Turning Nasal Drops into Eye Drops - not a good Idea from the FDA's Point of View

Recommendation

4/5 October 2022
Heidelberg, Germany

Process Validation in the light of the revised Annex 15 and FDA Requirements

In a Warning Letter, the FDA criticises the fact that eye drops from a Chinese manufacturer were not produced under sterile conditions. The manufacturer's response is somewhat bizarre. He argues that he manufactured the eye drops under non-sterile conditions as nasal drops. Of course, the FDA did not accept this argument. Citing the FDA Aseptic Guide, the Warning Letter shows what the FDA considers to be the state of the art in aseptic manufacturing.

FDA Requirements for Sterile Manufacturing

Among other things, the authority requires from the manufacturer a risk assessment with regard to contamination risks in relation to aseptic manufacturing. In particular, the following should be considered:

• all human interactions in the ISO 5 zone
•  Equipment placement and ergonomics 
• Air quality in and around zone 5 
• Layout of the premises 
• Personnel and material flow

Furthermore, a detailed overview of the validation programme is required, especially with regard to Process Performance Qualification (PPQ) and Continued Process Verification with the corresponding procedures. Furthermore, a timeline for the PPQ is required, as well as SOPs for qualification and sterilisation of the equipment.  An overview of the media fill programme is also required. The investigation of positive findings and the balancing of the filled units, with the corresponding procedures, are to be explicitly addressed. The FDA also asks for risk-based smoke studies on air flows at the filling line to be submitted.

Also addressed are updates to the environmental monitoring work instructions regarding:

• Frequency, location and duration of sampling 
• Size of sampling 
• Specific sampling equipment and techniques 
• Warning and action limits for each sampling location and a description of the function of that location and ISO classification 
• Measures to investigate results outside the limit 
• Identification of the microorganisms found in the samples

Furthermore, the FDA still addresses appropriate microbiological batch release specifications and requires all chemical, physical and microbiological test methods used to analyse the eye drops.

Conclusion: In this Warning Letter, the FDA shows what the authority considers to be the state of the art in aseptic manufacturing. You can find the Warning Letter on the FDA website.