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

Why were change management failures involving starting material cited in an FDA Warning Letter? Relying on information from laboratory-scale batches instead of full-scale validation batches plus failure to test validation batches of API for specific impurities drew the attention of FDA investigators.

At the International GMP Conference held virtually in March 2022 and co-sponsored by the University of Georgia at Athens and FDA, FDA Office of Regulatory Affairs National Drug Expert Captain Ileana Barreto-Pettit presented in-depth case studies from recent drug GMP inspections that illustrate agency findings and concerns.

[Related: Download a compilation of last year’s coverage of Ileana Barreto-Pettit’s case studies by Redica Systems Senior GMP Quality Expert Jerry Chapman.]

5 GMP Case Studies ad narrow

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 1 of this four-part series covers Barreto-Pettit’s discussion and analysis of change management system inadequacies found during manufacturing inspections. The remaining case studies will subsequently be covered in three parts.

Potential Impact of Changes to Product Quality

Barreto-Pettit’s first case study concerned inspection observations at an API manufacturer cited for failure to evaluate the potential effects that changes may have on the quality of their intermediates and API.

The firm was a manufacturer of a Sartan API that received five lots of its starting material from two different suppliers. Four of the five lots failed one of the specifications and were rejected. The firm then decided to conduct an R&D small-scale experiment to see if it could increase the specification of the starting material in order to accept the lots with a higher specification result.

The firm noted during the study that the increased specification for the starting material had the potential to form new impurities in the API, as the experimental batches showed the presence of new impurities at various stages of API manufacturing.

To address the issue, the manufacturer reportedly added a new purification step to remove the new impurities. It also widened the specifications of the study material and accepted the previously rejected batches to be used in the manufacturing of process validation batches with the new purification step.

The company, however, relied on information from laboratory-scale batches instead of full-scale validation batches. In addition, personnel also failed to test the validation batches of the API for the specific new impurities and relied on the existing related substances analytical method to detect new impurities without first determining if that method would detect them at low levels.

483 Response

In the firm’s response to the FDA 483, it included results of experimental spike and purge studies to demonstrate how the impurities were removed as part of the manufacturing process. However, this study was conducted after the company was cited for inadequate change control for approving a change in specifications for the starting material and the addition of the new process purification step without adequately assessing the impact on the quality of the APIs.

In the response to the firm’s 483 response, FDA asked it to provide a comprehensive, independent assessment of its change management system, including procedures to ensure changes are justified, reviewed, and approved by the quality unit before the implementation of the change and that their effectiveness is documented.

[Editor’s Note: For more information on how to respond to a 483, read the article, “The FDA Inspection is Over, What Happens Next?”.]

Change Control Findings During Inspections

In addition to relaying agency findings from a specific inspection involving an API firm, Barreto-Pettit shared issues with change management systems that she has seen when conducting inspections of pharma manufacturing companies.

“I find very often that change control procedures are not adequate, or if they are adequate, they are not followed,” she said. “Some of the procedures lack details on how to propose a change, how to approve it, or how to review it. Much of the documentation that I see for change control lacks adequate justification—showing the benefits as well as the risk that may come if a certain change is implemented.”

She has also observed that the impact of a change is not always assessed prior to implementation, including impact to the product. “Sometimes I see that the impact is determined after the change has been implemented.”

The company, however, relied on information from laboratory-scale batches instead of full-scale validation batches

Documentation for a change control often lacks the various activities or the actions that need to be performed in conjunction with the change, for example, revalidation of a process or if there was a change to the process, the equipment, or the qualification of the equipment if modifications were made, the FDA investigator noted. The SOPs that apply to the operation are sometimes not evaluated or not revised in light of the change.

No changes should be implemented before the employees are aware of the change and the SOP revisions and trained on them, she stressed. “That needs to be done before the change is implemented, and it needs to incorporate some effectiveness checks to determine if the changed method and the specified criteria are working the way they were intended to.

Also sometimes missed as part of a change proposal is an evaluation of how changes impact the drug application. Are there any regulatory notifications, whether you need a preapproval or whether it is an annual reportable change? That should be specified within the documentation of the change control.

Sometimes, Barreto-Pettit said, she sees changes that are implemented without change control. “I find this more often than I should. We should never find this. But it is not uncommon to find changes that were performed by manufacturing or maintenance personnel for which QA was not aware and did not go through change control.”

I find very often that change control procedures are not adequate, or if they are adequate, they are not followed

Sometimes unapproved changes are found through interviews of the operations or maintenance or calibration personnel. Sometimes the electronic data from the manufacturing equipment shows the changes that did not go through change control. “These are things you need to make sure are not happening in your facilities.”

Regarding renovation and construction in facilities while there are manufacturing operations going on, the FDA investigator has found “more than one example of facilities that are being renovated and construction activities started without having a change control approved to make sure that these areas are properly segregated and there is no impact or cross-contamination of the products that are being manufactured simultaneously.”

Sometimes she has seen changes to equipment or process modifications that have not been through a change control process, as well as facilities where the change control procedures are limited to document revisions and no other changes are documented. They may include changes to specifications or maybe laboratory methods, but if there is a change to the process or the facility, they do not include those changes in their procedures, Barreto-Pettit shared.

She has also seen companies that have very inefficient or inadequate change control procedures where the procedures are primarily a documentation process. “It is a requirement that you need to have this. So, therefore, many times they fill out the paperwork after the change has been implemented.”

The purpose of the change control system is to implement a risk-based decision-making process where the data and justification and reasons for the change are evaluated, she emphasized. It should include all the subject matter experts (SMEs) working together to decide on the best way to implement the change. SMEs must also determine how the change will impact the product or any other products and the activities that come along with that change.

Self-Evaluation: Change Management

Barreto-Pettit provided a series of questions that a company can use to perform an evaluation of the change management processes it uses.

  • Does your pharmaceutical quality system apply quality risk management (QRM) principles to change control activities? She suggested referencing the PIC/S document PI 045-1 on how companies can demonstrate the effectiveness of the pharmaceutical quality system in relation to risk-based change management.

PIC/S PI 045-1 contains detailed information on what the expectations are for an effective change management system. “It will be a very useful tool for you to use when looking at the company’s systems and see if they are meeting all the expectations.”

She recommended reviewing the guidance and asking if the company’s pharmaceutical quality system (PQS) applies quality risk management (QRM) principles to change control activities, specifically, whether the risk assessments adequately evaluated the potential risks and the benefits of changes to product quality, safety, and efficacy.

In the case study Barreto-Pettit presented at last year’s International GMP Conference, the company identified the formation of new impurities and added an additional purification step. However, it failed to generate data from commercial size validation batches to demonstrate the effectiveness of the purification process and that it had no impact on the safety and quality of the API.

Similarly, for the change in specifications of the starting material, it failed to demonstrate that these changes did not impact the finished API before approving the change.

  • Is QRM used to plan for any necessary process validation, verification, or requalification efforts? “In the case study I presented, I do not know if they used QRM or not, but they did not identify the risk of the test method possibly not detecting the new impurities,” Barreto-Pettit said. “And they failed to demonstrate that their current test method for related substances did not need modification and revalidation to detect the new impurities.”
  • Is an evaluation of the effectiveness of the change carried out in terms of whether the changes meet the intended objectives and predefined effectiveness criteria? If there are any residual risks, are those assessed and managed to acceptable levels? And are changes monitored after implementation via ongoing monitoring systems to ensure maintenance of a state of control?

Changes may include activities such as increased sampling, continuous process verification, or statistical assessments such as CpK and PpK to aid with a quantitative assessment of risk control. The CpK is the potential of a process to meet a specification short term while the PpK is how the process performed on a long-term basis.

Change Management and ICH Q10

In closing this change management case study, the FDA National Expert said, “I would like to remind you that effective change management is important not only in the context of GMP requirements but also in the context of ICH Q10: Pharmaceutical Quality System, which sets out the potential for risk-based regulatory oversight for companies that demonstrate that an effective PQS in place.”

[Editor’s Note: For more on ICH Q10, read the article, “Taking a Risk-Based Approach to QMS.”]

Implementation of the principles and concepts in the ICH Q10 guideline enables mature, risk-based change management within an effective PQS, which is considered a foundation to enable greater regulatory flexibility in reporting of post-approval changes.

“I know that industry has been very interested in getting regulatory flexibility as described in ICH Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management. But I can tell you, if your change management system is not up to expectations, this will be a very difficult thing to achieve. You will not have greater regulatory flexibility if your change management system is not good.”

Additional Resources

PIC/S PI 045-1 

Flawed Process Validation, Ineffective Quality Unit Cited in Warning Letter

Taking a Risk-Based Approach to QMS

The FDA Inspection is Over, What Happens Next?

5 GMP Case Studies ad narrow

Comparing and Analyzing Russian, UK, and US Top Ten Pharma Inspection Findings FY 2019

Webinar: Comparing and Analyzing Russian, UK, and US Top Ten Pharma Inspection Findings FY 2019

Presented by Jerry Chapman on October 29, 2020

What you will learn:

  • A comparison of 483 observations in FY2019
  • Top 10 Russian Ministry of Health inspection findings
  • Top 10 FDA Warning Letter findings
  • Top MHRA inspection findings
Redica Systems Enforcement Analytics

Get help choosing the right CRO.

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

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.

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

Compare two companies of your choice.

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

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.

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

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.

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

Redica Systems Enforcement Analytics

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

Champion of Change - 3Cs to Success

Webinar: Champion of Change - 3Cs to Success

Presented by Steve Greer on June 23, 2020

What you will learn:

  • The 3C Model to become a champion of change
  • How to identify game-changing habits and the steps to implement them
  • Ways to develop greater purpose-centered leadership
  • How to generate awareness along with actions to create changes in how you think about challenges and change putting you on a path to lead change successfully in your organization
  •  

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

 

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

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

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.

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
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.

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
  •  

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

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.

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.