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.

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.

483 observations report - specific observations

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 three case studies are:

Cleaning and cross-contamination issues with an encapsulator
Inadequate media fills at a sterile manufacturer when starting up after a shutdown
Microbiological issues at a large manufacturer of sterile injectable products produced by aseptic processing and lyophilization

These will be presented in a three-part series of blog posts. You can read the second part here.

Part 1: Cleaning and Cross-contamination Issues with an Encapsulator

The encapsulator in question was located at a large, global manufacturer of tablets and capsules. To kick off her discussion, Barreto-Pettit provided the following photograph:

The picture shows the upper block of the upper locking pin segment and the upper locking pin head of an encapsulator. The company’s investigation had been open for about two months on an encapsulator that is shared among multiple different products, she explained.

“One big problem that we had with it was the investigation was still open two months later,” Barreto-Pettit said. “They had continued to manufacture because they had identified that the problem was their cleaning SOP (standard operating procedure) was not specific enough to disassemble the encapsulator to the point of being able to clean it properly. They revised the SOP to ensure the removal and cleaning of the parts that could be contaminated, and they continued.”

However, she pointed out the yellow powder seen in the photo had been identified in the middle of a campaign. “They had done a major cleaning because the previous product was a different product. And they had done several minor cleanings, once every time they had changed the strength of the product they were manufacturing in the campaign. There is a potential for the powder to flake off into the body of the capsule right before the cap and body meet to lock together.”

Several employees had been involved in cleaning and inspection of this equipment during the campaign of a capsule filled with white powder. Whether a major or minor cleaning, the cleaning job is inspected and released. This piece of equipment was inspected and released multiple times. The previous product produced in this encapsulator contained a yellow powder.

Every batch manufactured using that piece of equipment that the company now knows could not be disassembled properly because their SOPs were inadequate is suspect. This ended up being cited in the 483 that resulted from the inspection and in the subsequent warning letter.

Yellow powder was found in the upper block of the upper locking pin segment and on the upper locking pin head of the encapsulator after a minor cleaning was performed after multiple batches in a campaign. This was found by an inspector after 16 batches in a campaign.

“If you find this in your facility, what should you do?” the FDA National Drug Expert asked. “You have 16 batches that you have already made. You have other batches you have made and released. There is inadequate cleaning of equipment that is shared between products. Any of the 16 batches that are still in the company’s control should be put in quarantine.”

She further noted that every batch manufactured using that piece of equipment that the company now knows could not be disassembled properly because their SOPs were inadequate is suspect. This ended up being cited in the 483 that resulted from the inspection and in the subsequent warning letter.

The Good Manufacturing Practices (GMP) issues cited included:

Inadequate procedures for the disassembly of the shared equipment for proper cleaning
Inadequate visual inspection of clean equipment after a major and several minor cleanings
Investigation did not extend to other potentially affected batches manufactured in this or similar equipment

Cross-contamination in a Fluid Bed Dryer

In a second example of potential cross-contamination in solid oral dose drug manufacturing, Barreto-Pettit shared an inspection case study regarding cross-contamination in a fluid bed dryer via the air inlet. According to this illustration from a case in 2012, drug fine particles went through the bag filter at the top and made it into the air inlet valve.

She explained that there was also some residue that fell back and ended up staying in the equipment. When the air came in for the next batch it cross-contaminated that product.

So, the problem was product remaining in the equipment between batches. The way the equipment was designed in the past it was not cleaned and it was not disassembled. But the air handling forces residue back into the fluid bed to the next product.

This happened in several cases some years ago that resulted in recalls due to cross-contamination. “One of the things that we do during inspections is check for procedures to clean this type of equipment. Most of the time I find firms that already have those procedures in place. They have modified the ductwork to have access to it—some sort of door—so it can be cleaned and inspected. I have seen some with spray balls companies have manufactured themselves to be able to reach the entire area that needs cleaned.”

Unfortunately, during an inspection in 2019 of a foreign generic drug manufacturer making many different drugs in non-dedicated fluid bed dryers, the investigator found this:

This is the inlet air duct, after cleaning. Not only was this issue found in fluid bed dryers, but also in other types of equipment that have permanent ductwork—in this case, a coater (see next picture). This is a US company.

The investigator had the company disassemble this and clean it. Material from multiple different products accumulated in this ductwork and contaminated the next batch.

“To make it even worse, there was analytical testing that confirmed how bad this issue was,” Barreto-Pettit explained. “The residues and swab samples were analyzed, and they confirmed that the material in the ductwork was carrying on to later products. So, they not only had the possibility of cross-contamination, they also had confirmation that it had taken place. You can only imagine the number of batches they had to recall.”

“You never want to be in this situation. Because everything that you manufactured on that piece of equipment will have to be recalled. There is no question about it,” she emphasized.

The Importance of Risk Assessments and Lessons Learned

The National Drug Expert emphasized the importance of performing risk assessments—especially regarding potential contamination issues—by any firm that has large equipment that is permanently installed.

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

Assess all manufacturing equipment including connected ductwork to identify potential areas that are not easily cleanable and can introduce cross-contamination?
Ensure written cleaning procedures include adequate disassembly and cleaning instructions?
Adequately train personnel performing visual inspections of clean equipment?
Randomly check cleanliness of equipment after release?

“I suggest you go back to your facilities and see if you can find potential routes for contamination that you have not identified yet. See if your procedures are adequate for the disassembly and the cleaning of your equipment.”

“When it comes to cleaning, maybe you have a clean-in-place program or you have robots cleaning your equipment, but you will have to have humans, and with that, human variability. How do you properly ensure that this perfect cleaning validation and perfect SOPs that you have are actually followed by your employees? How do you check that? How do you validate your employees? How about those on the third shift that are monitored even less? Are they skipping steps?”

When it comes to cleaning, maybe you have a clean-in-place program or you have robots cleaning your equipment, but you will have to have humans, and with that, human variability. How do you properly ensure that this perfect cleaning validation and perfect SOPs that you have are actually followed by your employees? How do you check that? How do you validate your employees? How about those on the third shift that are monitored even less? Are they skipping steps?

Barreto-Pettit said, “When I go on inspections, I love to interview the operators, because those are the ones doing the day-to-day operations. They are the experts in the specific operation they are doing. Not you in this audience. You are most likely sitting in an office. And you may think they are doing things by the SOP. But how often do you test your employees on that, maybe by just watching them without them knowing? Do you have cameras? If so, use that data, use that information to see if your employees are consistently following the SOPs that you put so much effort into.”

She shared a piece of advice regarding monitoring programs for equipment cleaning. “Many of you—I hope all of you—have monitoring programs for cleaning your equipment. You check every so often. I hope you are not giving production a heads up that you are going to be checking equipment after cleaning. If you do, they are going to clean them better that day. Make sure that you have surprise checks just to make sure that the equipment is being properly cleaned.”

Next Up

That’s it for Barreto-Pettit’s case study on cleaning and cross-contamination issues with an encapsulator. Next up:

Also of note—if you are interested in learning more about observations filtered by FDA issues/Keywords “cleaning” and “cross-contamination”, get your FREE 483 Observation Report and quickly determine who has been hit with these observations and more. Learn more here.