The issue of postapproval compendial changes also was discussed at the workshop. A postapproval change submission to an NDA
or ANDA application should be relevant to the information originally contained in the application. In general, changes in
an excipient specification to comply with compendial requirements would not require any notification to FDA for nonapplication
drug products. For drug products approved by the agency through an application, FDA's Guidance for Industry, Changes to an Approved NDA or ANDA; Specifications—Use of Enforcement Discretion for Compendial Changes, published in November 2004, recommends filing an annual report for all excipient specification changes made to comply with
the official compendium. FDA should revise regulations (e.g., 21 CFR 314.70) to clarify this issue.
Summary and recommendations
Continuous-flow manufacturing and skip-lot testing used for excipients.
Discussions with FDA resolved several issues beginning with definitions of batch and lot as applied to continuous-flow manufacturing. A batch means a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified
limits. A lot means a batch, or a specific identified portion of a batch. The continuous-flow manufacturing process may have a batch or
lot defined by agreement between the supplier or manufacturer and customer.
The term skip-lot testing does not correctly reflect current practice. Wherever an in-process or bulk-excipient test result is traceable to the final
package, that test result can be reported in the CoA.
A sampling plan based on (n + 1)0.5 containers sampled is appropriate for creating a composite sample. Common practice is to perform the identity test on the
composite sample. It was suggested that identity tests should be performed on samples collected from individual containers
and should not use a composite sample.
Characterization of excipient physical and chemical properties to help build quality into the drug product.
Additional functionality or processability testing beyond the compendial monograph testing is performed by a great majority
of excipient manufacturers, distributors, and drug-product manufacturers. This approach is consistent with FDA's QbD and CGMPs
for the 21st Century initiatives. As proposed by USP–NF, compendial support of functionality testing should be presented in
a General Chapter with references to tests appropriate to the desired function. The drug-product manufacturer and the excipient
manufacturer should mutually agree to the correct control strategy.
Communication to excipient users about a significant change in excipient physical and chemical property(ies) should occur
in a timely manner, even when the excipient would otherwise continue to meet all of its compendial specifications. The issue
of change control should be part of the quality agreement between an excipient user and the supplier.
Advantages of third-party audits.
Audits are a key part of supply chain management, and are commonly performed by the auditors of the drug-product manufacturer.
Audits should be based on a uniform standard such as the USP General Information Chapter ‹1078›, which is based on the IPEC GMP Guide for Bulk Pharmaceutical Excipients. The benefit to excipient manufacturers is a reduction in site audits and questionnaires from their customers. The benefit
to drug-product manufacturers is a more thorough and complete audit as a result of the additional time spent by the third
party. A small drug manufacturer would have a more credible assessment than by a questionnaire alone.
Strategies to increase the number of excipients labeled USP–NF.
The FD&C Act requires that official drug products and excipients that have pharmacopeial monographs must conform to compendial
standards regardless of whether they are labeled as USP or NF. Conformance to compendial specifications may be ensured by
adequate manufacturing process validation, in-process controls, and through in-process tests or measurements of excipient
quality.
About 40% of drug-product manufacturers experience the loss of an NF label for an excipient. When a compendial excipient is
not labeled USP or NF, the reason for not designating the component as USP or NF by the excipient manufacturer should be determined.
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