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Quality Considerations for Topical Ophthalmic Drug Products  Guidance for Industry 

DRAFT GUIDANCE 

This guidance document is being distributed for comment purposes only.



U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) 

December 2023 Pharmaceutical Quality/CMC


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IV.       EXTRACTABLES AND LEACHABLES


Ophthalmic drug products should be evaluated for extractables and leachables from the CCS.Leachables have the potential to interact with the formulated drug product, which could compromise product quality and therapeutic effect. The assessment of extractables and leachables should consider the primary, secondary, and tertiary packaging components of the CCS, including the labeling components.


Semipermeable CCSs can, over time, leach low molecular weight compounds (e.g., plasticizers, lubricants, pigments, stabilizers, antioxidants, binding agents) from CCS components or from labeling components (e.g., inks, adhesives, varnishes) into the drug product. However, this is less of a concern for products packaged in glass containers (e.g., biological products).


General tests for CCSs are described in USP General Chapters, such as <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. For more information about testing extractables and leachables, applicants and manufacturers should consult USP General Chapters <1663> Assessment of Extractables Associated With Pharmaceutical Packaging/Delivery Systems and <1664> Assessment of Drug Product Leachables Associated With Pharmaceutical Packaging/Delivery Systems. Applicants should also refer to the guidance for industry Container Closure Systems for Packaging Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Documentation (May 1999).




A.       Extractables Studies

Where extractables testing is conducted to comply with CGMP requirements, manufacturers should document the following information about their extractables studies, and applicants should provide this information in their application (see 21 CFR 211.194(a)).


  • A risk assessment in support of their study approach.
  • Data from their extractables studies, which generally should be conducted following the
  • framework provided in USP General Chapter <1663> and should take into account the primary, secondary, and tertiary packaging components.
  • Information on the use of extraction conditions (e.g., media, temperature, time, analytical techniques).
  • An assessment of the resultant extractables profile


Where a CCS has been used in an approved ophthalmic drug product, an applicant can refer to previously submitted information to address the recommendations above, when feasible and with adequate justification.





B.        Leachables Studies


Because leachables can stem from different sources and be formulation dependent, applicants and manufacturers 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.


Where leachables testing is conducted to comply with CGMP requirements, manufacturers should document the following information about their leachables studies, and applicants should provide this information in their application (see 21 CFR 211.194(a)).


  • Data from three primary stability batches, each of which generally should be followed through expiry as described in USP General Chapter <1664>.
  • Information on the use of analytical procedures (e.g., gas or liquid chromatography–mass spectrometry), including method validation information.
  • An assessment of the resultant leachables profiles.
  • The acceptance criteria contained in drug product specifications.


In addition to the leachables studies, a separate toxicological risk assessment of the leachables should be conducted.



C.        Safety Thresholds

Because of the variety of chemical species and the enormous capability of modern analytical techniques in detecting trace amounts of chemicals, it is neither practical nor necessary to identify all detected leachables for safety qualification. However, because ophthalmic drug products are applied directly to the eye, applicants and manufacturers should assess compatibility and safety concerns of any potential leachables exceeding the qualification threshold discussed below. The safety assessment should address the ocular toxicity and irritancy potential of such leachables, in addition to systemic safety, as appropriate. 


Applicants and manufacturers can use a safety threshold approach to assess the potential of leachables and extractables to leach into and/or interact with the formulated drug product. 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.


Manufacturers should document information about their safety thresholds, and applicants should list leachable impurities above the reporting threshold along with other impurities in the drug product specification section of NDAs and ANDAs, but not in BLAs (see 21 CFR 211.194).