摘要:

In December 2002, the Safety Working Party (SWP) of the European Committee for Proprietary Medicinal Products (CPMP) published a “Position paper on the limits of genotoxic impurities”. The European Union intended to supplement a gap in the International Conference on Harmonisation (ICH) guidelines on qualification of impurities, as it was deemed that impurities with genotoxic potential were a special case not specifically covered in terms of qualification by the Q3A and Q3B guidelines. In fact, the SWP’s proposed approach follows a safety factor-based risk assessment process similar to that in ICH Guideline Q3C on limits for residual solvents, rather than a qualification process as described in ICH Q3A and B.The need to provide particular advice for the control of drug substance impurities that bear the risk of non-reversible toxicity (e.g. genotoxic impurities) is widely acknowledged. If such impurities can be shown to exert their genotoxicity via a mechanism with a threshold, then control of the impurity according to calculated permitted daily exposures (PDEs) should not pose major problems. However, in most cases, threshold mechanisms for such genotoxic impurities will not have been demonstrated. Employing conservative uncertainty factors to calculate PDEs in such cases may lead to limits that could be out of proportion to the impurity qualification limits (as per ICH quality guidelines), normally 1500 parts per million (Ü 1.5mg/1g substance), and orders of magnitude lower than exposures to genotoxins via other sources, such as diet and the environment. Alternative approaches based on the calculation of a lifetime cancer risk of 1/105or 1/106, which have been recommended for control of carcinogens in other circumstances, should be considered. This could lead to more realistic limits for genotoxic impurities, e.g. an intake of up to 1.5 μg/day for most genotoxic impurities without evidence of a threshold is considered to be toxicologically insignificant. Control of ‘suspect’ or ‘known’ potentially genotoxic impurities at such a level is important when one considers that many genotoxins present in drug substance at much higher concentrations would escape detection during standard genotoxicity testing of drug substance. Whilst a generic limit of 1.5 μg/day of an identified genotoxin may be suitable for chronic use drugs in a wide patient population, higher levels may be acceptable for shorter duration use, and in circumstances involving closely-defined patient populations, for example, where a case-specific assessment is appropriate.

ISSN:1364-9027    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

Impurities in drug substances can arise from a variety of sources during the manufacturing process, and include residues from starting materials, by-products, intermediates, reagents, ligands and catalysts, as well as degradation products arising during storage. The Safety Working Party of the European Committee for Medicinal Products for Human Use (CHMP) is currently in a process of preparing a position paper intended to provide guidance on how to define acceptable limits of those impurities in new drug substances and novel excipients which have been found to be genotoxic. According to the existing International Conference on Harmonisation (ICH) Q3A(R)Guideline on Impurities in New Drug Substances, impurity acceptance criteria should be set no higher than the level that can be justified by safety data, and should be consistent with the level achievable by the manufacturing process and the analytical capability. How can these demands be applied to impurities with genotoxic properties? In current regulatory practice, genotoxic compounds are usually considered to operate by a non-threshold mode of action and, thus, any level of exposure carries − at least theoretically − a risk. This precautious view implies that pharmaceutical measurements should be guided by the so-called ‘ALARA’ principle, i.e. where avoidance is not possible, genotoxic impurities must be kept to a level ‘As Low As Reasonably Achievable’.From a toxicological point of view, different approaches for assessing acceptable limits are suggested depending on the availability of data.For known genotoxic carcinogens, where a full genotoxicity and carcinogenicity set of data is available, risk assessment can be carried out either by applying quantitative risk assessment based on mathematical modelling or using no effect levels of the carcinogenic response modified by uncertainty factors.Forin vivogenotoxins of unknown carcinogenicity, use of a ‘no-effect-level-uncertainty-factor approach’ is justified in those (probably rare) cases where adequate data for demonstrating a threshold for genotoxic effects are available. Whether such an approach is also applicable toin vivogenotoxins with no evidence of a threshold is currently a controversial issue.For most impurities, where there may only be limitedin vitrodata available, a pragmatic approach is needed, which recognises that the presence of very low levels of genotoxic impurities might be without appreciable risk. The application of a target level for an acceptable daily intake of 1.5 μg/day for most genotoxic impurities, based on the concept of threshold of toxicological concern (TTC), is currently under discussion for this purpose. From this threshold value, a permitted level in the drug substance can be calculated based on the expected dose to the patient. A higher threshold may be justified taking into consideration duration of treatment, as well as therapeutic indication and exposed populations. On the other hand, unusually potent genotoxic and/or carcinogenic impurities may have to be excluded from the TTC approach and may need individual risk assessment.

ISSN:1364-9027    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

The Safety Working Party (SWP) of the European Committee for Proprietary Medicinal Products (CPMP) published a draft “Position paper on the limits for genotoxic impurities” in December 2002. Genotoxic impurities was a topic selected for the joint Drug Information Association (DIA)/European Medicines Agency (EMEA) meeting that was organised in London on October 27−28, 2003, to facilitate the exchange of opinion and perspective between industry and regulatory scientists. Scientific and regulatory updates were presented and discussed in the light of case studies, which are described in this article. The four cases span a range of different scenarios that can be encountered in development:candidate for life-threatening indication − an alkylating reagent used in synthesis is an impurity in the active substance;late-stage candidate for non-life-threatening chronic indication − a route change leads to a new intermediate becoming a potential impurity − as it is an isolated intermediate, worker safety data is generated and needs to be risk managed;late-stage candidate for non-life-threatening chronic indication − a mutagenic and structural-alerting starting material − the commercial route confers excellent purging; andearly-stage candidate for non-life-threatening chronic indication − considers strategic approaches for impurities with structural-alerting functionality under different scenarios (dependent upon toxicological data available, daily dosing regimen, route of delivery etc.).The outcomes of the discussions of the cases at the DIA/EMEA Workshop are presented in a separate article in this issue of the journal.

ISSN:1364-9027    

出版商:ADIS    

年代:2004

数据来源: ADIS

ISSN:1364-9027    

出版商:ADIS    

年代:2004

数据来源: ADIS

ISSN:1364-9027    

出版商:ADIS    

年代:2004

数据来源: ADIS

ISSN:1364-9027    

出版商:ADIS    

年代:2004

数据来源: ADIS

ISSN:1364-9027    

出版商:ADIS    

年代:2004

数据来源: ADIS

ISSN:1364-9027    

出版商:ADIS    

年代:2004

数据来源: ADIS

ISSN:1364-9027    

出版商:ADIS    

年代:2004

数据来源: ADIS

ISSN:1364-9027    

出版商:ADIS    

年代:2004

数据来源: ADIS