When Investigation Excellence Meets Contamination Reality: Lessons from the Rechon Life Science Warning Letter

The FDA’s April 30, 2025 warning letter to Rechon Life Science AB serves as a great learning opportunity about the importance robust investigation systems to contamination control to drive meaningful improvements. This Swedish contract manufacturer’s experience offers profound lessons for quality professionals navigating the intersection of EU Annex 1‘s contamination control strategy requirements and increasingly regulatory expectations. It is a mistake to think that just because the FDA doesn’t embrace the prescriptive nature of Annex 1 the agency is not fully aligned with the intent.

This Warning Letter resonates with similar systemic failures at companies like LeMaitre Vascular, Sanofi and others. The Rechon warning letter demonstrates a troubling but instructive pattern: organizations that fail to conduct meaningful contamination investigations inevitably find themselves facing regulatory action that could have been prevented through better investigation practices and systematic contamination control approaches.

The Cascade of Investigation Failures: Rechon’s Contamination Control Breakdown

Aseptic Process Failures and the Investigation Gap

Rechon’s primary violation centered on a fundamental breakdown in aseptic processing—operators were routinely touching critical product contact surfaces with gloved hands, a practice that was not only observed but explicitly permitted in their standard operating procedures. This represents more than poor technique; it reveals an organization that had normalized contamination risks through inadequate investigation and assessment processes.

The FDA’s citation noted that Rechon failed to provide environmental monitoring trend data for surface swab samples, representing exactly the kind of “aspirational data” problem. When investigation systems don’t capture representative information about actual manufacturing conditions, organizations operate in a state of regulatory blindness, making decisions based on incomplete or misleading data.

This pattern reflects a broader failure in contamination investigation methodology: environmental monitoring excursions require systematic evaluation that includes all environmental data (i.e. viable and non-viable tests) and must include areas that are physically adjacent or where related activities are performed. Rechon’s investigation gaps suggest they lacked these fundamental systematic approaches.

Environmental Monitoring Investigations: When Trend Analysis Fails

Perhaps more concerning was Rechon’s approach to persistent contamination with objectionable microorganisms—gram-negative organisms and spore formers—in ISO 5 and 7 areas since 2022. Their investigation into eight occurrences of gram-negative organisms concluded that the root cause was “operators talking in ISO 7 areas and an increase of staff illness,” a conclusion that demonstrates fundamental misunderstanding of contamination investigation principles.

As an aside, ISO7/Grade C is not normally an area we see face masks.

Effective investigations must provide comprehensive evaluation including:

Background and chronology of events with detailed timeline analysis
Investigation and data gathering activities including interviews and training record reviews
SME assessments from qualified microbiology and manufacturing science experts
Historical data review and trend analysis encompassing the full investigation zone
Manufacturing process assessment to determine potential contributing factors
Environmental conditions evaluation including HVAC, maintenance, and cleaning activities

Rechon’s investigation lacked virtually all of these elements, focusing instead on convenient behavioral explanations that avoided addressing systematic contamination sources. The persistence of gram-negative organisms and spore formers over a three-year period represented a clear adverse trend requiring a comprehensive investigation approach.

The Annex 1 Contamination Control Strategy Imperative: Beyond Compliance to Integration

The Paradigm Shift in Contamination Control

The revised EU Annex 1, effective since August 2023 demonstrates the current status of regulatory expectations around contamination control, moving from isolated compliance activities toward integrated risk management systems. The mandatory Contamination Control Strategy (CCS) requires manufacturers to develop comprehensive, living documents that integrate all aspects of contamination risk identification, mitigation, and monitoring.

Industry implementation experience since 2023 has revealed that many organizations are faiing to make meaningful connections between existing quality systems and the Annex 1 CCS requirements. Organizations struggle with the time and resource requirements needed to map existing contamination controls into coherent strategies, which often leads to discovering significant gaps in their understanding of their own processes.

Representative Environmental Monitoring Under Annex 1

The updated guidelines place emphasis on continuous monitoring and representative sampling that reflects actual production conditions rather than idealized scenarios. Rechon’s failure to provide comprehensive trend data demonstrates exactly the kind of gap that Annex 1 was designed to address.

Environmental monitoring must function as part of an integrated knowledge system that combines explicit knowledge (documented monitoring data, facility design specifications, cleaning validation reports) with tacit knowledge about facility-specific contamination risks and operational nuances. This integration demands investigation systems capable of revealing actual contamination patterns rather than providing comfortable explanations for uncomfortable realities.

The Design-First Philosophy

One of Annex 1’s most significant philosophical shifts is the emphasis on design-based contamination control rather than monitoring-based approaches. As we see from Warning Letters, and other regulatory intelligence, design gaps are frequently being cited as primary compliance failures, reinforcing the principle that organizations cannot monitor or control their way out of poor design.

This design-first philosophy fundamentally changes how contamination investigations must be conducted. Instead of simply investigating excursions after they occur, robust investigation systems must evaluate whether facility and process designs create inherent contamination risks that make excursions inevitable. Rechon’s persistent contamination issues suggest their investigation systems never addressed these fundamental design questions.

Best Practice 1: Implement Comprehensive Microbial Assessment Frameworks

Structured Organism Characterization

Effective contamination investigations begin with proper microbial assessments that characterize organisms based on actual risk profiles rather than convenient categorizations.

Complete microorganism documentation encompassing organism type, Gram stain characteristics, potential sources, spore-forming capability, and objectionable organism status. The structured approach outlined in formal assessment templates ensures consistent evaluation across different sample types (in-process, environmental monitoring, water and critical utilities).
Quantitative occurrence assessment using standardized vulnerability scoring systems that combine occurrence levels (Low, Medium, High) with nature and history evaluations. This matrix approach prevents investigators from minimizing serious contamination events through subjective assessments.
Severity evaluation based on actual manufacturing impact rather than theoretical scenarios. For environmental monitoring excursions, severity assessments must consider whether microorganisms were detected in controlled environments during actual production activities, the potential for product contamination, and the effectiveness of downstream processing steps.
Risk determination through systematic integration of vulnerability scores and severity ratings, providing objective classification of contamination risks that drives appropriate corrective action responses.

Rechon’s superficial investigation approach suggests they lacked these systematic assessment frameworks, focusing instead on behavioral explanations that avoided comprehensive organism characterization and risk assessment.

Best Practice 2: Establish Cross-Functional Investigation Teams with Defined Competencies

Investigation Team Composition and Qualifications

Major contamination investigations require dedicated cross-functional teams with clearly defined responsibilities and demonstrated competencies. The investigation lead must possess not only appropriate training and experience but also technical knowledge of the process and cGMP/quality system requirements, and ability to apply problem-solving tools.

Minimum team composition requirements for major investigations must include:

Impacted Department representatives (Manufacturing, Facilities) with direct operational knowledge
Subject Matter Experts (Manufacturing Sciences and Technology, QC Microbiology) with specialized technical expertise
Contamination Control specialists serving as Quality Assurance approvers with regulatory and risk assessment expertise

Investigation scope requirements must encompass systematic evaluation including background/chronology documentation, comprehensive data gathering activities (interviews, training record reviews), SME assessments, impact statement development, historical data review and trend analysis, and laboratory investigation summaries.

Training and Competency Management

Investigation team effectiveness depends on systematic competency development and maintenance. Teams must demonstrate proficiency in:

Root cause analysis methodologies including fishbone analysis, why-why questioning, fault tree analysis, and failure mode and effects analysis approaches suited to contamination investigation contexts.
Contamination microbiology principles including organism identification, source determination, growth condition assessment, and disinfectant efficacy evaluation specific to pharmaceutical manufacturing environments.
Risk assessment and impact evaluation capabilities that can translate investigation findings into meaningful product, process, and equipment risk determinations.
Regulatory requirement understanding encompassing both domestic and international contamination control expectations, investigation documentation standards, and CAPA development requirements.

The superficial nature of Rechon’s gram-negative organism investigation suggests their teams lacked these fundamental competencies, resulting in conclusions that satisfied neither regulatory expectations nor contamination control best practices.

Best Practice 3: Conduct Meaningful Historical Data Review and Comprehensive Trend Analysis

Investigation Zone Definition and Data Integration

Effective contamination investigations require comprehensive trend analysis that extends beyond simple excursion counting to encompass systematic pattern identification across related operational areas. As established in detailed investigation procedures, historical data review must include:

Physically adjacent areas and related activities recognition that contamination events rarely occur in isolation. Processing activities spanning multiple rooms, secondary gowning areas leading to processing zones, material transfer airlocks, and all critical utility distribution points must be included in investigation zones.
Comprehensive environmental data analysis encompassing all environmental data (i.e. viable and non-viable tests) to identify potential correlations between different contamination indicators that might not be apparent when examining single test types in isolation.
Extended historical review capabilities for situations where limited or no routine monitoring was performed during the questioned time frame, requiring investigation teams to expand their analytical scope to capture relevant contamination patterns.
Microorganism identification pattern assessment to determine shifts in routine microflora or atypical or objectionable organisms, enabling detection of contamination source changes that might indicate facility or process deterioration.

Temporal Correlation Analysis

Sophisticated trend analysis must correlate contamination events with operational activities, environmental conditions, and facility modifications that might contribute to adverse trends:

Manufacturing activity correlation examining whether contamination patterns correlate with specific production campaigns, personnel schedules, cleaning activities, or maintenance operations that might introduce contamination sources.
Environmental condition assessment including HVAC system performance, pressure differential maintenance, temperature and humidity control, and compressed air quality that could influence contamination recovery patterns.
Facility modification impact evaluation determining whether physical environment changes, equipment installations, utility upgrades, or process modifications correlate with contamination trend emergence or intensification.

Rechon’s three-year history of gram-negative and spore-former recovery represented exactly the kind of adverse trend requiring this comprehensive analytical approach. Their failure to conduct meaningful trend analysis prevented identification of systematic contamination sources that behavioral explanations could never address.

Best Practice 4: Integrate Investigation Findings with Dynamic Contamination Control Strategy

Knowledge Management and CCS Integration

Under Annex 1 requirements, investigation findings must feed directly into the overall Contamination Control Strategy, creating continuous improvement cycles that enhance contamination risk understanding and control effectiveness. This integration requires sophisticated knowledge management systems that capture both explicit investigation data and tacit operational insights.

Explicit knowledge integration encompasses formal investigation reports, corrective action documentation, trending analysis results, and regulatory correspondence that must be systematically incorporated into CCS risk assessments and control measure evaluations.
Tacit knowledge capture including personnel experiences with contamination events, operational observations about facility or process vulnerabilities, and institutional understanding about contamination source patterns that may not be fully documented but represent critical CCS inputs.

Risk Assessment Dynamic Updates

CCS implementation demands that investigation findings trigger systematic risk assessment updates that reflect enhanced understanding of contamination vulnerabilities:

Contamination source identification updates based on investigation findings that reveal previously unrecognized or underestimated contamination pathways requiring additional control measures or monitoring enhancements.
Control measure effectiveness verification through post-investigation monitoring that demonstrates whether implemented corrective actions actually reduce contamination risks or require further enhancement.
Monitoring program optimization based on investigation insights about contamination patterns that may indicate needs for additional sampling locations, modified sampling frequencies, or enhanced analytical methods.

Continuous Improvement Integration

The CCS must function as a living document that evolves based on investigation findings rather than remaining static until the next formal review cycle:

Investigation-driven CCS updates that incorporate new contamination risk understanding into facility design assessments, process control evaluations, and personnel training requirements.
Performance metrics integration that tracks investigation quality indicators alongside traditional contamination control metrics to ensure investigation systems themselves contribute to contamination risk reduction.
Cross-site knowledge sharing mechanisms that enable investigation insights from one facility to enhance contamination control strategies at related manufacturing sites.

Best Practice 5: Establish Investigation Quality Metrics and Systematic Oversight

Investigation Completeness and Quality Assessment

Organizations must implement systematic approaches to ensure investigation quality and prevent the superficial analysis demonstrated by Rechon. This requires comprehensive quality metrics that evaluate both investigation process compliance and outcome effectiveness:

Investigation completeness verification using a rubric or other standardized checklists that ensure all required investigation elements have been addressed before investigation closure. These must verify background documentation adequacy, data gathering comprehensiveness, SME assessment completion, impact evaluation thoroughness, and corrective action appropriateness.
Root cause determination quality assessment evaluating whether investigation conclusions demonstrate scientific rigor and logical connection between identified causes and observed contamination events. This includes verification that root cause analysis employed appropriate methodologies and that conclusions can withstand independent technical review.
Corrective action effectiveness verification through systematic post-implementation monitoring that demonstrates whether corrective actions achieved their intended contamination risk reduction objectives.

Management Review and Challenge Processes

Effective investigation oversight requires management systems that actively challenge investigation conclusions and ensure scientific rationale supports all determinations:

Technical review panels comprising independent SMEs who evaluate investigation methodology, data interpretation, and conclusion validity before investigation closure approval for major and critical deviations. I strongly recommend this as part of qualification and re-qualification activities.
Regulatory perspective integration ensuring investigation approaches and conclusions align with current regulatory expectations and enforcement trends rather than relying on outdated compliance interpretations.
Cross-functional impact assessment verifying that investigation findings and corrective actions consider all affected operational areas and don’t create unintended contamination risks in other facility areas.

CAPA System Integration and Effectiveness Tracking

Investigation findings must integrate with robust CAPA systems that ensure systematic improvements rather than isolated fixes:

Systematic improvement identification that links investigation findings to broader facility or process enhancement opportunities rather than limiting corrective actions to immediate excursion sources.
CAPA implementation quality management including resource allocation verification, timeline adherence monitoring, and effectiveness verification protocols that ensure corrective actions achieve intended risk reduction.
Knowledge management integration that captures investigation insights for application to similar contamination risks across the organization and incorporates lessons learned into training programs and preventive maintenance activities.

Rechon’s continued contamination issues despite previous investigations suggest their CAPA processes lacked this systematic improvement approach, treating each contamination event as isolated rather than symptoms of broader contamination control weaknesses.

A visual diagram presents a "Living Contamination Control Strategy" progressing toward a "Holistic Approach" through a winding path marked by five key best practices. Each best practice is highlighted in a circular node along the colored pathway.

Best Practice 01: Comprehensive microbial assessment frameworks through structured organism characterization.

Best Practice 02: Cross functional teams with the right competencies.

Best Practice 03: Meaningful historic data through investigation zones and temporal correlation.

Best Practice 04: Investigations integrated with Contamination Control Strategy.

Best Practice 05: Systematic oversight through metrics and challenge process.

The diagram represents a continuous improvement journey from foundational practices focused on organism assessment and team competency to integrating data, investigations, and oversight, culminating in a holistic contamination control strategy.

The Investigation-Annex 1 Integration Challenge: Building Investigation Resilience

Holistic Contamination Risk Assessment

Contamination control requires investigation systems that function as integral components of comprehensive strategies rather than reactive compliance activities.

Design-Investigation Integration demands that investigation findings inform facility design assessments and process modification evaluations. When investigations reveal design-related contamination sources, CCS updates must address whether facility modifications or process changes can eliminate contamination risks at their source rather than relying on monitoring and control measures.

Process Knowledge Enhancement through investigation activities that systematically build organizational understanding of contamination vulnerabilities, control measure effectiveness, and operational factors that influence contamination risk profiles.

Personnel Competency Development that leverages investigation findings to identify training needs, competency gaps, and behavioral factors that contribute to contamination risks requiring systematic rather than individual corrective approaches.

Technology Integration and Future Investigation Capabilities

Advanced Monitoring and Investigation Support Systems

The increasing sophistication of regulatory expectations necessitates corresponding advances in investigation support technologies that enable more comprehensive and efficient contamination risk assessment:

Real-time monitoring integration that provides investigation teams with comprehensive environmental data streams enabling correlation analysis between contamination events and operational variables that might not be captured through traditional discrete sampling approaches.

Automated trend analysis capabilities that identify contamination patterns and correlations across multiple data sources, facility areas, and time periods that might not be apparent through manual analysis methods.

Integrated knowledge management platforms that capture investigation insights, corrective action outcomes, and operational observations in formats that enable systematic application to future contamination risk assessments and control strategy optimization.

Investigation Standardization and Quality Enhancement

Technology solutions must also address investigation process standardization and quality improvement:

Investigation workflow management systems that ensure consistent application of investigation methodologies, prevent shortcuts that compromise investigation quality, and provide audit trails demonstrating compliance with regulatory expectations.

Cross-site investigation coordination capabilities that enable investigation insights from one facility to inform contamination risk assessments and investigation approaches at related manufacturing sites.

Building Organizational Investigation Excellence

Cultural Transformation Requirements

The evolution from compliance-focused contamination investigations toward risk-based contamination control strategies requires fundamental cultural changes that extend beyond procedural updates:

Leadership commitment demonstration through resource allocation for investigation system enhancement, personnel competency development, and technology infrastructure investment that enables comprehensive contamination risk assessment rather than minimal compliance achievement.

Cross-functional collaboration enhancement that breaks down organizational silos preventing comprehensive investigation approaches and ensures investigation teams have access to all relevant operational expertise and information sources.

Continuous improvement mindset development that views contamination investigations as opportunities for systematic facility and process enhancement rather than unfortunate compliance burdens to be minimized.

Investigation as Strategic Asset

Organizations that excel in contamination investigation develop capabilities that provide competitive advantages beyond regulatory compliance:

Process optimization opportunities identification through investigation activities that reveal operational inefficiencies, equipment performance issues, and facility design limitations that, when addressed, improve both contamination control and operational effectiveness.

Risk management capability enhancement that enables proactive identification and mitigation of contamination risks before they result in regulatory scrutiny or product quality issues requiring costly remediation.

Regulatory relationship management through demonstration of investigation competence and commitment to continuous improvement that can influence regulatory inspection frequency and focus areas.

The Cost of Investigation Mediocrity: Lessons from Enforcement

Regulatory Consequences and Business Impact

Rechon’s experience demonstrates the ultimate cost of inadequate contamination investigations: comprehensive regulatory action that threatens market access and operational continuity. The FDA’s requirements for extensive remediation—including independent assessment of investigation systems, comprehensive personnel and environmental monitoring program reviews, and retrospective out-of-specification result analysis—represent exactly the kind of work that should be conducted proactively rather than reactively.

Resource Allocation and Opportunity Cost

The remediation requirements imposed on companies receiving warning letters far exceed the resource investment required for proactive investigation system development:

Independent consultant engagement costs for comprehensive facility and system assessment that could be avoided through internal investigation capability development and systematic contamination control strategy implementation.
Production disruption resulting from regulatory holds, additional sampling requirements, and corrective action implementation that interrupts normal manufacturing operations and delays product release.
Market access limitations including potential product recalls, import restrictions, and regulatory approval delays that affect revenue streams and competitive positioning.

Reputation and Trust Impact

Beyond immediate regulatory and financial consequences, investigation failures create lasting reputation damage that affects customer relationships, regulatory standing, and business development opportunities:

Customer confidence erosion when investigation failures become public through warning letters, regulatory databases, and industry communications that affect long-term business relationships.
Regulatory relationship deterioration that can influence future inspection focus areas, approval timelines, and enforcement approaches that extend far beyond the original contamination control issues.
Industry standing impact that affects ability to attract quality personnel, develop partnerships, and maintain competitive positioning in increasingly regulated markets.

Gap Assessment Framework: Organizational Investigation Readiness

Investigation System Evaluation Criteria

Organizations should systematically assess their investigation capabilities against current regulatory expectations and best practice standards. This assessment encompasses multiple evaluation dimensions:

Technical Competency Assessment
- Do investigation teams possess demonstrated expertise in contamination microbiology, facility design, process engineering, and regulatory requirements?
- Are investigation methodologies standardized, documented, and consistently applied across different contamination scenarios?
- Does investigation scope routinely include comprehensive trend analysis, adjacent area assessment, and environmental correlation analysis?
- Are investigation conclusions supported by scientific rationale and independent technical review?
Resource Adequacy Evaluation
- Are sufficient personnel resources allocated to enable comprehensive investigation completion within reasonable timeframes?
- Do investigation teams have access to necessary analytical capabilities, reference materials, and technical support resources?
- Are investigation budgets adequate to support comprehensive data gathering, expert consultation, and corrective action implementation?
- Does management demonstrate commitment through resource allocation and investigation priority establishment?
Integration and Effectiveness Assessment
- Are investigation findings systematically integrated into contamination control strategy updates and facility risk assessments?
- Do CAPA systems ensure investigation insights drive systematic improvements rather than isolated fixes?
- Are investigation outcomes tracked and verified to confirm contamination risk reduction achievement?
- Do knowledge management systems capture and apply investigation insights across the organization?

From Investigation Adequacy to Investigation Excellence

Rechon Life Science’s experience serves as a cautionary tale about the consequences of investigation mediocrity, but it also illustrates the transformation potential inherent in comprehensive contamination control strategy implementation. When organizations invest in systematic investigation capabilities—encompassing proper team composition, comprehensive analytical approaches, effective knowledge management, and continuous improvement integration—they build competitive advantages that extend far beyond regulatory compliance.

The key insight emerging from regulatory enforcement patterns is that contamination control has evolved from a specialized technical discipline into a comprehensive business capability that affects every aspect of pharmaceutical manufacturing. The quality of an organization’s contamination investigations often determines whether contamination events become learning opportunities that strengthen operations or regulatory nightmares that threaten business continuity.

For quality professionals responsible for contamination control, the message is unambiguous: investigation excellence is not an optional enhancement to existing compliance programs—it’s a fundamental requirement for sustainable pharmaceutical manufacturing in the modern regulatory environment. The organizations that recognize this reality and invest accordingly will find themselves well-positioned not only for regulatory success but for operational excellence that drives competitive advantage in increasingly complex global markets.

The regulatory landscape has fundamentally changed, and traditional approaches to contamination investigation are no longer sufficient. Organizations must decide whether to embrace the investigation excellence imperative or face the consequences of continuing with approaches that regulatory agencies have clearly indicated are inadequate. The choice is clear, but the window for proactive transformation is narrowing as regulatory expectations continue to evolve and enforcement intensifies.

The question facing every pharmaceutical manufacturer is not whether contamination control investigations will face increased scrutiny—it’s whether their investigation systems will demonstrate the excellence necessary to transform regulatory challenges into competitive advantages. Those that choose investigation excellence will thrive; those that don’t will join Rechon Life Science and others in explaining their investigation failures to regulatory agencies rather than celebrating their contamination control successes in the marketplace.

Causal Reasoning: A Transformative Approach to Root Cause Analysis

Energy Safety Canada recently published a white paper on causal reasoning that offers valuable insights for quality professionals across industries. As someone who has spent decades examining how we investigate deviations and perform root cause analysis, I found their framework refreshing and remarkably aligned with the challenges we face in pharmaceutical quality. The paper proposes a fundamental shift in how we approach investigations, moving from what they call “negative reasoning” to “causal reasoning” that could significantly improve our ability to prevent recurring issues and drive meaningful improvement.

The Problem with Traditional Root Cause Analysis

Many of us in quality have experienced the frustration of seeing the same types of deviations recur despite thorough investigations and seemingly robust CAPAs. The Energy Safety Canada white paper offers a compelling explanation for this phenomenon: our investigations often focus on what did not happen rather than what actually occurred.

This approach, which the authors term “negative reasoning,” leads investigators to identify counterfactuals-things that did not occur, such as “operators not following procedures” or “personnel not stopping work when they should have”. The problem is fundamental: what was not happening cannot create the outcomes we experienced. As the authors aptly state, these counterfactuals “exist only in retrospection and never actually influenced events,” yet they dominate many of our investigation conclusions.

This insight resonates strongly with what I’ve observed in pharmaceutical quality. Six years ago the MHRA’s 2019 citation of 210 companies for inadequate root cause analysis and CAPA development – including 6 critical findings – takes on renewed significance in light of Sanofi’s 2025 FDA warning letter. While most cited organizations likely believed their investigation processes were robust (as Sanofi presumably did before their contamination failures surfaced), these parallel cases across regulatory bodies and years expose a persistent industry-wide disconnect between perceived and actual investigation effectiveness. These continued failures exemplify how superficial root cause analysis creates dangerous illusions of control – precisely the systemic flaw the MHRA data highlighted six years prior.

Negative Reasoning vs. Causal Reasoning: A Critical Distinction

The white paper makes a distinction that I find particularly valuable: negative reasoning seeks to explain outcomes based on what was missing from the system, while causal reasoning looks for what was actually present or what happened. This difference may seem subtle, but it fundamentally changes the nature and outcomes of our investigations.

When we use negative reasoning, we create what the white paper calls “an illusion of cause without being causal”. We identify things like “failure to follow procedures” or “inadequate risk assessment,” which may feel satisfying but don’t explain why those conditions existed in the first place. These conclusions often lead to generic corrective actions that fail to address underlying issues.

In contrast, causal reasoning requires statements that have time, place, and magnitude. It focuses on what was necessary and sufficient to create the effect, building a logically tight cause-and-effect diagram. This approach helps reveal how work is actually done rather than comparing reality to an imagined ideal.

This distinction parallels the gap between “work-as-imagined” (the black line) and “work-as-done” (the blue line). Too often, our investigations focus only on deviations from work-as-imagined without trying to understand why work-as-done developed differently.

A Tale of Two Analyses: The Power of Causal Reasoning

The white paper presents a compelling case study involving a propane release and operator injury that illustrates the difference between these two approaches. When initially analyzed through negative reasoning, investigators concluded the operator:

Used an improper tool
Deviated from good practice
Failed to recognize hazards
Failed to learn from past experiences

These conclusions placed blame squarely on the individual and led leadership to consider terminating the operator.

However, when the same incident was examined through causal reasoning, a different picture emerged:

The operator used the pipe wrench because it was available at the pump specifically for this purpose
The pipe wrench had been deliberately left at that location because operators knew the valve was hard to close
The operator acted quickly because he perceived a risk to the plant and colleagues
Leadership had actually endorsed this workaround four years earlier during a turnaround

This causally reasoned analysis revealed that what appeared to be an individual failure was actually a system-level issue that had been normalized over time. Rather than punishing the operator, leadership recognized their own role in creating the conditions for the incident and implemented systemic improvements.

This example reminded me of our discussions on barrier analysis, where we examine barriers that failed, weren’t used, or didn’t exist. But causal reasoning takes this further by exploring why those conditions existed in the first place, creating a much richer understanding of how work actually happens.

First 24 Hours: Where Causal Reasoning Meets The Golden Day

In my recent post on “The Golden Start to a Deviation Investigation,” I emphasized how critical the first 24 hours are after discovering a deviation. This initial window represents our best opportunity to capture accurate information and set the stage for a successful investigation. The Energy Safety Canada white paper complements this concept perfectly by providing guidance on how to use those critical hours effectively.

When we apply causal reasoning during these early stages, we focus on collecting specific, factual information about what actually occurred rather than immediately jumping to what should have happened. This means documenting events with specificity (time, place, magnitude) and avoiding premature judgments about deviations from procedures or expectations.

As I’ve previously noted, clear and precise problem definition forms the foundation of any effective investigation. Causal reasoning enhances this process by ensuring we document using specific, factual language that describes what occurred rather than what didn’t happen. This creates a much stronger foundation for the entire investigation.

Beyond Human Error: System Thinking and Leadership’s Role

One of the most persistent challenges in our field is the tendency to attribute events to “human error.” As I’ve discussed before, when human error is suspected or identified as the cause, this should be justified only after ensuring that process, procedural, or system-based errors have not been overlooked. The white paper reinforces this point, noting that human actions and decisions are influenced by the system in which people work.

In fact, the paper presents a hierarchy of causes that resonates strongly with systems thinking principles I’ve advocated for previously. Outcomes arise from physical mechanisms influenced by human actions and decisions, which are in turn governed by systemic factors. If we only address physical mechanisms or human behaviors without changing the system, performance will eventually migrate back to where it has always been.

This connects directly to what I’ve written about quality culture being fundamental to providing quality. The white paper emphasizes that leadership involvement is directly correlated with performance improvement. When leaders engage to set conditions and provide resources, they create an environment where investigations can reveal systemic issues rather than just identify procedural deviations or human errors.

Implementing Causal Reasoning in Pharmaceutical Quality

For pharmaceutical quality professionals looking to implement causal reasoning in their investigation processes, I recommend starting with these practical steps:

1. Develop Investigator Competencies

As I’ve discussed in my analysis of Sanofi’s FDA warning letter, having competent investigators is crucial. Organizations should:

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

2. Shift from Counterfactuals to Causal Statements

Review your recent investigations and look for counterfactual statements like “operators did not follow the procedure.” Replace these with causal statements that describe what actually happened and why it made sense to the people involved at the time.

3. Implement a Sponsor-Driven Approach

The white paper emphasizes the importance of investigation sponsors (otherwise known as Area Managers) who set clear conditions and expectations. This aligns perfectly with my belief that quality culture requires alignment between top management behavior and quality system philosophy. Sponsors should:

Clearly define the purpose and intent of investigations
Specify that a causal reasoning orientation should be used
Provide resources and access needed to find data and translate it into causes
Remain engaged throughout the investigation process

Infographic capturing the 4 things a sponsor should do above

4. Use Structured Causal Analysis Tools

While the M-based frameworks I’ve discussed previously (4M, 5M, 6M) remain valuable for organizing contributing factors, they should be complemented with tools that support causal reasoning. The Cause-Consequence Analysis (CCA) I described in a recent post offers one such approach, combining elements of fault tree analysis and event tree analysis to provide a holistic view of risk scenarios.

From Understanding to Improvement

The Energy Safety Canada white paper’s emphasis on causal reasoning represents a valuable contribution to how we think about investigations across industries. For pharmaceutical quality professionals, this approach offers a way to move beyond compliance-focused investigations to truly understand how our systems operate and how to improve them.

As the authors note, “The capacity for an investigation to improve performance is dependent on the type of reasoning used by investigators”. By adopting causal reasoning, we can build investigations that reveal how work actually happens rather than simply identifying deviations from how we imagine it should happen.

This approach aligns perfectly with my long-standing belief that without a strong quality culture, people will not be ready to commit and involve themselves fully in building and supporting a robust quality management system. Causal reasoning creates the transparency and learning that form the foundation of such a culture.

I encourage quality professionals to download and read the full white paper, reflect on their current investigation practices, and consider how causal reasoning might enhance their approach to understanding and preventing deviations. The most important questions to consider are:

Do your investigation conclusions focus on what didn’t happen rather than what did?
How often do you identify “human error” without exploring the system conditions that made that error likely?
Are your leaders engaged as sponsors who set conditions for successful investigations?
What barriers exist in your organization that prevent learning from events?

As we continue to evolve our understanding of quality and safety, approaches like causal reasoning offer valuable tools for creating the transparency needed to navigate complexity and drive meaningful improvement.

Why ‘First-Time Right’ is a Dangerous Myth in Continuous Manufacturing

In manufacturing circles, “First-Time Right” (FTR) has become something of a sacred cow-a philosophy so universally accepted that questioning it feels almost heretical. Yet as continuous manufacturing processes increasingly replace traditional batch production, we need to critically examine whether this cherished doctrine serves us well or creates dangerous blind spots in our quality assurance frameworks.

The Seductive Promise of First-Time Right

Let’s start by acknowledging the compelling appeal of FTR. As commonly defined, First-Time Right is both a manufacturing principle and KPI that denotes the percentage of end-products leaving production without quality defects. The concept promises a manufacturing utopia: zero waste, minimal costs, maximum efficiency, and delighted customers receiving perfect products every time.

The math seems straightforward. If you produce 1,000 units and 920 are defect-free, your FTR is 92%. Continuous improvement efforts should steadily drive that percentage upward, reducing the resources wasted on imperfect units.

This principle finds its intellectual foundation in Six Sigma methodology, which can tend to give it an air of scientific inevitability. Yet even Six Sigma acknowledges that perfection remains elusive. This subtle but crucial nuance often gets lost when organizations embrace FTR as an absolute expectation rather than an aspiration.

First-Time Right in biologics drug substance manufacturing refers to the principle and performance metric of producing a biological drug substance that meets all predefined quality attributes and regulatory requirements on the first attempt, without the need for rework, reprocessing, or batch rejection. In this context, FTR emphasizes executing each step of the complex, multi-stage biologics manufacturing process correctly from the outset-starting with cell line development, through upstream (cell culture/fermentation) and downstream (purification, formulation) operations, to the final drug substance release.

Achieving FTR is especially challenging in biologics because these products are made from living systems and are highly sensitive to variations in raw materials, process parameters, and environmental conditions. Even minor deviations can lead to significant quality issues such as contamination, loss of potency, or batch failure, often requiring the entire batch to be discarded.

In biologics manufacturing, FTR is not just about minimizing waste and cost; it is critical for patient safety, regulatory compliance, and maintaining supply reliability. However, due to the inherent variability and complexity of biologics, FTR is best viewed as a continuous improvement goal rather than an absolute expectation. The focus is on designing and controlling processes to consistently deliver drug substances that meet all critical quality attributes-recognizing that, despite best efforts, some level of process variation and deviation is inevitable in biologics production

The Unique Complexities of Continuous Manufacturing

Traditional batch processing creates natural boundaries-discrete points where production pauses, quality can be assessed, and decisions about proceeding can be made. In contrast, continuous manufacturing operates without these convenient checkpoints, as raw materials are continuously fed into the manufacturing system, and finished products are continuously extracted, without interruption over the life of the production run.

This fundamental difference requires a complete rethinking of quality assurance approaches. In continuous environments:

Quality must be monitored and controlled in real-time, without stopping production
Deviations must be detected and addressed while the process continues running
The interconnected nature of production steps means issues can propagate rapidly through the system
Traceability becomes vastly more complex

Regulatory agencies recognize these unique challenges, acknowledging that understanding and managing risks is central to any decision to greenlight CM in a production-ready environment. When manufacturing processes never stop, quality assurance cannot rely on the same methodologies that worked for discrete batches.

The Dangerous Complacency of Perfect-First-Time Thinking

The most insidious danger of treating FTR as an achievable absolute is the complacency it breeds. When leadership becomes fixated on achieving perfect FTR scores, several dangerous patterns emerge:

Overconfidence in Automation

While automation can significantly improve quality, it is important to recognize the irreplaceable value of human oversight. Automated systems, no matter how advanced, are ultimately limited by their programming, design, and maintenance. Human operators bring critical thinking, intuition, and the ability to spot subtle anomalies that machines may overlook. A vigilant human presence can catch emerging defects or process deviations before they escalate, providing a layer of judgment and adaptability that automation alone cannot replicate. Relying solely on automation creates a dangerous blind spot-one where the absence of human insight can allow issues to go undetected until they become major problems. True quality excellence comes from the synergy of advanced technology and engaged, knowledgeable people working together.

Underinvestment in Deviation Management

If perfection is expected, why invest in systems to handle imperfections? Yet robust deviation management-the processes used to identify, document, investigate, and correct deviations becomes even more critical in continuous environments where problems can cascade rapidly. Organizations pursuing FTR often underinvest in the very systems that would help them identify and address the inevitable deviations.

False Sense of Process Robustness

Process robustness refers to the ability of a manufacturing process to tolerate the variability of raw materials, process equipment, operating conditions, environmental conditions and human factors. An obsession with FTR can mask underlying fragility in processes that appear to be performing well under normal conditions. When we pretend our processes are infallible, we stop asking critical questions about their resilience under stress.

Quality Culture Deterioration

When FTR becomes dogma, teams may become reluctant to report or escalate potential issues, fearing they’ll be seen as failures. This creates a culture of silence around deviations-precisely the opposite of what’s needed for effective quality management in continuous manufacturing. When perfection is the only acceptable outcome, people hide imperfections rather than address them.

Magical Thinking in Quality Management

The belief that we can eliminate all errors in complex manufacturing processes amounts to what organizational psychologists call “magical thinking” – the delusional belief that one can do the impossible. In manufacturing, this often manifests as pretending that doing more tasks with less resources will not hurt the work quality.

This is a pattern I’ve observed repeatedly in my investigations of quality failures. When leadership subscribes to the myth that perfection is not just desirable but achievable, they create the conditions for quality disasters. Teams stop preparing for how to handle deviations and start pretending deviations won’t occur.

The irony is that this approach actually undermines the very goal of FTR. By acknowledging the possibility of failure and building systems to detect and learn from it quickly, we actually increase the likelihood of getting things right.

Building a Healthier Quality Culture for Continuous Manufacturing

Rather than chasing the mirage of perfect FTR, organizations should focus on creating systems and cultures that:

Detect deviations rapidly: Continuous monitoring through advanced process control systems becomes essential for monitoring and regulating critical parameters throughout the production process. The question isn’t whether deviations will occur but how quickly you’ll know about them.
Investigate transparently: When issues occur, the focus should be on understanding root causes rather than assigning blame. The culture must prioritize learning over blame.
Implement robust corrective actions: Deviations should be thoroughly documented including details about when and where it occurred, who identified it, a detailed description of the nonconformance, initial actions taken, results of the investigation into the cause, actions taken to correct and prevent recurrence, and a final evaluation of the effectiveness of these actions.
Learn systematically: Each deviation represents a valuable opportunity to strengthen processes and prevent similar issues in the future. The organization that learns fastest wins, not the one that pretends to be perfect.

Breaking the Groupthink Cycle

The FTR myth thrives in environments characterized by groupthink, where challenging the prevailing wisdom is discouraged. When leaders obsess over FTR metrics while punishing those who report deviations, they create the perfect conditions for quality disasters.

This connects to a theme I’ve explored repeatedly on this blog: the dangers of losing institutional memory and critical thinking in quality organizations. When we forget that imperfection is inevitable, we stop building the systems and cultures needed to manage it effectively.

Embracing Humility, Vigilance, and Continuous Learning

True quality excellence comes not from pretending that errors don’t occur, but from embracing a more nuanced reality:

Perfection is a worthy aspiration but an impossible standard
Systems must be designed not just to prevent errors but to detect and address them
A healthy quality culture prizes transparency and learning over the appearance of perfection
Continuous improvement comes from acknowledging and understanding imperfections, not denying them

The path forward requires humility to recognize the limitations of our processes, vigilance to catch deviations quickly when they occur, and an unwavering commitment to learning and improving from each experience.

In the end, the most dangerous quality issues aren’t the ones we detect and address-they’re the ones our systems and culture allow to remain hidden because we’re too invested in the myth that they shouldn’t exist at all. First-Time Right should remain an aspiration that drives improvement, not a dogma that blinds us to reality.

From Perfect to Perpetually Improving

As continuous manufacturing becomes the norm rather than the exception, we need to move beyond the simplistic FTR myth toward a more sophisticated understanding of quality. Rather than asking, “Did we get it perfect the first time?” we should be asking:

How quickly do we detect when things go wrong?
How effectively do we contain and remediate issues?
How systematically do we learn from each deviation?
How resilient are our processes to the variations they inevitably encounter?

These questions acknowledge the reality of manufacturing-that imperfection is inevitable-while focusing our efforts on what truly matters: building systems and cultures capable of detecting, addressing, and learning from deviations to drive continuous improvement.

The companies that thrive in the continuous manufacturing future won’t be those with the most impressive FTR metrics on paper. They’ll be those with the humility to acknowledge imperfection, the systems to detect and address it quickly, and the learning cultures that turn each deviation into an opportunity for improvement.

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.

When to Widen the Investigation

“there is no retrospective review of batch records for batches within expiry, to identify any other process deviations performed without the appropriate corresponding documentation including risk assessment(s).” – 2025 Warning Letter from the US FDA to Sanofi

This comment is about an instance where Sanofi deviated from the validated process by using an unvalidated single use component. Instead of self-identifying, creating a deviation and doing the right change control activities, the company just kept on deviating by using a non-controlled document.

This is a big problem for lots of reasons, from uncontrolled documents, to not using the change control system, to breaking the validated state. What the language quoted above really brings to bear is the question, when should we evaluate our records for other similar instances of this happening, so we can address it.

When a deviation investigation reveals recurring bad decision-making, it is crucial to expand the investigation and conduct a retrospective review of batch records. A good cutoff of this can be only for batches within expiry. This expanded investigation helps identify any other process deviations that may have occurred but were not discovered or documented at the time. Here’s when and how to approach this situation:

Triggers for Expanding the Investigation

Recurring Deviations: If the same or similar deviations are found to be recurring, it indicates a systemic issue that requires a broader investigation.
Pattern of Human Errors: When a pattern of human errors or poor decision-making is identified, it suggests potential underlying issues in training, procedures, or processes.
Critical Deviations: For deviations classified as critical, a more thorough investigation is typically warranted, including a retrospective review.
Potential Impact on Product Quality: If there’s a strong possibility that undiscovered deviations could affect product quality or patient safety, an expanded investigation becomes necessary.

Conducting the Retrospective Review

Timeframe: Review batch records for all batches within expiry, typically covering at least two years of production. Similarily for issues in the FUSE program you might look since the last requalification, or from a decide to go backwards in concentric circles based on what you find.
Scope: Examine not only the specific process where the deviation was found but also related processes or areas that could be affected. Reviewing related processes is critical.
Data Analysis: Utilize statistical tools and trending analysis techniques to identify patterns or anomalies in the historical data.
Cross-Functional Approach: Involve a team of subject matter experts from relevant departments to ensure a comprehensive review.
Documentation Review: Examine batch production records, laboratory control records, equipment logs, and any other relevant documentation.
Root Cause Analysis: Apply root cause analysis techniques to understand the underlying reasons for the recurring issues.

Key Considerations

Risk Assessment: Prioritize the review based on the potential risk to product quality and patient safety.
Data Integrity: Ensure that any retrospective data used is reliable and has maintained its integrity.
Corrective Actions: Develop and implement corrective and preventive actions (CAPAs) based on the findings of the expanded investigation.
Regulatory Reporting: Assess the need for notifying regulatory authorities based on the severity and impact of the findings.

By conducting a thorough retrospective review when recurring bad decision-making is identified, companies can uncover hidden issues, improve their quality systems, and prevent future deviations. This proactive approach not only enhances compliance but also contributes to continuous improvement in pharmaceutical manufacturing processes.

In the case of an issue that rises to a regulatory observation this becomes a firm must. The agency has raised a significant concern and they will want proof that this is a limited issue or that you are holistically dealing with it across the organization.

Concentric Circles of Investigation

Each layer of the investigation may require holistic looks. Utilizing the example above we have:

Layer of Problem	Further Investigation to Answer
Use of unassessed component outside of GMP controls	What other unassessed components were used in the manufacturing process(s)
Failure to document a temporary change	Where else were temporary changes not executed
Deviated from validated process	Where else were there significant deviations from validated processes there were not reported
Problems with components	What other components are having problems that are not being reported and addressed

Take a risk-based approach here is critical.