Approximately 40% of drug-product manufacturers and one out of four distributors reported that they had difficulty finding
a manufacturer of a USP–NF grade excipient. The survey findings indicated that most of the excipient manufacturers and distributors
who responded label their excipients as compendial grade. However, it is noteworthy that 11% of excipient manufacturers and
one out of five excipient distributors are not choosing to label their products as compendial grade. The reason(s) for not
labeling their excipients as compendial grade could not be accurately determined from the responses to this survey. The authors
have experienced a growing number of situations in which excipient manufacturers are dropping the compendial-grade label suffix
(i.e., USP, NF, PhEur, JP), either because of the increasing CGMP expectations and/or low volumes sold to the pharmaceutical
market, combined with efforts required to meet pharmaceutical manufacturers' expectations. The current situation was explored
by the workshop participants.
Compendia and compliance.
Currently, FDA's Compliance Policy Guide (CPG) Section 420.400 "Performance of Tests for Compendial Requirements on Compendial Products" states, "Compendial methods
need only be applied, as a batch release test, where a firm has made specific commitments to do so (as in a new drug application
[NDA]), or where the official method is the only appropriate test. It should be noted that neither USP–NF nor the CGMP regulations necessarily require a firm to utilize, as a batch-release test, the methods and procedures stated
in the official compendia." Scientifically sound alternate tests (including in-process analyses) can therefore be used in
lieu of USP tests. However, in the event of a dispute as to whether a compendial article meets the standard, the pharmacopeial
method and analytical procedures will be applied as the referee test (14).
More specifically, official drug products are required to conform to the compendial standards and monograph requirements.
This conformance must be ensured by suitable means, including adequate manufacturing process validation and control. Scientifically
sound alternative test methods may be acceptable for the purpose of batch-release testing. This applies to official substances,
official preparations (finished dosage forms), and excipients.
CPG Section 420.400 continues,
Where an official product purports to conform to the standards of USP–NF, the manufacturer must assure that each batch conforms
to each monograph requirement. This assurance must be achieved by appropriate means, including process validation and controls
and end product testing. However, the nature and extent of end-product testing which is needed will depend upon the circumstances.
Factors to consider in determining the need to test each batch for a given monograph requirement include: the adequacy of
the manufacturer's process validation, adequacy of in-process manufacturing controls, and the nature of the particular product
characteristic which is the subject of the specification (e.g., potency, sterility, content uniformity). Therefore, in some
cases it may not be necessary for a manufacturer to test each batch for each monograph requirement.
In postworkshop meetings, FDA representatives said that CPG Section 420.400 is under revision. The intent of this CPG is not
to provide for a skip-test approach. There must be appropriate testing and measurement of in-process and/or finished-product
samples from each batch to ensure that the finished material complies with all compendial requirements.
Federal Food, Drug, and Cosmetic Act and 21 CFR.
During the workshop and at the closing session, it was noted that Section 501(b) of the FD&C Act applies to all articles recognized
in an official compendium. Further, section 201(g) of the FD&C Act defines a drug in part as an article recognized in the
official USP and NF, as well as an article intended for use as a component of a drug or drug product. Consequently, USP–NF excipients intended for the drug market must comply with USP–NF standards, regardless of whether the labeling on shipments of the excipient include the USP–NF designation.