// November 28, 2023

FDA's Draft Guidance for Topical Ophthalmic Drug Products: USP Standards

woman looking at eyedrop medicine

This year has seen a flurry of activity by the U.S. Food and Drug Administration surrounding ophthalmic products. By mid-November, the FDA had issued warnings to consumers to stop using 29 over-the-counter (OTC) eye drops due to potential risk for eye infections that could result in partial vision loss or blindness. Some of these products have been voluntarily recalled. The manufacturers of the products, which were sold by major retailers and manufacturers including CVS, Rite Aid, Target, Walmart, Leader, Rugby, and Velocity Pharma, were found to have unsanitary conditions in their manufacturing facilities.

While the FDA has not yet received reports of eye infections associated with these 29 products, the agency published a draft guidance in October 2023 titled “Quality Considerations for Topical Ophthalmic Drug Products,” marking the first instance of the FDA providing specific guidance for this product category. The draft guidance provides recommendations and insights into quality considerations for ophthalmic drug products, including solutions, suspensions, emulsions, gels, ointments, and creams, intended for topical application in and around the eye.

The FDA draft guidance discusses:

  • “Approaches to evaluating visible particulate matter, extractables and leachables, and impurities and degradation products.
    • The use of a robust visual inspection program and the implementation of CGMP requirements are important to ensure products are not adulterated.
    • Ophthalmic drug products with names recognized in the USP are generally required to also meet the particulate matter requirements in USP General Chapter <771>Ophthalmic Products—Quality Tests. Noncompendial ophthalmic drug products should also follow the above USP 65 General Chapter.
    • The following recommended leachables thresholds are expressed in parts per million (ppm) (i.e., the parts of a leachable per unit mass of the ophthalmic drug product): 
      • Reporting threshold: 1 ppm.
      • Identification threshold: 10 ppm.
      • Qualification threshold: 20 ppm
    • “Use of in-vitro drug release/dissolution testing as an optional quality control strategy for certain ophthalmic dosage forms.
    • “Recommendations for design, delivery, and dispensing features of container closure systems (CCSs).
    • “Recommendations for stability studies.”

One notable aspect of this guidance is its emphasis on aligning with specific United States Pharmacopeia (USP) standards for topical ophthalmic products, including those available over the counter. This is a crucial step in safeguarding the quality and safety of these products. USP's thousands of science-based standards set the bar for the development, manufacture, distribution and administration of medicines and other health products. Governments and manufacturers rely on them to increase the availability of safe, quality medicines and to build patient and health provider trust in the global supply of medicine.

General Chapters mentioned in the draft guidance

Visible particulate matter: USP General Chapter <771> was introduced to address the absence of documents outlining quality test requirements for ophthalmic products and became recognized in USP39. USP's forward-thinking approach in creating General Chapter <771> emphasizes our commitment to leading the way in establishing essential quality tests to safeguard patients. FDA’s draft guidance document states that all marketed ophthalmic product should follow General Chapter <771> specifications, even where there is not a specific USP monograph for the product. A complimentary training course is available from USP at “All the Particulars on Particles Ophthalmic Products—USP General Chapters 771 and 789.”

Extractables and leachables: USP standards and compendial methods can be used to assess and address leachables exceeding these thresholds, further highlighting the importance of aligning with USP criteria. The evaluation of extractables and leachables from container closure systems is a critical quality consideration. Leachables have the potential to interact with the drug product and compromise its quality. The guidance recommends following USP General Chapter <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems and <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems for extractables and leachables studies, respectively. Additionally, it refers manufacturers to the requirements in USP General Chapter <87> Biological Reactivity Tests, In Vitro; <88> Biological Reactivity Tests, In Vivo; <660> Containers—Glass; and <661> Plastic Packaging Systems and Their Materials of Construction, and guidance for industry Container Closure Systems for Packaging Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Documentation (May 1999).

Impurities and degradation products: The guidance also highlights that FDA's recommended thresholds for individual unspecified degradation products or impurities in ophthalmic drug products differ from ICH recommendations due to the local application of these products and the limited understanding of their potential effects. For New Drug Applications (NDAs), Abbreviated New Drug Applications (ANDAs), and OTC monograph drugs, the guidance advises following the principles outlined in the International Council for Harmonisation (ICH) guidance for industry Q3B(R2). The guidance also states that OTC manufacturers should generally establish thresholds and acceptance criteria in accordance with USP General Chapter <1086> Impurities in Drug Substances and Drug Products. When addressing impurity considerations for ophthalmic biological products, it is crucial to encompass not only degradation products but also product-related substances and impurities. Establishing acceptance criteria for impurities, which encompass leachables and process impurities, is essential to maintaining control over product quality, safety, and efficacy. Further details are available in USP General Chapter <1086> Impurities in Drug Substances and Drug Products.

Quality for OTC drugs

As we can see in the case of these eye drops, not adhering to quality measures can have financial and reputational consequences. Instilling a “culture of quality” that prioritizes quality throughout the entire drug product lifecycle – from development to patient – is a critical element for manufacturers.

The FDA's recent draft guidance on topical ophthalmic drugs emphasizes the crucial importance of maintaining adherence to quality standards. It is imperative to establish specifications for impurities and degradation products to ensure the quality of drug products. USP standards play a vital role in safeguarding the quality, safety, and efficacy of ophthalmic drug products. Manufacturers are strongly encouraged to incorporate these standards into their quality control processes and documentation as an integral part of the regulatory approval process. Learn more in a complimentary course “USP Certificate of Document and Reference Standards.”

FDA will accept comments on the draft guidance at any time, but to ensure comments are considered prior to the agency beginning work on the final guidance, comments should be submitted by December 12, 2023. Comments can be submitted through www.regulations.gov using the docket number FDA-2023-D-4177.