Endotoxin Testing for Single-Use Intraocular Ophthalmic Devices
This guidance applies to single-use intraocular ophthalmic devices used within the eye, including: - Intraocular fluids (Class III viscoelastic surgical aids) - Anterior segment solid devices like intraocular lenses, capsular tension rings, glaucoma devices - Phacofragmentation system accessories (irrigation/aspiration sleeves and tubing) The guidance specifically focuses on endotoxin testing recommendations to prevent Toxic Anterior Segment Syndrome (TASS).
What You Need to Know? 👇
What is the FDA-recommended endotoxin limit for ophthalmic viscosurgical devices (OVDs)?
The FDA recommends an endotoxin limit of ≤0.2 EU/mL for OVDs, regardless of whether they’re used in anterior or posterior segments. This is stricter than the ISO 15798 standard of 0.5 EU/mL, which FDA doesn’t recognize due to inflammation risks.
How should endotoxin testing be validated for viscous ophthalmic devices?
Validation should include recovery testing using three lots of OVD spiked with endotoxin at 0.1, 0.2, and 0.5 EU/mL concentrations. Each test must be conducted in triplicate. For high molecular weight HA-based OVDs, enzyme digestion may be needed to improve endotoxin accessibility.
What endotoxin limit applies to intraocular lenses and other solid anterior segment devices?
The recommended limit is ≤0.2 EU/device for all anterior segment solid devices including IOLs, iris reconstruction lenses, capsular tension rings, and the anterior chamber portions of glaucoma devices. This is more stringent than existing ISO standards.
What extraction conditions does FDA recommend for solid intraocular devices?
FDA recommends extraction at 37°-40°C with agitation for minimum 60 minutes to maximize efficiency. For cannulated devices, fill the fluid pathway with pre-warmed extracting medium and hold at 37°±1°C for at least 60 minutes.
What is TASS and why is endotoxin testing critical for preventing it?
TASS (Toxic Anterior Segment Syndrome) is a sterile inflammatory condition following intraocular surgery that can cause vision loss and require additional surgeries. Endotoxin contamination from medical devices is a major cause, with incidence increasing from 1 in 1,000 to 2 in 100 cases.
Can ophthalmic viscosurgical devices be labeled as “non-inflammatory”?
No, the phrase “non-inflammatory” should not be used in OVD labeling since some inflammation may occur. Devices may be labeled as having “low inflammatory potential” if animal testing or validated inflammation detection methods are performed as product release tests.
What You Need to Do 👇
Recommended Actions
- Implement endotoxin testing as part of release testing for all applicable devices
- Validate endotoxin test methods specifically for OVDs following the prescribed protocol
- Adjust extraction parameters for solid devices based on size while maintaining required sensitivity
- Review and update product labeling to ensure compliance with inflammatory claims guidance
- Consider submitting a Pre-Submission to FDA for feedback if planning animal testing for OVDs
- Ensure test methods account for device-specific characteristics (e.g., high molecular weight materials)
- Document validation of all test methods and maintain records of endotoxin testing results
- Review existing quality control procedures to prevent endotoxin contamination during manufacturing
Key Considerations
Non-clinical testing
- For OVDs: Endotoxin test method validation required with 3 lots tested in triplicate at 0.1, 0.2 and 0.5 EU/mL
- For solid devices: Extraction testing at 37-40°C with agitation for minimum 60 minutes
- Animal testing optional for OVDs to support “low inflammatory potential” claim - requires intracameral injection and 72-hour monitoring
Labelling
- OVDs should not use “non-inflammatory” claim
- “Low inflammatory potential” claim allowed only with supporting animal testing data
Biocompatibility
- Endotoxin limit for OVDs: ≤0.2 EU/mL
- Endotoxin limit for anterior segment solid devices: ≤0.2 EU/device
Safety
- Special consideration for high molecular weight OVDs may require enzyme digestion
- For cannulated/lumened devices, fluid pathway must be tested
- Standard 40mL/device extraction ratio can be adjusted for small devices
Relevant Guidances đź”—
- Immunological Testing for Medical Devices: Evaluation and Assessment of Adverse Effects
- Use of ISO 10993-1 for Biological Evaluation and Testing of Medical Devices
Related references and norms đź“‚
- USP <85>: Bacterial Endotoxin Test
- ANSI/AAMI ST72: Bacterial Endotoxins - Test Methodologies, Routine Monitoring and Alternatives to Batch Testing
- ISO 15798: Ophthalmic implants - Ophthalmic viscosurgical devices
- ISO 11979-8: Ophthalmic implants - Intraocular lenses - part 8: Fundamental requirements Amendment 1