EMEA Clarifies Ambiguities in Genotoxicity Guideline

EMEA explains genotoxic standard that was cited in Roche's Viracept recall

The European Medicines Agency has issued a new question-and-answer guide that clarifies certain ambiguities related to an earlier 2006 standard which sets first-ever thresholds for genotoxic impurities in new drugs.

The document is called "Question and Answers on the CHMP Guideline on the Limits of Genotoxic Impurities."

EMEA's "Guideline on the Limits of Genotoxic Impurities," which was adopted June 28, 2006, and took effect in January 2007, was designed to tightly limit substances possessing genotoxic potential.

It requires pharmaceutical manufacturers to apply a 1.5 microgram daily exposure limit for genotoxic impurities in new drugs. The limit is called the threshold of toxicological concern (TTC). Higher limits may be justified under certain conditions, such as short-term exposure periods.

The guideline contains a decision tree to assist manufacturers in their assessment of acceptability of genotoxic impurities.

The guideline notes that "a TTC value higher than 1.5 ug/day may be acceptable under certain conditions, e.g. short-term exposure, for treatment of a life-threatening condition, when life expectancy is less than five years. Or where the impurity is a known substance and human exposure will be much greater from other sources (e.g. food). Genotoxic impurities that are also significant metabolites may be assessed based on the acceptability of the metabolites."

EMEA states in the 2006 guidance that these new requirements will not be applied retrospectively to approved drugs "unless there is a specific cause for concern."

The question-and-answer guidance explains what is meant by the term "cause for concern."

It states that "if a manufacturing procedure for API remains essentially unchanged a re-evaluation with respect to the presence of potentially genotoxic impurities is generally not needed. However, new knowledge may indicate a previously unknown cause for concern. One example is the mesylate salt drug substances for which a few years ago, a concern regarding the potential for formation of genotoxic alkyl mesylates was raised. This concern resulted in the 'Production Statement' requesting a specific evaluation of the potential for formation of these highly toxic products now included as part of the PhEur monographs for all the mesylates salts."

The 2006 guideline indicates that it is necessary to reduce a known or suspected mutagenic impurity to "as low as reasonably practicable" (ALARP) even if the level is already below the 1.5 ug TTC level.

EMEA clarified, however, that if the level of a mutagenic impurity is below the TTC level, it will not be necessary to apply ALARP standards, unless it is a structure of "very high concern," such as N-nitroso, aflatoxin-like and azoxy-like compounds.

Another area of confusion was with structural alerts. The 2006 guidance noted that when a potential impurity contains structural alerts, additional genotoxicity testing of the impurity, typically in a bacterial reverse mutation assay, should be performed by manufacturers.

EMEA noted that "a negative Ames test conducted to regulatory acceptable standards will overrule a structural alert and no further studies would be required, providing that the level remain below ICH Q3A/B limits."

Before the guidance, genotoxic impurities were not really addressed by EMEA. The setting of impurity thresholds had been addressed as a footnote in ICH Q3A R2 Impurities in New Drug Substances which set the routine determination of certain impurities at 0.05 percent. However, the ICH guideline did not specifically address genotoxic impurities per se. The 2006 guidance was the first time that genotoxic impurities were addressed.

EU Genotoxic Limits Impacted Roche's Viracept

Genotoxicity concerns last year led to a recall and suspension of authority for Roche to market an HIV treatment, Viracept (nelfinavir mesylate) in the EU.

The problem came to light after contaminated batches reached the market in March 2007, and patients began reporting that the tablets smelled strange.

Upon investigation, Roche determined that in the last few months of 2006 and in early 2007, some batches of the active substance had become contaminated with a known genotoxic substance, ethyl mesylate, also known as ethyl methanesulfonate.

Roche in June 2007 initiated a recall affecting all markets except Canada, Japan and the U.S., which did not receive contaminated batches of the API, and temporarily stopped production.

The European Commission suspended marketing authorization in August, then lifted the suspension in September based on Roche's responses to EMEA's questions and the findings of Swissmedic officials who in June had inspected the facility in Basel, Switzerland, where Roche had produced the contaminated batches.

Roche told EMEA the contamination occurred after a holding tank was cleaned using ethanol. Before the tank had dried out properly, it was filled with methane sulfonic acid, a chemical used to manufacture Viracept.

The remaining ethanol reacted in the holding tank with the methane sulfonic acid to form very high levels of ethyl mesylate, which wound up in some finished batches.

Roche explained to EMEA that it has changed the manufacturing process so that it no longer uses a holding tank. Roche also introduced checks to ensure that if ethyl mesylate forms during manufacture of Viracept, it would be quickly detected.

The company also set acceptable maximum limits for the active substance and the finished product in accordance with EMEA's guideline on genotoxic impurities.

After reviewing data from Roche and the recommendations of ad-hoc groups of toxicology and pharmacovigilance experts, EMEA determined that the threshold of toxicological concern should be 0.6 ppm.

Roche also was required to perform non-clinical studies to better quality the risk to patients, and to establish a registry of patients exposed to 1,000 ppm or more of ethyl mesylate.

In response to Roche's recall, FDA in June 2007 asked Pfizer, which manufactures Viracept for the U.S. market, to set a specification limiting the allowable level of ethyl mesylate.

Pfizer began testing for the contaminant in its supplies of the active ingredient, and found that it was present, but at levels much lower than Roche had seen in Europe.

Pfizer and FDA agreed on interim specifications consistent with a theoretical lifetime cancer risk of 17 cases per 100,000 exposed, and long term specifications of one case per 100,000 exposed.

Given that lifetime cancer risk for pediatric patients is three times higher, FDA and Pfizer agreed that, while the benefit-risk ratio is still favorable for pediatric patients already taking Viracept, that for the time being, pediatric patients should not start taking it, Pfizer said in a September 2007 letter to healthcare professionals.

- Joanne S. Eglovitch ([email protected]) and Bowman Cox ([email protected])