FDA Warning Letter.
Mold deviation investigation.
U.S. Food and Drug Administration.
The FDA, U.S. Food and Drug Administration, issued a warning letter to Sun Pharma India, which included an investigation into mold deviations.
Some of the original texts are as follows.
your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 cfr 211.192).
your investigations into water leaks in your cleanroom were inadequate because they lacked appropriate capa and failed to extend to other potentially affected batches.
for example, water leaked from the service floor through the heating, ventilation, and air conditioning (hvac) duct floor and into the ceiling directly above the iso 5 filling area. your investigation report noted water accumulated on the service floor due to a leak from an old, punctured (b)(4). water then collected over the (b)(4) partition ceiling prior to entering the aseptic filling room where medroxyprogesterone acetate injectable suspension usp, was manufactured. your personnel confirmed there was substantial water accumulation on the service floor.
although you sealed gaps in the ceiling, you did not sufficiently inspect the service floor, (b)(4) laf ceiling, and hvac duct floor for mold growth and water damage after the repairs were made. you also failed to extend the scope of your investigation to potentially impacted batches of medroxyprogesterone acetate injectable suspension usp manufactured in this room since the last preventive maintenance of the (b)(4), approximately two months before the leak was observed.
in your response, you state the leak was isolated to the day it was observed. you acknowledge that your investigation did not evaluate the impact of the leak to other batches. you initiated a recall on may 17, 2022, for all marketed batches of medroxyprogesterone acetate injectable suspension usp, 150 mg/ml, 1 ml vials manufactured on this line, for events unrelated to this investigation.
your response is inadequate. while we acknowledge you initiated actions to address this specific leak, your investigation failed to sufficiently address facility damage and the potential for microbial (i.e., particularly fungal) contamination that could persist in the facility due to water leaks and moisture.
in response to this letter, provide a comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, oos results, and failures. provide a detailed action plan to remediate this system. your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, capa effectiveness, quality assurance unit oversight, and written procedures. address how your firm will ensure all phases of investigations are appropriately conducted.
Summary of key points.
In the injection workshop of the pharmaceutical factory, medroxyprogesterone acetate injection suspension is produced. Mould was found during daily monitoring in the filling room.
After the mold was discovered, the deviation investigation began, and it was found that the technical interlayer of the filling room was leaking, which happened to enter the filling room, causing the mold to occur.
The pharmaceutical plant took measures: it sealed the gaps in the ceiling.
But the FDA believes that sealing the gaps in the ceiling is not enough. For example, the comprehensive inspection of the technical mezzanine, the treatment of other rooms and mezzanine caused by water leakage has not been done.
Whether the air conditioning system is contaminated by mold has not been investigated and treated. If the air-conditioning system is polluted, it will become a serious hidden danger, and the pollution of the air-conditioning system is difficult to deal with.
FDA requirements: A comprehensive, independent assessment of the entire system to investigate deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate the system. Your action plan should include, but is not limited to, significant improvements in investigative capabilities, scoping determination, root cause assessments, CAPA effectiveness, quality assurance unit oversight, and written procedures. Explain how your company will ensure that all stages of the investigation are conducted appropriately.
Mold is terrible for a cleanroom.
The most common mold in pharmaceutical cleanrooms (Penicillium).
The hyphae are usually colorless and the conidia are blue-green in color.
Conidia are the main mode of dispersal of the bacterium, but not all Penicillium are blue-green, but also white or green.
The genus prefers a moist, shady environment.
Penicillium is also a common environmental fungus that can be isolated in indoor air and dust.
It can even survive on the ceiling.
It is also easy to detect in lactose, a pharmaceutical raw material.
According to one study, the total detection rate of clear fungi in cleanrooms was 51%.
Mold in the condition of matter, humidity and nutrients, can be detected in the return air duct of the air conditioning system within 3 days.
Fantong engineers can do it.
Tracing the source of mold discovery: using molecular biotechnology, determine whether the contamination is from a technical interlayer or a raw material.
Other rooms (including technical intersections) for mold monitoring, typing.
Assessment of contamination in air conditioning systems.
The clean area includes a technical mezzanine with a comprehensive disinfection process.