When Water Systems Fail: Unpacking the LeMaitre Vascular Warning Letter

The FDA’s August 11, 2025 warning letter to LeMaitre Vascular reads like a masterclass in how fundamental water system deficiencies can cascade into comprehensive quality system failures. This warning letter offers lessons about the interconnected nature of pharmaceutical water systems and the regulatory expectations that surround them.

The Foundation Cracks

What makes this warning letter particularly instructive is how it demonstrates that water systems aren’t just utilities—they’re critical manufacturing infrastructure whose failures ripple through every aspect of product quality. LeMaitre’s North Brunswick facility, which manufactures Artegraft Collagen Vascular Grafts, found itself facing six major violations, with water system inadequacies serving as the primary catalyst.

The Artegraft device itself—a bovine carotid artery graft processed through enzymatic digestion and preserved in USP purified water and ethyl alcohol—places unique demands on water system reliability. When that foundation fails, everything built upon it becomes suspect.

Water Sampling: The Devil in the Details

The first violation strikes at something discussed extensively in previous posts: representative sampling. LeMaitre’s USP water sampling procedures contained what the FDA termed “inconsistent and conflicting requirements” that fundamentally compromised the representativeness of their sampling.

Consider the regulatory expectation here. As outlined in ISPE guideline, “sampling a POU must include any pathway that the water travels to reach the process”. Yet LeMaitre was taking samples through methods that included purging, flushing, and disinfection steps that bore no resemblance to actual production use. This isn’t just a procedural misstep—it’s a fundamental misunderstanding of what water sampling is meant to accomplish.

The FDA’s criticism centers on three critical sampling failures:

Sampling Location Discrepancies: Taking samples through different pathways than production water actually follows. This violates the basic principle that quality control sampling should “mimic the way the water is used for manufacturing”.
Pre-Sampling Conditioning: The procedures required extensive purging and cleaning before sampling—activities that would never occur during normal production use. This creates “aspirational data”—results that reflect what we wish our system looked like rather than how it actually performs.
Inconsistent Documentation: Failure to document required replacement activities during sampling, creating gaps in the very records meant to demonstrate control.

The Sterilant Switcheroo

Perhaps more concerning was LeMaitre’s unauthorized change of sterilant solutions for their USP water system sanitization. The company switched sterilants sometime in 2024 without documenting the change control, assessing biocompatibility impacts, or evaluating potential contaminant differences.

This represents a fundamental failure in change control—one of the most basic requirements in pharmaceutical manufacturing. Every change to a validated system requires formal assessment, particularly when that change could affect product safety. The fact that LeMaitre couldn’t provide documentation allowing for this change during inspection suggests a broader systemic issue with their change control processes.

Environmental Monitoring: Missing the Forest for the Trees

The second major violation addressed LeMaitre’s environmental monitoring program—specifically, their practice of cleaning surfaces before sampling. This mirrors issues we see repeatedly in pharmaceutical manufacturing, where the desire for “good” data overrides the need for representative data.

Environmental monitoring serves a specific purpose: to detect contamination that could reasonably be expected to occur during normal operations. When you clean surfaces before sampling, you’re essentially asking, “How clean can we make things when we try really hard?” rather than “How clean are things under normal operating conditions?”

The regulatory expectation is clear: environmental monitoring should reflect actual production conditions, including normal personnel traffic and operational activities. LeMaitre’s procedures required cleaning surfaces and minimizing personnel traffic around air samplers—creating an artificial environment that bore little resemblance to actual production conditions.

Sterilization Validation: Building on Shaky Ground

The third violation highlighted inadequate sterilization process validation for the Artegraft products. LeMaitre failed to consider bioburden of raw materials, their storage conditions, and environmental controls during manufacturing—all fundamental requirements for sterilization validation.

This connects directly back to the water system failures. When your water system monitoring doesn’t provide representative data, and your environmental monitoring doesn’t reflect actual conditions, how can you adequately assess the bioburden challenges your sterilization process must overcome?

The FDA noted that LeMaitre had six out-of-specification bioburden results between September 2024 and March 2025, yet took no action to evaluate whether testing frequency should be increased. This represents a fundamental misunderstanding of how bioburden data should inform sterilization validation and ongoing process control.

CAPA: When Process Discipline Breaks Down

The final violations addressed LeMaitre’s Corrective and Preventive Action (CAPA) system, where multiple CAPAs exceeded their own established timeframes by significant margins. A high-risk CAPA took 81 days instead of the required timeframe, while medium and low-risk CAPAs exceeded deadlines by 120-216 days.

This isn’t just about missing deadlines—it’s about the erosion of process discipline. When CAPA systems lose their urgency and rigor, it signals a broader cultural issue where quality requirements become suggestions rather than requirements.

The Recall That Wasn’t

Perhaps most concerning was LeMaitre’s failure to report a device recall to the FDA. The company distributed grafts manufactured using raw material from a non-approved supplier, with one graft implanted in a patient before the recall was initiated. This constituted a reportable removal under 21 CFR Part 806, yet LeMaitre failed to notify the FDA as required.

This represents the ultimate failure: when quality system breakdowns reach patients. The cascade from water system failures to inadequate environmental monitoring to poor change control ultimately resulted in a product safety issue that required patient intervention.

Gap Assessment Questions

For organizations conducting their own gap assessments based on this warning letter, consider these critical questions:

Water System Controls

Are your water sampling procedures representative of actual production use conditions?
Do you have documented change control for any modifications to water system sterilants or sanitization procedures?
Are all water system sampling activities properly documented, including any maintenance or replacement activities?
Have you assessed the impact of any sterilant changes on product biocompatibility?

Environmental Monitoring

Do your environmental monitoring procedures reflect normal production conditions?
Are surfaces cleaned before environmental sampling, and if so, is this representative of normal operations?
Does your environmental monitoring capture the impact of actual personnel traffic and operational activities?
Are your sampling frequencies and locations justified by risk assessment?

Sterilization and Bioburden Control

Does your sterilization validation consider bioburden from all raw materials and components?
Have you established appropriate bioburden testing frequencies based on historical data and risk assessment?
Do you have procedures for evaluating when bioburden testing frequency should be increased based on out-of-specification results?
Are bioburden results from raw materials and packaging components included in your sterilization validation?

CAPA System Integrity

Are CAPA timelines consistently met according to your established procedures?
Do you have documented rationales for any CAPA deadline extensions?
Is CAPA effectiveness verification consistently performed and documented?
Are supplier corrective actions properly tracked and their effectiveness verified?

Change Control and Documentation

Are all changes to validated systems properly documented and assessed?
Do you have procedures for notifying relevant departments when suppliers change materials or processes?
Are the impacts of changes on product quality and safety systematically evaluated?
Is there a formal process for assessing when changes require revalidation?

Regulatory Compliance

Are all required reports (corrections, removals, MDRs) submitted within regulatory timeframes?
Do you have systems in place to identify when product removals constitute reportable events?
Are all regulatory communications properly documented and tracked?

Learning from LeMaitre’s Missteps

This warning letter serves as a reminder that pharmaceutical manufacturing is a system of interconnected controls, where failures in fundamental areas like water systems can cascade through every aspect of operations. The path from water sampling deficiencies to patient safety issues is shorter than many organizations realize.

The most sobering aspect of this warning letter is how preventable these violations were. Representative sampling, proper change control, and timely CAPA completion aren’t cutting-edge regulatory science—they’re fundamental GMP requirements that have been established for decades.

For quality professionals, this warning letter reinforces the importance of treating utility systems with the same rigor we apply to manufacturing processes. Water isn’t just a raw material—it’s a critical quality attribute that deserves the same level of control, monitoring, and validation as any other aspect of your manufacturing process.

The question isn’t whether your water system works when everything goes perfectly. The question is whether your monitoring and control systems will detect problems before they become patient safety issues. Based on LeMaitre’s experience, that’s a question worth asking—and answering—before the FDA does it for you.

The Role of the HACCP

Reading Strukmyer LLC’s recent FDA Warning Letter, and reflecting back to last year’s Colgate-Palmolive/Tom’s of Maine, Inc. Warning Letter, has me thinking of common language In both warning letters where the FDA asks for “A comprehensive, independent assessment of the design and control of your firm’s manufacturing operations, with a detailed and thorough review of all microbiological hazards.”

Water, Water, Everywhere

It is hard to read that as anything else than a clarion call to use a HACCP.

If that isn’t a HACCP, I don’t know what is. Given the FDA’s rich history and connection to the tool, it is difficult to imagine them thinking of any other tool. Sure, I can invent about 7 other ways to do that, but why bother when there is a great tool, full of powerful uses, waiting to be used that the regulators pretty much have in their DNA.

The Evolution of HACCP in FDA Regulation: A Journey to Enhanced Food Safety

The Hazard Analysis and Critical Control Points (HACCP) system has a fascinating history that is deeply intertwined with FDA regulations. Initially developed in the 1960s by NASA, the Pillsbury Company, and the U.S. Army, HACCP was designed to ensure safe food for space missions. This pioneering collaboration aimed to prevent food safety issues by identifying and controlling critical points in food processing. The success of HACCP in space missions soon led to its application in commercial food production.

In the 1970s, Pillsbury applied HACCP to its commercial operations, driven by incidents such as the contamination of farina with glass. This prompted Pillsbury to adopt HACCP more widely across its production lines. A significant event in 1971 was a panel discussion at the National Conference on Food Protection, which led to the FDA’s involvement in promoting HACCP for food safety inspections. The FDA recognized the potential of HACCP to enhance food safety standards and began to integrate it into its regulatory framework.

As HACCP gained prominence as a food safety standard in the 1980s and 1990s, the National Advisory Committee on Microbiological Criteria for Foods (NACMCF) refined its principles. The committee added preliminary steps and solidified the seven core principles of HACCP, which include hazard analysis, critical control points identification, establishing critical limits, monitoring procedures, corrective actions, verification procedures, and record-keeping. This structured approach helped standardize HACCP implementation across different sectors of the food industry.

A major milestone in the history of HACCP was the implementation of the Pathogen Reduction/HACCP Systems rule by the USDA’s Food Safety and Inspection Service (FSIS) in 1996. This rule mandated HACCP in meat and poultry processing facilities, marking a significant shift towards preventive food safety measures. By the late 1990s, HACCP became a requirement for all food businesses, with some exceptions for smaller operations. This widespread adoption underscored the importance of proactive food safety management.

The Food Safety Modernization Act (FSMA) of 2011 further emphasized preventive controls, including HACCP, to enhance food safety across the industry. FSMA shifted the focus from responding to food safety issues to preventing them, aligning with the core principles of HACCP. Today, HACCP remains a cornerstone of food safety management globally, with ongoing training and certification programs available to ensure compliance with evolving regulations. The FDA continues to support HACCP as part of its broader efforts to protect public health through safe food production and processing practices. As the food industry continues to evolve, the principles of HACCP remain essential for maintaining high standards of food safety and quality.

Why is a HACCP Useful in Biotech Manufacturing

The HACCP seeks to map a process – the manufacturing process, one cleanroom, a series of interlinked cleanrooms, or the water system – and identifies hazards (a point of contamination) by understanding the personnel, material, waste, and other parts of the operational flow. These hazards are assessed at each step in the process for their likelihood and severity. Mitigations are taken to reduce the risk the hazard presents (“a contamination control point”). Where a risk cannot be adequately minimized (either in terms of its likelihood of occurrence, the severity of its nature, or both), this “contamination control point” should be subject to a form of detection so that the facility has an understanding of whether the microbial hazard was potentially present at a given time, for a given operation. In other words, the “critical control point” provides a reasoned area for selecting a monitoring location. For aseptic processing, for example, the target is elimination, even if this cannot be absolutely demonstrated.

The HACCP approach can easily be applied to pharmaceutical manufacturing where it proves very useful for microbial control. Although alternative risk tools exist, such as Failure Modes and Effects Analysis, the HACCP approach is better for microbial control.

The HACCP is a core part of an effective layers of control analysis.

Conducting a HACCP

HACCP provides a systematic approach to identifying and controlling potential hazards throughout the production process.

Step 1: Conduct a Hazard Analysis

List All Process Steps: Begin by detailing every step involved in your biotech manufacturing process, from raw material sourcing to final product packaging. Make sure to walk down the process thoroughly.
Identify Potential Hazards: At each step, identify potential biological, chemical, and physical hazards. Biological hazards might include microbial contamination, while chemical hazards could involve chemical impurities or inappropriate reagents. Physical hazards might include particulates or inappropriate packaging materials.
Evaluate Severity and Likelihood: Assess the severity and likelihood of each identified hazard. This evaluation helps prioritize which hazards require immediate attention.
Determine Preventive Measures: Develop strategies to control significant hazards. This might involve adjusting process conditions, improving cleaning protocols, or enhancing monitoring systems.
Document Justifications: Record the rationale behind including or excluding hazards from your analysis. This documentation is essential for transparency and regulatory compliance.

Step 2: Determine Critical Control Points (CCPs)

Identify Control Points: Any step where biological, chemical, or physical factors can be controlled is considered a control point.
Determine CCPs: Use a decision tree to identify which control points are critical. A CCP is a step at which control can be applied and is essential to prevent or eliminate a hazard or reduce it to an acceptable level.
Establish Critical Limits: For each CCP, define the maximum or minimum values to which parameters must be controlled. These limits ensure that hazards are effectively managed.

Control Points	Critical Control Points
Process steps where a control measure (mitigation activity) is necessary to prevent the hazard from occurring	Process steps where both control and monitoring are necessary to assure product quality and patient safety
Are not necessarily critical control points (CCPs)	Are also control points
Determined from the risk associated with the hazard	Determined through a decision tree

Step 3: Establish Monitoring Procedures

Develop Monitoring Plans: Create detailed plans for monitoring each CCP. This includes specifying what to monitor, how often, and who is responsible.
Implement Monitoring Tools: Use appropriate tools and equipment to monitor CCPs effectively. This might include temperature sensors, microbial testing kits, or chemical analyzers.
Record Monitoring Data: Ensure that all monitoring data is accurately recorded and stored for future reference.

Step 4: Establish Corrective Actions

Define Corrective Actions: Develop procedures for when monitoring indicates that a CCP is not within its critical limits. These actions should restore control and prevent hazards.
Proceduralize: You are establishing alternative control strategies here so make sure they are appropriately verified and controlled by process/procedure in the quality system.
Train Staff: Ensure that all personnel understand and can implement corrective actions promptly.

Step 5: Establish Verification Procedures

Regular Audits: Conduct regular audits to verify that the HACCP system is functioning correctly. This includes reviewing monitoring data and observing process operations.
Validation Studies: Perform validation studies to confirm that CCPs are effective in controlling hazards.
Continuous Improvement: Use audit findings to improve the HACCP system over time.

Step 6: Establish Documentation and Record-Keeping

Maintain Detailed Records: Keep comprehensive records of all aspects of the HACCP system, including hazard analyses, CCPs, monitoring data, corrective actions, and verification activities.
Ensure Traceability: Use documentation to ensure traceability throughout the production process, facilitating quick responses to any safety issues.

Step 7: Implement and Review the HACCP Plan

Implement the Plan: Ensure that all personnel involved in biotech manufacturing understand and follow the HACCP plan.
Regular Review: Regularly review and update the HACCP plan to reflect changes in processes, new hazards, or lessons learned from audits and incidents.

Determining Causative Laboratory Error in Bioburden, Endotoxin, and Environmental Monitoring OOS Results

In the previous post, we discussed the critical importance of thorough investigations into deviations, as highlighted by the recent FDA warning letter to Sanofi. Let us delve deeper into a specific aspect of these investigations: determining whether an invalidated out-of-specification (OOS) result for bioburden, endotoxin, or environmental monitoring action limit excursions conclusively demonstrates causative laboratory error.

When faced with an OOS result in microbiological testing, it’s crucial to conduct a thorough investigation before invalidating the result. The FDA expects companies to provide scientific justification and evidence that conclusively demonstrates a causative laboratory error if a result is to be invalidated.

Key Steps in Evaluating Laboratory Error

1. Review of Test Method and Procedure

Examine the standard operating procedure (SOP) for the test method
Verify that all steps were followed correctly
Check for any deviations from the established procedure

2. Evaluation of Equipment and Materials

Evaluation of Equipment and Materials is a critical step in determining whether laboratory error caused an out-of-specification (OOS) result, particularly for bioburden, endotoxin, or environmental monitoring tests. Here’s a detailed approach to performing this evaluation:

Equipment Assessment

Functionality Check

Run performance verification tests on key equipment used in the analysis
Review equipment logs for any recent malfunctions or irregularities
Verify that all equipment settings were correct for the specific test performed

Calibration Review

Check calibration records to ensure equipment was within its calibration period
Verify that calibration standards used were traceable and not expired
Review any recent calibration data for trends or shifts

Maintenance Evaluation

Examine maintenance logs for adherence to scheduled maintenance
Look for any recent repairs or adjustments that could affect performance
Verify that all preventive maintenance tasks were completed as required

Materials Evaluation

Reagent Quality Control

Check expiration dates of all reagents used in the test
Review storage conditions to ensure reagents were stored properly
Verify that quality control checks were performed on reagents before use

Media Assessment (for Bioburden and Environmental Monitoring)

Review growth promotion test results for culture media
Check pH and sterility of prepared media
Verify that media was stored at the correct temperature

Water Quality (for Endotoxin Testing)

Review records of water quality used for reagent preparation
Check for any recent changes in water purification systems
Verify endotoxin levels in water used for testing

Environmental Factors

Laboratory Conditions

Review temperature and humidity logs for the testing area
Check for any unusual events (e.g., power outages, HVAC issues) around the time of testing
Verify that environmental conditions met the requirements for the test method

Contamination Control

Examine cleaning logs for the laboratory area and equipment
Review recent environmental monitoring results for the testing area
Check for any breaches in aseptic technique during testing

Documentation Review

Standard Operating Procedures (SOPs)

Verify that the most current version of the SOP was used
Check for any recent changes to the SOP that might affect the test
Ensure all steps in the SOP were followed and documented

Equipment and Material Certifications

Review certificates of analysis for critical reagents and standards
Check equipment qualification documents (IQ/OQ/PQ) for compliance
Verify that all required certifications were current at the time of testing

By thoroughly evaluating equipment and materials using these detailed steps, laboratories can more conclusively determine whether an OOS result was due to laboratory error or represents a true product quality issue. This comprehensive approach helps ensure the integrity of microbiological testing and supports robust quality control in pharmaceutical manufacturing.

3. Assessment of Analyst Performance

Here are key aspects to consider when evaluating analyst performance during an OOS investigation:

Review Training Records

Examine the analyst’s training documentation to ensure they are qualified to perform the specific test method.
Verify that the analyst has completed all required periodic refresher training.
Check if the analyst has demonstrated proficiency in the particular test method recently.

Evaluate Recent Performance History

Review the analyst’s performance on similar tests over the past few months.
Look for any patterns or trends in the analyst’s results, such as consistently high or low readings.
Compare the analyst’s results with those of other analysts performing the same tests.

Conduct Interviews

Interview the analyst who performed the test to gather detailed information about the testing process.
Ask open-ended questions to encourage the analyst to describe any unusual occurrences or deviations from standard procedures.
Inquire about the analyst’s workload and any potential distractions during testing.

Observe Technique

If possible, have the analyst demonstrate the test method while being observed by a supervisor or senior analyst.
Pay attention to the analyst’s technique, including sample handling, reagent preparation, and equipment operation.
Note any deviations from standard operating procedures (SOPs) or good practices.

Review Documentation Practices

Examine the analyst’s laboratory notebooks and test records for completeness and accuracy.
Verify that all required information was recorded contemporaneously.
Check for any unusual notations or corrections in the documentation.

Assess Knowledge of Method and Equipment

Quiz the analyst on critical aspects of the test method and equipment operation.
Verify their understanding of acceptance criteria, potential sources of error, and troubleshooting procedures.
Ensure the analyst is aware of recent changes to SOPs or equipment calibration requirements.

Evaluate Workload and Environment

Consider the analyst’s workload at the time of testing, including any time pressures or competing priorities.
Assess the laboratory environment for potential distractions or interruptions that could have affected performance.
Review any recent changes in the analyst’s responsibilities or work schedule.

Perform Comparative Testing

Have another qualified analyst repeat the test using the same sample and equipment, if possible.
Compare the results to determine if there are significant discrepancies between analysts.
If discrepancies exist, investigate potential reasons for the differences.

Review Equipment Use Records

Check equipment logbooks to verify proper use and any noted issues during the time of testing.
Confirm that the analyst used the correct equipment and that it was properly calibrated and maintained.

Consider Human Factors

Assess any personal factors that could have affected the analyst’s performance, such as fatigue, illness, or personal stress.
Review the analyst’s work schedule leading up to the OOS result for any unusual patterns or extended hours.

By thoroughly assessing analyst performance using these methods, investigators can determine whether human error contributed to the OOS result and identify areas for improvement in training, procedures, or work environment. It’s important to approach this assessment objectively and supportively, focusing on systemic improvements rather than individual blame.

4. Examination of Environmental Factors

Review environmental monitoring data for the testing area
Check for any unusual events or conditions that could have affected the test

5. Data Analysis and Trending

Compare the OOS result with historical data and trends
Look for any patterns or anomalies that might explain the result

Conclusive vs. Inconclusive Evidence

Conclusive Evidence of Laboratory Error

To conclusively demonstrate laboratory error, you should be able to:

Identify a specific, documented error in the testing process
Reproduce the error and show how it leads to the OOS result
Demonstrate that correcting the error leads to an in-specification result

Examples of conclusive evidence might include:

Documented use of an expired reagent
Verified malfunction of testing equipment
Confirmed contamination of a negative control

Inconclusive Evidence

If the investigation reveals potential issues but cannot definitively link them to the OOS result, the evidence is considered inconclusive. This might include:

Minor deviations from SOPs that don’t clearly impact the result
Slight variations in environmental conditions
Analyst performance issues that aren’t directly tied to the specific test

Special Considerations for Microbiological Testing

Bioburden, endotoxin, and environmental monitoring tests present unique challenges due to their biological nature.

Bioburden Testing

Consider the possibility of sample contamination during collection or processing
Evaluate the recovery efficiency of the test method
Assess the potential for microbial growth during sample storage

Endotoxin Testing

Review the sample preparation process, including any dilution steps
Evaluate the potential for endotoxin masking or enhancement
Consider the impact of product formulation on the test method

Environmental Monitoring

Assess the sampling technique and equipment used
Consider the potential for transient environmental contamination
Evaluate the impact of recent cleaning or maintenance activities

Documenting the Investigation

Regardless of the outcome, it’s crucial to thoroughly document the investigation process. This documentation should include:

A clear description of the OOS result and initial observations
Detailed accounts of all investigative steps taken
Raw data and analytical results from the investigation
A comprehensive analysis of the evidence
A scientifically justified conclusion

Conclusion

Determining whether an invalidated OOS result conclusively demonstrates causative laboratory error requires a systematic, thorough, and well-documented investigation. For microbiological tests like bioburden, endotoxin, and environmental monitoring, this process can be particularly challenging due to the complex and sometimes variable nature of biological systems.

Remember, the goal is not to simply invalidate OOS results, but to understand the root cause and implement corrective and preventive actions. Only through rigorous investigation and continuous improvement can we ensure the quality and safety of pharmaceutical products. When investigating environmental and in-process results we are investigating the whole house of contamination control.

Risk Assessment for Environmental Monitoring

Maybe you’ve been there too, you need to take a risk-based approach to determine environmental monitoring, so you go to a HAACP or FMEA and realize those tools just do not work to provide information to determine how to distribute monitoring to best verify that processes are operating under control.

What you want to do is build a heat map showing the relative probability of contamination in a defined area or room| covering six areas:

Amenability of equipment and surfaces to cleaning and sanitization
Personnel presence and flow
Material flow
Proximity to open product or exposed direct product-contact material
Interventions/operations by personnel and their complexity
Frequency of interventions/process operations.

This approach builds off of the design activities and is part of a set of living risk assessments that inform the environmental monitoring part of your contamination control strategy.

Hope to see you in Bethesda to discuss more!