Also Section 501(a)(2)(B) of the FD&C Act requires that drugs, including excipients meeting the definition of a drug in Section
201(g) of the Act, be manufactured in conformance with current good manufacturing practice. Hence, according to the Act, all
excipients intended for use in the manufacture of a drug product, whether or not the excipient is listed in the official USP–NF, must be manufactured in conformance with current good manufacturing practice. However, FDA has not promulgated CGMP regulations
for excipients. CGMP regulations in 21 CFR Parts 210 and 211 apply to the manufacture of finished drug products and not to the manufacturing of APIs or excipients.
Therefore, GMP guidance for pharmaceutical excipients has been jointly published by IPEC and PQG (15).
Issue of excipient manufacturers removing USP or NF designation from the label.
During the workshop it was noted that some manufacturers of pharmaceutical excipients remove the USP or NF designation from
labeling to avoid having to conform to CGMP and official USP–NF standards. FDA noted, however, that removing the USP or NF labeling does not obviate the requirement to meet applicable CGMP
and official USP–NF standards.
Workshop participants highlighted several questions and answers. The first question was, What is industry's burden in supplying
analytical methods validation data to regulatory agency for excipients no longer labeled USP or NF? This is an important topic,
and there was no real answer at the conference. However, a drug-product manufacturer must find out the reason for the excipient
manufacturer's removal of the USP or NF designation. Possible reasons include the manufacturer's inability to meet specification
or GMP issues. If the reason is specification issues, excipient manufacturers can work with USP. For GMP issues, a drug-product
manufacturer must carefully assess the suitability of its supplier's GMPs for the intended use. If the supplier stopped designating
the excipient as USP or NF for GMP reasons, then the material from such a supplier should not be used, and a different acceptable
supplier for that material should be found.
A second question was, If the drug manufacturer references the excipient manufacturer's DMF, does the drug manufacturer need
to supply the analytical methods validation data? The answer was that no additional analytical methods validation data need
to be supplied in an abbreviated new drug application (ANDA) or NDA if FDA determines the DMF to be adequate in support of
After the workshop, the PQRI Excipient Working Group discussed the regulatory and implementation recommendations to address
these two topics. These recommendations are summarized in the following paragraphs.
Analytical methods validation data for noncompendial analytical procedures used for testing noncompendial designated excipients.
When an excipient manufacturer or drug-product manufacturer uses a noncompendial (or other FDA-recognized public standard)
analytical procedure for testing a not-novel, noncompendial-designated component for which official USP–NF monograph exists, the analytical methods validation data for such test procedures should be made available for review by
the regulatory agency (e.g., FDA) at the site of excipient testing. If the excipient manufacturer were to submit the alternative
analytical procedure and its analytical methods validation data in a Type 4 DMF, then the drug product manufacturers can reference
it in their drug applications and need not submit the same information again for the agency's review (16, 17).
A not-novel or a new excipient can be a non-GRAS (referenced as substances Generally Recognized As Safe, according to 21 CFR Parts 182, 184, and 186) component used for the first time in a human drug product, or a previously used drug-product component
proposed for use in higher quantity per dose or per daily human exposure, or by a new route of administration, or for a longer
duration of human use than previously evaluated and allowed by FDA. Additional details on this subject can be found in FDA's
Guidance for Industry (18, 19).