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 are presented in a three-part series of blog posts (click here for Part 1, and here for Part 2).

[NOTE: Are you interested in learning more about observations filtered by FDA issue/Keyword “Aseptic Processing”? Get your FREE 483 Observation Report and you can quickly determine who has been hit with this observation and more. Learn more here.]

Get your 483 Observation Report

Part 3: Microbiological Issues with Aseptic Processing and Lyophilization

Ileana Barreto-Pettit relayed this GMP inspection case study as a story. Following are her complete remarks.

In this case—which was someone else’s case—a national expert investigator went on inspection with a microbiologist, who found a bag of used petri plates that had been read that day and were going to be disposed of.

The plates were examined and compared to what had been recorded. The interesting thing is that this company knew we were coming, because it is a foreign inspection. They get notified ahead of time, and issues like this still happen.

For every petri dish the microbiologist examined, the reading did not match what had been recorded. For example, for a purified water sample, how many CFUs (colony forming units) do you see (in the picture below)? The official report recorded six CFUs:

This was one of the worst ones, but many of them had between three and seven CFUs and reported zero. This happened with environmental monitoring plates as well as with purified water samples. The purified water is used for cleaning equipment. Obviously, their purified water system was not in control.

LOD (loss on drying) results for several batches of API and sterile drug product did not meet specification when tested during the inspection. The investigator in this case was a chemist who is familiar with this test. He used to work in an FDA laboratory. While investigating at this company, he found lyophilized products with a lot of defects. He also found that there were some OOS (out-of-specification) investigations for assay and impurities.

He looked at some retain samples and saw defects on batches that were released. He selected several API (active pharmaceutical ingredient) and finished product batches and asked the company to test them for loss on drying.

The investigator found that the only way to change the results was to alter the sample weights. That is what they were doing. The analysts were changing the sample weights to make the LOD result pass at release.

He was in the laboratory from 8:00 am until 10:30 pm because the samples take six hours each in the oven before testing. All the samples that had passed in months prior failed, with results as much as 50% different. There was an average 31% difference between release test results and re-test results during the inspection.  These products—lyophilized antibiotics—should be stable. That is one of the reasons products are lyophilized. There should be no change. This variation was not expected at all, especially within a month.

In addition, he found that the analysts in the lab were not recording the drying time. Even though they were required to record it, it was not being recorded. So, there was no way of knowing how long the samples were in the oven before testing.

The investigator found that the only way to change the results was to alter the sample weights. That is what they were doing. The analysts were changing the sample weights to make the LOD result pass at release.

This is a global US company with facilities in foreign countries. This was a foreign plant of a big pharma company. How does this happen? It is beyond my understanding.

As a result, CAPAs were not implemented to address lyophilization issues leading to high defect rates. The company ended up recalling all batches distributed to the U.S. Even though this facility was foreign, 100% of their products went to the US.

At the same company he observed excessive critical drug quality defects, such as melt back and cake collapse in lyophilized product and in reserve samples. Company investigations did not identify root causes for high defect rates. Some were saying it was power failures and compressor tripping of the lyophilizer that disrupted the lyophilization cycle leading to insufficient and non-uniform water removal, leading to failures in assay, impurities, and water content. They were blaming it on equipment.

However, there were some lots that did not have power failures that also had critical defects. The Quality Unit did not detect the adverse signals of excessive defects and major manufacturing deviations to re-assess process design and controls. As a result, CAPAs (corrective actions and preventive actions) were not implemented to address lyophilization issues leading to high defect rates. The company ended up recalling all batches distributed to the U.S. Even though this facility was foreign, 100% of their products went to the US.

The Consequences

Once you have this kind of data integrity issue in more than one place, what can be trusted? The company tested all the batches that were on the market, and they were sub-potent because their moisture content was too high, and the product was degrading. So, they were not meeting purity and they were sub-potent. Some were penicillin products.

In addition to recalling all the products, the company was placed on import alert, meaning that we will not allow any products coming from that facility into the US. The warning letter required the company to perform comprehensive investigations into the extent of the inaccuracies in data, records, and reporting, as well as a current risk assessment of the potential effects of these observed failures on the quality of the drugs.

Finally, it required a management strategy that includes a global corrective and preventive action plan. Remember, this company has facilities around the globe. We are requiring it to address not just the facility where the issues were found, but globally. We had better not find the same problems at a plant run by the same company in a different country.

Avoid Making the Same Mistakes

Does your Quality Unit…

  • Have controls to prevent data integrity issues in manufacturing and control laboratories (micro and analytical)?
  • Have a system to detect discrepancies in data integrity?  How do you know it works?
  • Conduct effective internal audits to identify practices that are not in conformance with cGMPs?
  • Monitor adverse signals to identify quality issues in a timely manner and implement corrective and preventive action?

It should not be us finding discrepancies in the few days that we are there. That is your job. They are not that hard to find. Why are you not finding these issues in your internal audits?

I would like you to take a look at your company’s quality culture.

Is your quality system on the immature or mature side of the quality system? Are you reacting to problems or are you proactively looking for gaps and deficiencies to correct those before they become big problems?

Also of note—if you are interested in learning more about observations filtered by FDA issue/Keyword “Aseptic Processing”, get your FREE 483 Observation Report and quickly determine who has been hit with this observation and more. Learn more here.

Get your 483 Observation Report

Download the Special Report

Quality Week report sidebar

What You Will Learn from This Report:

How a major pharmaceutical company designed a program to train future leaders in quality

An industry-led initiative to advance the state of quality in the pharma industry

A pharma GMP leader’s tips for supporting quality culture within an organization

An update on FDA’s Quality Maturity Model

Redica Systems Enforcement Analytics

Compare two companies of your choice.

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

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.

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.

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.

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

Prepare for your next inspection.

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

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.

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
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.

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

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.

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

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_Vert_Periwinkle_RGB_Large

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.

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

Upgrade your inspection strategy.

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

Impact of the Global Pandemic on Recent Data Integrity and Regulatory Non-compliance Trends

Webinar: Impact of the Global Pandemic on Recent Data Integrity and Regulatory Non-compliance Trends

Presented by Paul Smith, Agilent Technologies on Aug. 26, 2020

What you will learn:

  • Examples of essential laboratory actions to remain compliant during the pandemic
  • Recent data integrity non-compliance findings and trends
  • Essential strategies to find, understand, and leverage regulatory non-compliance data

Get the scoop on recent data integrity 483 observations!

  • FY 2020 Data Integrity 483 Observations
  • Data Integrity Observations for Human Drugs
  • Observations Falling Under GMP
  •  

Past, Present, and Future of Quality Culture

Presented by Regulatory Compliance Associates Distinguished Fellow Susan Schniepp

What you will learn:

  • How the 2014 FDA quality metrics initiative led to greater focus on quality culture
  • New quality culture tools and standards under development by PDA and other organizations
  • Best practices for quality culture, including case studies with lessons learned

Changing Medical Device Regulations

Presented by Redica Systems 

What you will learn:

  • The latest developments regarding the EU MDR
  • Quality Systems requirements for medical devices
  • Regulatory updates affecting medical devices

Download the Special Report

Combination Product Report

What You Will Learn from This Report:

The latest U.S. and European regulatory developments

The impact of smart combination products

How the EU MDR impacts drug-device combination products

Download the Special Report

5 GMP Case Studies Report

What You Will Learn from This Report:

In-depth analysis of the findings

Lessons learned

How companies can avoid similar shortcomings.

Experience the Power of Redica Systems

Redica Systems Expert Jerry Chapman to Present at SQA Annual Meeting

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.

Download the 510(k) Sample

What You Will Learn from This Sample:

See how a 510(k) submission is structured

Find out what information to include

Review correspondence between sponsor and FDA

Redica Systems Enforcement Analytics

Unlimited Access to Reports and Data

Enter your email address and someone will contact you shortly.

Download the Special Report

5 GMP Case Studies Report

What You Will Learn from This Report:

The first countrywide import alert issued by FDA

An inadequate deviation investigation

An inadequate product specifications and a product recall

Process validation issues at a CMO

A different perspective on process validation and the culpability of the quality unit

 

A.I. for Quality and Compliance Teams

August 3 webinar

Presented by Redica Systems Senior GMP Quality Expert Jerry Chapman

What you will learn:

  • A basic understanding of data sources, machine learning, NLP, and A.I. tools
  • Building and applying Expert Models
  • Two case studies, one on sterile manufacturing/503B and one on data integrity

Human Factors – Compliance and Applications

June webinar

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

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

Experience the Power of Redica Systems

Redica Systems Enforcement Analytics

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

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

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 monitoring strategy.

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.

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.