In September 2022, an FDA inspection found that a company in Puerto Rico had released numerous batches of an infusion product – i.e., destined to be put directly into the human bloodstream – even though microbiological plate testing showed the product contained high levels of a microbiological contaminant, designated Too Numerous to Count (TNTC).

The products were approved based on “parametric release,” – a practice that relies on process control rather than testing to assure the sterility of products. However, the company had “no procedures or practices to consider bioburden results as part of parametric release of products,” according to the FDA Form 483 issued after the inspection.

The product went through a terminal sterilization process, prior to release, but no actual sterility testing was conducted to determine product sterility.

At the 48th annual International GMP Conference held in early March 2024 at the University of Georgia in Athens, Georgia, Parexel Vice President, Technical-Strategic Compliance Consulting, and former FDA Drug National Expert Investigator Ileana Barreto-Pettit analyzed the 483 from this inspection and the resulting warning letter and provided her insights.

The first observation from the September 2022 483 issued to Fenwal International, a Fresenius Kabi company, “the most significant one in the 483,” she pointed out, began, “Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to final specifications prior to release.”

Barreto-Pettit explained that investigators found the TNTC results for bioburden documented in one of the company’s annual product review documents.

“If you have any inspections with the FDA, or if you are familiar with the compliance programs that the FDA follow, like [CPG] 7356.002, the first thing in the quality system that an investigator must cover is the annual product reviews. Investigators can detect this on the first day if they follow the compliance program.”

The annual product reviews for 2021 and 2022 documented that several products had TNTC bioburden results, then were put through a terminal sterilization process and released based on parametric release with no sterility testing.

Did Bioburden Result from Cleaning Issues?

The former FDA National Expert commented that issues regarding cleaning of the equipment and facilities are likely related to the bioburden observations.

She noted that in the 483, “the investigators took these TNTC bioburden results and tied it to equipment and facilities issues. It doesn’t say that in the 483, but that is what they did. Where did the contamination come from?”

Observation 3 states, “Equipment and utensils are not cleaned and maintained at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality or purity of the drug product. Specifically, equipment and facilities are not adequately maintained and cleaned.”

During a walk-through of the facility, investigators found numerous facility and cleaning shortcomings. Barreto-Pettit highlighted the following:

  • A yellow water catchment tarp full of water in the technical space above the ceiling.
  • Apparent black biological growth on room supply HEPA filters in the mixing room.
  • Cracked and peeling surfaces on the floor and the walls of the mixing room and flaking paint
  • A diffusion grate above the filling nozzles had broken edges and residue spots
  • Tubing ports missing
  • Brown residue and spots on filling equipment surfaces.

“When investigators find these kinds of issues, I always wonder, because I found these types of issues myself, what is the company looking at?” she asked.

“Do the operators see these things? Are they reporting them to the supervisor or to the quality unit? Everybody is responsible. These things should not be happening. You have an FDA investigator, and they are walking around, and they are seeing black stuff on your HEPA filters, gaps in the ceiling, and equipment that looks like it is not clean.”

“When you get a laundry list like this of maintenance issues,” she commented, “this is either an aging facility that is not well maintained, or you have, obviously, a quality unit that is not doing its job, and a company that has not empowered the employees to report these types of issues.”

FDA Warning Letter Issued

The nine-day September 2022 inspection of the Fenwal International facility in Maricao, Puerto Rico, resulted in a drug GMP warning letter issued to Bad Homburg, Germany-based parent company Fresenius Kabi, almost exactly one year later.

The primary citation was for inadequate deviation investigations, i.e., “Failure to follow established, approved written procedures and thoroughly investigate any unexplained discrepancy or the 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].

That citation resulted from not performing investigations into at least 28 batches of terminally sterilized products that exceeded the bioburden limit, including TNTC “swarming organisms.”

The bioburden as represented on the microbiological plates, Barreto-Pettit emphasized, was “too numerous to count.” Addressing the site personnel, she said, “and you released it. You did not investigate. You trusted that your sterilization process will take care of all these bacteria.”

The letter also notes the issue with not conducting failure investigations is a repeat observation: “Your firm’s failure to conduct adequate failure investigations is a repeat deficiency noted during our 2010, 2012, 2013 and 2021 inspections.”

Also cited was the firm’s calculation of the sterility assurance level (SAL) of finished products. Sterility assurance level is the probability that a single unit that has been subjected to sterilization still contains a microorganism that survived the sterilization process. For example, if the probability of a spore surviving were one in one million, the SAL would be 10−6. It is based on a calculation that requires knowing the beginning bioburden level and cannot be calculated without that number; TNTC is not a number.

The form 483 stated that investigators “observed apparent black biological growth on room supply HEPA filters” in a mixing room. The warning letter reports that the company tested the material and said that the residue on six of the HEPA filters was identified as mold.

“So what do you have here?” Barreto-Pettit asked. “You have a facility that is completely out of control.”

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