*Author’s Note: We’ve updated this post with fresh up-to-date data from the Redica Systems dataset, in the last section titled Issues with HEPA Filters Continue*

GMP Case Studies Presented by FDA Investigator Ileana Barreto-Pettit: Part III

During an inspection of a firm performing aseptic manufacturing of sterile products, FDA investigators observed HEPA filters in the manufacturing area that were discolored. In response to this observation, the company told the agency that the discoloration of the filters was due to a fumigating agent and that the filters had been “recolored.”

[Related: Download a FREE compilation of this and the other three articles in this four-part series by Jerry Chapman here.]

4 GMP Case Studies

This and other aseptic manufacturing problems discovered during that inspection were the subject of a GMP case study presented at the International GMP Conference held virtually in March 2022 co-sponsored by the University of Georgia at Athens and FDA. It was one of four case studies shared by FDA Office of Regulatory Affairs National Drug Expert Captain Ileana Barreto-Pettit from recent drug Good Manufacturing Practice (GMP) inspections that were used to illustrate agency findings and concerns.

Barreto-Pettit has been with FDA for 23 years. She has been a drug investigator since 1999 and a Drug National Expert Investigator since 2017, and is a Captain in the U.S. Public Health Service Commissioned Corps.

The GMP inspection case studies Barreto-Pettit provided include an in-depth analysis of the findings, lessons learned, and how companies can avoid similar shortcomings. Areas examined in the case studies are:

Part I covering change management findings in Warning Letters is available here. Part II covering cross-contamination in pharma manufacturing facilities is available here. This part covers deficiencies in aseptic manufacturing. The final case study will be covered in the last part.

Poor Aseptic Capability

Barreto-Pettit presented a case study from a company that she characterized as having “low capability aseptic technology” as evidenced by “poor barrier protection,” a manually-intensive operation, and a processing line that was “poorly designed, resulting in inadequate protection from contamination hazards.” The company manufactured ophthalmic drugs.

A Warning Letter issued to the company stated, “the barriers used to separate the ISO 5 area from the ISO 7 area in the aseptic filling room had substantial gaps and provided insufficient barrier protection.”

Additionally, the firm did not perform studies on the static or dynamic conditions of the aseptic processing line to determine if airflow was unidirectional.

Based on the deficiencies identified during the inspection, the filling room and the processing line were found to be improperly designed to support the manufacturer of aseptically filled drug products. In addition, agency investigators observed excessive numbers of personnel performing the aseptic production, poor line design, and a lack of proper aseptic technique.

The letter further alleged that, “manual or mechanical manipulations of the sterilized drug, the components, containers, and closures before or during the aseptic assembly can pose contamination hazards and require strict control.”

ISO 5 Area Examined

The FDA National Expert Investigator also shared contamination concerns found in the ISO 5 area of the drug manufacturing facility.

One concern was an ISO 5 area including HEPA filters that appear “either dirty or stained and could potentially be a hazard to the sterility of the product that is directly below them.”

In Figure 1, “note there is a gap between curtains that looks like it is about one foot wide that is connected to the ISO 7 area,” she said. “That could potentially be a hazard.”

Figure 1 Aseptic Filling
FIGURE 1 | Aseptic Filling

It is hard to see in the photo but the operators are not wearing goggles that cover all exposed skin on the face. Instead, they wear goggles that partially cover their eyes while skin is exposed on their foreheads and on the side of the goggles, Ileana Barreto-Pettit explained.

“Also, both sides of the filling line seem to be cluttered with boxes or trays that could potentially bring some dirty air into the filling line. And there is another operator that has his skin exposed, and, in addition, touches the curtains with his hands.”

Additionally, the firm did not perform studies on the static or dynamic conditions of the aseptic processing line

In the area where the product was being filled, boxes are being stored. “Just imagine the airflow [see the red arrows in the photo] potentially bringing contaminants into the critical zone. It is interesting to see how this is organized. And then on top of it, they had no smoke studies, so we could not determine what the airflow is. But I imagine it would not pass a smoke study, because there is just too much going on in this very small ISO 5 area.”

[Related: Our data shows that of the human drug FDA 483 observations from the previous five years, 22 primary citations and 391 secondary citations concerned smoke studies. Want to learn more about how to generate reports on the 483 observations involving aseptic processes? Contact us to schedule a tour of our Enforcement Analytics and take your inspection preparation to the next level.]

Smoke Studies

Sterility Failures Lead to Import Alert

Issues discovered in the facility on inspection were likely causes of multiple sterility failures discovered when products were tested.

“We tested a lot that was shipped to the United States and it failed sterility testing. We cited the company’s quality unit for failing to perform an investigation when personal monitoring results for operators engaged in the manufacturer of this drug product exceeded the firm’s action limits,” she said.

Testing identified the presence of gram-positive rods. “Even though they had exceeded the action limits, and they had gram-positive rods, they approved the personal monitoring report as compliant, and the product was approved by the quality unit and distributed to the United States,” the FDA investigator lamented. “The company did not think it was necessary to investigate and or reject this particular batch.”

When FDA tested product upon entry into the United States, it confirmed that the purportedly sterile drug product was contaminated with multiple microorganisms. Testing showed gram-positive coccobacillus, gram-positive spore-forming rods, and gram-positive cocci, as well gram-negative rods.

The company was placed on import alert, which means FDA will not allow any of the product to come into the United States until corrective actions are taken.

Response Inadequate

In response to the 483 issued by the agency, the firm sent a response to the 483 that further indicated a lack of understanding of contamination and sterility control.

The company responded that no investigation was conducted regarding the sterility failure because the lot of the drug product in question was the last one of that product to be manufactured.

The company did not think it was necessary to investigate

“That is never a reason not to conduct an investigation for a sterility failure,” Barreto-Pettit stressed. “As we say in the Warning Letter to them, a sterility failure signals severe hazards in the operation and it is indicative of the overall capability of the aseptic process.”

Investigations must be conducted for any sterility failure, even if no additional lots of that specific drug are manufactured. Investigations identify deficiencies in the aseptic process that may have affected other drug products produced by the firm.

Information Requested by FDA

In the Warning Letter that was issued to this firm, FDA requested the firm provide a comprehensive identification of all contamination hazards with respect to its aseptic processes, equipment, and facilities.

In addition, the agency requested the firm provide an independent risk assessment that includes, but is not limited to:

  • All human interactions with the ISO 5 (Class 100) area
  • Equipment placement and ergonomics
  • Air quality in the ISO 5 (Class 100) area and surrounding room
  • Facility layout
  • Personnel flow
  • Material flow
  • Classified room design and construction

“This is not anything new,” the FDA investigator maintained. “These are things that you should have when you are conducting aseptic process operations. You need to have a risk assessment. You need to identify hazards to properly design the facility and the process. In this case, this company seemed to not have any of these basic requirements,” she maintained.

The Color of HEPA Filters

Barreto-Pettit provided another photo taken during the inspection of HEPA filters that she characterized as “stained” (Figure 2).

Figure 2 Discolored HEPA Filters
FIGURE 2 | Discolored HEPA Filters

In the Warning Letter, the agency stated, “the filling machine and high efficiency particulate air (HEPA) filters located directly above the filling machine in the filling room were significantly discolored with an unknown substance.”

Barreto-Pettit commented, “you can see it looks like it has some orange type stains, not only in the filter, but also around in the frame of the filters that obviously could not be cleaned.”

In response to the 483, the company told FDA that the discoloration of the HEPA filters and the filling machine was due to a fumigation agent it used. “However, they did not provide any evidence or justification demonstrating the source of the staining,” she reported.

“And even more interesting, they said in response to the 483 that the discolored HEPA filters are now recolored. In my 20 plus years’ experience I have never seen this. The Warning Letters said that it is unacceptable to recolor HEPA filters. We are not sure what they meant by this. But they did not provide an assessment of the impact of the residues on HEPA filter performance, or the contamination hazard that it can pose to the drug products exposed to these filters.”

Issues with HEPA Filters Continue

An updated look at Redica Systems’ collection of FDA 483s shows that of the 169 Drug GMP 483s in the Redica Systems dataset that were issued in 2022, 19, or 11%, had observations regarding HEPA filters. While none are as unusual as a firm “recoloring” the filters, they do indicate serious issues with the design, function, and maintenance of the filters used to assure sterile environments during drug manufacturing.

Issues noted by FDA investigators during facility inspections in 2022 include HEPA filters that were:

Not functioning properly:

  • “There is no laminar air flow coming from the HEPA filter units… We observed on 05/26/2022 two HEPA filter units obstructed/blocked with metal covers preventing laminar air flow in the mixing room without any written justification/rationale.”

Not properly documented:

  • “There are no engineering architectural diagrams (e.g., As Built, P and ID or diagrams for the HEPA filter air ducts) for the HVAC units to support that the HVAC units are appropriately installed.”

Not properly certified:

  • “The firm has failed to adequately recertify the control and critical areas within their sterile manufacturing suite of Building C in that not all HEPA filters met their predefined specifications after certification by their vendor.”

Not properly maintained:

  • “Screens that cover the HEPA filter are not cleaned and sanitized during pre and post manufacturing in the Vial Filling and Stoppering Machine ID #PID/C/067. These (b)(4)screens are used to aid homogeneous diffusion of the air from HEPA into the (b)(4)~~~~grade A filling area.”

Stained and rusty:

  • “On 06/10/22, we identified(b)(4)~~~ HEPA (b)(4)~~~~~~~~~~~~~~~~ containing brown stains. These laminar flow hoods are used to perform aseptic operations for drug products purported to be sterile. Per the Compounding Supervisor, the brown stains are suspected to be product.”
  • “We observed apparent surface rust on the screws holding the HEPA filters in place on the ceilings located in class 100/ISO 5 filling clean rooms. Multiple screws were observed with apparent rust throughout the class 100/ISO 5 filling clean rooms.”

Identified in a previous inspection with issues that were not corrected prior to a subsequent inspection:

  • “On 9/27/2021, during the walkthrough of the facility, we observed four HEPA filter panels in the first row near the entrance of your ISO 5 Cleanroom (b)(4) had dark stains on them. This was brought to the attention of the Plant Manager, and your firm corrected this finding by replacing the stained HEPA panels in Cleanroom (b)(4). On 2/22/2022, we observed in the same Cleanroom (b)(4) one HEPA filter panel in the second row near the fire sprinkler; one HEPA filter panel from the third row, and one HEPA filter panel in corner of fourth row, were found to have multiple dark stains on them. These stained HEPA filter panes were located on each side of the…Your firm was manufacturing…on 2/22/2022 in cleanroom (b)(4).”
  • “Additionally, on 9/27/2021, during the walkthrough of the facility, we observed two HEPA filter panels in the first row near the entrance of your ISO 5 Cleanroom…had dark stains on them. These stained HEPA filter panels were not replaced as of 2/2/2022.”

In Part IV find out why FDA investigators are concerned about the potential for contamination from perforated tables.

Additional Resources

Change Management Failures Documented in FDA Warning Letter

Inadequate Equipment Cleaning Leads to Cross Contamination, FDA Warnings

Microbiological Issues with Aseptic Processing and Lyophilization

4 GMP Case Studies