Teva Active Pharmaceutical Ingredients - Control of genotoxic impurities as a critical quality attribute

Teva Active Pharmaceutical Ingredients supplies APIs to nearly 1,000 customers in over 100 countries. With large-scale investment in R&D, 15 new products, on average, are generated each year. Efforts are being made by TAPI to control impurities to assure the safety of the pharmaceutical products, read on to learn more about the process.

For the past few years, identification and control of genotoxic impurities in pharmaceutical products have become key issues globally in the development and commercialisation of products. Since some of these impurities may cause mutations, and potentially a cancer, there are efforts to avoid and/or keep them to minimal levels, to limit the potential carcinogenic risks, and ensure the safety of the products. Consequently, drug developers and drug producers, including API suppliers, are investing vast resources in assessment of potential impurities in their products, and in developing analytical methods to determine and control toxicity to assure compliance of their products with the relevant health regulations.

Genotoxic impurities in pharmaceutical products

Impurities in pharmaceutical products result from synthesis and/or subsequent degradation, and so impurities cannot be avoided completely. Impurities are defined as substances that yield no therapeutic benefit, but have the potential to cause adverse effects. Thus, impurity levels in the products must be controlled to ensure safety. Some of the impurities are genotoxic and may cause deleterious changes in the genetic material of cells. The genotoxic compounds, which have a potential to directly damage DNA through chemical reactions, even if present at very low levels, lead to mutations, and also potentially cause a cancer, are denominated as DNA-reactive or mutagenic. They may also act as mutagenic carcinogens. Thus, they should be controlled at levels expected to pose negligible carcinogenic risks. These levels are much lower than those for ordinary impurities. Other types of genotoxic compounds that are non-mutagenic, such as clastogens, typically have threshold mechanisms and usually do not pose any carcinogenic risks to humans at the level ordinarily present as impurities.

Tackling impurities through regulation

There are several regulatory guidelines to control impurities in pharmaceutical products. Since the guidelines for the ordinary impurities do not specify any acceptable levels for the genotoxic impurities, regulatory authorities specifically addressed this in: A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity', Muller et al, 2006; 'Guideline on the limits of genotoxic impurities', EMA, 2007; 'Questions and answers on the guideline on the limits of genotoxic impurities', EMA, 2010; 'Guidance for industry: genotoxic and carcinogenic impurities in drug substances and products: recommended approaches', FDA, 2008; 'Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic', ICH M7, 2014; and a recently published addendum to ICH M7, 2015; 'Application of the principles of the ICH M7 guideline to calculation of compound-specific acceptable intakes'.

The purpose of these guidelines is to provide a practical framework that can be applied to the identification, categorisation, qualification, and control of genotoxic impurities to help limit potential carcinogenic risks.

Toxicological assessments

All actual and potential impurities with known structures that are likely to arise during synthesis and storage of a drug substance and a drug product should be assessed for genotoxicity by literature searches for carcinogenicity and mutagenicity data. If no data are available, an assessment of structure-activity relationship (SAR) should be performed by a computational toxicology assessment (QSAR - quantitative SAR software) using one rule-based system (for example, Derek) and one statistical-based system (for example, Sarah) to identify presence of alterting structures in molecules predicting mutagenicity in bacteria. The impurities are then categorised to classes one to five (Müller's approach). Based on literature data, known mutagenic carcinogens are classified as class one, known mutagens with unknown carcinogenic potential as class two, and compounds with sufficient evidence of no mutagenic and carcinogenic effects as class five. Compounds with structural alerts, which are not related to the structure of the drug substance, are classified as class three, and those with the structural alerts related to the structure of the drug substance, which has been proved to be non-mutagenic, as class four. Compounds with no structural alerts are class five. The outcomes of the computer programs should be reviewed by experts to provide additional supportive evidence of the results. Since the bacterial mutagenicity assay is able to detect mutagenic carcinogens in rodents and humans, the positive structural alerts may be overruled by negative results of this assay. Optionally, if there are positive results from the in-vitro test in bacteria, their relevance can be further investigated using appropriate in-vivo tests.

Risk characterisation

Acceptable intakes must be set for the impurities of classes one to three, while the impurities of classes four and five are treated as non-mutagenic impurities. In cases of class one, compound-specific limits can be derived either from their rodent carcinogenic potency, if there are positive carcinogenicity data, or their non-observed effect levels, if there is evidence of a practical threshold. The compound-specific acceptable intakes can also be based on recommended values published by internationally recognised bodies, such as WHO and US EPA.

To control the genotoxic impurities without sufficient toxicological data, namely class two and three compounds, a concept of threshold of toxicological concern (TTC) has been proposed. The TTC concept defines an acceptable intake of any unstudied chemical that poses a negligible risk of carcinogenicity or other toxic effects.

This concept takes into account the fact that duration of exposure is a key factor impacting on the probability of a carcinogenic response. A daily intake of a genotoxic impurity at a level of 1.5µg a day, over a lifetime, is considered to be associated with a negligible carcinogenic risk of <10-5. Accordingly, the acceptable cumulative lifetime dose is 38.3mg - 1.5µg a day over 25,550 days. Then, if there are exposures of less than lifetime measurements, the cumulative lifetime dose is distributed over the total number of days during the exposure.

The recommended limits for daily intakes of individual genotoxic impurities are: 1.5, 10.0, 20.0 and 120.0µg a day for more than ten years to lifetime, one to ten years, one to 12 months and less than one month, respectively. However, higher intakes may be justified in some cases, for example, when human exposure is much greater from other sources, indications for severe disease, reduced life expectancy, late onset but chronic disease, or with limited therapeutic alternatives.

Options to control genotoxic impurities in APIs

The strategy for monitoring genotoxic impurities is based on understanding product and manufacturing process, and utilises risk-management principles, aimed at ensuring process performance and product quality. The impurity may be tested in the drug substance, or raw or intermediate material at, or below, the acceptable limit. Or it can be tested at an intermediate stage with a higher limit, if its fate and purge lead to the levels in the drug substance at or below 30% of the acceptable limit. If the impurity is effectively purged due to its physico-chemical properties and manufacturing process, no testing of the impurity is required.


Efforts are being made to control impurities, particularly those that are DNA-reactive and are identified by toxicity assessments, to assure the safety of the pharmaceutical products. It means extensive investment in resources, which may include the redesigning of the synthetic process to avoid introducing unsafe impurities and modification of relevant process parameters to remove or reduce such impurities to an acceptable carcinogenic risk level, and to take additional considerable measures for controlling the impurities at very low concentrations.

For more information about related issues and TAPI's approach - please find the contact details on its website provided below.

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