Regulating impurities in pharmaceutical products: a tolerability of risk approach?

This paper explores the implications of the EMEA guideline EMEA/CHMP/QWP/251344/2006 for pharmaceutical risk decisions. The guidelines propose to consider the intake of 1.5 µg/day of a genotoxic impurity as a ‘threshold of toxicological concern’, and to treat this level as an acceptable risk (excess cancer risk of <10^-5 over a lifetime). The guidance document also introduces a specific decision-tree to assess the acceptability of genotoxic impurities. According to this decision-tree, when the presence of genotoxic impurities is unavoidable, their levels should be reduced ‘as low as reasonably practicable’ (ALARP). In the UK, the Health and Safety Executive has developed a ‘tolerability of risk’ (ToR) model to support ALARP requirements. The paper compares the EMEA risk-reduction requirements and the ToR model. EMEA/CHMP/QWP/251344/2006 introduces a risk-avoidance principle based on a controversial interpretation of ‘pollution control’. The paper supports the view that this model is not optimal from a risk-management point of view. Using a ToR model could bring improvements to pharmaceutical risk decisions and would support a more practical and consensual approach to meeting the ALARP requirements.     

Progress in QSAR toxicity screening of pharmaceutical impurities and other FDA regulated products

Active ingredients in pharmaceutical products undergo extensive testing to ensure their safety before being made available to the American public. A consideration during the regulatory review process is the safety of pharmaceutical contaminants and degradents which may be present in the drug product at low levels. Several published guidances are available that outline the criteria for further testing of these impurities to assess their toxic potential, where further testing is in the form of a battery of toxicology assays and the identification of known structural alerts. However, recent advances in the development of computational methods have made available additional resources for safety assessment such as structure similarity searching and quantitative structure-activity relationship (QSAR) models. These methods offer a rapid and cost-effective first-pass screening capability to assess toxicity when conventional toxicology data are limited or lacking, with the potential to identify compounds that would be appropriate for further testing. This article discusses some of the considerations when using computational toxicology methods for regulatory decision support and gives examples of how the technology is currently being applied at the US Food and Drug Administration.     

基因毒性杂质的毒理学评估策略

基因毒性杂质的限度确定是药物安全研究的重要内容.有潜在基因毒性的杂质根据其结构特征和毒理学数据可分为5类:已知有致突变性及致癌性的杂质、有致突变性但致癌性未知的杂质、含有与药物活性成分结构无关的警示结构但无致突变性数据的杂质、含与药物活性成分相关警示结构的杂质以及致癌风险高的特殊杂质.本文以毒理学评价的方法,分类对基因...     

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.     

Toxicological overview of cigarette smoking on angiogenesis

Angiogenesis is the process of generating new capillary blood vessels. It occurs under tight regulation in the female reproductive system, during wound healing and during embryogenesis. Angiogenesis also plays an important role in the pregnancy-associated changes in the reproductive tract. Cigarette smoke inhibits processes that may hinder normal process of angiogenesis resulting in abnormal blood supply to tissues, decreased repair and remodeling. This report summarizes the evidences of the causal association between tobacco smoking and disruption of angiogenesis. Application of small amount of nicotine on day 5 old chorioallantoic membranes (CAMs) did not disrupt the process of angiogenesis, while application of mainstream smokes (MSS) solutions to CAMs caused varying levels of disruption on normal process of angiogenesis and adversely affect capillary plexus formation, diameters of secondary and tertiary vessels. We have also observed that at equivalent doses, sidestream smoke (SSS) can significantly be more potent than MSS and can alter the normal process of angiogenesis more drastically than MSS. It suggests that SSS either contains a toxicant(s) not present in MSS or that the toxicant(s) that produces these effects is present in higher concentration in SSS than in MSS. Therefore, it is undisputed that smoking can interfere the normal process of angiogenesis, which is a vital process to maintain pregnancy and development of fetus. Smoking during pregnancy is harmful to fetal development and is associated with an increased risk of miscarriage, perinatal death and sudden infant death syndrome. Smoking-cessation programs remain a crucial strategy for preventing poor birth outcomes and decreasing the social and financial costs of smoking during pregnancy.     

Toxicological data on NOx: an overview

This overview is based on experimental and epidemiological studies of NOx toxicity during the past decade. Approximately 130 published studies are cited and about one-fourth of these are discussed briefly under one of the following headings: acute and subacute studies, chronic low-level studies, human studies, and special studies. The latter section examines a selection of comparatively unique investigations, including several devoted to the pulmonary uptake and retention of NO2, and several examining the potential tumorigenicity of NO2. For each major section of the overview, a critical evaluation is attempted in terms of the impact of the appropriate studies on the extant NOx toxicological data base and on the current and planned air quality standards for NOx.     

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.     

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.     

替格瑞洛中7个异构体的毒理评价及含量测定研究

目的 研究替格瑞洛中7个异构体的毒理性质,并建立高效液相色谱法对7个异构体的含量进行测定。方法 通过ADMET Predictor软件分析7个异构体的毒理性质,构建7个异构体的统一检验分析方法,并通过该方法对179批次样品的异构体含量进行测定。结果 替格瑞洛片中部分异构体存在肝脏毒性及小鼠致癌的可能性;建立的检验方法可以准确测定各异构体的含量且各异构体间分离度符合要求,179批次样品中7个异构体的含量均符合规定。结论 该系列异构体毒性预测均较小,但其实际效果需具体试验论证,该检验方法能系统地鉴别和测定各异构体的类型和含量,为统一替格瑞洛检验方法提供了重要的参考。     

Eliminating pharmaceutical impurities: Recent advances in detection techniques

The elimination of organic impurities to produce highly pure drug substances is an important goal of process chemistry. For the detection of general impurities, hyphenated techniques (eg, liquid chromatography-mass spectrometry [LC-MS]) play a critical role in rapid structural identification (qualitative detection) and in understanding the mechanisms of formation of the impurities, enabling informed decisions to control and eliminate the impurities resulting from the chemical process where possible. Concern regarding genotoxic impurities (GTIs), which must typically be controlled at low parts-per-million limits, continues to increase, and significant advances have been achieved in recent years for the selective and sensitive quantitation (quantitative detection) of such impurities. Conventional detection techniques, such as ultraviolet (UV) detection, are often inadequate for the detection of potentially minute quantities of GTIs; therefore, various advanced MS-based detection strategies, either stand-alone or in conjunction with chemical approaches, are playing an increasing role in this field. The primary aim of this review is to highlight recent advances in qualitative and quantitative detection of impurities at trace levels, with a particular focus on GTIs.     

Determination of cobalt in pharmaceutical products

The aim of this paper is to determine the content of cobalt in pharmaceutical products (B(12) vitamin powder, B(12) ampoules, Centrum, Spectrum ABC and Optima Forte) by spectrometric (FAAS, GFAAS and ICP-AES) and electrometric (AdSV) analytical techniques. The samples (approximately 0.5g) were treated with a mixture of 6mL HNO(3) and 1mL H(2)O(2) in the microwave oven. Due to the matrix effects the method of standard addition is preferred. The validity of the methods was tested by recovery studies of standard addition and results were found to be satisfactory.     

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.