Evidence Hub

Quality decisions in regulated environments must be defensible, traceable, and repeatable.

The Evidence Hub presents representative engagements illustrating how ENQUAL supports medical device, combination product, and biopharmaceutical organizations in making inspection-ready quality decisions across the full product and process lifecycle.

Each case study reflects real-world Quality Engineering and Quality System work, presented in an anonymized and regulator-conservative manner. Rather than focusing on outcomes or claims, these examples highlight the decision logic, documentation discipline, statistical rigor, and risk-based approach required to sustain compliance in design controls, manufacturing processes, risk management, and change governance under FDA and EU regulatory expectations.

The case studies are intentionally sequenced to reflect how quality credibility is established in practice:

• Design Verification: Statistical Rationale — demonstrating how objective data analysis, statistical assumptions, and traceability form the foundation of defensible design verification.

• Lifecycle Risk Management System (ISO 14971) — illustrating how verification evidence and manufacturing knowledge are integrated into coherent, maintainable risk management files across legacy and active products.

• Process Stability & Continued Verification — showing how manufacturing processes and system behaviors are evaluated, stabilized, and monitored to maintain a validated state over time.

Together, these examples represent ENQUAL’s approach to risk-informed decision-making, design control integrity, manufacturing process control, and inspection-ready quality execution throughout the product lifecycle.   In some engagements, this decision-making also requires system-level investigation and verification where quality conclusions depend on objective technical evidence. 

A representative engagement demonstrating how statistical assumptions, verification data, and traceability were aligned to produce regulator-defensible design verification evidence. 

A portfolio of parenteral combination delivery systems required defensible design verification evidence to support ongoing lifecycle activities under FDA and EU regulatory expectations. Functional verification studies had been executed, but the statistical assumptions, acceptance logic, and linkage to design requirements were not consistently documented in a way that would withstand regulatory scrutiny.

The organization needed verification outputs that were not only technically correct, but statistically justified, traceable, and inspection-ready, with clear alignment to Design History File (DHF) and Risk Management File expectations.

ENQUAL supported the development of a standardized design verification reporting framework that defined:

• Statistical strategy and assumptions (including normality assessment and hypothesis testing approach)
   
• Sample size rationale aligned to design requirements and risk
   
• Clear acceptance criteria and decision logic
   
• Traceability between User Needs, Design Inputs, verification evidence, and risk controls
   

Functional verification data were analyzed using Minitab and JMP, applying appropriate statistical methods to support objective verification conclusions. Outputs were integrated into DHF-supporting documentation, including:

• Verification summary reports
   
• Traceability matrices linking requirements, verification results, and risk controls
   
• DHF index and supporting document updates
   
• Verification, build, shipping, and conditioning protocols and reports based on laboratory data
   

This approach ensured verification evidence was both technically sound and regulator-defensible, with consistent documentation that could be reused across lifecycle activities.

The engagement resulted in inspection-ready verification documentation that supported ongoing design control, change management, and risk management activities for parenteral combination products. Statistical rationales were clearly documented, traceable, and aligned to regulatory expectations, enabling confident quality decision-making and sustained DHF integrity throughout the product lifecycle.

A representative engagement illustrating the development of a coherent, inspection-ready risk management framework integrating hazard analysis, FMEA, and user-related risk across the product lifecycle. 

Legacy and active combination products required alignment with current ISO 14971 risk management expectations across the full product lifecycle. Existing risk documentation had evolved over time, resulting in fragmented Hazard Analyses, inconsistent linkage between verification evidence and risk controls, and limited traceability from User Needs through residual risk acceptance.

The organization needed a structured, inspection-ready risk management system that could support ongoing design changes, verification activities, and regulatory expectations without disrupting established quality systems.

ENQUAL supported the development and implementation of a standardized lifecycle Risk Management File framework aligned with ISO 14971 principles. This included:

• Development and remediation of Hazard Analyses aligned to intended use and user interaction
   
• Integration of cross-functional risk analyses, including Design FMEA (dFMEA), Use FMEA (uFMEA), and Process FMEA (pFMEA)
   
• Creation and alignment of User Task Analysis and user-related risk documentation (URRA) to support usability and human factors considerations
   
• Establishment of Risk Management Plans and Risk Management Summary Reports to ensure consistent governance and residual risk justification
   
• Alignment of risk controls to design inputs, verification evidence, and traceability matrices to maintain DHF and RMF integrity
   

This system-level approach ensured risk management activities were repeatable, traceable, and maintainable across lifecycle events.

The resulting Risk Management Files provided a coherent, regulator-ready view of product risk, supporting ongoing design verification, change control, and inspection readiness activities. Risk documentation was standardized, traceable, and aligned to ISO 14971 expectations, enabling confident quality decision-making across both legacy and evolving combination products. 

A representative engagement showing how design, process, and sterilization changes were assessed and implemented while preserving DHF, RMF, and inspection readiness. 

Ongoing lifecycle management of parenteral combination products required robust Quality oversight of design, process, and sterilization changes driven by both external vendors and internal manufacturing sites. Changes included material updates, process modifications, and sterilization-related adjustments that had the potential to impact product performance, design verification, and residual risk profiles.

The organization needed a disciplined, repeatable approach to design change impact assessment that preserved Design History File (DHF) and Risk Management File (RMF) integrity while enabling timely implementation of necessary changes across multiple stakeholders.

ENQUAL supported Quality governance for design and process change assessments, ensuring changes were evaluated holistically across design controls, verification, and risk management. Key activities included:

• Quality impact assessment of vendor-driven and internally driven design and process changes, including changes associated with sterilization methods and parameters
   
• Evaluation of change impact on design inputs, design verification evidence, and traceability matrices
   
• Assessment of downstream effects on Risk Management Files, including Hazard Analysis and applicable FMEA documentation
   
• Coordination with cross-functional teams (R&D, Manufacturing, Suppliers) to ensure alignment on change scope, documentation updates, and verification needs
   
• Support of change control documentation to maintain DHF and RMF consistency throughout implementation
   

This approach ensured changes were not evaluated in isolation, but within the context of design intent, verification evidence, and residual risk.

Design and process changes were implemented with clear, documented justification and traceability, preserving inspection readiness across lifecycle activities. Change assessments supported consistent decision-making, minimized unintended risk introduction, and maintained alignment between design controls, verification, and risk management documentation for combination products operating under FDA and EU regulatory expectations.

 This representative engagement reflects ENQUAL’s approach to lifecycle risk management, design control integration, and inspection-ready quality systems for combination products.  

A mature manufacturing process supporting a regulated filtration-based medical product experienced recurring out-of-specification (OOS) defects associated with mechanical deformation (“bent pleats”). Although the process had previously met qualification requirements, defect trends indicated loss of effective control under routine production conditions.

The challenge was not limited to resolving individual deviations. The underlying concern was whether the existing control strategy and monitoring approach were sufficient to maintain a validated state over time, consistent with lifecycle expectations under ISO 13485 and EU MDR.

The response followed a lifecycle-based process validation approach, emphasizing data integrity, statistical rigor, and sustainable control rather than short-term containment.

Key elements included:

• Process & Risk Framing
  The defect mechanism was mapped within the full process flow to identify critical process parameters (CPPs) and critical quality attributes (CQAs) influencing pleat geometry. The issue was treated as a process performance risk, aligning the investigation with continued process verification principles.
   
• Measurement System & Statistical Analysis
  Measurement system capability was verified to ensure observed variability reflected true process behavior. A structured Design of Experiments (DOE) was then applied to evaluate the effects and interactions of thermal parameters, including annealing temperature, dwell time, and cooling profiles.
   
• Control Strategy Redesign
  Based on statistically significant drivers, validated operating ranges were defined and a revised thermal and cooling control strategy was implemented. Automation and control logic were updated to reduce operator-dependent variability and support consistent execution.
   
• Monitoring & Verification Planning
  Expectations for ongoing data trending were established to enable continued monitoring of process stability, rather than reliance on episodic deviation response.
   

This ensured corrective actions were grounded in process understanding and quantified cause-and-effect relationships.

The updated control strategy resulted in a sustained reduction in defect occurrence, improved yield stability, and clearer linkage between monitored parameters and product performance.

From a lifecycle and regulatory perspective, the work:

• Re-established the process in a state of control
   
• Enabled Continued Process Verification (CPV) through defined indicators and trend-based monitoring
   
• Reduced reliance on reactive deviation handling by strengthening upstream controls
   
• Supported ongoing compliance with ISO 13485:2016, FDA QMSR expectations, and EU MDR 2017/745 requirements for manufacturing process control and lifecycle maintenance of conformity
   

The approach also aligns with the direction of proposed EU MDR updates emphasizing stronger linkage between manufacturing data, risk management, and post-market surveillance.

A tangential flow filtration (TFF) unit operation supporting biopharmaceutical manufacturing experienced out-of-specification performance and process instability associated with membrane cassette behavior. Variability was observed across operating conditions and cassette lifecycles, raising concerns related to process robustness, validation assumptions, and ongoing state of control.

The challenge extended beyond immediate deviation resolution. The organization required a defensible approach to:

• Re-establish validated operating ranges
   
• Demonstrate process understanding aligned with FDA Process Validation Stage 3 (Continued Process Verification) principles
   
• Ensure alignment with ISO 13485:2016 requirements for monitoring, measurement, and process control, as applicable to filtration systems supporting regulated products
   

This effort needed to integrate engineering, manufacturing, and quality disciplines while preserving product safety and supply continuity.

A structured, data-driven remediation and verification approach was implemented to restore and sustain process control.

Process Characterization & Statistical Analysis

• Conducted in-depth evaluation of key TFF process parameters (e.g., transmembrane pressure, flow rates, cassette performance indicators).
   
• Applied statistical techniques consistent with Six Sigma methodology to assess variability, identify contributing factors, and distinguish special cause from common cause variation.
   
• Established statistically justified operating ranges and acceptance criteria to support validation and ongoing monitoring.
   

Validation & Lifecycle Control

• Supported development and execution of IQ/OQ/PQ activities for the TFF system, ensuring equipment configuration, operational limits, and performance outcomes were appropriately challenged and documented.
   
• Integrated cassette care, use, cleaning, and storage considerations into validation and operational controls to reduce lifecycle-related variability.
   
• Aligned validation rationale with FDA Process Validation guidance and industry best practices for TFF operations.
   

Continued Process Verification Framework

• Defined a CPV-aligned monitoring strategy incorporating trending of critical process indicators and membrane performance metrics.
   
• Enabled routine review of process data to confirm continued state of control and early detection of drift.
   
• Established clear linkage between manufacturing data, quality review, and decision-making.

• Process Stability Restored: Variability associated with TFF cassette performance was reduced through statistically supported operating controls and standardized practices.
   
• Validation Confidence Strengthened: The filtration process was supported by a defensible validation and verification strategy aligned with regulatory expectations for lifecycle management.
   
• Sustained State of Control: Implementation of CPV principles provided ongoing assurance of process performance, supporting ISO 13485 requirements for monitoring, measurement, and improvement.
   
• Cross-Functional Clarity: Engineering, manufacturing, and quality teams gained a shared, data-based understanding of process behavior, enabling consistent execution and informed change management.

A regulated extracorporeal therapy system exhibited recurrent alarm events related to red blood cell (RBC) and system pressure behavior during routine operation. While alarms functioned as intended from a safety standpoint, their frequency and variability raised concerns regarding system stability, operator burden, and long-term control.

The challenge was not to suppress alarms, but to determine whether the underlying process signals and control logic appropriately reflected expected physiological and operational variability. The organization required a defensible, data-based approach to distinguish normal process behavior from true fault conditions while maintaining compliance with quality system and risk management expectations.

A structured, statistically driven investigation was conducted to restore confidence in system performance and alarm behavior.

Signal Definition & Process Understanding

• Developed a detailed process and system interaction model to understand how flow, pressure, and blood properties interacted under normal and stressed operating conditions.
   
• Framed alarm behavior as a process signal stability issue, rather than isolated events.
   

Statistical & Experimental Analysis

• Applied statistical analysis and Design of Experiments (DOE) techniques to evaluate the influence and interaction of key variables affecting pressure and RBC response.
   
• Quantified sensitivity of alarm thresholds to expected operational variability, enabling distinction between common-cause and special-cause conditions.
   

Control Logic & Risk Alignment

• Supported refinement of alarm logic and control thresholds to ensure alignment with validated operating ranges and risk assumptions.
   
• Ensured changes were traceable to system performance requirements and risk management considerations, maintaining integrity of the overall control strategy.
   

Verification & Monitoring

• Verified that updated logic maintained safety intent while reducing unnecessary alarm frequency.
   
• Established expectations for ongoing monitoring to confirm sustained system stability over time.

• Improved System Stability: Alarm behavior more accurately reflected true fault conditions rather than normal operational variability.
   
• Clearer Signal Interpretation: Operators and engineering teams gained improved clarity between expected process behavior and actionable deviations.
   
• Lifecycle Control Reinforced: The approach supported continued monitoring and verification of system performance rather than reactive investigation.
   
• Regulatory Alignment Maintained: Work was consistent with quality system expectations for monitoring, analysis of data, risk management integration, and control of changes.

A complex electromechanical medical device experienced repeat performance anomalies identified through production testing and post-verification monitoring. The observed issues included temperature- and pressure-related behaviors that could not be isolated to a single component and were not adequately explained by existing design verification or risk documentation.

The situation was complicated by the interaction of multiple subsystems (mechanical motion, thermal behavior, sensing, alarms, and control logic), as well as procedural and environmental factors associated with normal operation. Existing records demonstrated compliance with documented requirements but lacked a clear, defensible explanation linking observed behavior to design intent, risk controls, and verification evidence—creating potential inspection exposure if left unresolved.

A structured, system-level investigation was initiated to move beyond isolated root cause hypotheses and evaluate the device as an integrated system.

Key activities included:

• Failure Mode Characterization: Conducted targeted investigations to characterize thermal, mechanical, and system response under defined operating conditions, focusing on repeatability, boundary conditions, and failure triggers rather than anecdotal symptoms.
   
• Subsystem Interaction Analysis: Evaluated interactions between hardware components, sensors, alarms, and control logic to identify contributing factors not evident in component-level testing alone.
   
• Root Cause & Risk Linkage: Mapped investigation findings back to existing hazard analyses and risk controls, identifying gaps where failure modes were insufficiently characterized or where residual risk justification relied on assumptions rather than objective evidence.
   
• Verification of Corrective Actions: Developed and executed focused verification activities to confirm that implemented corrective actions effectively addressed the identified failure mechanisms and did not introduce unintended system-level effects.
   
• Documentation Discipline: Updated investigation records, verification summaries, and risk documentation to clearly articulate decision logic, assumptions, and evidence in a manner suitable for regulatory review.

• Defensible Root Cause Resolution: Established a clear, evidence-based understanding of system-level failure mechanisms, replacing fragmented hypotheses with a coherent technical rationale.
   
• Verification Integrity Restored: Demonstrated through objective testing that corrective actions resolved the observed issues and aligned system behavior with design intent across defined operating conditions.
   
• Risk Management Alignment: Strengthened linkage between system behavior, hazard analysis, and risk controls, supporting a more robust residual risk justification.
   
• Inspection Readiness Improved: Produced inspection-ready documentation that clearly traced observed issues through investigation, decision-making, verification, and risk updates—supporting confident responses to regulatory inquiries.