A USP monograph lists the minimum set of impurity tests that must be conducted. Currently, a company making an API must comply
with all the tests listed in the published USP monograph, even if the company uses a synthetic route that is different from the original and therefore has an impurity profile
that may or may not contain all the impurities listed in the monograph. Even if the company knows for certain (either because
of the route of synthesis or some other scientifically justifiable means) that some monograph impurities will not be present,
it must still test for every substance on the list. In addition, the company would still have to test for any other impurities
that might be in its compound.
Flexible monographs were designed to eliminate redundant testing. They allow scientists to conduct only those tests that are
relevant to their compound. If a company's API has an impurity profile that is different than the original, the company could
conduct a full scientific evaluation of the material and file information with USP. Moreover, the company must notify FDA
upfront that it plans to submit a different impurity profile, including the limits on each impurity as part of its drug application.
The monograph would become effective upon FDA approval of the product.
Not surprisingly, generics companies stand to benefit from the flexible monographs program. Still, these companies face technical
challenges in qualifying impurities (see sidebar, "Qualification of impurities in ANDAs").
"GPhA has not put out a unified public statement or position on flexible monographs," says Gordon Johnson, vice-president
regulatory affairs for Generic Pharmaceutical Association (Arlington, VA). "However, we have been supportive of this effort
in a number of stakeholder meetings with USP."
While API scientists aim to eliminate or control impurities, excipient makers are trying to move away from the impurity mindset
and instead are advocating a better understanding of excipient composition and components, especially if these components
are essential to some performance of the material or the drug product.
"Right now, there is a gross misunderstanding of this issue. Excipients come from a lot of different areas. They are from
sources that are not synthetic chemistry, and by design they are not supposed to be pure. They are not in a drug product to
be pure, they are there to be functional," says Dave Schoneker, director, Global Regulatory Affairs, Colorcon (West Point,
PA) and Chair-Elect of the International Pharmaceutical Excipients Council of the Americas (IPEC Americas).
Sometimes the overall performance can be attributed to the presence of a minor component (USP refers to these as concomitant components; they have also been called essential minor components). "So 'pure' excipients are not necessarily good excipients, depending on performance," says Schoneker.
For example, microcrystalline cellulose contains several components, including pulp residues, sugar residues from the hydrolysis,
and hemicelluloses. When too much of these "impurities" are removed, it can compromise performance of the excipient. Determining
how much is too much, though, is not an easy task.
"It's a bit complicated because we don't have the analytical methods and understanding that we really need to be able to say
'These are the definitive limits for this component,'" says Chris Moreton, vice-president of Pharmaceutical Sciences at Idenix
(Cambridge, MA). The only limitation, for safety reasons, is on toxic components, especially for parenteral preparations such
as parenteral grade dextrose, mannitol, or povidone that also have restrictions on endotoxins.
"We don't have a good enough understanding of any excipient to be able to say, 'This is the item that needs to be controlled
and it will be the same for every formulation,'" says Moreton.
"The big issue is the overall compositional profile and understanding how that relates to the use of the excipient," says
Schoneker. "Users sometimes ask for an impurity profile when they should be asking for composition." This understanding is
especially critical when users contemplate switching suppliers. Although both materials may meet all specifications, they
may have different concomitant components, and so their performance during actual processing may differ.
Obtaining a useful compositional profile will again put the focus on good analytical methods.