimetric ultraviolet-visible spectrophotometric, chromatographic and electrochemical techniques are discussed.     

2008年上半年美国FDA批准的新药

2008年上半年,美国FDA共批准了7个新分子实体和2个新生物制剂。本文按获批时间,就这些新药情况作一简要介绍。1新分子实体1.1依曲韦林(etravirine/Intelence)Tibotec制药公司开发,2008年1月18日经优先审批程序获得批准,用于联用其它抗逆转录病毒药物治疗已经在先抗逆转录病毒疗     

Mineral oil in food,cosmetic products,and in products regulated by other legislations

Abstract

For a few years, mineral oils and their potential adverse health effects have been a constant issue of concern in many regulatory areas such as food, cosmetics, other consumer products, and industrial chemicals. Analytically, two fractions can be distinguished: mineral oil saturated hydrocarbons (MOSH) and mineral oil aromatic hydrocarbons (MOAH). This paper aims at assessing the bioaccumulative potential and associated histopathological effects of MOSH as well as the carcinogenic potential of MOAH for consumer-relevant mineral oils. It also covers the absorption, distribution, metabolism, and excretion of MOSH and MOAH upon oral and dermal exposures. The use and occurrence of consumer-relevant, highly refined mineral oils in food, cosmetics and medicinal products are summarized, and estimates for the exposure of consumers are provided. Also addressed are the challenges in characterizing the substance identity of mineral oil products under REACH. Evidence from more recent autopsy and biopsy studies, along with information on decreasing food contamination levels, indicates a low risk for adverse hepatic lesions that may arise from the retention of MOSH in the liver. With respect to MOAH, at present there is no indication of any carcinogenic effects in animals dermally or orally exposed to highly refined mineral oils and waxes. Such products are used not only in cosmetics but also in medicinal products and as additives in food contact materials. The safety of these mineral oil-containing products is thus indirectly documented by their prevalent and long-term use, with a simultaneous lack of clinical and epidemiological evidence for adverse health effects.     

In vitro and in silico genetic toxicity screening of flavor compounds and other ingredients in tobacco products with emphasis on ENDS

Electronic nicotine delivery systems (ENDS) are regulated tobacco products and often contain flavor compounds. Given the concern of increased use and the appeal of ENDS by young people, evaluating the potential of flavors to induce DNA damage is important for health hazard identification. In this study, alternative methods were used as prioritization tools to study the genotoxic mode of action (MoA) of 150 flavor compounds. In particular, clastogen-sensitive (γH2AX and p53) and aneugen-sensitive (p-H3 and polyploidy) biomarkers of DNA damage in human TK6 cells were aggregated through a supervised three-pronged ensemble machine learning prediction model to prioritize chemicals based on genotoxicity. In addition, in silico quantitative structure-activity relationship (QSAR) models were used to predict genotoxicity and carcinogenic potential. The in vitro assay identified 25 flavors as positive for genotoxicity: 15 clastogenic, eight aneugenic and two with a mixed MoA (clastogenic and aneugenic). Twenty-three of these 25 flavors predicted to induce DNA damage in vitro are documented in public literature to be in e-liquid or in the aerosols produced by ENDS products with youth-appealing flavors and names. QSAR models predicted 46 (31%) of 150 compounds having at least one positive call for mutagenicity, clastogenicity or rodent carcinogenicity, 49 (33%) compounds were predicted negative for all three endpoints, and remaining compounds had no prediction call. The parallel use of these predictive technologies to elucidate MoAs for potential genetic damage, hold utility as a screening strategy. This study is the first high-content and high-throughput genotoxicity screening study with an emphasis on flavors in ENDS products.     

Improving the detection of degradants and impurities in pharmaceutical drug products by applying mass spectral and chromatographic searching

Liquid chromatography/mass spectrometry (LC/MS) and NMR are commonly used to identify metabolites, impurities and degradation products in the pharmaceutical industry. To more efficiently deal with the large volumes of data these techniques generate, software programs have been developed by various vendors to assist in the identification of these compounds through the use of spectral and chromatographic search algorithms. The feasibility of using such programs for detecting drug degradants and impurities is assessed. A number of compounds encompassing a wide range of both chemical and pharmaceutical properties were tested using LC/UV/MS and the spectral/chromatographic search algorithm MetaboLynx (Micromass UK Ltd.) to determine the feasibility of detecting analytes at low concentrations. In addition, drug product and stressed drug substance samples containing quinapril hydrochloride, the active ingredient in Accupril tablets, were determined by liquid chromatography with atmospheric pressure ionization-time-of-flight (API LC-TOF) and an API LC-quadrupole (Q) mass spectrometer, and the resulting data was processed using MetaboLynx. The ability of this program to detect and list a variety of analytes known to be present in the samples was evaluated. The combination of LC/UV, LC/MS and spectral/chromatographic searching is a valuable tool for the detection of impurities at low levels.     

肝素等专利权属纠纷案给我们的启示

随着国民专利保护意识的逐步增强,我国专利申请的数量逐年上升,质量逐步提高,但与此同时,专利纠纷的发生率也逐年上升。本人认为,企业在处理好这些纠纷、避免损失的同时,更重要的是要从中吸取教训,以免重蹈覆辙。     

Control and analysis of hydrazine, hydrazides and hydrazones--genotoxic impurities in active pharmaceutical ingredients (APIs) and drug products

This is the latest of a series of reviews focused on the analysis of genotoxic impurities. This review summarises the analytical approaches reported in the literature relating to hydrazine, hydrazines, hydrazides and hydrazones. It is intended to provide guidance for analysts needing to develop procedures to control such impurities, particularly where this is due to concerns relating to their potential genotoxicity. Of particular note is the wide variety of techniques employed, both chromatographic and spectroscopic, with most involving derivatisation. Such a wide variety of options allow the analyst a real choice in terms of selecting the most appropriate technique specific to their requirements. Several generic methodologies, covering the three main analytical approaches; i.e. HPLC (high performance liquid chromatography), GC (gas chromatography) and IC (ion chromatography), are also described.     

An FDA review of sulfamethazine toxicity

Recently, changes have been proposed in the criteria historically used in the evaluation of the applicability to humans of some of the results obtained from the rodent carcinogenicity bioassay data. These questions center on the suitability of the rodent model for agents that exert their toxic effects via specific enzyme interactions and endocrine mechanisms which appear to be inoperative within humans. Within the U.S. Food and Drug Administration (FDA), this issue has been brought to the forefront of concern with the recent application for a New Animal Drug Application for sulfamethazine (SMZ). A panel of FDA experts from the National Center for Toxicological Research (NCTR), the Center for Veterinary Medicine (CVM), and the Center for Food Safety and Applied Nutrition has reviewed the sum of the scientific evidence available on the toxicology of SMZ. They noted that, in previous feeding studies at NCTR, high doses of SMZ were associated with significant incidences of thyroid tumors in mice and rats. The panel also notes that the tumorigenic activity of SMZ in rodents was due to its goitrogenic activity, resulting in constant stimulation of the thyroid by TSH. Humans, on the other hand, were found to be insensitive to the SMZ-like inhibition of thyroid function. Further, apart from X-irradiation and radioactive iodine, there are no other physical or chemical agents known to cause thyroid tumors in humans. Thus, the expert panel concludes that the best scientific information available indicates that elevated levels of TSH and the consequent thyroid tumors would not be produced under approved use conditions of SMZ. This conclusion is in agreement with recommendations made by three other panels, viz. the World Health Organization, the U.S. Environmental Protection Agency, and CVM, which also evaluated the public health risk of SMZ.     

FDA toxicity databases and real-time data entry

Structure-searchable electronic databases are valuable new tools that are assisting the FDA in its mission to promptly and efficiently review incoming submissions for regulatory approval of new food additives and food contact substances. The Center for Food Safety and Applied Nutrition's Office of Food Additive Safety (CFSAN/OFAS), in collaboration with Leadscope, Inc., is consolidating genetic toxicity data submitted in food additive petitions from the 1960s to the present day. The Center for Drug Evaluation and Research, Office of Pharmaceutical Science's Informatics and Computational Safety Analysis Staff (CDER/OPS/ICSAS) is separately gathering similar information from their submissions. Presently, these data are distributed in various locations such as paper files, microfiche, and non-standardized toxicology memoranda. The organization of the data into a consistent, searchable format will reduce paperwork, expedite the toxicology review process, and provide valuable information to industry that is currently available only to the FDA. Furthermore, by combining chemical structures with genetic toxicity information, biologically active moieties can be identified and used to develop quantitative structure-activity relationship (QSAR) modeling and testing guidelines. Additionally, chemicals devoid of toxicity data can be compared to known structures, allowing for improved safety review through the identification and analysis of structural analogs. Four database frameworks have been created: bacterial mutagenesis, in vitro chromosome aberration, in vitro mammalian mutagenesis, and in vivo micronucleus. Controlled vocabularies for these databases have been established. The four separate genetic toxicity databases are compiled into a single, structurally-searchable database for easy accessibility of the toxicity information. Beyond the genetic toxicity databases described here, additional databases for subchronic, chronic, and teratogenicity studies have been prepared.     

The acute oral toxicity of 369 pesticidal, pharmaceutical and other chemicals to wild birds

The acute po toxicity of 369 chemicals was determined for 1 or more species of wild birds, always including either red-winged blackbirds or starlings. Of these, 180 chemicals were toxic to 1 or more species at 100 mg/kg or less. Statistical comparison of redwing, starling and rat data indicated that redwings were more sensitive to chemicals than starlings, and both were more sensitive than rats.     

Determination of impurities in pharmaceutical preparations containing folic acid

In the presented study, the HPLC method was used for the determination of impurities (p-aminobenzoic acid and p-aminobenzoyl-L-glutamic acid) in single-component pharmaceutical products containing folic acid. The determination was performed using a spectrophotometric detector at lambda = 269 nm wavelength.     

Recent advances in trace analysis of pharmaceutical genotoxic impurities

Genotoxic impurities (GTIs) in pharmaceuticals at trace levels are of increasing concerns to both pharmaceutical industries and regulatory agencies due to their potentials for human carcinogenesis. Determination of these impurities at ppm levels requires highly sensitive analytical methodologies, which poses tremendous challenges on analytical communities in pharmaceutical R&D. Practical guidance with respect to the analytical determination of diverse classes of GTIs is currently lacking in the literature. This article provides an industrial perspective with regard to the analysis of various structural classes of GTIs that are commonly encountered during chemical development. The recent literatures will be reviewed, and several practical approaches for enhancing analyte detectability developed in recent years will be highlighted. As such, this article is organized into the following main sections: (1) trace analysis toolbox including sample introduction, separation, and detection techniques, as well as several ‘general’ approaches for enhancing detectability; (2) method development: chemical structure and property-based approaches; (3) method validation considerations; and (4) testing and control strategies in process chemistry. The general approaches for enhancing detection sensitivity to be discussed include chemical derivatization, ‘matrix deactivation’, and ‘coordination ion spray-mass spectrometry’. Leveraging the use of these general approaches in method development greatly facilitates the analysis of poorly detectable or unstable/reactive GTIs. It is the authors’ intent to provide a contemporary perspective on method development and validation that can guide analytical scientists in the pharmaceutical industries.     

取代苯酚和苯胺类化合物的QSAR毒性研究

目前定量结构-活性相关性（QSAR）研究在国际上已成为一个相当活跃的研究领域，是环境化学、药物化学、计算机化学及农业化学中的一个前沿课题，国内学者对此研究也取得了较好的结果。取代苯酚和苯胺类化合物对生物的毒性较大，我们以其为研究对象，对方法进行修正，建构了拓扑指数^mT，并研究了^mT与取代苯酚和苯胺的理化参数及毒性的相关性，取得了等于或优于文献的结果。