BRIEFING

 Anhydrous Lactose. This proposal is based on the version of the monograph official as of May 1, 2020. As part of the USP modernization initiative and on the basis of stakeholders’ needs, the Excipients Monographs 2 Expert Committee proposed in PF 46(5) [Sept.–Oct. 2020] to update the Anhydrous Lactose and Lactose Monohydrate monographs to include the use of Lactose in inhalation and injectable dosage forms. A Stimuli article, Revisions to the USP–NF Lactose Monographs—Focusing on Inhalation and Injection Grades, was also published in the same issue of PF 46(5) and provided a detailed explanation about the phase approach to updating the Lactose monographs.

 Since a significant number of comments were received after the PF 46(5) publications, the USP Lactose Joint Subcommittee (JS) and the Simple Excipients Expert Committee (SE EC) discussed all comments and proposed to publish the updated Lactose monographs proposals along with the second Stimuli article, USP Responses to Comments on Stimuli Article “Revisions to the USP–NF Lactose Monographs—Focusing on Inhalation and Injection Grades”, elsewhere in this issue of PF.

 Again, the inclusion of the requirements for inhalation grades and injection grades are proposed in this phase 1 revision using the USP regular revision process as USP local requirements. In the phase 2 revisions, a new assay and related substances test using an instrumental analysis methodology and an update to the Protein and Light-Absorbing Impurities test will be included through the Pharmacopeial Discussion Group (PDG) harmonization process. The phase 2 revisions will be published in a future issue of PF.

 An updated revision proposal for the Lactose Monohydrate monograph can be found in this issue of PF. USP welcomes your comments on both the Stimuli article and the updated revision proposals for Lactose.

 On the basis of comments received, the proposal in PF 46(5) has been deferred and is being replaced with a new proposal. Compared to the current monograph, the following changes are proposed:

1. Identification B. The Thin-Layer Chromatographic Identification Test is proposed to be removed to align with USP policy to contribute to the global efforts to minimize negative environmental impact. Most importantly, Lactose Monohydrate and Anhydrous Lactose are sufficiently identified by their infrared (IR) spectra and can be differentiated from other sugars. Therefore, the thin-layer chromatography (TLC) test does not provide additional confirmatory evidence. This test is also removed from the list of harmonized attributes in the PDG sign-off document.

2. Microbial Limits. The PDG includes Microbial Enumeration Tests 〈61〉 and Tests for Specified Microorganisms 〈62〉 as harmonized attributes in the PDG sign-off document for non-inhalation and non-injection grades. USP proposes to include the requirements for inhalation grades and injection grades of Lactose. In addition, USP proposes to add a cross-reference to Tests for Burkholderia Cepacia Complex 〈60〉 because it applies to the test for Burkholderia cepacia. Although the PDG has agreed to include the requirement of microbial limits for the inhalation grades and injectable grades, it has not yet been included in the PDG harmonization text, so it is marked with symbols (^⧫ _⧫) in this USP revision proposal at this time.

3. Bacterial Endotoxins Test. Include this new requirement to control the bioburden for Lactose inhalation grades and injection grades. Although the PDG has agreed to include this test for the inhalation grades and injectable grades, it has not yet been included in the PDG harmonization text, so it is marked with symbols (^⧫ _⧫) in this USP revision proposal at this time.

4. Labeling. Significant changes are proposed for this section to include the labeling requirements for inhalation grades and injection grades of Lactose in addition to other labeling requirements. The proposed performance-related tests that are only applicable for inhalation grades are non-harmonized attributes in the PDG and they are included under the Other Requirements in the Labeling section. The proposed tests include: Particle Size Distribution, Amorphous Content, Particle Shape and Morphology, and Content of Alpha and Beta Anomers. Please note that the testing procedure is removed from the Amorphous Content test, compared to the previous proposal in PF 46(5).

   No acceptance criteria for such tests are included in the monograph because it would be impossible for all possible limits for such tests to be included in a USP monograph. The link between excipient performance and medicinal product performance can only be determined by the excipient user (medicinal product manufacturer). A more detailed discussion can be found in the Stimuli article in this issue of PF. Since the Labeling section is a non-harmonized attribute in this monograph, USP utilizes this section to implement these non-harmonized performance-related tests for the Lactose inhalation grades. Therefore, the Content of Alpha and Beta Anomers test was moved from the Other Components section to the Labeling section.

5. Definition, Identification A, Residue on Ignition, Clarity and Color of Solution, Loss on Drying, Water Determination, Protein and Light-Absorbing Impurities, Acidity or Alkalinity, and Optical Rotation. Currently, there are no changes for these harmonized attributes.

6. Packaging and Storage. There are no changes from the existing USP–NF text. This is currently a non-harmonized attribute. Future decision on inclusion as a non-harmonized attribute or as a local requirement will be discussed with the PDG.

7. USP Reference Standards. Deleted USP Dextrose RS, USP Fructose RS, and USP Sucrose RS, due to the deletion of the TLC identification test.

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

 (SE: J. Liu)

 Correspondence Number—C318391