Excipient Manufacturers and Pharmaceutical Companies Raise Concerns Over Guidelines for Genotoxic Impurities

AAPS, San Antonio (Oct. 31)-Excipient manufacturers are raising concerns over recently adopted European guidelines, set to become effective January 1, 2007, which provide a framework and approach for dealing with genotoxic impurities in new active substances.

The European Medicines Agency (EMEA, London, www.emea.eu.int) issued a June 2006 “Guideline on the Limits of Genotoxic Impurities,” www.emea.europa.eu/pdfs/human/swp/519902en.pdf) to address a void in existing guidelines on the acceptable dose levels for genotoxic impurities for new drug substances authorized for marketing by the EMEA. The new guideline does not apply retrospectively to previously authorized products unless there is a specific cause for concern. The new guidelines are the first regulatory provisions to directly address genotoxic impurities.

Genotoxic compounds are usually considered as presumptive in vivo mutagens and carcinogens. In the context of the new guidelines, a compound (impurity) is classified as genotoxic when the threshold of toxicological concern (TTC) value is 1.5 µg/person/day. The TTC value was developed to define a common exposure level for any unstudied chemical that will not pose a risk of significant carcinogenicity or other toxic effects.

A TTC value of 1.5 µg/day intake of a genotoxic impurity is considered to be associated with an acceptable risk (excess cancer risk of <1 in 100,000 over a lifetime) for most pharmaceuticals. From this threshold value, a permitted level in the active substance may be calculated based on the expected daily dose. Higher limits may be justified under certain conditions, such as short-term exposures. The TTC was originally developed as a “threshold of regulation” at the US Food and Drug Administration (Rockville, MD, www.fda.gov) for food-contact materials, according to the European guidelines.

The new guideline focuses on the actual and potential impurities that are most likely to arise during the synthesis, purification, and storage of the new drug substance. The guidelines recommend that these impurities should be identified based on a sound scientific appraisal of the chemical reactions involved in the synthesis, impurities associated with raw materials that could contribute to the impurity profile of the new drug substance, and possible degradation products.

Excipient manufacturers are concerned over the impact the new guidelines may have on the sale and use of excipients in the European market. European regulators have said that this guideline will apply to excipients as well as to active substances, according to industry feedback.

“This issue is a critical concern for excipient manufacturers and pharmaceutical users,” said David R. Schoneker, chairman-elect of the International Pharmaceutical Excipients Council of the Americas (IPEC Americas, Arlington, VA, www.ipecamericas.org), who raised the issue in a question-and-answer portion of a session on “Low Level Impurities and Their Impact on Pharmaceutical Development,” presented here at the Annual Meeting and Exposition of the American Association of Pharmaceutical Scientists (Arlington, VA, www.aapspharmaceutica.com). “We are concerned that the TTC limit of 1.5 µg/day may mean that certain excipients will not be able to be used any longer in Europe, which could create huge issues for many existing drug products,” explained Schoneker. “Many products could need to be reformulated even though the excipients impacted by this guideline are common food additives that are safely consumed at much higher levels of use in food applications than would happen from their use in drugs. A significantly high number of excipients (and the associated drug products) could be impacted.”

Schoneker said that IPEC Americas and its sister associations-the International Pharmaceutical Excipients Council Europe (www.ipec-europe.org/) and the Japan Pharmaceutical Excipients Council (www.jpec.gr.jp/english/)-plan to issue a white paper in the near future to specify the associations’ position on the applying the new guidelines to excipients. They hope to bring a reality check to European regulatory agencies regarding this issue and to highlight the reasons why this guideline should not be applied to excipients. 

Industry groups such as the Pharmaceutical Research and Manufacturers of America (Washington, DC, www.phrma.org),  through its task force on genotoxic impurities, have examined the issue of genotoxic impurities as well, recommending an approach using a staged TTC that takes into account the dose and the duration of treatment and administration. A draft guidance is being developed by FDA on the subject. FDA has already told IPEC Americas that it does not intend to address excipients in the same manner as drug substances in the United States when it develops the guideline.