Others point out that the original TTC design purposefully excluded consideration of the impact of the human body's natural
DNA repair system, and the fact that the underpinning scientific studies were conducted in rodents, which have DNA repair
systems that are about 10-fold less effective than those in humans. "There is an approximate two to three orders of magnitude
of extra conservatism built into the original TTC limit that for some reason didn't seem to get much attention in translating
the concept to pharmaceutical usage," another industry scientist points out.
Meanwhile, the industry is waiting for the release of an FDA draft guidance on genotoxic impurities, which should clarify
"Right now (the draft guidance) is going through some internal editing and clearing through various levels of CDER. It is
still in draft form and hopefully in the not too distant future we will get it out for comment," said Tim McGovern, supervisory
pharmacologist, Division of Pulmonary and Allergy products at FDA.
In preparing to issue its own draft guidance, FDA experts have studied both the EMEA and PhRMA proposal for limits on genotoxic
impurities. "We've taken a look at both of those. In various meetings where we've presented on the issue, we've said that
1.5 μg/day appears to be a good threshold limit. We also thought that a staged approach, especially during clinical development,
was a reasonable approach to take. So our plan right now is to incorporate a staged TTC approach into the document," says
"We've dealt with issues regarding genotoxic impurities for a number of years. It got to a point where the issue was coming
up on a regular-enough basis that we thought a guidance document would be helpful," says McGovern. "We would have developed
a guidance regardless of whether EMEA had or not."
Scientists continue to challenge both the EMEA and PhRMA TTC proposals and raise concerns that they may add significant burden
on the development of virtually all small-molecule projects in the pharmaceutical industry.
"Any compound that has structural alerts needs to be tested by an Ames test," says Modi. Structural alerts are functional
groups associated with genotoxic or carcinogenic potential" says Modi. Based on reports, 20–25% of all intermediates can be
expected to test Ames positive (see Figure 2) (5, 6). These intermediates are traditionally used in "standard" chemical reactions
in the synthesis of new drug substances.
Figure 2: Structural alerts. Substances containing these structures should be tested for genotoxic or carcinogenic potential.
"Considering the fact that only 10% of compounds are successful in reaching the market, this means 90% of the efforts will
not produce anything meaningful for patients," says Modi.
IPEC is also concerned that the EMEA limits will eventually apply to excipients. Although the document states the focus is
specifically on APIs, there has been some discussion about its future extension into excipients.
"We know many people in the industry have heard comments from European regulators in different venues where they have said
that their intention is to apply it to excipients," says Schoneker. "This could be a big problem because the levels (the EMEA)
are discussing can be exceeded easily."
IPEC plans to address genotoxic impurities in its composition guideline. It also intends to write a position paper describing
its concern about the possibility of having the EMEA limits for genotoxic impurities applied to excipients. In addition to
other difficulties, this application could create conflicts in international regulation: "In our discussions with FDA, they
have clearly said they have no intention of applying this to excipients," says Schoneker.
"There is a lot of common ground (among) the various approaches. We'll eventually get to a point where we'll at least be in
a place where everybody is comfortable, (although) they may not agree to all the details," says McGovern.