The Impact of Impurity Analysis on Future Regulations - Pharmaceutical Technology

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The Impact of Impurity Analysis on Future Regulations
As technology for impurity analysis improves, scientists are gaining better information and asking for more regulatory guidance.

Pharmaceutical Technology

"Some of the hyphenated techniques such as LC–MS may be able to reveal components that were never seen before. And if we are ever able to get a good solvent that will dissolve celluloses easily, we might be able to get more information. In order to go deeper into the composition of excipients we're going to need better applications or new analytical techniques to understand what we are doing," says Moreton.

Even if these techniques were available, the data generated might not be meaningful. "I would want to see data going over several years to see what the inherent variability of those components were in relation to time of year, harvest, and so forth. Without that, just introducing the technique is not going to help. In fact, it's going to make things worse."

Collaborating with the Japanese and European branches of TriPEC, IPEC-Americas is working on a composition guideline to help excipient suppliers communicate the overall composition of their products and why the components are present while retaining confidential proprietary information.

"We are trying to initiate a better dialogue between makers and users so that users understand what it is they are working with, using good science to determine how materials should be described," says Schoneker.

The IPEC guideline is the first step. Afterward, the biggest challenge will be getting excipient users to think of excipients in the correct framework.

"We want to educate the industry that they cannot think in traditional API terminology when they are dealing with excipients," says Moreton. "They simply don't work the same way."

Limiting genotoxic impurities

A major change in impurity testing involves a new regulatory guidance designed to tightly limit substances possessing potential for genotoxicity. The European Agency for the Evaluation of Medicinal Products (EMEA) guidance on genotoxic impurities, which became effective on Jan. 1, 2007, now applies a 1.5 μg daily exposure limit for such substances in most pharmaceuticals based on a precedent application of the threshold of toxicological concern (TTC) concept to food additives and food contact materials. Before the EMEA draft guidance, genotoxic impurities had been addressed only as a footnote in ICH Q3A (R2) "Impurities in New Drug Substances" (see Table I).

Table II: Staged TTC approach proposed by PhRMA.
In 2004, the Pharmaceutical Research and Manufacturers of America (PhRMA) formed a task force to discuss genotoxic impurity limits. Concerned the 1.5 μg/day limit would be applied to drugs synthesized in the United States, even while these drugs were still in clinical development, the PhRMA group proposed a staged TTC approach that ties permissible impurity levels to the stage of development (see Table II) (4). Because clinical studies are conducted with limited duration of dosing, the group reasoned that total exposure is very low, and thus higher intake levels should be allowable during early clinical studies without a net increase in risk. PhRMA's staged TTC approach applies to all clinical routes and to compounds at all stages of development, for identified and predicted impurities. The TTC limits would not apply to already marketed products.

Some questions surrounding both the EMEA and PhRMA positions could be heard, however, at last fall's annual meeting of the American Association of Pharmaceutical Scientists (AAPS).

"There's certainly a need to draw the line somewhere, but in my view it's gone overboard. It would appear that both the regulators and industry have become so focused on positions, that the bigger question of whether the new work processes created are actually benefiting the pharmaceutical consumer is being overlooked," commented one industry scientist (name withheld by request) .


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