Failure to Investigate Critical Deviations: A Cautionary Tale from Sanofi’s FDA Warning Letter

The recent FDA warning letter issued to Sanofi on January 15, 2025 highlights a critical issue that continues to plague pharmaceutical manufacturers – inadequate investigation of deviations. Specifically, the FDA cited Sanofi for “failure to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed.”

This observation underscores the importance of robust deviation investigation and CAPA (Corrective and Preventive Action) systems.

The Importance of Thorough Investigations

Investigating deviations is not just a regulatory requirement – it’s a critical part of ensuring product quality and patient safety. The objective of an investigation is not merely to perform the investigation, but to improve the reliability of our manufacturing operations, the ultimate objective being increased quality and availability of those regulated healthcare products.

When companies fail to thoroughly investigate deviations, they miss opportunities to:

Identify root causes of quality issues
Implement effective corrective actions
Prevent recurrence of similar problems
Improve overall manufacturing processes and controls

Common Pitfalls in Deviation Investigations

Some common reasons why deviation investigations fall short include:

Lack of trained, competent investigators
Inadequate time and resources allocated to investigations
Pressure to close investigations quickly
Failure to look beyond the immediate symptoms to identify true root causes
Over-reliance on “human error” as a root cause
Poor documentation of investigation activities and rationale

Building Better Investigation and CAPA Processes

To overcome these challenges and build more effective investigation and CAPA systems, companies should consider the following approaches:

1. Develop Investigator Competencies

Having competent investigators is crucial. Companies should:

Define required competencies for investigators
Provide comprehensive training on investigation techniques and tools
Implement mentoring programs for new investigators
Regularly assess and refresh investigator skills

2. Implement a Risk-Based Approach

Not all deviations require the same level of investigation. Using a risk-based approach allows companies to:

Prioritize critical deviations for in-depth investigation
Allocate appropriate resources based on potential impact
Ensure thorough investigations for high-risk issues

3. Use Structured Investigation Methods

Adopting structured investigation methods helps ensure consistency and thoroughness. Some useful tools include:

Fishbone diagrams for brainstorming potential causes
Why-Why analysis for drilling down to root causes
Fault tree analysis for complex issues
Timeline analysis to understand the sequence of events

4. Look Beyond Human Error

Human error is not a root cause. Instead of stopping at “operator error”, investigators should dig deeper to understand:

Why the error occurred
What system or process factors contributed to the error
How similar errors can be prevented in the future

5. Improve Documentation Practices

Thorough documentation is essential for demonstrating the adequacy of investigations to regulators. Key elements include:

Clear description of the deviation
Investigation steps taken
Data and evidence collected
Root cause analysis
Rationale for conclusions
Corrective and preventive actions

6. Implement Effective CAPAs

The investigation is only the first step – implementing effective corrective and preventive actions is crucial. Companies should:

Ensure CAPAs directly address identified root causes
Consider both short-term corrections and long-term preventive measures
Assess potential risks of proposed CAPAs
Establish clear timelines and accountability for CAPA implementation
Conduct effectiveness checks to verify CAPA impact

7. Foster a Culture of Quality

Management plays a critical role in creating an environment that supports thorough investigations.

Providing adequate time and resources for investigations
Encouraging open reporting of deviations without fear of blame
Recognizing and rewarding thorough investigation practices
Leading by example in prioritizing quality and patient safety

Common Pitfalls in Investigating Microbiological Contamination Events

When investigating microbiological contamination events there are often several pitfalls that can hinder the effectiveness of their investigations.

Inadequate Root Cause Analysis

One of the most significant pitfalls is failing to conduct a thorough root cause analysis. Investigators may be tempted to attribute contamination to superficial causes like “human error” without digging deeper into systemic issues. This shallow approach often leads to ineffective corrective actions that fail to prevent recurrence. Build in safeguards to avoid jumping to conclusion.

Overlooking Environmental Factors

Investigators sometimes neglect to consider the broader environmental context of contamination events. Factors such as air handling systems, water quality, and even compressed air can harbor contaminants. Failing to examine these potential sources may result in missed opportunities for identifying the true origin of contamination.

Insufficient Microbial Identification

Relying solely on phenotypic identification methods can lead to misidentification of contaminants. Phenotypic results can incorrectly point to laboratory contamination, while genotypic testing revealed a production-related issue. Using a combination of identification methods, including genotypic techniques, can provide more accurate and actionable results.

Premature Conclusion of Investigations

Pressure to close investigations quickly can lead to premature conclusions. This was evident in the Sanofi warning letter, where the FDA noted that investigations into critical deviations, including multiple microbiological contamination events, were inadequate. Rushing the process can result in overlooking important details and failing to implement effective corrective actions.

Failure to Consider Cross-Contamination

Investigators may not always consider the possibility of cross-contamination between products or areas within the facility. The presence of drug-resistant microbial contaminants, as observed in some studies, underscores the importance of examining potential routes of transmission and implementing strict hygiene procedures.

Inadequate Documentation

Poor documentation of investigation activities and rationale can undermine the credibility of findings and make it difficult to justify conclusions to regulators. The FDA’s warning letter to Sanofi highlighted this issue, noting that not all investigational activities were documented.

Neglecting Trending and Data Analysis

Failing to analyze contamination events in the context of historical data and trends can lead to missed patterns and recurring issues. Establishing and maintaining a comprehensive microflora database is essential for effective contamination control strategies and can provide valuable insights for investigations.

Insufficient Training of Investigators

Lack of properly trained and competent investigators can significantly impact the quality of contamination investigations. Ensuring that personnel have the necessary skills and knowledge to conduct thorough, science-based investigations is crucial for identifying true root causes and implementing effective corrective actions.

Conclusion

The Sanofi warning letter serves as a reminder of the critical importance of thorough deviation investigations in pharmaceutical manufacturing. By implementing robust investigation and CAPA processes, companies can not only avoid regulatory action but also drive continuous improvement in their operations. This requires ongoing commitment to developing investigator competencies, using structured methods, looking beyond superficial causes, and fostering a culture that values quality and learning from deviations.

As the industry continues to evolve, effective investigation practices will be essential for ensuring product quality, patient safety, and regulatory compliance. By viewing deviations not as failures but as opportunities for improvement, pharmaceutical manufacturers can build more resilient and reliable production systems.

When Your Deviation/CAPA Program Runs Smoothly Expect a Period of Increased Deviations

One reason to invest in the CAPA program is that you will see fewer deviations over time as you fix issues. That is true, but it takes time. Yes, you’ve dealt with your backlog, improved your investigations, integrated risk management, built problem-solving into your processes, and are truly driving preventative actions. And yet your deviations remain high. What is going on?

It’s because you are getting good at things and working your way through the bolus of problems. Here’s what is going on:

Improved Detection and Reporting: As a CAPA program matures, it enhances an organization’s ability to detect and report deviations. Employees become more adept at identifying and documenting deviations due to better training and awareness, leading to a temporary increase in reported deviations.
Thorough Root Cause Analysis: A well-functioning CAPA program emphasizes thorough root cause analysis. This process often uncovers previously unnoticed issues and identifies additional deviations that need to be addressed.
Increased Scrutiny and Compliance: As the CAPA program gains momentum, management usually scrutinizes it more, which can lead to the discovery of more deviations. Organizations become more vigilant in maintaining compliance, resulting in more deviations being reported and documented.
Systematic Process Improvements: The CAPA process often leads to systemic improvements in processes and procedures. As these improvements are implemented, any deviations from the new standards are more likely to be identified and recorded, contributing to an initial rise in deviation reports.
Cultural Shift Towards Quality: A successful CAPA program fosters a culture of quality and continuous improvement. Employees may feel more empowered and responsible for reporting deviations, increasing the number of deviations captured.

Expect these changes and build your metric program around them. Avoid introducing a metric like a reduction in deviations in the first year, as such a metric will drive bad behavior. Instead, focus on metrics that demonstrate the success of the changes and, over time, introduce metrics to see the overall benefits.

Best Ways to Address a Deviation Backlog

A deviation backlog in a regulated industry, such as pharmaceuticals, can pose significant risks to compliance, product quality, and overall operational efficiency. Addressing this backlog effectively requires a structured approach that prioritizes risk management, resource allocation, and continuous improvement.

You need to do two things first:

Prioritize Urgent Requests

Identify Critical Issues: Focus on resolving high-priority and time-sensitive deviations first to drive compliance.

Isolate and Organize

Separate Backlog from Ongoing Deviations: Create distinct queues for backlog deviations and new deviations to streamline management.
Create a Backlog Team: Assign a dedicated team to tackle the backlog, ensuring that regular support operations continue smoothly.

From there, you can then proceed into the next steps to tackle a deviation backlog:

1. Prioritize Based on Risk

Not all deviations have the same impact. Prioritizing the backlog based on the severity and risk part of each deviation is crucial. This involves:

Assessing Severity: Evaluate the potential impact of each deviation on product quality, patient safety, and regulatory compliance. Ideally you already classify deviations into categories such as minor, moderate, and major. based on those you will need to additional work to prioritize the backlog.
Risk-Based Approach: Focus on resolving high-risk deviations first to mitigate the most critical issues promptly.

2. Allocate Adequate Resources

Addressing a backlog efficiently often requires additional resources. Consider the following actions:

Increase Staffing: Temporarily augment your team with additional personnel or external consultants to handle the increased workload.
Specialized Teams: Form dedicated teams to focus solely on backlog reduction, ensuring that regular operations are not disrupted.

3. Improve and Make Robust Deviation Management Processes

A systematic approach to deviation management helps prevent backlogs from recurring. Key steps include:

Root Cause Analysis (RCA): Conduct thorough investigations to identify the underlying causes of deviations.
Corrective and Preventive Actions (CAPA): Develop and implement CAPA plans to address root causes and prevent future deviations. Ensure these plans are reviewed and approved by relevant stakeholders.

4. Regular Monitoring and Review

Continuous monitoring and regular reviews are essential to keep the backlog under control:

Track Progress: Use metrics and key performance indicators (KPIs) to monitor the progress of backlog reduction efforts. Tools like burndown charts can be helpful.
Periodic Reviews: Conduct regular review meetings to assess the status of the backlog and make necessary adjustments to the plan.

5. Enhance Deviation Management Systems

Improving your deviation management system can prevent future backlogs and streamline the resolution process:

Automation and Software Tools: Implement a eQMS or evaluate and improve the current one.
Training and Education: Ensure that all employees are well-trained in deviation management processes and understand the importance of timely reporting and resolution.

6. Foster a Culture of Continuous Improvement

Promote a culture that values continuous improvement and proactive problem-solving:

Encourage Reporting: Create an environment where employees feel comfortable reporting deviations without fear of retribution.
Learn from Deviations: Analyze deviation trends to identify areas for process improvement and implement changes to prevent recurrence.

7. Set Clear Goals and Deadlines

Establish clear goals and deadlines for backlog reduction:

Set Due Dates: Assign due dates for resolving backlog items to ensure timely action. Items that exceed their due dates should be reviewed and either expedited or reassessed for relevance.
Regular Updates: Keep all stakeholders informed about the progress and any changes to the plan through regular updates and communication.

Conclusion

Addressing a deviation backlog effectively requires a combination of prioritization, resource allocation, robust processes, continuous monitoring, and a culture of improvement. By implementing these strategies, organizations can reduce their backlog, improve compliance, and enhance overall product quality and safety.

Causal Factor

A causal factor is a significant contributor to an incident, event, or problem that, if eliminated or addressed, would have prevented the occurrence or reduced its severity or frequency. Here are the key points to understand about causal factors:

Definition: A causal factor is a major unplanned, unintended contributor to an incident (a negative event or undesirable condition) that, if eliminated, would have either prevented the occurrence of the incident or reduced its severity or frequency.
Distinction from root cause: While a causal factor contributes to an incident, it is not necessarily the primary driver. The root cause, on the other hand, is the fundamental reason for the occurrence of a problem or event. (Pay attention to the deficiencies of the model)
Multiple contributors: An incident may have multiple causal factors, and eliminating one causal factor might not prevent the incident entirely but could reduce its likelihood or impact. Swiss-Cheese Model.
Identification methods: Causal factors can be identified through various techniques, including: Root cause analysis (including such tools as fishbone diagrams (Ishikawa diagrams) or the Why-Why technique), Causal Learning Cycle(CLC) analysis, and Causal factor charting.
Importance in problem-solving: Identifying causal factors is crucial for developing effective preventive measures and improving safety, quality, and efficiency.
Characteristics: Causal factors must be mistakes, errors, or failures that directly lead to an incident or fail to mitigate its consequences. They should not contain other causal factors within them.
Distinction from root causes: It’s important to note that root causes are not causal factors but rather lead to causal factors. Examples of root causes often mistaken for causal factors include inadequate procedures, improper training, or poor work culture.

Human Factors are not always Causal Factors, but can be!

Human factor and human error are related concepts but are not the same. A human error is always a causal factor, and the human factor explains why human errors can happen.

Human Error

Human error refers to an unintentional action or decision that fails to achieve the intended outcome. It encompasses mistakes, slips, lapses, and violations that can lead to accidents or incidents. There are two types:

Unintentional Errors include slips (attentional failures) and lapses (memory failures) caused by distractions, interruptions, fatigue, or stress.
Intentional Errors are violations in which an individual knowingly deviates from safe practices, procedures, or regulations. They are often categorized into routine, situational, or exceptional violations.

Human Factors

Human factors is a broader field that studies how humans interact with various system elements, including tools, machines, environments, and processes. It aims to optimize human well-being and overall system performance by understanding human capabilities, limitations, behaviors, and characteristics.

Physical Ergonomics focuses on human anatomical, anthropometric, physiological, and biomechanical characteristics.
Cognitive Ergonomics deals with mental processes such as perception, memory, reasoning, and motor response.
Organizational Ergonomics involves optimizing organizational structures, policies, and processes to improve overall system performance and worker well-being.

Relationship Between Human Factors and Human Error

Causal Relationship: Human factors delve into the underlying reasons why human errors occur. They consider the conditions and systems that contribute to errors, such as poor design, inadequate training, high workload, and environmental factors.
Error Prevention: By addressing human factors, organizations can design systems and processes that minimize the likelihood of human errors. This includes implementing error-proofing solutions, improving ergonomics, and enhancing training and supervision.

Key Differences

Focus:
- Human Error: Focuses on the outcome of an action or decision that fails to achieve the intended result.
- Human Factors: Focuses on the broader context and conditions that influence human performance and behavior.
Approach:
- Human Error: Often addressed through training, disciplinary actions, and procedural changes.
- Human Factors: Involves a multidisciplinary approach to design systems, environments, and processes that support optimal human performance and reduce the risk of errors.

Avoiding Logical Pitfalls

When documenting a root cause analysis or risk assessment or any of the myriad other technical reports we are making a logical argument. In this post, I want to evaluate six common pitfalls to avoid in your writing.

Claiming to follow logically: Non Sequiturs and Genetic Fallacies

Non-sequiturs and genetic fallacies involve statements that are offered in a way that suggests they follow logically one from the other, when in fact no such link exists.

Non-sequiturs (meaning ‘that which does not follow’) often happens when we make connective explanations without justification. Genetic fallacies occur when we draw assumptions about something by tracing its origins back even though no necessary link can be made between the present situation and the claimed original one.

This is a very common mistake and usually stems from poor use of causal thinking. The best way to address it in an organization is continuing to build discipline in thought processes and documenting the connections and why things are connected.

Making Assumptions: Begging the Question

Begging the question, assuming the very point at issue happens a lot in investigations. One of the best ways to avoid this is to ensure a proper problem statement.

Restricting the Options to Two: ‘Black and White’ Thinking

In black and white thinking or the false dichotomy, the arguer gives only two options when other alternatives are possible.

Being Unclear: Equivocation and Ambiguity

Lexical: Refers to individual words
Referential: Occurs when the context is unclear
Syntactical: Results from grammatical confusions

Just think of all the various meanings of validation and you can understand this problem.

Thinking Wishfully

Good problem-solving will drive down the tendency to assume conclusions, but these probably exist in every organization.

Detecting the Whiff of Red Herrings

Human error is the biggest red herring of them all.