Since inadequate failure investigations continue to be a major Good Manufacturing Practice (GMP) deficiency, it is important to recognize the value of appropriately conducting a proper root cause analysis (RCA) and documenting failure investigations.
To provide context, we point to the 1993 Barr Decision, formally known as the Barr Laboratories, Inc. v. United States case, a landmark legal ruling by the U.S. District Court for the District of New Jersey. The FDA brought charges against Barr Laboratories for failing to comply with GMPs. The FDA’s primary concern was Barr’s inadequate investigation into discrepancies and failures in their quality control processes.
The court found that Barr Laboratories had not adequately investigated the root causes of these discrepancies and deviations. Although the judge noted in his decision that FDA’s “ … cGMP regulations are vague…” and did not exactly spell out how to handle out-of-specification (OOS) laboratory results, his decision emphasized the importance of thorough and systematic root cause analysis in pharmaceutical manufacturing.
The decision made it clear what is acceptable and what is not acceptable in handling OOS, noting that a failure of a batch or its components to meet any of its specifications indicates non-compliance with specifications and must prompt a “failure investigation.”
Overall, the Barr Decision reinforced the critical role of RCA in maintaining product quality and regulatory compliance within the biopharmaceutical industry. As noted in FDA 21 CFR Part 211:
“ … Any unexplained discrepancy … or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and follow up (Sec. 211.192 Production record review).”
“There shall be a quality control unit that shall have the responsibility and authority … to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated (Sec. 211.22 Responsibilities of quality control unit).”
Furthermore, they note that any unexplained discrepancy in master production and control records or the failure of a batch, or any of its components, to meet specifications must be thoroughly investigated, whether or not the batch has already been distributed. Also the investigation shall extend to other batches of the same drug product and other drug products that may be associated with the specific failure or discrepancy. And a written record must be made and include the conclusions and follow-up. To be clear, US and EU regulations note all investigations shall be thorough, documented, and include conclusion and follow-up.
Goals of a RCA
A RCA has several goals:
Collect contributing causes of the problem (equipment, procedure, people, process, etc.).
Eliminate non-contributing causes.
Select causes that need verification.
Determine root (probable) causes that need corrective action.
To be thoroughly investigated means to ensure the application and practical, hands-on aspects of a RCA. This includes knowing the principles and techniques involved in identifying failures and deviations, categorizing problems, assigning responsibility, and tracking team activities.
For anyone in Manufacturing and Packaging, Quality Assurance / Quality Control who initiates, conducts and/or manages investigations in a pharmaceutical, clinical manufacturing, biologics and medical device environment, having a working knowledge of RCA and investigative techniques can be effective in identifying corrective and / or preventive actions towards successful remediation.
The RCA Process
A process of a RCA consists of:
Describing the OOS to include an initial assessment (what was the event, when and where did it occur, what was the extent of it, and why did it occur).
Preliminary Investigation that assesses operators and equipment.
If evidence of lab error remains unclear or no meaningful errors were made, then a full-scale OOS investigation must take place.
A full-scale OOS investigation that is timely, thorough, and involves a well-documented review that includes:
A clear statement of the reason for the investigation.
A summary of the aspects of the manufacturing process that may have caused the problem.
The results of a documentation review, with the assignment of an actual or a probable cause.
The results of a review to determine if the problem has occurred previously.
A description of corrective actions.
It may also extend to process or batch-related investigation to include other batches of the same drug product or associated drug products that may have similar, specific failure or discrepancy. Finally, it may also involve additional laboratory work to identify a root cause.
It’s important to remember that as part of a pharmaceutical quality system, the owner is ultimately responsible for ensuring that processes are in place to assure the control of outsourced activities and quality of purchased materials.
A RCA Doesn’t Assign Blame
When commencing a RCA, remember industry research has shown that 95% of problems are related to processes and procedures – only 5% are related to human error. However, most organizations spend far more time looking at affixing blame to personnel rather than processes, which can lead to misdirected efforts that seldom address the root cause.
A structured approach will help in a number of ways. Problems are best solved by attempting to correct or eliminate root causes, as opposed to merely addressing the immediately obvious symptoms. When determining root cause (or beginning to solve a problem), it is best to:
Create and work in an atmosphere of trust, openness, and honesty.
Examine factors that could lead to an event (e.g., deviation, equipment malfunction).
Consider various possibilities and probable causes / solutions / reasons.
Proceed to rule-out / disprove possibilities.
Determine actions to eliminate / prevent the issue from happening again.
The Barr Decision Impact on RCAs Today
Thanks to the Barr decision, RCA has taken on a very structured approach. This decision by Judge Wolin in 1993 has had a significant impact and has led to:
Heightened Regulatory Expectations: The decision underscored FDA’s expectations for companies to conduct detailed and effective root cause analyses for any deviations or non-conformances in their processes.
Improved Systematic Approach: Pharmaceutical companies adopted more structured and rigorous methodologies for identifying and addressing the root causes of issues. This often involves tools like Fishbone Diagrams, the Five Whys, and Failure Mode and Effects Analysis (FMEA).
Enhanced Documentation and Transparency: Companies improved their documentation practices, ensuring that all investigations are well-documented, transparent, and easily reviewable by regulatory bodies.
Greater Preventative Measures: The ruling highlighted the need for corrective and preventative actions (CAPAs) to not only address the immediate issue but also to implement measures that prevent recurrence.
Industry Standardization: The Barr Decision contributed to the standardization of root cause analysis procedures across the pharmaceutical industry, promoting best practices and consistency in quality management.
A Matter of When – Not If
Unexpected events happen – it’s always a matter of when, not if. But when a company conducts a well-documented investigation, it informs the process of developing a therapy. As a result of such a RCA, formulation or process changes can be made, and internal documentation can be updated and improved, all helping to inform a range of critical decisions that can improve the process resulting in safer, higher quality therapeutics.
Investigations and associated CAPAs are some of the most important documents a company generates as they provide the rationale and thought process for the decisions made to provide high-quality products.
When companies perform investigations properly and find root causes, they are creating some of the best, most information-rich and meaningful sources of metrics. With such information and findings, companies can ensure that high-quality drug products are getting to the market and helping patients who need relief.
As one attendee noted about such RCA training, “The course was well-planned, timed, and executed. The instructor was able to keep the group engaged by performing multiple group activities (case studies, projects). I took away the important lesson of drilling down to the true ROOT cause, defining the scope, and not jumping ahead before truly defining the root cause or truly ruling out any additional scenarios.”
Click here to learn more about an upcoming Root Cause Analysis course.
