BRIEFING

 General Notices and Requirements. This proposal is based on the version of the General Notices and Requirements official as of December 1, 2022. The previous proposal, published in PF 48(5) [Sept.–Oct. 2022], is canceled.

 This new proposal contains revisions to the following sections:

1. Section 3.10 Applicability of Standards: It is proposed to revise this section to better reflect alignment of current pharmacopeial text in monograph definitions. The proposed revision is necessary to avoid the potential misinterpretation that all official text under definition is a requirement for compliance with the official compendium. A thorough review of the existing monographs revealed that definitions may contain statements that are not compendial requirements, such as allowance for addition of other substances, explanatory and/or cautionary notes, footnotes, information about aspect, general manufacturing information, and regulatory information related to the article. The revision clarifies that those statements are, in fact, part of existing definitions but not necessarily requirements for compliance.

2. Section 5.15 Definition: This new section describes where the text related to the definitions of USP–NF articles is located and the type of statements that may be found within the "Definition" section of monographs. It specifies what statements are to be considered requirements and clarifies that any other statement found in definitions is not a requirement. Informational text may include, for example, explanatory and/or cautionary notes, footnotes, allowance for added substances (see section 5.20 Added Substances), or information about aspect and description of the article.

3. Section 5.60 Impurities and Foreign Substances: Several changes are proposed to this section and its subsections, as outlined below.

   • The following changes to the beginning of the section are proposed:

     • Replace the term “foreign substances” with “contaminants” and change the section title to “Impurities and Contaminants in Official Articles”.

     • Delete the reference to Impurities in Drug Substances and Drug Products 〈1086〉. This chapter, previously titled “Impurities in Official Articles”, has undergone a major revision which became official on May 1, 2021, and is no longer applicable to all official articles.

     • Revise the second paragraph to introduce a statement that it is not always practical to include in each monograph a test for every impurity or contaminant that might be present. In this revised paragraph, the term “nonmonograph tests” is omitted and the language is strengthened to emphasize the need to detect and control such impurities and contaminants, where reasonably expected to be present, by employing necessary tests, in addition to the tests included in a monograph.

   • Delete the subsection 5.60.10 Other Impurities in USP and NF Articles. This subsection was added to the General Notices in the early 1990s. It referenced Ordinary Impurities 〈466〉 in an attempt to create a unified approach to control impurities in pharmacopeial monographs, independently from differences in maximum daily doses. With the introduction of the threshold-based ICH Q3A Impurities in New Drug Substances and ICH Q3B Impurities in New Drug Products approach, the majority of references to Ordinary Impurities 〈466〉 in monographs were removed and replaced with procedures aligned with current science-based and regulatory approaches. In addition, the Other Impurities subsection did not exempt excipients from its requirements, which created problems for several articles. In response, several excipient monographs now include a statement that certain classes of impurities, if detected, are exempt from the 5.60.10 Other Impurities requirement. These monographs are being updated to reflect the proposed deletion of this subsection.

   • Add a new subsection, 5.60.10 Impurities that are Unusually Toxic and/or Mutagenic, to communicate the requirement to identify and control mutagenic and unusually toxic impurities at levels appropriate to ensure safety of the product as required by the applicable regulatory authority or as described in ICH M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. An earlier proposal to add this subsection via Interim Revision Announcement in PF 46(3) was deferred and subsequently canceled because of significant comments received from the FDA (see https://www.uspnf.com/notices/gn-deferral-gen-announcement-20200930 and https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/usp-nf-notices/gn-pf-46-3-ira-public-comments.pdf).

   • Make an editorial change for clarity in 5.60.20 Residual Solvents in USP and NF Articles.

   • Change the title of subsection 5.60.30 to "Elemental Impurities in USP Drug Products and Elemental Contaminants in Dietary Supplements" for consistency with the title of the general chapter Elemental Contaminants in Dietary Supplements 〈2232〉.

   • Add a new subsection, 5.60.40 Organic Impurities in Drug Substances and Drug Products, as the first phase of providing additional guidance pertaining to specific types of articles. In the future, similar subsections are expected to be proposed for control of impurities and contaminants in other types of standards, such as excipients and/or dietary ingredients and dietary supplement finished dosage forms, after relevant general informational chapters for these types of articles are developed and finalized. This new subsection covers the following topics:

     • A reference to Impurities in Drug Substances and Drug Products 〈1086〉 for nonmandatory definitions and additional information.

     • Expanded general concepts that are applicable to monograph tests based on chromatographic procedures.

     • A clarified approach to accommodate different impurity profiles, which could be achieved by including several tests as outlined in 4.10.10 Applicability of Test Procedures (known as a “flexible monograph approach”), or by marking certain impurities with the phrase “if present” to indicate that they may not be relevant to some of the articles.

     • A reference to Verification of Compendial Procedures 〈1226〉 with an emphasis on the importance of procedure verification for confirming the impurity profile of the article.

4. Section 5.80 USP Reference Standards: The current wording of section of 5.80 is limited to physical materials. General chapter 〈11〉 USP Reference Standards already considered other type of references: digital and visual. It is proposed to delete "authentic specimens" (physical materials) as the only type of USP Reference Standards. The revision enables use of USP Reference Standards to future applications in a digital environment.

 Associated content: Due to the proposed deletion of 5.60.10 Other Impurities as described above, the following excipients monographs are being revised in this issue of PF:

• Sorbitol

• Maltitol

• Sorbitol Solution

• Maltitol Solution

• Maltose

• Sorbitol Sorbitan Solution

• Noncrystallizing Sorbitol Solution

 The following chapters will also require updates to keep their references to revised sections of the General Notices current: Impurities in Drug Substances and Drug Products 〈1086〉, Injections and Implanted Drug Products (Parenterals)—Product Quality Tests 〈1〉, and Oral Drug Products—Product Quality Tests 〈2〉.

 Additionally, minor editorial changes have been made to update the text to current USP style.

 (COE: G.I. Giancaspro)

 Correspondence Number—C325353