The U.S. Food and Drug Administration (FDA) published a revised draft guidance on December 28, 2023, outlining its current thinking on current good manufacturing practice (CGMP) and other quality considerations for topical ophthalmic drug products. The revised draft guidance, entitled “Quality Considerations for Topical Ophthalmic Drug Products,” updates FDA’s October 2023 draft guidance to specifically address “microbiological considerations related to product sterility for all ophthalmic drug products and the prevention of contamination of ophthalmic drug products packaged in multidose containers.”1
This revised draft guidance comes on the heels of several recent recalls2 of ophthalmic drug products and reports of serious adverse health consequences, including death, from microbiologically contaminated ophthalmic drug products. The revised draft guidance also clarifies the scope of the guidance to also include “other drugs that, while also subject to CGMP requirements, are not marketed under a drug application,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.”3
Notably, our recent experiences suggest that even prior to publishing the draft guidance, FDA has been emphasizing the concepts set forth in the revised draft guidance. A number of manufacturers already are addressing FDA requests for information and FDA inspectional observations that are essentially focused around visual inspection, particulate matter controls, and microbial contamination. We expect further FDA enforcement in this area. Accordingly, manufacturers of topical ophthalmic drug products, including both solutions and ointments, should carefully review the revised draft guidance and gap assess their existing controls against FDA’s recommendations.
FDA Offers Guidance on Microbiological Considerations and Visual Inspection
The revised draft guidance focuses on the following five key areas:
- microbiological considerations
- evaluation of “visible particulate matter, extractables and leachables, and impurities and degradation products”4
- in vitro drug release/dissolution testing for use in quality control
- container closure system (CCS) features
- stability studies
With respect to microbiological considerations, the revised draft guidance focuses on product sterility and multidose drug products. The focus on product sterility appears to be a result of “[r]ecent cases of microbially contaminated ophthalmic drug products” that led to reports of serious injury and death as well as recalls.5 Further, FDA notes the risk of multidose drug products and highlights the importance of appropriate protections against foreseeable external factors in storage and use that can cause deterioration or contamination, which may include preservatives or other suitable substances to preserve the product.
Like the October 2023 draft guidance, the revised draft guidance includes a discussion of visible particulate matter. Specifically, the revised draft guidance notes that “use of a robust visual inspection program and the implementation of CGMP requirements are important to ensure products are not adulterated.”6 The revised draft guidance further notes that manufacturers should consider alternative inspection techniques — such as x-ray inspections or destructive testing — to assess products in opaque containers for visible particles. While the revised draft guidance does not expressly mention USP <790> or the expectation that topical ophthalmic products be “essentially free of visible particles,” manufacturers should consider the USP <790> framework when establishing a “robust visual inspection program.”7
Regarding extractables and leachables, the draft guidance highlights the importance of evaluation of these from the CCS and details the information that manufacturers should document and that applicants should provide in their application when testing is conducted. FDA then notes that a safety threshold approach can be used “to assess the potential of leachables and extractables to leach into and/or interact with the formulated drug product” and then provides recommended leachable thresholds.8
The draft guidance then discusses impurities and degradation products and divides its discussion into two parts: new drug application (NDA), abbreviated NDA (ANDA), and over-the-counter monograph drugs; and biologics license applications (BLAs). The first section notes that NDA and ANDA applicants should generally follow International Council for Harmonisation (ICH) guidance principles9 and manufacturers should generally follow USP10 requirements and provides information to be documented by manufacturers and included by applicants in NDAs or ANDAs. FDA also emphasizes that recommended thresholds for ophthalmic drug products vary from ICH thresholds for the same dose range and provides specific recommendations. The BLA section notes that for biological products, impurity considerations “should include product-related substances in addition to degradation products and product-related impurities.”11
The document then briefly touches on the potential use of in vitro drug release/dissolution testing as a method of quality control and then includes an in-depth section on the design and delivery and dispensing characteristics of CCSs.
The draft guidance concludes with a discussion of stability and provides recommendations to be considered when developing required stability testing programs. Considerations include container orientation during storage, water loss, freeze/thaw studies for emulsions or suspensions, and in-use stability studies.
FDA has taken a number of regulatory actions against manufacturers of topical ophthalmic products in recent months. The public health events leading to recalls from multiple manufacturers have further increased FDA’s scrutiny of the controls assuring quality of the ophthalmic drug products, specifically due to microbiological and particulate matter contamination. We anticipate that this enhanced scrutiny will continue into 2024 and that FDA investigators will be inspecting manufacturers against the revised draft guidance. We anticipate that FDA’s review during the application assessment and during the inspections (preapproval and surveillance) will focus heavily on visual inspection and particulate matter controls as well as microbial contamination, including for both solution and ointment products. Manufacturers should assess their visual inspection programs and any trends to determine whether additional actions can be taken to strengthen such programs prior to an FDA inspection. Manufacturers of topical ophthalmic products in opaque containers should also assess whether their particulate matter control programs should include the use of alternative inspection technologies or destructive testing. Finally, manufacturers should perform comprehensive assessments of their manufacturing processes to identify potential contamination pathways and take action to address such pathways as needed.
1Draft Guidance, Quality Considerations for Ophthalmic Drug Products, FDA, December 2023, at 5 (Draft Ophthalmic Guidance).
2FDA warns consumers not to purchase or use certain eye drops from several major brands due to risk of eye infection, FDA, last updated Nov. 16, 2023, available at https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-consumers-not-purchase-or-use-certain-eye-drops-several-major-brands-due-risk-eye.
3Notice of Availability, Quality Considerations for Topical Ophthalmic Drug Products; Revised Draft Guidance for Industry, 88 Fed. Reg. 89706, 89707, Dec. 28, 2023.
4Draft Ophthalmic Guidance, at 4.
5Id. at 5-6.
6Id. at 7.
8Id. at 10.
9See Q3B(R2) Impurities in New Drug Products, ICH, Aug. 2006; see ANDAs: Impurities in Drug Products, ICH, Nov. 2010.
10See 1086, Impurities in Drug Substances and Drug Products, USP.
11Draft Ophthalmic Guidance, at 11.
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