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.

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).

Get your 483 Observation Report

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.
Get your 483 Observation Report

Human Factors – Compliance and Applications

June webinar

Presented by Alison Sathe, Founder, Regulatory Mark & Valerie Fenster, Director of Insights and  Human Factors, Kaleidoscope Innovation 

June 29, 1:30 p.m. EST

What you will learn:

  • Human factors strategies from simple drug products to complex surgical devices
  • Primary and secondary labeling development and evaluation for usability
  • Human factors activities from product development to post-market
  • International strategies: expectations for human factors in regulatory submissions in international markets

Panel Discussion – Remote Audits

Panel Discussion opt in image

Featuring Panelists:
—Barbara W. Unger, Unger Consulting, Inc.
—Jerry Chapman, Redica Systems
—Stephanie Gaulding, Pharmatech Associates

Who Will Benefit?
This session will be valuable to GMP quality, regulatory, compliance, and management personnel in FDA-regulated industries who want to have a conversation on remote audits and get to know what is going on in the industry.

Redica Systems Enforcement Analytics

Prepare for your next inspection.

Enter your email address and someone will contact you shortly to explore observations and trends. 

Redica Systems Enforcement Analytics

Prepare for your next inspection.

Enter your email address and someone will contact you shortly to run your custom report.

Redica Systems Enforcement Analytics

Get help choosing the right CRO.

Enter your email address and someone will contact you shortly to customize your insights.

Redica Systems Enforcement Analytics

Compare two companies of your choice.

Enter your email address and someone will contact you shortly to customize your report.

Download the Special Report

Download your copy of THE FDA INSPECTION LANDSCAPE IN MID-2020 AND A LOOK AT VIRTUAL INSPECTION

In this summary we identify:

  • Trend analysis of FDA inspections through mid-2020
  • Strategies for preparing and hosting virtual inspections
  • New technologies to support remote inspections

Download the Special Report

CDMO Comparison opt-in

In this summary we identify:

FY2018-FY2020 GMP data for Lonza & Catalent

Top GMP primary citations

Top FDA 483 observations

Turning Failure into Success

Presented on Tuesday, April 27, 2021 by Steve Greer, Executive Coach, Genesis Assist, and former Quality Leader, Procter and Gamble

What you will learn:

  • How to use the Leadership SOS Model to transform quality culture
  • How to strengthen quality systems to eliminate human error
  • How to generate ideas on how to set your organization up for success for shareholders, FDA, and staff
Redica Systems Enforcement Analytics

Prepare for inspections of Clinical Investigator sites.

Enter your email address and someone will contact you shortly to provide more Clinical Investigator data about your sites.

Redica Systems Enforcement Analytics

Get Full Access to Redica Enforcement Analytics

Enter your email address and someone will contact you shortly to answer all of your questions and get you started.

Quality Management Systems for Small Pharma and Biotech Firms

Webinar: QMS for Small Pharma and Biotech Firms

Presented by Fenton Fong, Founder, Managing Director, & Principal at xCellarate

Get instant access to the webinar video and slides.

What you will learn:

  • Common challenges small pharma firms face when developing a QMS
    Recent enforcement trends involving the Quality Unit
    Impact of the COVID-19 pandemic

Download the Special Report

APAC ad

In this summary we identify:

GMP data from FY2017 to FY2020 for the Asia-Pacific region

Top 3 GMP primary and secondary citations

Top 3 483 observations

Download the Special Report

An Analysis Of MHRA’s Latest Annual GMP Inspection Deficiencies Report

In this summary we identify:

  • Data from 2019 UK MHRA Inspections
  • Trends from 2015, 2016, 2018, and 2019 inspections
  • Conclusions drawn from an analysis of drug inspection data

Experience the Power of Redica Systems

Redica Pro Free

Sign up for your FREE account today and get instant access to:

SEARCH Find the inspection records you want by inspector’s name, company name, site, city, country, etc.

WARNING LETTERS Easily search the largest database of FDA Warning Letters by date, company, FDA office, or subject

SITES Quickly assess inspection records including dates and inspectors across all of your sites

INSPECTIONS Complete list of FDA inspections by date, company, category, and country

Get Complete Access to the Redica Systems Platform

Please submit your email address and one of our team members will contact you shortly to answer all of your questions and get you started with the new Enforcement Analytics platform.

Redica Systems Enforcement Analytics

Prepare for your next inspection.

Enter your email address and someone will contact you shortly to explore enforcement trends. 

Redica Systems Enforcement Analytics

Monitor compliance at your Clinical Investigator sites.

Enter your email address and someone will contact you shortly to get you started.

Experience the Power of Redica Systems

Redica Systems Enforcement Analytics

Let us know who you are and we’ll be in touch to answer all of your questions and get you started.

Redica Systems Enforcement Analytics

Upgrade your CDMO monitoring strategy.

Enter your email address and someone will contact you shortly to get the data and analysis you need.

Redica Systems Enforcement Analytics

Keep up with the latest Regulatory Developments on Clinical Trials

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

Save your team valuable time when using External Monitoring.

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

Save time and Resources when using External Monitoring.

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

Get immediate access to the news that matters to your sites.

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

See how we can help you eliminate yet another spreadsheet.

Enter your email address and someone will contact you shortly. 

Redica Systems Enforcement Analytics

Stay ahead of changing regulations.

Enter your email address and someone will contact you shortly to get the data and analysis you need.

Redica Systems Enforcement Analytics

Upgrade your CDMO management strategy.

Enter your email address and someone will contact you shortly to get the reports and analysis you need.

Redica Systems Enforcement Analytics

Compare the enforcement history of your CDMOs.

Enter your email address and someone will contact you shortly to customize your report.

Experience the Power of Redica Systems

Redica Systems Enforcement Analytics

Sign up for your FREE account today and get instant access to Enforcement Analytics.

Redica Systems Enforcement Analytics

Upgrade your inspection strategy.

Enter your email address and someone will contact you shortly to get the reports and analysis you need.

Redica Systems Enforcement Analytics

Upgrade your inspection strategy.

Enter your email address and someone will contact you shortly to get the reports and analysis you need to prepare for your next inspection.

Experience the Power of Redica Systems

Complete the form and one of our experts will reach out to you to schedule a demo and answer questions about our subscription options.

INDEX INFORMATION  Redica consolidates regulatory data in real-time on the single largest database for quality, safety, and compliance intelligence.

STRENGTHEN DATASETS Redica machine intelligence algorithms identify and triage risk signals to derive meaning from vast amounts of private and public data.

ANALYZE & INTERPRET PATTERNS Redica instantly models the customer-specific regulatory risks, trends, and opportunities that stand to fundamentally change compliance operations.

Redica Systems Enforcement Analytics

Evaluate Your CDMOs

Enter your email address and someone will contact you shortly to customize your report.

Redica Systems Enforcement Analytics

Compare the inspection history of your CDMO sites.

Enter your email address and someone will contact you shortly to customize your report.

Discover the power of the most comprehensive database of 483s in existence.

Our database of over 20,000 483s is retyped and tagged, making it easy to create an Observation Report in seconds.

Eliminate days of work and get your FREE personalized 483 Observation Report.