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.

[Related: Click here to download a FREE compilation of this four-part article series on FDA GMP inspection findings.]

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.

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:

Inadequate change management systems
Cross-contamination in solid oral dosage facilities
Inadequacies and potential contamination hazards in aseptic manufacturing
Perforated tables and work surfaces in cleanrooms

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.”

In Part II, learn why FDA investigators are increasingly concerned about effective cleaning procedures for equipment and the potential for cross-contamination if performed inadequately.