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Regulatory Developments in Ophthalmology: Applying New FDA Guidance, Part Two

In this second of our two-part series, we continue our discussion about significant recent developments regarding the regulation of ophthalmic products and discuss what to expect in the months ahead.

Unsurprisingly, the U.S. Food and Drug Administration’s (FDA) released updated guidance following the landmark Genus Medical Technologies LLC v. United States Food and Drug Administration court decision. In March of 2022, the agency issued a guidance document titled Certain Ophthalmic Products: Policy Regarding Compliance With 21 CFR Part 4. All regulated parties, including ophthalmic drug and device manufacturers, should take note.

The guidance provides information to biopharma manufacturers regarding ophthalmic drugs packaged with eye cups, eye droppers, or other ophthalmic dispensers, where those articles meet the device definition. FDA says it will “regulate these products as drug-led combination products composed of a drug constituent part that provides the primary mode of action and a device constituent part (an ophthalmic dispenser).” In addition, the new guidance also applies to approved products, those with pending applications, and over-the-counter marketed monograph drugs.

Key Takeaways

Our Premier Consulting regulatory experts help biopharma clients stay abreast of evolving FDA guidance documents and their importance to sponsors in 2023 and beyond. So, what might the new guidance mean for the ophthalmic industry? We have five key takeaways.

  1. The FDA clarified that ophthalmic dispensers are now regulated as devices, and a drug and device together are regulated as a combination product. This regulation has become a critical consideration for development and post-approval activities, and all affected applicants or manufacturers are expected to be compliant with current good manufacturing practice (cGMP) regulations and 21 CFR Part 4.
  2. Approved applications and products on the market when the ophthalmic products guidance was issued were expected to have aligned with the new guidance by the end of February 2023. The FDA granted a 12-month period for the affected applicants and manufacturers to develop appropriate policies and procedures to ensure compliance with the new requirements.
  3. Manufacturers and applicants of affected ophthalmic products under development were expected to submit updated information, identifying the product as a combination product and listing all the manufacturing and release facilities for all constituents. These products were also expected to be compliant with the new guidance by the end of February 2023.
  4. For single-entity combination products and co-packaged combination products, the guidance details two options for demonstrating compliance with cGMP requirements:
    • Option A – Demonstrate compliance with all cGMP regulations applicable to each of the constituent parts included in the combination product. We recommend this option for high-risk products and devices (e.g., injectables).
    • Option B – Implement a streamlined approach for combination products that include a drug and a device. This involves demonstrating compliance with either the drug cGMPs or the device quality system regulation, as well as compliance with specified provisions from the other set of cGMP requirements. We recommend this option for low-risk products and devices (e.g., solution eyedrops).
  1. For combination products with a low-risk profile, the FDA will likely assess compliance with applicable device quality system (QS) requirements during a site inspection. For all other combination products, information to demonstrate compliance with the device QS regulation should be submitted as part of the quality assessment of the application.

Real-World Examples

The following case studies help illustrate these complex issues with real-world examples and results.

Case 1: Approved Product

The October 2021 approval documentation for Vuity™ (pilocarpine HCl ophthalmic solution, 1.25%) indicated that the product was reclassified as a drug-device combination product according to the Genus decision. A Center for Devices and Radiological Health (CDRH) QS-GMP consultation was deemed unnecessary because of the simplicity of the container closure system.

Case 2: Approved Product

Omlonti® (omidenepag isopropyl ophthalmic solution, 0.002%), was approved in September 2022. The quality review stated that a CDRH QS review and facility consultation was not needed and that information demonstrating compliance with 21 CFR Part 4 would be assessed during inspection (rather than review), based on the risk profile of the combination product.

Case 3: Pre-Approval Product 1

The marketing application for Product 1 was submitted before issuance of the new guidance. The product was not developed as a combination product, although the container closure system had significant device elements such as dose control and dose placement. Although the dossier was submitted as a conventional (noncombination) drug product, available device-related information (such as biocompatibility, performance characteristics, and accelerated aging data) was included in the container closure sections of the New Drug Application (NDA). After issuing the guidance, the FDA requested additional information during review of the NDA, including design elements, additional performance data, and information demonstrating that the product’s manufacturing process conformed with applicable sections of quality risk management regulations. At the time of this writing, this information has satisfied the agency’s requests.

Case 4: Pre-Approval Product 2

Product 2 had a container closure that was a much simpler dropper-type configuration compared with Product 1 and was initially documented as a simple, sterile vial. However, it was reclassified as a device after the guidance was issued. The development activities occurred at approximately the same time as the release of the FDA’s position on future ophthalmic products (based on the Genus ruling). Because of the timing, the NDA sponsor was able to include dose delivery and performance data as well as vendor qualification and biocompatibility information in appropriate sections of the NDA. This supplemental documentation for the container closure system helped fulfill the new regulatory requirements. Under an agreement with the FDA, study data for a detailed human factors evaluation were omitted because of the simplicity of the container closure system and its similarity to containers already approved for noncombination products.

In summary, developers of both marketed ophthalmic products and products in development must understand and satisfy these new regulatory guidelines based on each product’s risk profile. We encourage you to read our article Update on FDA regulation of ophthalmic combination products in Regulatory Focus to gain more insight into the new FDA guidance.

Premier Consulting’s regulatory scientists have the skills and experience to help you understand the regulations that are applicable to your program, conduct a multidisciplinary risk assessment, and identify the appropriate development and regulatory path for your product.

Contact us to learn how we can support you in applying these guidance documents to your development program.


Olu Aloba, PhD
Vice President, CMC Services

Marianthi Karakatsani, PhD
Director, Regulatory Affairs CMC

Laura Kilgore, RAC
Vice President, Regulatory Affairs, CMC