Excipients used as active ingredients in pharmaceutical products, otherwise known as atypical actives, have received much
attention during the past several months. Industry is questioning whether—and why—these unique ingredients need to comply
with the International Conference on Harmonization's Q7 guideline on GMPS for active pharmaceutical ingredients (1). Pharmaceutical Technology spoke to David R. Schoneker, past chair of the International Pharmaceutical Excipients Council, to gain some insight into
the ongoing debate.
A typical actives, defined as excipients that are used as active ingredients in pharmaceutical products, have been around
for decades and presumably represent little or no risk to patients. They can be found in many common over-the-counter items
such as rubbing alcohol (the atypical active is isopropyl alcohol) and antacids (the atypical active is calcium carbonate).
So why all the recent attention over their use?
Since the International Conference on Harmonization (ICH) finalized its Q7 guideline on GMPs for active pharmaceutical ingredients
(APIs) in 2000, actives have received greater scrutiny. Quality-by-design approaches and recent supply-chain security problems
have encouraged this in-depth review. Industry thinking is that, even though ICH Q7 is not a legal requirement, excipients
used as APIs should adhere to the guideline (1). However, most excipients are not designed to be used as an active and are
produced using GMPs aligned with the 2006 International Pharmaceutical Excipients Council–Pharmaceutical Quality Group (IPEC–PQG)
Excipient GMP guide (2). Requirements between the two guidelines differ, and there is controversy regarding what should be
expected in terms of compliance for atypical actives.
To understand why this difference exists, it is important to step back and look at the excipient industry in general. The
chemicals used as excipients are used in many industries, including chemicals and petrochemicals, food, and plastics. Only
a small percentage of all these chemicals used as excipients are found in pharmaceuticals. Excipients that are supplied to
the pharmaceutical industry are largely produced and intended for use as inactive ingredients in drug formulations, not as
There are processing differences, too, explains David R. Schoneker, past chair of IPEC and director of global regulatory affairs
at Colorcon. "In general, full GMPs for APIs begin to be applied early in their manufacturing process, whereas GMPs for excipients
are applied later in the process, such as during final finishing steps," he says. API makers know from the start that their
material is going to be used in a pharmaceutical product. Excipient makers may not have this same knowledge. The degree of
documentation and oversight of the manufacturing process also varies between APIs and excipients. "Although the principles
and areas of concern are the same, there are additional second checks and oversight (e.g., additional validation) with APIs,
and there is a significant cost associated with this," adds Schoneker.
At present, there are no official FDA GMP regulations that exist specifically for excipients. "They are considered drugs according
to the federal Food, Drug, and Cosmetic Act, but that document only says that 'appropriate GMPs must be used,'" explains Schoneker.
For this reason, the IPEC–PQG Excipient GMP guide is helpful to excipient makers looking to apply best practices. In fact,
IPEC and PQG, with FDA collaboration, are working to get their excipient GMP guide approved as an official ANSI standard by
the end of 2011. If this occurs, the document will become the national standard for Excipient GMP in the US, and FDA will
be able to use it and reference it officially as the acceptable GMP practice for excipient manufacture during inspections.
The IPEC–PQG guide and the pending ANSI standard would apply to general pharmaceutical excipients, however, and not to excipients
used as actives. And this is where a resolution is needed, says Schoneker.
Many FDA investigators expect ICH Q7 to be adhered to when excipients are manufactured for use as actives in a drug product,
he says. ICH Q7 has been used by FDA as the GMP standard in a number of inspections of excipient manufacturers that were not
aware that a pharmaceutical company was using its excipient as an active. In these cases, the excipients manufacturer is often
caught off guard. When FDA shows up to do a routine preapproval inspection, it can result in a Warning Letter for noncompliance
to ICH Q7 even though the excipient manufacturer may inform FDA that it had no intent for is material to be used as an active
by its customers.