FDA challenges quality requirements for ophthalmic drugs with revised draft guidance

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The FDA has announced a revised draft guidance discussing certain quality considerations for ophthalmic drug products in response to the increasing number of recalls and instances of consumer injury and death in 2023.

This revised draft guidance revises guidance of the same name from October 2023, “Quality Considerations for Topical Ophthalmic Drug Products.” Specifically, the revision discusses microbiological considerations related to product sterility for all ophthalmic drug products subject to current good manufacturing practice (CGMP) requirements. It is intended for the prevention of contamination of ophthalmic drug products packaged in multidose containers.¹

Quality considerations for ophthalmic drugs such as gels, ointments, creams, and liquid formulations such as solutions, suspensions, and emulsions, intended for topical delivery in and around the eye, are addressed in the revision.

According to an announcement by the FDA, the revised draft guidance applies to “marketed products including ophthalmic drug products approved under new drug applications (NDAs), abbreviated new drug applications (ANDAs), and biologics license applications (BLAs), as well as to over-the-counter (OTC) monograph drugs, drugs compounded by outsourcing facilities, and the drug or biological product constituent part of a combination product.”¹

The FDA also states it is revising the guidance to “clarify its related scope.” When originally published, the scope explicitly included NDA, ANDA, and BLA products regulated by the Center for Drug Evaluation and Research, as well as OTC monograph drugs marketed under section 505G of the FD&C Act. The FDA stated it was “not the intention to specifically exclude products that are not marketed under an approved application or under section 505G of the FD&C Act; however, the draft guidance may have been interpreted that way.”¹

Thus, the FDA is expanding the scope to “other drugs that, while also subject to CGMP requirements, are not marketed under a drug application, including drugs compounded by outsourcing facilities pursuant to section 503B of the FD&C Act.”²

The guidance adds microbiological studies to the tests manufacturers should perform to assess the quality of topical ophthalmics. Other tests include visible particle studies, extractables and leachable studies, container closure system (CCS) studies, and studies to assess impurities and degradation products.²

The revised draft states that “product sterility is a critical quality attribute (CQA) for ophthalmic drug products,” and failure to comply with the CGMP requirements will cause affected products to be deemed adulterated.²

The FDA also goes more in-depth on the guidance of container closure systems (CCS) to prevent contamination as multidose CCSs are opened multiple times during the course of use, which can lead to a greater risk of contamination.

Regarding ophthalmic drugs in multidose containers, the guidance states “liquid ophthalmic drug products packaged in multidose containers should contain one or more suitable substances that will preserve the product and minimize the hazard of injury resulting from incidental contamination during use.”²

The FDA states that if a drug does not have an inherent antimicrobial activity, it should include an appropriate preservative. Furthermore, the FDA states “preservatives are critical to ensuring that the multidose drug product remains free from harmful contamination following potential microbial ingress.”

The FDA also warned manufacturers against the use of preservatives with silver sulfate or other silver-containing compounds because of “significant safety concerns associated 102 with applying silver directly to the eye, including argyria (an irreversible discoloration of the skin and eyes) and granular deposits of silver in the conjunctiva and cornea.”²

Stakeholders have until February 26, 2024, to comment on the guidance either online or by mail. The FDA states it will “consider comment[s] on this revised draft guidance before it begins work on the final version of the guidance.” The FDA also noted that its guidance documents do not establish legally enforceable responsibilities, but describe current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited.²

References

1. Quality Considerations for Topical Ophthalmic Drug Products; Revised Draft Guidance for Industry; Availability; Accessed January 4, 2024. https://www.federalregister.gov/documents/2023/12/28/2023-28595/quality-considerations-for-topical-ophthalmic-drug-products-revised-draft-guidance-for-industry

2. Quality Considerations for Topical Ophthalmic Drug Products Guidance for Industry. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) December 2023 Pharmaceutical Quality/CMC Revision 1. https://www.fda.gov/media/172937/download