FDA revise Quality guidance for Ophthalmic drug products

FDA has published a revised guidance on quality considerations for topical ophthalmic drug products – Gels, Ointments, Creams, Solutions, Suspensions and emulsions. The revised guideline is an update to the initial guidance published in October 2023. This revision adds Microbiological considerations and sterility for all ophthalmic products & Prevention of microbial contamination of products in multidose containers (typical product presentation for ophthalmic products like solutions, gels etc). Product sterility is a critical quality attribute (CQA) for ophthalmic drug products and the guidance makes it explicit that manufacturers must comply with CGMP requirements to ensure product sterility. The Multidose Ophthalmic drug products should have preservatives to ensure the product remains free from harmful contamination / microbial ingress during usage, unless it has inherent antimicrobial activity or a Container Closure System (CCS) design to eliminate potential for in-use microbial contamination. Manufacturers also should implement a well-designed and rigorous antimicrobial effectiveness testing program that covers the product’s shelf life.

The guidance discusses:

• Microbiological considerations.
• Approaches to evaluating visible particulate matter, extractables and leachables, and impurities and degradation products.
• 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.

The guidance specify for Visible particulate matter, the Ophthalmic drug products should comply with the USP General Chapter <771> Ophthalmic Products— Quality Tests and recommend appropriate technologies like X-ray spectroscopy to identify particulates.  The CCS (container closure system) should be assessed for Extractables and Leachables and assessment should cover primary, secondary and tertiary packaging components. Extractables should comply with USP General Chapter <1663>. For Leachables toxicological risk assessment should be conducted and acceptance criteria defined in drug product specifications.  The guidance recommends thresholds for individual unspecified degradation products or impurities tighter than ICH Q3C – 0.1% for drug products strength above 0.1% upto 1.0% & 1% or 1ppm where drug product strength is less than or equal to 0.1%. The guidance recommend dissolution testing as a quality control strategy for ophthalmic dosage forms like suspensions, emulsions, semi-solids to ensure consistent product quality. For CCS design, containers of ophthalmic drug products must be sterile at the time of filling and closing and sealed. The guidance define the drop size in multidose containers to be between 20 and 70 microliters and data should be provided & also one time dose uniformity study with at least three batches shall be performed to demonstrate that the drug substance is uniformly dispersed and the labeled dose can be consistently delivered. Stability studies should evaluate storage conditions in different orientations and use the worst-case orientation in commercial stability studies; stability programme shall cover In – Use stability as well. For Ophthalmic drug products Freeze/Thaw thermal cycling study studies shall be conducted with temperatures cycling between freezing (-20 °C to 0 °C) and ambient (25 °C to 35 °C) temperatures for a cumulative minimum of 3 days.

FDA Announcement

Guidance