A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity

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Abstract

The synthesis of pharmaceutical products frequently involves the use of reactive reagents and the formation of intermediates and by-products. Low levels of some of these may be present in the final drug substance and drug product as impurities. Such chemically reactive impurities may have at the same time the potential for unwanted toxicities including genotoxicity and carcinogenicity and hence can have an impact on product risk assessment. This paper outlines a procedure for testing, classification, qualification, toxicological risk assessment, and control of impurities possessing genotoxic potential in pharmaceutical products. Referencing accepted principles of cancer risk assessment, this document proposes a staged threshold of toxicological concern (TTC) approach for the intake of genotoxic impurities over various periods of exposure. This staged TTC is based on knowledge about tumorigenic potency of a wide range of genotoxic carcinogens and can be used for genotoxic compounds, for which cancer data are limited or not available. The delineated acceptable daily intake values of between ∼1.5 μg/day for ∼ lifetime intake and ∼120 μg/day for ⩽1 month are virtually safe doses. Based on sound scientific reasoning, these virtually safe intake values do not pose an unacceptable risk to either human volunteers or patients at any stage of clinical development and marketing of a pharmaceutical product. The intake levels are estimated to give an excess cancer risk of 1 in 100,000 to 1 in a million over a lifetime, and are extremely conservative given the current lifetime cancer risk in the population of over 1 in 4 (http://seer.cancer.gov/statfacts/html/all.html). The proposals in this document apply to all clinical routes of administration and to compounds at all stages of clinical development. It is important to note that certain types of products, such as those for life-threatening indications for which there are no safer alternatives, allow for special considerations using adaptations of the principles outlined in this paper.

Introduction

Residual impurities resulting from manufacturing and formulation, or from degradation of the active pharmaceutical ingredient (API)1 and excipients, may be present in pharmaceutical products. A subset of these impurities may present a potential for genotoxicity and therefore pose an additional safety concern to clinical subjects and patients.

The pharmaceutical industry and those that regulate it recognize their respective obligation to limit genotoxic impurities. Therefore, substantial efforts are made during development to control all impurities at safe concentrations. However, the effort made to limit impurities must be commensurate with the risk assessed at each phase of clinical development, taking into account the extent of the hazard, the disease indication, the size and characteristics of the exposed population, and the duration of that exposure, as well as the likely delay in the availability of beneficial medicines if the burden of limiting or controlling impurity levels is disproportionate. A balance of these considerations can be described best as the “as low as reasonably practicable” (ALARP)2 principle.

It follows that the presence of impurities with genotoxic (mutagenic3) potential may be unavoidable in clinical trial and ultimately in approved and marketed materials. ICH Guideline Q3A(R), 2002, ICH Guideline Q3B(R), 2003, ICH Guideline Q3C, 1997. However, no specific guidance for determining acceptable levels for genotoxic impurities is provided in these documents other than to recognize the fact that unusually toxic impurities may require tighter limits of control. Toxicological assessment and justifications of limits per these ICH guidelines are normally based on the qualification of representative batches of the API including its impurities in pivotal toxicity studies that include genetic toxicology tests. The European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) has issued a Draft Guideline on the Limits of Genotoxic Impurities, which describes an approach for assessing genotoxic impurities of unknown carcinogenic potential or potency based on the TTC4 concept (CHMP, 2004). The proposals detailed in this paper extend the CHMP approach to include the concept of a staged TTC that establishes allowable daily intakes of impurities based upon duration of exposure. It should be noted, however, that the CHMP draft document attempts to provide guidance to industry on how to address specifications for impurities possessing genotoxic potential in marketing applications for new drug products and does not consider how such impurities should be handled in the exploratory stage of drug development, i.e., for clinical trial materials.

This paper describes a process for testing, classifying, and controlling of such impurities in a way that balances therapeutic benefit with the potential risks associated with a medicinal product and concomitant levels of potentially mutagenic impurities. The process seeks to establish rational acceptance criteria that take into account the stage of clinical development, the duration of a clinical trial, subject safety, and the feasibility of adequately sensitive analytical methods. In the early stages of clinical development process and impurity information is limited and hence the emphasis is placed on known reagents, intermediates, and reaction products in the synthetic process. Both structurally identified impurities (those for which the chemical structure is known) and readily predicted impurities (those that a technical review of the synthetic process suggests might be present) are assessed and classified. After impurities are classified, acceptance criteria for impurity levels are set based on structural analysis, data from genotoxicity testing, and by using a conservative risk-based approach based on the staged TTC. Since genotoxicity data are normally not suitable for a quantitative risk assessment, the (staged) TTC is based on animal carcinogenicity data and the knowledge about correlations between genotoxic processes and carcinogenesis for a substantial number of carcinogens.

Section snippets

Considerations on testing of impurities for genotoxic potential

The general framework for genotoxicity testing of pharmaceuticals is given in two internationally agreed ICH safety guidelines (ICH S2A, 1995, ICH S2B, 1997). One of these guidelines (ICH S2B, 1997) describes the standard battery of tests for genotoxicity for drug substance, which consists of:

  • (i)

    A test for gene mutation in bacteria.

  • (ii)

    An in vitro test with cytogenetic evaluation of chromosomal damage in mammalian cells or an in vitro mouse lymphoma tk assay.

  • (iii)

    An in vivo test for chromosomal damage in

Qualification of impurities

The relevant ICH guidelines concerning the qualification of impurities in commercial manufacture are Q3A(R) and Q3B(R) that focus on impurities in drug substances and drug products, respectively, while Q3C recommends limits for residual solvents in the drug product. The guidance given in these regulatory documents is considered to be applicable at the time of registration of a new pharmaceutical entity. The first two guidelines describe threshold levels above which impurities are required to be

Balancing toxicologically driven genotoxic impurity limits with generally acknowledged and achievable quality goals

One of the critical quality-related attributes of the drug substance and drug product is the impurity profile, which needs to be controlled according to certain specified concentrations. The presence of a small amount of an impurity will result in a low concentration when dispersed in a large amount of drug substance, thereby posing significant testing and manufacturing challenges. Conversely, unacceptably high concentrations of the impurity may result if the same amount of impurity is

Conclusions

The control of impurities bearing a genotoxic potential in pharmaceutical products has received more and more attention over the past years. The inherent difficulties of true or hypothesized linear dose effect relationships have led to diverse strategies and risk calculations to achieve a rational level of control. Hence, a unified approach for pharmaceutical product development and marketing would be useful. The ultimate risk concern for genotoxicants is carcinogenicity but carcinogenicity

Acknowledgments

The input of various colleagues from the pharmaceutical industry at large and in particular of members of the PhRMA Drusafe Genotoxicity subgroup is acknowledged. The authors wish also to acknowledge Janice Fiori and Joel Bercu (Eli Lilly and Company) for their important contributions to development of the risk assessment methodology and the ADI approach for mutagenic compounds.

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