The IPEC–Americas procedure
The development of a regulatory strategy for novel excipient review has been an IPEC–Americas priority since the organization's
inception in the early 1990s. At that time, the IPEC–Americas Safety Committee held a series of meetings that culminated in
a publication of recommendations for excipient-safety testing based on route of administration (5). In 2002, the chairman
and deputy chairman of FDA's Center for Drug Evaluation and Research (CDER) Inactive Ingredients Subcommittee published a
proposal for excipient safety review largely based on the IPEC recommendations (6). The agency proposal was finalized in 2005.
The ICH M3 document on nonclinical safety studies for conducting human clinical trials is also relevant in this context (7).
In August 2005, IPEC–Americas presented a proposal for an independent excipient evaluation procedure to FDA staff. FDA agreed
to review the first excipient-safety evaluation expert committee submission for consistency with FDA procedures. Over the
next two years, the IPEC Safety Committee convened the expert committee, developed procedures, and solicited the first submission.
In September 2007, the expert committee reviewed the safety package for Solutol HS 15 and submitted their conclusions to the
sponsor. In May 2008, in a letter to IPEC, FDA concluded that, "The issues considered by the expert committee reviewers in
the weight-of-evidence determination on the safety of Solutol HS 15 are the same as would be considered by a reviewing division,"
indicating that the IPEC process provides a reasonable proxy for FDA review.
NEEC's primary function is to evaluate compliance of excipient data with the FDA guidance on safety evaluation and to make
recommendations to the excipient manufacturer if data gaps are noted in the excipient dossier. The expert committee acts independently
of the IPEC-Americas Safety Committee and its members must have confidentiality agreements in place. NEEC is comprised of
three experts in general toxicology and, ideally, members have experience in industrial, academic, or regulatory toxicology,
including experience in toxicology laboratories. Committee members may rotate off the committee every two to three years to
provide new expertise to the process. If the committee decides that an expert in one facet of toxicology is needed to help
in decision-making, a request to the excipient manufacturer will be made for permission to include the expert in the deliberations.
This expert must also sign a confidentiality agreement. Aclairo PDG administers this review procedure.
An excipient safety dossier in common technical document (CTD) format (to facilitate subsequent FDA review) is submitted to
Aclairo PDG who sends it to the expert committee chairperson, who in turn distributes it to other committee members. Review
times will depend upon the quantity of the information within or absent from the dossiers but are anticipated to take one
to three months; in most cases, costs will not exceed a total of 50 hours of review plus administrative overhead. The chairperson
or a designee collates the comments of the committee members and writes a draft report that will be sent to each member for
concurrence or further discussion. Once agreement is reached, the final draft is sent to the excipient sponsor for review
and comment. If the expert committee cannot reach agreement on one or more points in the final draft, the sponsor is told
about the disagreements and the reasons for them. The sponsor may discuss the final draft with the expert committee, request
clarifications or explanations and when satisfied, the final report is signed by the chairperson and sent to the sponsor who
is the sole owner of the committee report. The committee report will contain at a minimum:
1. A discussion of chemical and toxicological data and human safety concerns based upon intended use of the excipient
2. Opinions on conformance with data needs according to the FDA guidance on safety evaluation for excipients
3. Identification of any data gaps
4. Points of reviewer disagreement if not resolved with the reasons identified in the final draft.