A review of Warning Letters issued in 2023 and 2024 (to date) by the U.S. FDA to manufacturers of drug products and cosmetics shows the presence of some findings that are seen more frequently than others. One of these is the following:

“Your firm failed to test samples of each component for conformity with all appropriate written specifications for purity, strength, and quality (21 CFR 211.84(d)(2)).”

The deficiencies that trigger this observation predominantly come in two different forms (and sometimes both):

  • Failure by the manufacturer to perform the appropriate testing because the manufacturer relied on the results from the vendor CoA (without properly qualifying the vendor’s testing program). This deficiency – an unsupported application by the manufacturer of reduced testing – will be addressed in another blog.
  • Omission of tests that are required, either because they simply were not executed or because they were not on the manufacturer’s specification for an incoming component. This blog will focus on this deficiency.

It would seem to be a straightforward fix for a manufacturer to execute the right tests – make sure the specification for the incoming component to be released has the right tests and limits and run those tests when a batch of the incoming component comes into the facility!

Interestingly, review of Warning Letters reveals that the problem of not running the right tests occurs with components that are compendial articles (those with a monograph in the United States Pharmacopoeia (USP), National Formulary (NF), or Homeopathic Pharmacopeia of the United States (HPUS)) for which the required tests should be easily known.

For compendial articles, the minimum regulatory requirements for tests to be run and corresponding specification limits are straightforward: the set of tests and limits to be applied are those prescribed in the corresponding monograph for the article. (The “minimum” is related to the small “c” in “cGMP.” For example, the FDA expects manufacturers to be current with expectations for testing for impurities even if a monograph is old and does not have a test for impurities in it.)

Where does one find that this is a minimum requirement? Answering this question is, surprisingly, not straightforward! It requires understanding requirements from multiple sections of Title 21 (Food and Drugs) of the United States Federal Code of Regulations (CFR) and the General Notices Chapter of the USP. The relevant sections and content are presented below:

(1) Title 21, Chapter 9, Subchapter II, Part 321(g)(1) – The term “drug” means: (A) articles recognized in the official United States Pharmacopoeia, official Homeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of any article specified in clause (A), (B), or (C).

(2) Title 21, Chapter I, Subchapter C, Part 210(b)(3) – Component means any ingredient intended for use in the manufacture of a drug product, including those that may not appear in such drug product.

(3) Title 21, Chapter 9, Subchapter V, Part A, Section 351 Adulterated drugs and devices – A drug or device shall be deemed to be adulterated –

(b) Strength, quality, or purity differing from official compendium

If it purports to be or is represented as a drug the name of which is recognized in an official compendium and its strength differs from, or its quality or purity falls below, the standard set forth in such compendium. Such determination as to strength, quality, or purity shall be made in accordance with the tests or methods of assay set forth in such compendium…

(4) USP-NF General Notices and Requirements, 3.10.10. Applicability of Standards to Drug Products, Drug Substances, and Excipients – The applicable USP or NF standard applies to any article marketed in the United States that (1) is recognized in the compendium and (2) is intended or labeled for use as a drug or as an ingredient in a drug. Such articles (drug products, drug substances, and excipients) include both human drugs (whether dispensed by prescription, “over the counter,” or otherwise), as well as animal drugs. The applicable standard applies to such articles whether or not the added designation “USP” or “NF” is used. The standards apply equally to articles bearing the official titles or names derived by transposition of the definitive words of official titles or transposition in the order of the names of two or more drug substances in official titles, or where there is use of synonyms with the intent or effect of suggesting a significant degree of identity with the official title or name.

(5) USP-NF General Notices and Requirements, 3.20. Indicating Conformance –

A drug product, drug substance, or excipient may use the designation “USP” or “NF” in conjunction with its official title or elsewhere on the label only when (1) a monograph is provided in the specified compendium and (2) the article complies with the identity prescribed in the specified compendium.

When a drug product, drug substance, compounded preparation, or excipient differs from the relevant USP or NF standard of strength, quality, or purity, as determined by the application of the tests, procedures, and acceptance criteria set forth in the relevant compendium, its difference shall be plainly stated on its label.

Putting it all together (for components): If a drug substance or excipient is a recognized article in an official compendium, it must meet the requirements of the applicable monograph and any applicable general chapters. This requirement applies whether or not the drug substance or excipient is labeled with the initials of the respective compendium. When a drug substance or excipient does not meet corresponding compendial requirements, the difference must have been clearly indicated on the label of the component or the component is considered adulterated.

Extending this further to a drug product recognized as a compendial article, not only must the drug product meet compendial requirements but components of that product also must meet compendial requirements (for any of those components recognized as compendial articles). If this is not the case, the difference(s) must be clearly indicated on the label of the drug product or the drug product is considered adulterated.

While the concept is rather simple to understand, implementation, according to the numerous citations in Warning Letters reviewed, often appears to be lacking. If your firm needs any guidance regarding appropriate testing strategies, Lachman can help! Please reach out to us at LCS@LachmanConsultants.com for a consultation.