At the International GMP Conference at the University of Georgia in Athens, Georgia, in early March 2020 co-sponsored by FDA, FDA Office of Regulatory Affairs National Drug Expert Captain Ileana Barreto-Pettit presented FDA drug GMP warning letter trends over recent years and provided in-depth case studies from Current Good Manufacturing Practice (CGMP) inspections.

Warning Letters FY2020 and FY2021

Barreto-Pettit has been with FDA for 21 years. She has been a drug investigator since 1999 and a Drug National Expert Investigator since 2017 and is a Captain in the US Public Health Service Commissioned Corps.

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

These will be presented in a three-part series of blog posts (click here for a link to Part 1).

Part 2: Inadequate Media Fills at a Sterile Manufacturer When Starting up After a Shutdown

This case study involves a large, foreign manufacturer of injectable drug products. The product in question is a combination product.

This company had a shutdown, as many companies do, to perform maintenance and engineering projects that cannot be done during production. Once a sterile facility shuts down its HVAC and disassembles and cleans equipment and the facility, it should perform a media fill prior to resuming manufacturing operations, Barreto-Pettit said.

In this case, this company was shut down for about a month and did a lot of work in its Class A areas, including work on the floors. Everything was cleaned up, and operations were resumed.

A media fill was performed a few days before the shutdown. Barreto-Pettit asked the quality director why a media fill was performed before the shutdown. He said he wanted to be sure that everything stayed in control since the previous media fill before shutting down. That bracketed a time period and provided some assurance that during that period the conditions within the aseptic lines were acceptable.

The company’s SOP required a media fill be performed before operations could be resumed. The company indicated that the one performed before the shutdown satisfied that requirement, ‘showing that the director of quality did not understand their SOP and the purpose of the media fill.’

She asked why another media fill was not performed after all the work that was done, including HVAC filters being removed and replaced. He said that there were no changes made to the equipment or the process, so a media fill was not necessary.

“Does that mean that media fills are only required when a change is made to the equipment or the process?” Barreto-Pettit asked the conference audience. “To answer that, think about the purpose of performing an aseptic process simulation. It is to show that the conditions within the room are acceptable, the practices of your operators are fine, there is nothing that became contaminated during the operations, and the environment is under control.”

The company’s SOP required a media fill be performed before operations could be resumed. The company indicated that the one performed before the shutdown satisfied that requirement, “showing that the director of quality did not understand their SOP and the purpose of the media fill,” she maintained.

Product Complexity Requires Additional Simulations

Barreto-Pettit explained that the product in question is a combination product—a syringe that was filled with a powder, and in a different chamber of the syringe there was a diluent. It was an operation involving filling the syringe chamber with the diluent, which then goes through terminal sterilization. Then the powder that was lyophilized in a separate area is put into the syringe.

This company does multiple subdivisions of the lyophilized powder, which is already sterile. “The company needs to do a media fill for the subdivision of containers,” she maintained. “There is one container of lyophilized powder that is subdivided into 12 containers in a hood.”

The company does not require the operators to do media fills for this critical subdivision of product that is already sterile and will not undergo further sterilization before going into a syringe. “This is a problem,” Barreto-Pettit said. “The operators need to go through that exercise at least once a year.”

Remember, as an investigator, I am looking for changes in patterns, discrepancies, things that are different. That is a little thread that we continue to pull on until everything falls apart.

Even though they did not do a media fill after starting back up from a shutdown, this company did a trial batch with water and mannitol as the powder. “It was supposed to ensure that the assembly of the needle and components and the filling went well. It was a full-size batch—3,000 syringes—filled with water and mannitol. Interestingly, there was no batch record for it.”

She found out about the trial batch through the combination of an interview and a review of the autoclave equipment use log “that had funny numbers that were different than a regular batch. I asked what it was.”

“Remember,” the FDA expert advised, “as an investigator, I am looking for changes in patterns, discrepancies, things that are different. That is a little thread that we continue to pull on until everything falls apart.”

Her concern about the trial batches was that without a batch record there was no accountability of the syringes produced that look exactly like the product. “What is the risk of having syringes that look exactly like the product, but have water instead of diluent and mannitol instead of the lyophilized drug product? Where did these 3,000 syringes go? There were no records.”

“I asked why there were no controls, and the answer was that it was not product, that quality control is only needed when making product. When I get an answer like this on a foreign inspection I wonder if it was a translation error,” she quipped.

Better Equipment Does Not Mean Better Processes

Barreto-Pettit had inspected the company in 2012, and “they were terrible,” she said. “I went back in 2019 and they had improved. They had RABS (Restricted Access Barrier Systems). Initially, they had open aseptic lines with curtains. Now with RABS at least there is an additional barrier.”

“But they do not know how to work with RABS. I watched a video of their personnel unloading gloves from the autoclave that go into the RABS. I saw them grab the gloves from the racks in the autoclave, putting them in a box, then install them in the RABS. Those gloves had potential contamination already put in the glove that was going to be used inside the RABS.”

To test for glove integrity, the company’s SOP said to fill the glove with water and check for pinholes. “Exactly how do they do that?” the drug expert asked. “How did they validate it? With modern technology there are many pieces of equipment that will perform integrity checks for gloves, give you measurement data, and let you know whether you have pinholes or not.”

In addition, the SOP did not say how much water to use. Should personnel fill the glove halfway, all the way, or just the fingers? There were no instructions. “And to make it worse, when the operators found holes, they just replaced the gloves. Shouldn’t there be an investigation? At a minimum, I would want to know if the hole in the glove had any impact. Was it being worn during manipulations in the previous run and could have possibly compromised the product? This company did the same thing with gowns that were found to be compromised—they just replaced them.”

Barreto-Pettit posed the following questions for companies to ask themselves to help prevent issues like the ones discussed.

Does your company:

  • Closely monitor employee behavior and aseptic practices to ensure written procedures are followed?
  • Have written procedures that are clear and specific enough to ensure consistent operations that meet all GMP requirements? Conduct periodic assessments?
  • Adequately train personnel on written procedures and aseptic practices? If so, how do you monitor your employee behavior and aseptic practices to ensure procedures are followed—for example, the operators who were unloading sterilized gloves from the autoclave? This is an older facility with no windows, but they have cameras everywhere. That is the only way they could actually see what employees were doing. That is a great tool. But it did not appear that they were being watched.
  • Periodically review your written procedures to ensure they are still adequate? Do you do a good review? Do you interview your operators to get feedback from them on how the procedure could be improved? Are there instructions that they do not follow, and why?

Next Up

So concludes the second case study in our series by Barreto-Pettit’s case study on inadequate media fills at a sterile manufacturer when starting up after a shutdown. Next up:

  • Microbiological issues at a large manufacturer of sterile injectable products produced by aseptic processing and lyophilization.
Warning Letters FY2020 and FY2021

Get a Demo

We’ll can show you insights into any of your key suppliers, FDA investigators, inspection trends, and much more.

Request a Demo