FDA writes warning to Nephron, calls response to violations ‘inadequate’

Nephron has been the subject of multiple recalls impacting millions of doses of medication.
Nephron has been the subject of multiple recalls impacting millions of doses of medication.(WIS News 10)
Published: Oct. 25, 2022 at 11:18 AM EDT
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WEST COLUMBIA, S.C. (WIS) - The FDA filed a letter warning a West Columbia pharmaceutical company to correct violations or it may face seizure or injunction.

Nephron Pharmaceutical has been under observation over the last year by the regulatory body. It has issued several recalls, impacting millions of units.

PREVIOUS COVERAGE

The latest letter is dated Oct. 11 and addresses Lou W. Kennedy, the Chief Executive Officer and Owner of the company. The letter says the FDA inspected the facility at 4500 12th St from March 28 to April 20 this year and is reviewing the company’s response from May 11.

The letter says there were several violations observed.

1. 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).

In the first violation subsection, the FDA wrote, “Your firm failed to conduct adequate and timely investigations relating to products made by both terminal sterilization and aseptic processing.”

It says Nephron testing found cross-contamination in at least three lots of drug products. The FDA said, “You failed to adequately identify the root cause or scope of potentially impacted lots in a timely manner.”

The FDA wrote that Nephron attributed the root cause to sterilization cycles and permeability on the container closure system used in production.

The FDA warned, “It is essential that your firm does not introduce risks through overlap of your outsourcing and conventional production operations by sharing equipment, facilities, processes, or personnel, as the applicable standards significantly differ in certain respects. The attempt to mix these operations and follow two different standards increases complexity and product hazards.”

Another investigation was opened on April 30, 2021, and remained open at the time of the FDA inspection on March 28, 2022. The FDA said the company continued to manufacture drug products with the same container system.

They said of Nephron’s conclusions, “Your response is inadequate. Your investigation does not consider other sources of contamination. With only limited data, you conclude that the measured level of cross-contamination was “negligible.”

2. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

In the second violation subsection, the FDA leads their warning with, “You did not establish appropriate environmental monitoring (EM) action levels for the ISO 5 critical area where drugs are most vulnerable to contamination.”

The FDA notes that Nephron revised its action levels for air, surface, and personnel monitoring. The organization again says, “However, your response is inadequate...”

3. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).

In the third violation subsection, the FDA tells Nephron, “You failed to demonstrate that the method used for sample collection for EM (e.g., use of tubing with a length of about (b)(4) and material) provides a meaningful and representative sample of conditions during production.”

The letter details the use of tubing and says Nephron’s response, “...You provide rationale for the sampling procedure and agree that the sampling should be collected as close to the point of fill as possible without impacting the airflow within the blow fill seal machine environment.”

The FDA highlights for a third time, “Your response is inadequate because, you did not provide supportive studies evaluating whether your sampling method is capable of adequality monitoring your ISO 5 environment as intended.”

FDA’S RECOMMENDATIONS AND CONCLUSIONS

The FDA recommended Nephron work with a qualified consultant to insure it is in compliance with FDA regulations.

The administration wrote that Nephron had recalled Ketorolac Tromethamine Injection after a phone call from the FDA on Aug. 2. This was in addition to four outsourcing facilities compounding drug products. Nephron planned to resume operations on Aug. 23.

The FDA said “Resumption of manufacturing your drugs terminally sterilized by moist heat should only occur once you have implemented effective CAPA and completed appropriate submission requirements.”

The FDA said their inspection indicated Nephron is in violation of Field Alert reporting requirements. Specifically, it notes a violation on April 2, 2021, and on May 27, 2022,

“We are concerned with the CGMP violations demonstrated at your facility and failure to submit FAR-related events within three days of becoming aware of a problem. Please include in your written response the corrective action you plan to take regarding distributed products manufactured at your facility that may be affected by the violations.”

The FDA said the violations highlighted in the letter are not an all-inclusive list of violations at the Nephron facility. It advised the company it is responsible for investigating violations and preventing future instances.

It warned Nephron, “Correct any violations promptly. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure and injunction. Unresolved violations may also prevent other Federal agencies from awarding contracts.”

Nephron has 15 days from the date of receiving the letter to respond and specify what they have done to prevent future issues.

To read the full letter click the link here.

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