FDA issues guidance on assessing quality of topical ophthalmic drugs
The US Food and Drug Administration (FDA) issued new draft guidance recommending a battery of studies that manufacturers should use to assess the quality of topical ophthalmic drugs.The assessment includes visible particle studies, extractables and leachables studies, container closure system studies, as well as studies to assess impurities and degradation products.
FDA’s guidance was issued is a response to multiple recent incidents of contaminated eye drops, including an April 2023 warning letter to Pharmedica for making eye drops that could potentially cause blindness. In February 2023, FDA also notified consumers to stop using sterile eye drops made in India from Global Pharmaceutical Healthcare because of microbial contamination (RELATED: FDA warns Pharmedica over contamination controls for sterile eye drops, Regulatory Focus, 16 May 2023).
The draft guidance, issued on 13 October 2023, covers new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), and over-the-counter monograph drugs. It applies to solutions, suspensions, emulsions, gels, ointments, and creams intended for topical delivery in and around the eye.
In the guidance, FDA recommends the use of a “robust” visual inspection program to assess products for visible particles in products. The agency also recommends the use of X-ray spectroscopy or destructive testing to identify particles when products are packaged in opaque containers.
Manufacturers should also assess containers for the presence of extractables and leachables. “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 [container closure system], including the labeling components,” FDA wrote in the guidance.
For extractables studies, manufacturers should submit a risk assessment to support the study approach, as well as data from these studies. The studies should follow the framework set out in USP General Chapter <1663>.
For leachables studies, manufacturers should submit data from three primary stability batches and describe the type of analytical procedure used, such as gas or liquid chromatography-mass spectrometry. Manufacturers should also describe how these methods were validated.
Due to the variety of chemical species and the “enormous” capability of modern analytical techniques, it is not practical to identify all detected leachables for safety qualification, according to FDA. Instead, manufacturers should address compatibility and safety concerns of any potential leachables that exceed the qualification threshold. The safety assessment should address the ocular toxicity and irritancy potential of these leachables.
In the guidance, FDA recommends the following safety thresholds (expressed in parts per million or ppm):
- Reporting threshold of 1 ppm
- Identification threshold of 10 ppm
- Qualification threshold of 20 ppm
FDA recommends that NDA and ANDA applicants generally follow the International Council for Harmonisation’s (ICH) guidance for industry Q3B(R2) Impurities in New Drug Products, issued in August 2006 for reporting, identifying, and qualifying degradation products and impurities.
In cases when the CCS that holds an ophthalmic drug also delivers it, the delivery system may be considered a device constituent part and together with the drug may be regulated as a combination product.
“All containers of ophthalmic drugs must be sterile at the time of filling and closing and sealed to prevent product use without destruction of the seal. Additionally, ophthalmic drugs that are OTC drugs must comply with the tamper-evident packaging requirements of 21 CFR 211.132,” FDA wrote in the guidance.
The deadline for submitting comments is 12 December 2023. Comments can be submitted through regulations.gov using the docket number FDA-2023-D-4177.
Draft guidance
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