The recent FDA warning letter to Sanofi highlights a critical issue in biopharmaceutical manufacturing: the integrity of single-use systems (SUS) and the prevention of leaks. This incident serves as a stark reminder of the importance of robust control strategies in bioprocessing, particularly when it comes to high-pressure events and product leakage.
The Sanofi Case: A Cautionary Tale
In January 2025, the FDA issued a warning letter to Sanofi regarding their Genzyme facility in Framingham, Massachusetts. The letter cited significant deviations from Current Good Manufacturing Practice (CGMP) for active pharmaceutical ingredients (APIs). One of the key issues highlighted was the company’s failure to address high-pressure events that resulted in in-process product leakage.
Sanofi had been using an unapproved workaround, replacing shipping bags to control the frequency of high-pressure and in-process leaking events. This deviation was not properly documented or the solution validated.
A proper control strategy in this context would likely involve:
A validated process modification to prevent or mitigate high-pressure events
Engineering controls or equipment upgrades to handle pressure fluctuations safely
Improved monitoring and alarm systems to detect potential high-pressure situations
Validated procedures for responding to high-pressure events if they occur
A comprehensive risk assessment and mitigation plan related to pressure control in the manufacturing process
The Importance of Leak Prevention in Single-Use Systems
Single-use technologies have become increasingly prevalent in biopharmaceutical manufacturing due to their numerous advantages, including reduced risk of cross-contamination and increased flexibility. For all this to work, the integrity of these systems is paramount to ensure product quality and patient safety.
To address the challenges posed by leaks in single-use systems, manufacturers need to consider implementing a comprehensive control strategy. Here are some key approaches:
1. Integrity Testing
Implementing robust integrity testing protocols is crucial. Two non-destructive testing methods are particularly suitable for single-use systems:
Pressure-based tests: These tests can detect leaks by inflating components with air to a defined pressure. They can identify defects as small as 10 µm in flat bags and 100 µm in large-volume 3D systems.
Trace-gas-based tests: Typically using helium, these tests offer the highest level of sterility assurance and can detect even smaller defects.
2. Risk-Based Quality by Design (QbD) Approach
Single-use components and the manufacturing process must be established and maintained using a risk-based QbD approach that can help identify potential failure points and implement appropriate controls. This should include:
Comprehensive risk assessments
Validated procedures for responding to high-pressure events
Instead of using unapproved workarounds, companies need to develop and validate process modifications to prevent or mitigate high-pressure events. One thing to be extra cautious about is the worry of a temporary solution becoming a permanent one.
Conclusion
The Sanofi warning letter serves as a crucial reminder of the importance of maintaining the integrity of single-use systems in biopharmaceutical manufacturing. By implementing comprehensive control strategies, including robust integrity testing, risk-based approaches, and validated process modifications, manufacturers can significantly reduce the risk of leaks and ensure compliance with cGMP standards.
As the industry continues to embrace single-use technologies, it’s imperative that we remain vigilant in addressing these challenges to maintain product quality, patient safety, and regulatory compliance.
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:
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.
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.
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.
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.
Regulatory agencies have continually continued to make it clear that when a Contract Manufacturing Organization (CMO) or Contract Research Organization (CRO) experiences a deviation, the sponsor/Marketing Authorization Holder (MAH) has several key responsibilities:
Review the deviation: The sponsor must thoroughly review the deviation to ensure it was appropriately defined and investigated. This review is crucial as the sponsor cannot delegate their responsibility to ensure the drug product is safe, effective, and conforms to specifications and regulatory commitments.
Assess product impact: The sponsor should ensure that the CMO has properly assessed the impact of the deviation on the product. This includes evaluating whether the deviation affected material quality, safety, or efficacy.
Verify appropriate material control: It’s the sponsor’s responsibility to ensure the CMO has appropriately controlled the affected material and extended this control to any other potentially affected materials.
Make disposition decisions: Ultimately, the sponsor is responsible for deciding whether the product should be released, reprocessed, or rejected. This decision is especially critical if the deviation affected material in clinical trials.
Oversee corrective and preventive actions: The sponsor should understand how the CMO’s corrective and preventive action (CAPA) system operates and ensure appropriate measures are taken to prevent recurrence of the deviation.
Maintain oversight: While the quality agreement defines the CMO’s responsibilities, the sponsor retains 100% oversight, including executed batch record review, change control, and deviation review and approval.
Risk-based approach: For major or critical deviations, sponsors should employ a risk-based approach to assess the severity and potential impact.
To simplify the deviation notification process with a Contract Organization (CxO), sponsors and can implement several strategies:
Clear Communication and Documentation
Establish a Well-Defined Quality Agreement: Create a comprehensive quality agreement that clearly outlines the deviation notification process, including timelines, classification criteria, and reporting requirements.
Implement Standardized Templates: Develop and provide standardized templates for deviation reporting to ensure consistency and completeness of information.
Set Clear Notification Timelines: Agree on specific timelines for different deviation categories. For example, critical and major deviations should be reported within one business day.
Risk-Based Approach
Adopt a Quality Risk Management (QRM) Mindset: Approach the partnership with a focus on risk management, ensuring that both parties understand the potential impact of deviations on product quality and patient safety.
Calibrate Risk Classification: Align the deviation classification system between the sponsor and CxO to avoid discrepancies in severity assessment.
Streamlined Processes
Utilize Electronic Quality Management Systems: Implement digital tools to facilitate real-time reporting and tracking of deviations, improving efficiency and transparency. Yes, the sponsor should be taking a risk based approach to tracking deviations in their eQMS that captures the important sponsor/MAH decision making.
Define Clear Roles and Responsibilities: Clearly delineate who is responsible for each step of the deviation management process, from identification to reporting and investigation.
Training and Support
Provide Comprehensive Training: Ensure that CxO staff are well-trained on the sponsor’s quality expectations, deviation reporting procedures, and the use of any specific tools or systems.
Offer Ongoing Support: Establish a dedicated point of contact or support team to assist the CxO with questions or issues related to deviation reporting.
Regular Review and Improvement
Conduct Periodic Reviews: Schedule regular meetings to review the deviation notification process, discuss any challenges, and identify areas for improvement.
Encourage Open Dialogue: Foster an environment where the CMO feels comfortable reporting issues promptly without fear of punitive action.
I strongly believe that a CxO needs to implement these strategies (do not put it only on the MAH’s shoulders) as part of their client onboarding and management process to create a more efficient and effective deviation notification process. This approach not only simplifies the process but also ensures that critical quality information is communicated promptly and accurately, ultimately contributing to better product quality and regulatory compliance. Add some value and don’t make the sponsor beg for information.
Investigations of a Dog 