Reasons an excipient manufacturer drops the USP or NF designation include low volumes sold to the pharmaceutical industry
and the perceived cost of maintaining GMP compliance. These challenges can be overcome by quality and risk assessments such
as audits to verify GMP compliance and compendial testing. During the workshop, attendees expressed that when an excipient
source does not maintain GMP compliance, the drug-product manufacturer must obtain a new source for that material.
Alternative test methods may be used for batch-release testing, but if there is a dispute, then the compendial test is applied
as the standard. Using alternative test methods such as those of the American Chemical Society, AOAC International, PhEur, or JP will generally require verification but not validation. Analytical test method validation data in support of alternative
analytical procedures should be kept for inspection at the excipient testing site. When a DMF is referenced in an NDA or ANDA,
the drug-product manufacturer does not need to submit additional analytical test method validation data unless FDA determines
the DMF to be inadequate.
When an excipient monograph is not found in USP–NF, contact USP for resources to create the monograph. The workshop found that additional FDA guidance to excipient manufacturers
may alleviate some of these issues. USP has published the Joint IPEC–PQG GMP Guide, and this guideline also may educate drug manufacturers regarding excipient GMP and specific ways GMPs apply to excipient
Use of reduced testing as a result of the use of compendial harmonization.
More than half of excipient and drug-product manufactures reduce redundant testing by selecting the most stringent method
or specification for confirming compliance with more than one compendium. The addition of more harmonized monographs is very
helpful to industry, but further success depends on either full harmonization or mutual acceptance of the other pharmacopeias
Conference participants indicated that the term test in 21 CFR 211.84 creates confusion in the excipient industry. Postworkshop conversations with FDA reminded us that 21 CFR 211.84 applies to drug products. Especially for continuous manufacturing processes, the excipient industry should apply "tests
and measurements" in the control strategies of excipients. These control strategies are viewed as good examples of PAT concepts
in practice. The tests and online measurements can give assurance of compliance to compendial standards. Assurance of compliance
is demonstrated if test and measurement methods are validated, compared with compendial test method results, and linked to
the excipient in the final package. Such documentation justifies the reporting content of the excipient CoA and should be
available at the excipient manufacturing or testing site.
When USP publishes a harmonization chapter with delayed implementation dates, FDA will not enforce the new chapter until the
implementation date. Either the current official procedure or the new published procedure may be voluntarily used between
publishing a change and the implementation date.
Workshop participants stated that in general, changes in excipient specifications to comply with compendial requirements would
not require any notification to FDA for non-application (e.g., over-the-counter) drug products. For drug products approved
by the agency through an application (e.g., NDA, ANDA, biologics license application), FDA's Guidance for Industry: Changes to an Approved NDA or ANDA; Specifications—Use of Enforcement Discretion for Compendial Changes recommends filing an annual report for all excipient specification changes made to comply with the official compendium.
Further discussions are scheduled at the 2007 IPEC-Americas Regulatory Affairs Conference, Sept. 10–11, in Alexandria, Virginia.
In particular, this article will be the basis for the section "Excipient Testing, Control and Communication: Findings of a
PQRI Working Group." Stakeholders may further benefit by attending this conference.