Guest Column | November 2, 2023

FDA Seeks Comment On Quality Considerations For Topical Ophthalmic Drug Products Draft Guidance

By Susan Shockey, Clarkston Consulting

eye drops-GettyImages-1406386094

On Oct. 13, 2023, the FDA published draft guidance titled Quality Considerations for Topical Ophthalmic Drug Products1 to address quality considerations for ophthalmic drug products consistent with the current good manufacturing practice (cGMP) requirements. The guidance also provides recommendations to the industry on the documentation that should be submitted in the chemistry, manufacturing, and controls (CMC) section of NDAs, ANDAs, and BLAs for certain CMC attributes for ophthalmic drug products. It is intended to provide additional guidance on specific quality requirements for the manufacturing and testing of ophthalmic drug products.

This guidance was issued as a response to several recent observations regarding the contamination of eye drops. These included an April 2023 warning letter to Pharmedica for making eye drops that could potentially cause blindness, and a February 2023 FDA notification to consumers to stop using sterile eye drops made in India by Global Pharmaceutical Healthcare due to microbial contamination.

Key Takeaways For Quality Considerations For Topical Ophthalmic Drug Products

This draft guidance discusses certain quality considerations for ophthalmic drug products (such as solutions, suspensions, emulsions, gels, ointments, and creams) intended for topical delivery in and around the eye. Specifically, it addresses the following four topics:

  • 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.

Below, we dive deeper into each of these areas and provide a summary of the recommendations.

Approach To Evaluation

Visible Particulate Matter: For topical ophthalmic drug products packaged in opaque containers, appropriate technologies (e.g., X-ray spectroscopy) or destructive testing should be used to identify particulates within the accepted visible size range.

Extractables and Leachables: Ophthalmic drug products should be evaluated for extractables and leachables from the CCS. Because leachables can stem from different sources and be formulation-dependent, applicants should have adequate data to identify and characterize the potential risks associated with the leachables from the CCS and describe how these risks are mitigated, such as by conducting leachables studies. Extractables studies should include information on the use of extraction conditions and analytical procedures used. The assessment of extractables and leachables should also consider the primary, secondary, and tertiary packaging components of the CCS, including the labeling components. Risk assessments in support of the study approach should be provided. Because ophthalmic drug products are applied directly to the eye, applicants should assess compatibility and safety concerns of any potential contamination. The safety assessment should address the ocular toxicity and irritancy potential of such leachables, in addition to systemic safety, as appropriate.

Impurities and Degradation Products: Applicants should generally follow the principles of reporting, identifying, and qualifying degradation products and impurities outlined in the International Council for Harmonisation (ICH) guidance for industry Q3B(R2) Impurities in New Drug Products (August 2006).2 For ophthalmic biological products, impurity considerations should include product-related substances in addition to degradation products and product-related impurities. Acceptance criteria should be established for impurities, including leachables and process impurities, as required to control product quality, safety, and efficacy.

In-Vitro Drug Release/Dissolution Testing For Quality Control

Applicants can consider the use of in-vitro drug release/dissolution testing as part of the quality control strategy for certain ophthalmic dosage forms (e.g., suspensions, emulsions, and semi-solids) to ensure consistent quality related to formulation and process variants. Scientific justification for how the control strategy will ensure consistent product quality should be provided.

Container Closure Systems

CCS Design Characteristics: Containers of ophthalmic drugs must be sterile and sealed and comply with the tamper-evident packaging requirements of 21 CFR 211.132.3 Single-step procedures are recommended for opening tips that are sealed, with consideration of torque specifications for CCS. Torque must be low enough that special populations, such as the elderly, can open caps, but high enough so that caps remain in place during manufacturing, shipping, and handling. The FDA recommends color coding the caps of ophthalmic drug products using a uniform color-coding system as described in the American Academy of Ophthalmology’s Color Codes for Topical Ocular Medications4 policy statement.

Delivery and Dispensing Characteristics: The FDA provides maximum fill volumes for unit dose containers and recommends that they cannot be recapped. For multi-dose containers, the FDA provides drop size recommendations and suggests a volume/drop weight study be conducted to determine drop size. Additionally, the FDA recommends that tests be performed to demonstrate that the drug substance is uniformly dispersed and the labeled dose can be consistently delivered. Submissions should include information on the testing conditions used.


Manufacturers of drug products, including over-the-counter (OTC) manufacturers, must establish a program to evaluate the stability of drug products and use the results of the stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166). The following stability recommendations should be considered when developing a stability testing program:

  • Container Orientation During Storage: Applicants should evaluate storage conditions in two different orientations — an upright position and either an inverted or horizontal position. Data should be used to capture and characterize differences in quality attributes, if any, and determine the worst-case orientation. NDA applicants should use this worst-case orientation for stability studies, and all applicants should include justification for the orientation used.
  • Water Loss: Applicants and manufacturers must conduct water loss studies and provide documentation on test methods and acceptance criteria used.
  • Freeze/Thaw studies for Emulsions and Suspensions: Applicants and manufacturers should perform a freeze/thaw thermal cycling study to evaluate the effects of any high- and low-temperature variations that may be encountered during shipping and handling, which could affect the quality and performance of the drug product.
  • In-Use Stability Studies: In-use stability studies are used to determine expiration dates and support labeling claims for appropriate storage conditions that may change after opening, such as a change in temperature or light exposure.

Next Steps

Guidance documents represent the FDA's current thinking on a topic, while draft guidance is issued to solicit public input prior to implementation. Generally, the public has 60 days to provide comments to FDA on draft guidances. Comments on this draft guidance are due Dec. 12, 2023, and can be submitted through using the docket number FDA-2023-D-4177.


  1. U.S. Food and Drug Administration. (2023, October 13). Quality Considerations for Topical Ophthalmic Drug Products.
  2. U.S. Food and Drug Administration. (2021, September 29). Q3B(R) Impurities in New Drug Products (Revision 3).
  3. U.S. Food and Drug Administration (2023, June 7). Code of Federal Regulations Title 21.
  4. American Academy of Ophthalmology. Color Codes for Topical Ocular Medications.

About The Author:

Susan Shockey is a director with Clarkston Consulting and has wide-ranging experience in quality and regulatory compliance. She has 18 years in the life sciences area, focusing on quality systems, quality process improvement, and inspection preparation and remediation. Prior to that, she spent 15 years in quality assurance engineering supporting manufacturing, testing, and validation of NASA space flight and military hardware.