FDA Guidance on Quality Considerations for Topical Ophthalmic Drug Products

Key Takeaways for Manufacturers of Topical Ophthalmic Drug Products

• The FDA’s draft quality considerations for topical ophthalmic drug products introduces updated expectations for stability, impurities, and microbiological quality.
• The extractables and leachables FDA guidance framework requires thorough risk assessments and alignment with USP chapters for topical ophthalmic use.
• Applicants developing products for topical ophthalmic administration must ensure CCS design supports sterility, dosing accuracy, and compatibility.
• The FDA guidance for ophthalmic products reinforces the need for robust impurity control strategies across ANDA, NDA, BLA, and OTC pathways.

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In December 2023, FDA issued the draft guidance Quality Considerations for Topical Ophthalmic Drug Products[1] for public comments. This guidance applies to ANDA, NDA, BLA and OTC monograph products. It aims to inform applicants of a few current FDA review practices for topical ophthalmic drug products, including liquid (solution, suspension, emulsion) and semi-solid (gel, cream, ointment) dosage forms. However, it does not apply to other ophthalmic dosage forms such as implants, inserts, and contact lenses. The draft guidance touches on seven areas:

• Microbiological considerations
• Visible particulate matter
• Extractables and leachables
• Impurities and degradation products
• In vitro drug release/dissolution testing
• Container closure system design, delivery, and dispensing characteristics
• Stability

1. Microbiological Considerations

This section emphasizes the various approaches to ensure sterility of topical ophthalmic products. 

• Unopened ophthalmic drug products must demonstrate product sterility at batch release and during storage.
• For preservative-free unit-dose products, once they are opened, they should be used immediately and discarded.
• For multidose products, unless the product is self-preserved, a preservative is commonly added to minimize the hazard of injury resulting from incidental contamination during use. The multidose products must maintain antimicrobial effectiveness during storage and the intended use period.  Adsorptive loss of preservatives to the LDPE bottle can occur during storage. The associated microbiological risk is generally managed by confirming preservative efficacy at the lower limit of the preservative assay acceptance criteria. However, the potential loss of auxiliary excipients, such as sodium sulfite, which has minor antimicrobial activity, due to oxidation in the aqueous solution during storage, is sometimes overlooked. There have been cases where multidose ophthalmic solution products failed antimicrobial effectiveness test due to degradation/adsorption of these auxiliary excipients.
• For preservative-free multidose products, the container closure system (CCS) design must ensure product sterility during the intended use period. Currently, there is only one approved multidose preservative-free product, Restasis, using a patented Aptar CCS. There are a few multidose OTC monograph products in preservative-free format, as no regulatory approval is needed to market OTC monograph products in the US.

Good aseptic practices during manufacturing are essential to ensure microbiological safety of topical ophthalmic products, even when an antimicrobial preservative is present.

2. Visible Particulate Matter

USP <771> states that topical ophthalmic products must comply with USP <790> Visible Particulates in Injections. To comply with the acceptance criteria of “essentially free of visible foreign particles,” the draft guidance recommends evaluating topical ophthalmic products packaged in opaque bottles using non-destructive methods such as X-ray or destructive methods such as transferring the contents to another clear container for visual inspection. Before May 1, 2024, USP <789> was titled Particulate Matter in Ophthalmic Solutions; its title has now changed to Subvisible Particulate Matter in Intraocular Solutions to emphasize that USP <789> applies only to intraocular solutions and not to topical ophthalmic products. Intraocular solution products must comply with both USP<790> and USP<789>.

3. Extractables and Leachables

The draft guidance discusses how extractables and leachables studies should be performed for CCSs and provide thresholds for reporting, identification, and qualification. It recommends that applicants evaluate the primary, secondary, and tertiary packaging components because semi-permeable CCSs can, over time, leach low molecular weight compounds (e.g., plasticizers, lubricants, pigments, stabilizers, antioxidants, binding agents) or label-related substances (e.g., inks, adhesives, varnishes) into the drug product. The CCS should also comply with USP<87>, <88>, <660>, and <661>.  Compliance with USP<87>, <88> may be satisfied by statements from the resin vendors.  USP<660> and <661> are performance tests for the CCS.

3.1. Extractables

The guidance states that applicants should provide the following information in their application for extractables studies:

• A risk assessment in support of their study approach.
• Data from their extractables studies, which should be conducted following the framework provided in USP General Chapter <1663> on primary (bottle, tip, cap), secondary (carton), and tertiary packaging components (label, wrapping etc.).
• Information about the use of extraction conditions (e.g., media, temperature, time, analytical techniques).
• An assessment of the resultant extractables profiles.
• For CCSs used in approved products marketed by applicants, the applicant could refer to the approved ANDA and NDA.

Neither this guidance nor USP <1663> provides specific action limits above which extractables should be evaluated. The common industry practice is to further evaluate extractables above the analytical evaluation threshold (AET) based on the daily maximum intake of these extractables. The analytical method used should have an LOQ that is less than or equal to the AET to ensure accurate detection and evaluation of extractables.

3.2. Leachables

Leachables monitored during storage are primarily those extractables that exceed the AET in the extractables studies. The following are required to properly characterize leachables:

• Data from three primary stability batches, each of which should be followed through expiry as described in USP General Chapter <1664>.
• Information about analytical procedures (e.g., gas or liquid chromatography-mass spectrometry), including method validation information.
• Leachables should be reported in ppm per unit volume or mass of the drug product.
• Set acceptance criteria for leachables in drug product specifications based on the following thresholds for NDA products: 
  • Reporting threshold (RT): 1 ppm
  • Identification threshold (IT): 10 ppm
  • Quantification threshold (QT): 20 ppm
• A toxicological risk assessment of leachables above QT.
• The analytical method used should have an LOQ that is less than or equal to the IT for leachables.

The author notes that the thresholds for leachables listed in the guidance are based on FDA review practice first presented at a PQRI meeting in 2011.  

The guidance does not address the role of simulated use leachables studies, which better represents the expected levels of leachables on stability. Since the guidance primarily provides a framework for extractables and leachable studies, applicants are advised to consult extractables and leachables subject matter expert as well as to engage with the Agency to discuss the study design and safety assessments.

4. Impurities and Degradation Products

4.1 NDA, ANDA, and OTC Monograph Drugs

In the guidance, a two-tier acceptance criterion, rather than those of ICH Q3B, is used for unspecific impurities (see table below).

FDA’s Recommended Thresholds for Unspecified Degradation Products or Impurities[2]

Drug Product Strength (% w/v)	Recommended Identification and Qualification Threshold
Greater than 0.1% to less than or equal to 1%[3] (> 0.1% to ≤ 1%)	0.1%
Less than or equal to 0.1% (≤ 0.1%)	1% or 1 ppm[4]

FDA adopts thresholds that differ from the ICH thresholds for unspecified impurities for two reasons. First, topical ophthalmic products are applied directly to the eye in small volumes, potentially resulting in high local concentrations that may cause local toxicity and irritation. Second, there are limited data on the potential effects of unspecified impurities. The author hopes that the FDA will continue to reevaluate the acceptance criteria for unspecified impurities and align them with the recommended ICH thresholds. Particularly for short-term use products, given the small amount of drug deposited onto the eye and given the effective removal mechanisms provided by blinking and lacrimal drainage.  However, until any future revisions are made, applicants must adhere to the recommended two-tier acceptance criterion for unspecified impurities.

4.2 BLA

• For a BLA, in addition to degradation products and product-related impurities, impurity considerations for ophthalmic biological products should include product-related substances. For example, charge variant profiles are known to be reflective of the mixture of product-related substances in addition to product-related impurities.
• Process impurities controls at product release based on risk assessments of the impurities of historical data and process clearance.
• Impurity amounts should be clearly defined as a percentage of the active ingredient or in current conventional units for ophthalmic biological products [e.g., milligram/milliliter (mg/mL), microgram/milliliter (µg/mL), nanogram/milligram (ng/mg)].

The key message for BLA products is to consider other product related substances in addition to the traditional paradigm of impurity evaluation.

5. In-vitro Drug Release/Dissolution Testing for Quality Control 

The use of in vitro drug release/dissolution testing is an optional quality control strategy for certain ophthalmic dosage forms such as suspension, emulsion, and semi-solid formulations. Justification is needed if one or more critical quality attributes (CQAs) that are sensitive to formulation and process variations are used in place of in vitro drug release/dissolution testing.

One of the biggest challenges in developing a biorelevant in vitro release testing methodology for topical ophthalmic products is their short residence time in the cul-de-sac. Therefore, it is encouraging to see that applicants could use CQAs as an alternative to in-vitro release test when appropriately justified.

6. Container Closure System (CCS) Design

The guidance provides a few points to consider when choosing a CCS; see below for the salient considerations.

6.1. CCS Design

6.1.1. Tamper-evident: The tamper-evident ring should remain attached to bottle after it is open. Applicants should be vigilant when the supplier of the tamper-evident ring CCS changes the manufacturing site, as even a slight change in the tolerance limit may result in a loose ring after the cap is opened.

6.1.2. Sealed tip: The activation process of a sealed tip that requires piercing prior to use should be a single piercing step.

6.1.3. Torque force: The torque force of unscrewing the cap should be easy enough to open but will not come loose easily during storage and transport.

6.1.4. Color coding: The American Academy of Ophthalmology’s Color Codes for Topical Ocular Medications policy statement should be followed.

6.2. Delivery and Dispensing Characteristics

6.2.1. Unit dose

The fill volume should be no more than (NMT) 0.5 mL for liquid and NMT 1 g for semi-solid.

6.2.2. Multidose

Drop Size: The selection of drop size for a multidose CCS is a balance between minimizing water loss and providing the appropriate number of doses for the course of treatment. For ANDA products, applicants should perform a one-time drop size study to demonstrate that the drop size is within ± 10% of the reference listed drug (RLD) throughout the product’s use. However, there is flexibility for drop size exceeding 30 µL, as the maximum volume the cul-de-sac can transiently accommodate is about 30 µL. Any drop size above 30 µL results in spillage onto the cheek. Therefore, if the RLD product’s drop size is greater than 30 µL, the ANDA product may use a different drop size tip, provided that it can deliver a similar number of doses as the RLD.

Applicants should include details on the measurement of drop volume or drop weight along with testing conditions such as the number of drops in the container and the angle of the container during dosing. A common industry practice is to evaluate drop size at both 45 and 90 degrees.

Dose Uniformity: The applicant should perform a one-time labeled dose uniformity study during use on three pilot/exhibit or clinical batches of a multi-dose suspension. These studies should be conducted throughout the product shelf life at the beginning, middle and end of use of the suspension in the bottle to ensure dose uniformity and dose consistency.

7. Stability Studies

7.1. Storage Orientation

NDA: The orientation of the primary batches and commercial batches should be set based on the worst-case orientation observed in the stability of the development batches (upright or inverted/horizontal).

BLA: The orientation of the primary batches and commercial batches must be determined by primary batches  

ANDA: For ANDA products, both conditions (upright or inverted/horizontal) should be evaluated for exhibit batches and the worst case of storage position for commercial batches.

7.2. Water Loss

Water loss data should be included in the application to support product stability.  A common industry practice is to set aside 10 bottles packaged in a secondary package for the water loss study.

7.3. Freeze-thaw Study for Emulsion/Suspension

A freeze-thaw study should be performed once, with 3 cycles at temperatures ranging from -20°C to 0°C and ambient temperatures (25°C to 35°C) for a cumulative minimum of 3 days with full testing at the end of each cycle (12 hours) and compared to the control product to assess any potential impact on product quality.

7.4. In-Use Stability Studies

In-use stability studies are used to establish expiration dates and support labeling claims for appropriate storage conditions after opening, such as a change in temperature or light exposure [see 21 CFR 211.166, 21 CFR 211.137(b)]. However, these cited CFR regulations pertain to establishing expiration date for unopened bottles. Currently, the FDA has not provided guidance on in-use study requirements for opened bottles. Therefore, applicants should consult subject matter experts and discuss their in-use stability protocol with the FDA beforehand to ensure compliance with regulatory expectations.

7.5. Expiry Dating

• The expiry date of drug product is approved based on stability data from 6-month accelerated and 12-month long-term conditions of the primary batches in the submissions. For small molecules, 2-year expiry date stored at long-term at controlled room temperature will be granted based on satisfactory 12-month long-term and 6-month accelerated data. For biologics, extrapolation is generally not permitted, and the expiration date is assigned based on real-time stability data.
• The expiry date for OTC products is set by individual companies based on their internal policies. According to FDA regulations, OTC products with no dosage limitations and are demonstrated to be stable for 3 years, supported by stability data, are not required to display an expiry date on the label.  However, companies may still choose to include an expiration date as part of their quality assurance practices.

Conclusions

The FDA draft guidance provides the current FDA thinking on several quality considerations for ANDA, NDA and BLA submissions of topical ophthalmic drug products. The guidance is not exhaustive and in draft form, subject to future revision. However, applicants should consider and follow the recommendations in the draft guidance until it is updated. 

The acceptance criteria of unspecified impurities in chemical drugs have been relaxed with a two-tier acceptance criteria approach, depending on the concentration of the ophthalmic product. However, industry comments suggest that there is no reason that the ICH recommended threshold could not be used. The concern for local toxicity may be exaggerated, considering the low dose and rapid clearance of the liquid formulation from the precorneal area. 

Although some sections in the guidance are prescriptive, others lack specifics or require clarifications. The Agency should clarify whether approved products are grandfathered under the guidance. If the guidance applies to approved products, FDA should specify what kind of data and how the data should be submitted.

How ELIQUENT Life Sciences Supports FDA Submissions for Ophthalmic Drug Products

ELIQUENT Life Sciences provides deep regulatory and CMC expertise to help Sponsors interpret and execute the FDA’s quality considerations for topical ophthalmic drug products. From microbiological controls and impurities to CCS design and extractables and leachables FDA guidance, we guide you through the complex expectations for ophthalmic drug products intended for topical ophthalmic use.

Because elements of the FDA guidance for ophthalmic products remain open to interpretation, our experts – drawing on extensive industry and FDA review experience – help clarify requirements, develop phase-appropriate strategies, and support IND, ANDA, NDA, and BLA submissions. We ensure dossiers are written clearly, accurately, and in alignment with FDA expectations, helping Sponsors avoid review delays and secure timely approvals.

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[1] Quality Considerations for Topical Ophthalmic Drug Products, December 2023, https://www.fda.gov/media/172937/download

[2] These recommended thresholds apply to OTC monograph ophthalmic drug products and ophthalmic drug products submitted under NDAs and ANDAs.

[3] Limits above 1% will be evaluated on a case-by-case basis.

[4] Whichever is higher; ppm = parts per million (i.e., parts of a leachable per unit mass of the ophthalmic drug product).