Regulatory Changes I am Watching – July 2025

The environment for commissioning, qualification, and validation (CQV) professionals remains defined by persistent challenges. Rapid technological advancements—most notably in artificial intelligence, machine learning, and automation—are constantly reshaping the expectations for validation. Compliance requirements are in frequent flux as agencies modernize guidance, while the complexity of novel biologics and therapies demands ever-higher standards of sterility, traceability, and process control. The shift towards digital systems has introduced significant hurdles in data management and integration, often stretching already limited resources. At the same time, organizations are expected to fully embrace risk-based, science-first approaches, which require new methodologies and skills. Finally, true validation now hinges on effective collaboration and knowledge-sharing among increasingly cross-functional and global teams.

Overlaying these challenges, three major regulatory paradigm shifts are transforming the expectations around risk management, contamination control, and data integrity. Data integrity in particular has become an international touchpoint. Since the landmark PIC/S guidance in 2021 and matching World Health Organization updates, agencies have made it clear that trustworthy, accurate, and defendable data—whether paper-based or digital—are the foundation of regulatory confidence. Comprehensive data governance, end-to-end traceability, and robust documentation are now all non-negotiable.

Contamination control is experiencing its own revolution. The August 2023 overhaul of EU GMP Annex 1 set a new benchmark for sterile manufacturing. The core concept, the Contamination Control Strategy (CCS), formalizes expectations: every manufacturer must systematically identify, map, and control contamination risks across the entire product lifecycle. From supply chain vigilance to environmental monitoring, regulators are pushing for a proactive, science-driven, and holistic approach, far beyond previous practices that too often relied on reactive measures. We this reflected in recent USP drafts as well.

Quality risk management (QRM) also has a new regulatory backbone. The ICH Q9(R1) revision, finalized in 2023, addresses long-standing shortcomings—particularly subjectivity and lack of consistency—in how risks are identified and managed. The European Medicines Agency’s ongoing revision of EudraLex Chapter 1, now aiming for finalization in 2026, will further require organizations to embed preventative, science-based risk management within globalized and complex supply chain operations. Modern products and supply webs simply cannot be managed with last-generation compliance thinking.

The EU Digital Modernization: Chapter 4, Annex 11, and Annex 22

With the rapid digitalization of pharma, the European Union has embarked on an ambitious modernization of its GMP framework. At the heart of these changes are the upcoming revisions to Chapter 4 (Documentation), Annex 11 (Computerised Systems), and the anticipated implementation of Annex 22 (Artificial Intelligence).

Chapter 4—Documentation is being thoroughly updated in parallel with Annex 11. The current chapter, which governs all aspects of documentation in GMP environments, was last revised in 2011. Its modernization is a direct response to the prevalence of digital tools—electronic records, digital signatures, and interconnected documentation systems. The revised Chapter 4 is expected to provide much clearer requirements for the management, review, retention, and security of both paper and electronic records, ensuring that information flows align seamlessly with the increasingly digital processes described in Annex 11. Together, these updates will enable companies to phase out paper where possible, provided electronic systems are validated, auditable, and secure.

Annex 11—Computerised Systems will see its most significant overhaul since the dawn of digital pharma. The new guidance, scheduled for publication and adoption in 2026, directly addresses areas that the previous version left insufficiently covered. The scope now embraces the tectonic shift toward AI, machine learning, cloud-based services, agile project management, and advanced digital workflows. For instance, close attention is being paid to the robustness of electronic signatures, demanding multi-factor authentication, time-zoned audit trails, and explicit provisions for non-repudiation. Hybrid (wet-ink/digital) records will only be acceptable if they can demonstrate tamper-evidence via hashes or equivalent mechanisms. Especially significant is the regulation of “open systems” such as SaaS and cloud platforms. Here, organizations can no longer rely on traditional username/password models; instead, compliance with standards like eIDAS for trusted digital providers is expected, with more of the technical compliance burden shifting onto certified digital partners.

The new Annex 11 also calls for enhanced technical controls throughout computerized systems, proportional risk management protocols for new technologies, and a far greater emphasis on continuous supplier oversight and lifecycle validation. Integration with the revised Chapter 4 ensures that documentation requirements and data management are harmonized across the digital value chain.

Posts on the Draft Annex 11:

Annex 22—a forthcoming addition—artificial intelligence

The introduction of Annex 22 represents a pivotal moment in the regulatory landscape for pharmaceutical manufacturing in Europe. This annex is the EU’s first dedicated framework addressing the use of Artificial Intelligence (AI) and machine learning in the production of active substances and medicinal products, responding to the rapid digital transformation now reshaping the industry.

Annex 22 sets out explicit requirements to ensure that any AI-based systems integrated into GMP-regulated environments are rigorously controlled and demonstrably trustworthy. It starts by mandating that manufacturers clearly define the intended use of any AI model deployed, ensuring its purpose is scientifically justified and risk-appropriate.

Quality risk management forms the backbone of Annex 22. Manufacturers must establish performance metrics tailored to the specific application and product risk profile of AI, and they are required to demonstrate the suitability and adequacy of all data used for model training, validation, and testing. Strong data governance principles apply: manufacturers need robust controls over data quality, traceability, and security throughout the AI system’s lifecycle.

The annex foresees a continuous oversight regime. This includes change control processes for AI models, ongoing monitoring of performance to detect drift or failures, and formally documented procedures for human intervention where necessary. The emphasis is on ensuring that, even as AI augments or automates manufacturing processes, human review and responsibility remain central for all quality- and safety-critical steps.

By introducing these requirements, Annex 22 aims to provide sufficient flexibility to enable innovation, while anchoring AI applications within a robust regulatory framework that safeguards product quality and patient safety at every stage. Together with the updates to Chapter 4 and Annex 11, Annex 22 gives companies clear, actionable expectations for responsibly harnessing digital innovation in the manufacturing environment.

Posts on Annex 22

Life Cycle Integration, Analytical Validation, and AI/ML Guidance

Across global regulators, a clear consensus has taken shape: validation must be seen as a continuous lifecycle process, not as a “check-the-box” activity. The latest WHO technical reports, the USP’s evolving chapters (notably <1058> and <1220>), and the harmonized ICH Q14 all signal a new age of ongoing qualification, continuous assurance, change management, and systematic performance verification. The scope of validation stretches from the design qualification stage through annual review and revalidation after every significant change.

A parallel wave of guidance for AI and machine learning is cresting. The EMA, FDA, MHRA, and WHO are now releasing coordinated documents addressing everything from transparent model architecture and dataset controls to rigorous “human-in-the-loop” safeguards for critical manufacturing decisions, including the new draft Annex 22. Data governance—traceability, security, and data quality—has never been under more scrutiny.

Regulatory BodyDocument TitlePublication DateStatusKey Focus Areas
EMAReflection Paper on the Use of Artificial Intelligence in the Medicinal Product LifecycleOct-24FinalRisk-based approach for AI/ML development, deployment, and performance monitoring across product lifecycle including manufacturing
EMA/HMAMulti-annual AI Workplan 2023-2028Dec-23FinalStrategic framework for European medicines regulatory network to utilize AI while managing risks
EMAAnnex 22 Artificial IntelligenceJul-25DraftEstablishes requirements for the use of AI and machine learning in the manufacturing of active substances and medicinal products.
FDAConsiderations for the Use of AI to Support Regulatory Decision Making for Drug and Biological ProductsFeb-25DraftGuidelines for using AI to generate information for regulatory submissions
FDADiscussion Paper on AI in the Manufacture of MedicinesMay-23PublishedConsiderations for cloud applications, IoT data management, regulatory oversight of AI in manufacturing
FDA/Health Canada/MHRAGood Machine Learning Practice for Medical Device Development Guiding PrinciplesMar-25Final10 principles to inform development of Good Machine Learning Practice
WHOGuidelines for AI Regulation in Health CareOct-23FinalSix regulatory areas including transparency, risk management, data quality
MHRAAI Regulatory StrategyApr-24FinalStrategic approach based on safety, transparency, fairness, accountability, and contestability principles
EFPIAPosition Paper on Application of AI in a GMP Manufacturing EnvironmentSep-24PublishedIndustry position on using existing GMP framework to embrace AI/ML solutions

The Time is Now

The world of validation is no longer controlled by periodic updates or leisurely transitions. Change is the new baseline. Regulatory authorities have codified the digital, risk-based, and globally harmonized future—are your systems, people, and partners ready?

Cognitive Foundations of Risk Management Excellence

The Hidden Architecture of Risk Assessment Failure

Peter Baker‘s blunt assessment, “We allowed all these players into the market who never should have been there in the first place, ” hits at something we all recognize but rarely talk about openly. Here’s the uncomfortable truth: even seasoned quality professionals with decades of experience and proven methodologies can miss critical risks that seem obvious in hindsight. Recognizing this truth is not about competence or dedication. It is about acknowledging that our expertise, no matter how extensive, operates within cognitive frameworks that can create blind spots. The real opportunity lies in understanding how these mental patterns shape our decisions and building knowledge systems that help us see what we might otherwise miss. When we’re honest about these limitations, we can strengthen our approaches and create more robust quality systems.

The framework of risk management, designed to help avoid the monsters of bad decision-making, can all too often fail us. Luckily, the Pharmaceutical Inspection Co-operation Scheme (PIC/S) guidance document PI 038-2 “Assessment of Quality Risk Management Implementation” identifies three critical observations that reveal systematic vulnerabilities in risk management practice: unjustified assumptions, incomplete identification of risks or inadequate information, and lack of relevant experience with inappropriate use of risk assessment tools. These observations represent something more profound than procedural failures—they expose cognitive and knowledge management vulnerabilities that can undermine even the most well-intentioned quality systems..

Understanding these vulnerabilities through the lens of cognitive behavioral science and knowledge management principles provides a pathway to more robust and resilient quality systems. Instead of viewing these failures as isolated incidents or individual shortcomings, we should recognize them as predictable patterns that emerge from systematic limitations in how humans process information and organizations manage knowledge. This recognition opens the door to designing quality systems that work with, rather than against, these cognitive realities

The Framework Foundation of Risk Management Excellence

Risk management operates fundamentally as a framework rather than a rigid methodology, providing the structural architecture that enables systematic approaches to identifying, assessing, and controlling uncertainties that could impact pharmaceutical quality objectives. This distinction proves crucial for understanding how cognitive biases manifest within risk management systems and how excellence-driven quality systems can effectively address them.

A framework establishes the high-level structure, principles, and processes for managing risks systematically while allowing flexibility in execution and adaptation to specific organizational contexts. The framework defines structural components like governance and culture, strategy and objective-setting, and performance monitoring that establish the scaffolding for risk management without prescribing inflexible procedures.

Within this framework structure, organizations deploy specific methodological elements as tools for executing particular risk management tasks. These methodologies include techniques such as Failure Mode and Effects Analysis (FMEA), brainstorming sessions, SWOT analysis, and risk surveys for identification activities, while assessment methodologies encompass qualitative and quantitative approaches including statistical models and scenario analysis. The critical insight is that frameworks provide the systematic architecture that counters cognitive biases, while methodologies are specific techniques deployed within this structure.

This framework approach directly addresses the three PIC/S observations by establishing systematic requirements that counter natural cognitive tendencies. Standardized framework processes force systematic consideration of risk factors rather than allowing teams to rely on intuitive pattern recognition that might be influenced by availability bias or anchoring on familiar scenarios. Documented decision rationales required by framework approaches make assumptions explicit and subject to challenge, preventing the perpetuation of unjustified beliefs that may have become embedded in organizational practices.

The governance components inherent in risk management frameworks address the expertise and knowledge management challenges identified in PIC/S guidance by establishing clear roles, responsibilities, and requirements for appropriate expertise involvement in risk assessment activities. Rather than leaving expertise requirements to chance or individual judgment, frameworks systematically define when specialized knowledge is required and how it should be accessed and validated.

ICH Q9’s approach to Quality Risk Management in pharmaceuticals demonstrates this framework principle through its emphasis on scientific knowledge and proportionate formality. The guideline establishes framework requirements that risk assessments be “based on scientific knowledge and linked to patient protection” while allowing methodological flexibility in how these requirements are met. This framework approach provides systematic protection against the cognitive biases that lead to unjustified assumptions while supporting the knowledge management processes necessary for complete risk identification and appropriate tool application.

The continuous improvement cycles embedded in mature risk management frameworks provide ongoing validation of cognitive bias mitigation effectiveness through operational performance data. These systematic feedback loops enable organizations to identify when initial assumptions prove incorrect or when changing conditions alter risk profiles, supporting the adaptive learning required for sustained excellence in pharmaceutical risk management.

The Systematic Nature of Risk Assessment Failure

Unjustified Assumptions: When Experience Becomes Liability

The first PIC/S observation—unjustified assumptions—represents perhaps the most insidious failure mode in pharmaceutical risk management. These are decisions made without sufficient scientific evidence or rational basis, often arising from what appears to be strength: extensive experience with familiar processes. The irony is that the very expertise we rely upon can become a source of systematic error when it leads to unfounded confidence in our understanding.

This phenomenon manifests most clearly in what cognitive scientists call anchoring bias—the tendency to rely too heavily on the first piece of information encountered when making decisions. In pharmaceutical risk assessments, this might appear as teams anchoring on historical performance data without adequately considering how process changes, equipment aging, or supply chain modifications might alter risk profiles. The assumption becomes: “This process has worked safely for five years, so the risk profile remains unchanged.”

Confirmation bias compounds this issue by causing assessors to seek information that confirms their existing beliefs while ignoring contradictory evidence. Teams may unconsciously filter available data to support predetermined conclusions about process reliability or control effectiveness. This creates a self-reinforcing cycle where assumptions become accepted facts, protected from challenge by selective attention to supporting evidence.

The knowledge management dimension of this failure is equally significant. Organizations often lack systematic approaches to capturing and validating the assumptions embedded in institutional knowledge. Tacit knowledge—the experiential, intuitive understanding that experts develop over time—becomes problematic when it remains unexamined and unchallenged. Without explicit processes to surface and test these assumptions, they become invisible constraints on risk assessment effectiveness.

Incomplete Risk Identification: The Boundaries of Awareness

The second observation—incomplete identification of risks or inadequate information—reflects systematic failures in the scope and depth of risk assessment activities. This represents more than simple oversight; it demonstrates how cognitive limitations and organizational boundaries constrain our ability to identify potential hazards comprehensively.

Availability bias plays a central role in this failure mode. Risk assessment teams naturally focus on hazards that are easily recalled or recently experienced, leading to overemphasis on dramatic but unlikely events while underestimating more probable but less memorable risks. A team might spend considerable time analyzing the risk of catastrophic equipment failure while overlooking the cumulative impact of gradual process drift or material variability.

The knowledge management implications are profound. Organizations often struggle with knowledge that exists in isolated pockets of expertise. Critical information about process behaviors, failure modes, or control limitations may be trapped within specific functional areas or individual experts. Without systematic mechanisms to aggregate and synthesize distributed knowledge, risk assessments operate on fundamentally incomplete information.

Groupthink and organizational boundaries further constrain risk identification. When risk assessment teams are composed of individuals from similar backgrounds or organizational levels, they may share common blind spots that prevent recognition of certain hazard categories. The pressure to reach consensus can suppress dissenting views that might identify overlooked risks.

Inappropriate Tool Application: When Methodology Becomes Mythology

The third observation—lack of relevant experience with process assessment and inappropriate use of risk assessment tools—reveals how methodological sophistication can mask fundamental misunderstanding. This failure mode is particularly dangerous because it generates false confidence in risk assessment conclusions while obscuring the limitations of the analysis.

Overconfidence bias drives teams to believe they have more expertise than they actually possess, leading to misapplication of complex risk assessment methodologies. A team might apply Failure Mode and Effects Analysis (FMEA) to a novel process without adequate understanding of either the methodology’s limitations or the process’s unique characteristics. The resulting analysis appears scientifically rigorous while providing misleading conclusions about risk levels and control effectiveness.

This connects directly to knowledge management failures in expertise distribution and access. Organizations may lack systematic approaches to identifying when specialized knowledge is required for risk assessments and ensuring that appropriate expertise is available when needed. The result is risk assessments conducted by well-intentioned teams who lack the specific knowledge required for accurate analysis.

The problem is compounded when organizations rely heavily on external consultants or standardized methodologies without developing internal capabilities for critical evaluation. While external expertise can be valuable, sole reliance on these resources may result in inappropriate conclusions or a lack of ownership of the assessment, as the PIC/S guidance explicitly warns.

The Role of Negative Reasoning in Risk Assessment

The research on causal reasoning versus negative reasoning from Energy Safety Canada provides additional insight into systematic failures in pharmaceutical risk assessments. Traditional root cause analysis often focuses on what did not happen rather than what actually occurred—identifying “counterfactuals” such as “operators not following procedures” or “personnel not stopping work when they should have.”

This approach, termed “negative reasoning,” is fundamentally flawed because what was not happening cannot create the outcomes we experienced. These counterfactuals “exist only in retrospection and never actually influenced events,” yet they dominate many investigation conclusions. In risk assessment contexts, this manifests as teams focusing on the absence of desired behaviors or controls rather than understanding the positive factors that actually influence system performance.

The shift toward causal reasoning requires understanding what actually occurred and what factors positively influenced the outcomes observed.

Knowledge-Enabled Decision Making

The intersection of cognitive science and knowledge management reveals how organizations can design systems that support better risk assessment decisions. Knowledge-enabled decision making requires structures that make relevant information accessible at the point of decision while supporting the cognitive processes necessary for accurate analysis.

This involves several key elements:

Structured knowledge capture that explicitly identifies assumptions, limitations, and context for recorded information. Rather than simply documenting conclusions, organizations must capture the reasoning process and evidence base that supports risk assessment decisions.

Knowledge validation systems that systematically test assumptions embedded in organizational knowledge. This includes processes for challenging accepted wisdom and updating mental models when new evidence emerges.

Expertise networks that connect decision-makers with relevant specialized knowledge when required. Rather than relying on generalist teams for all risk assessments, organizations need systematic approaches to accessing specialized expertise when process complexity or novelty demands it.

Decision support systems that prompt systematic consideration of potential biases and alternative explanations.

Alt Text for Risk Management Decision-Making Process Diagram
Main Title: Risk Management as Part of Decision Making

Overall Layout: The diagram is organized into three horizontal sections - Analysts' Domain (top), Analysis Community Domain (middle), and Users' Domain (bottom), with various interconnected process boxes and workflow arrows.

Left Side Input Elements:

Scope Judgments (top)

Assumptions

Data

SMEs (Subject Matter Experts)

Elicitation (connecting SMEs to the main process flow)

Central Process Flow (Analysts' Domain):
Two main blue boxes containing:

Risk Analysis - includes bullet points for Scenario initiation, Scenario unfolding, Completeness, Adversary decisions, and Uncertainty

Report Communication with metrics - includes Metrically Valid, Meaningful, Caveated, and Full Disclosure

Transparency Documentation - includes Analytic and Narrative components

Decision-Making Process Flow (Users' Domain):
A series of connected teal/green boxes showing:

Risk Management Decision Making Process

Desired Implementation of Risk Management

Actual Implementation of Risk Management

Final Consequences, Residual Risk

Secondary Process Elements:

Third Party Review → Demonstrated Validity

Stakeholder Review → Trust

Implementers Acceptance and Stakeholders Acceptance (shown in parallel)

Key Decision Points:

"Engagement, or Not, in Decision Making Process" (shown in light blue box at top)

"Acceptance or Not" (shown in gray box in middle section)

Visual Design Elements:

Uses blue boxes for analytical processes

Uses teal/green boxes for decision-making and implementation processes

Shows workflow with directional arrows connecting all elements

Includes small icons next to major process boxes

Divides content into clearly labeled domain sections at bottom

The diagram illustrates the complete flow from initial risk analysis through stakeholder engagement to final implementation and residual risk outcomes, emphasizing the interconnected nature of analytical work and decision-making processes.

Excellence and Elegance: Designing Quality Systems for Cognitive Reality

Structured Decision-Making Processes

Excellence in pharmaceutical quality systems requires moving beyond hoping that individuals will overcome cognitive limitations through awareness alone. Instead, organizations must design structured decision-making processes that systematically counter known biases while supporting comprehensive risk identification and analysis.

Forced systematic consideration involves using checklists, templates, and protocols that require teams to address specific risk categories and evidence types before reaching conclusions. Rather than relying on free-form discussion that may be influenced by availability bias or groupthink, these tools ensure comprehensive coverage of relevant factors.

Devil’s advocate processes systematically introduce alternative perspectives and challenge preferred conclusions. By assigning specific individuals to argue against prevailing views or identify overlooked risks, organizations can counter confirmation bias and overconfidence while identifying blind spots in risk assessments.

Staged decision-making separates risk identification from risk evaluation, preventing premature closure and ensuring adequate time for comprehensive hazard identification before moving to analysis and control decisions.

Structured Decision Making infographic showing three interconnected hexagonal components. At the top left, an orange hexagon labeled 'Forced systematic consideration' with a head and gears icon, describing 'Use tools that require teams to address specific risk categories and evidence types before reaching conclusions.' At the top right, a dark blue hexagon labeled 'Devil Advocates' with a lightbulb and compass icon, describing 'Counter confirmation bias and overconfidence while identifying blind spots in risk assessments.' At the bottom, a gray hexagon labeled 'Staged Decision Making' with a briefcase icon, describing 'Separate risk identification from risk evaluation to analysis and control decisions.' The three hexagons are connected by curved arrows indicating a cyclical process.

Multi-Perspective Analysis and Diverse Assessment Teams

Cognitive diversity in risk assessment teams provides natural protection against individual and group biases. This goes beyond simple functional representation to include differences in experience, training, organizational level, and thinking styles that can identify risks and solutions that homogeneous teams might miss.

Cross-functional integration ensures that risk assessments benefit from different perspectives on process performance, control effectiveness, and potential failure modes. Manufacturing, quality assurance, regulatory affairs, and technical development professionals each bring different knowledge bases and mental models that can reveal different aspects of risk.

External perspectives through consultants, subject matter experts from other sites, or industry benchmarking can provide additional protection against organizational blind spots. However, as the PIC/S guidance emphasizes, these external resources should facilitate and advise rather than replace internal ownership and accountability.

Rotating team membership for ongoing risk assessment activities prevents the development of group biases and ensures fresh perspectives on familiar processes. This also supports knowledge transfer and prevents critical risk assessment capabilities from becoming concentrated in specific individuals.

Evidence-Based Analysis Requirements

Scientific justification for all risk assessment conclusions requires teams to base their analysis on objective, verifiable data rather than assumptions or intuitive judgments. This includes collecting comprehensive information about process performance, material characteristics, equipment reliability, and environmental factors before drawing conclusions about risk levels.

Assumption documentation makes implicit beliefs explicit and subject to challenge. Any assumptions made during risk assessment must be clearly identified, justified with available evidence, and flagged for future validation. This transparency helps identify areas where additional data collection may be needed and prevents assumptions from becoming accepted facts over time.

Evidence quality assessment evaluates the strength and reliability of information used to support risk assessment conclusions. This includes understanding limitations, uncertainties, and potential sources of bias in the data itself.

Structured uncertainty analysis explicitly addresses areas where knowledge is incomplete or confidence is low. Rather than treating uncertainty as a weakness to be minimized, mature quality systems acknowledge uncertainty and design controls that remain effective despite incomplete information.

Continuous Monitoring and Reassessment Systems

Performance validation provides ongoing verification of risk assessment accuracy through operational performance data. The PIC/S guidance emphasizes that risk assessments should be “periodically reviewed for currency and effectiveness” with systems to track how well predicted risks align with actual experience.

Assumption testing uses operational data to validate or refute assumptions embedded in risk assessments. When monitoring reveals discrepancies between predicted and actual performance, this triggers systematic review of the original assessment to identify potential sources of bias or incomplete analysis.

Feedback loops ensure that lessons learned from risk assessment performance are incorporated into future assessments. This includes both successful risk predictions and instances where significant risks were initially overlooked.

Adaptive learning systems use accumulated experience to improve risk assessment methodologies and training programs. Organizations can track patterns in assessment effectiveness to identify systematic biases or knowledge gaps that require attention.

Knowledge Management as the Foundation of Cognitive Excellence

The Critical Challenge of Tacit Knowledge Capture

ICH Q10’s definition of knowledge management as “a systematic approach to acquiring, analysing, storing and disseminating information related to products, manufacturing processes and components” provides the regulatory framework, but the cognitive dimensions of knowledge management are equally critical. The distinction between tacit knowledge (experiential, intuitive understanding) and explicit knowledge (documented procedures and data) becomes crucial when designing systems to support effective risk assessment.

Infographic depicting the knowledge iceberg model used in knowledge management. The small visible portion above water labeled 'Explicit Knowledge' contains documented, codified information like manuals, procedures, and databases. The large hidden portion below water labeled 'Tacit Knowledge' represents uncodified knowledge including individual skills, expertise, cultural beliefs, and mental models that are difficult to transfer or document.

Tacit knowledge capture represents one of the most significant challenges in pharmaceutical quality systems. The experienced process engineer who can “feel” when a process is running correctly possesses invaluable knowledge, but this knowledge remains vulnerable to loss through retirements, organizational changes, or simply the passage of time. More critically, tacit knowledge often contains embedded assumptions that may become outdated as processes, materials, or environmental conditions change.

Structured knowledge elicitation processes systematically capture not just what experts know, but how they know it—the cues, patterns, and reasoning processes that guide their decision-making. This involves techniques such as cognitive interviewing, scenario-based discussions, and systematic documentation of decision rationales that make implicit knowledge explicit and subject to validation.

Knowledge validation and updating cycles ensure that captured knowledge remains current and accurate. This is particularly important for tacit knowledge, which may be based on historical conditions that no longer apply. Systematic processes for testing and updating knowledge prevent the accumulation of outdated assumptions that can compromise risk assessment effectiveness.

Expertise Distribution and Access

Knowledge networks provide systematic approaches to connecting decision-makers with relevant expertise when complex risk assessments require specialized knowledge. Rather than assuming that generalist teams can address all risk assessment challenges, mature organizations develop capabilities to identify when specialized expertise is required and ensure it is accessible when needed.

Expertise mapping creates systematic inventories of knowledge and capabilities distributed throughout the organization. This includes not just formal qualifications and roles, but understanding of specific process knowledge, problem-solving experience, and decision-making capabilities that may be relevant to risk assessment activities.

Dynamic expertise allocation ensures that appropriate knowledge is available for specific risk assessment challenges. This might involve bringing in experts from other sites for novel process assessments, engaging specialists for complex technical evaluations, or providing access to external expertise when internal capabilities are insufficient.

Knowledge accessibility systems make relevant information available at the point of decision-making through searchable databases, expert recommendation systems, and structured repositories that support rapid access to historical decisions, lessons learned, and validated approaches.

Knowledge Quality and Validation

Systematic assumption identification makes embedded beliefs explicit and subject to validation. Knowledge management systems must capture not just conclusions and procedures, but the assumptions and reasoning that support them. This enables systematic testing and updating when new evidence emerges.

Evidence-based knowledge validation uses operational performance data, scientific literature, and systematic observation to test the accuracy and currency of organizational knowledge. This includes both confirming successful applications and identifying instances where accepted knowledge may be incomplete or outdated.

Knowledge audit processes systematically evaluate the quality, completeness, and accessibility of knowledge required for effective risk assessment. This includes identifying knowledge gaps that may compromise assessment effectiveness and developing plans to address critical deficiencies.

Continuous knowledge improvement integrates lessons learned from risk assessment performance into organizational knowledge bases. When assessments prove accurate or identify overlooked risks, these experiences become part of organizational learning that improves future performance.

Integration with Risk Assessment Processes

Knowledge-enabled risk assessment systematically integrates relevant organizational knowledge into risk evaluation processes. This includes access to historical performance data, previous risk assessments for similar situations, lessons learned from comparable processes, and validated assumptions about process behaviors and control effectiveness.

Decision support integration provides risk assessment teams with structured access to relevant knowledge at each stage of the assessment process. This might include automated recommendations for relevant expertise, access to similar historical assessments, or prompts to consider specific knowledge domains that may be relevant.

Knowledge visualization and analytics help teams identify patterns, relationships, and insights that might not be apparent from individual data sources. This includes trend analysis, correlation identification, and systematic approaches to integrating information from multiple sources.

Real-time knowledge validation uses ongoing operational performance to continuously test and refine knowledge used in risk assessments. Rather than treating knowledge as static, these systems enable dynamic updating based on accumulating evidence and changing conditions.

A Maturity Model for Cognitive Excellence in Risk Management

Level 1: Reactive – The Bias-Blind Organization

Organizations at the reactive level operate with ad hoc risk assessments that rely heavily on individual judgment with minimal recognition of cognitive bias effects. Risk assessments are typically performed by whoever is available rather than teams with appropriate expertise, and conclusions are based primarily on immediate experience or intuitive responses.

Knowledge management characteristics at this level include isolated expertise with no systematic capture or sharing mechanisms. Critical knowledge exists primarily as tacit knowledge held by specific individuals, creating vulnerabilities when personnel changes occur. Documentation is minimal and typically focused on conclusions rather than reasoning processes or supporting evidence.

Cognitive bias manifestations are pervasive but unrecognized. Teams routinely fall prey to anchoring, confirmation bias, and availability bias without awareness of these influences on their conclusions. Unjustified assumptions are common and remain unchallenged because there are no systematic processes to identify or test them.

Decision-making processes lack structure and repeatability. Risk assessments may produce different conclusions when performed by different teams or at different times, even when addressing identical situations. There are no systematic approaches to ensuring comprehensive risk identification or validating assessment conclusions.

Typical challenges include recurring problems despite seemingly adequate risk assessments, inconsistent risk assessment quality across different teams or situations, and limited ability to learn from assessment experience. Organizations at this level often experience surprise failures where significant risks were not identified during formal risk assessment processes.

Level 2: Awareness – Recognizing the Problem

Organizations advancing to the awareness level demonstrate basic recognition of cognitive bias risks with inconsistent application of structured methods. There is growing understanding that human judgment limitations can affect risk assessment quality, but systematic approaches to addressing these limitations are incomplete or irregularly applied.

Knowledge management progress includes beginning attempts at knowledge documentation and expert identification. Organizations start to recognize the value of capturing expertise and may implement basic documentation requirements or expert directories. However, these efforts are often fragmented and lack systematic integration with risk assessment processes.

Cognitive bias recognition becomes more systematic, with training programs that help personnel understand common bias types and their potential effects on decision-making. However, awareness does not consistently translate into behavior change, and bias mitigation techniques are applied inconsistently across different assessment situations.

Decision-making improvements include basic templates or checklists that promote more systematic consideration of risk factors. However, these tools may be applied mechanically without deep understanding of their purpose or integration with broader quality system objectives.

Emerging capabilities include better documentation of assessment rationales, more systematic involvement of diverse perspectives in some assessments, and beginning recognition of the need for external expertise in complex situations. However, these practices are not yet embedded consistently throughout the organization.

Level 3: Systematic – Building Structured Defenses

Level 3 organizations implement standardized risk assessment protocols with built-in bias checks and documented decision rationales. There is systematic recognition that cognitive limitations require structured countermeasures, and processes are designed to promote more reliable decision-making.

Knowledge management formalization includes formal knowledge management processes including expert networks and structured knowledge capture. Organizations develop systematic approaches to identifying, documenting, and sharing expertise relevant to risk assessment activities. Knowledge is increasingly treated as a strategic asset requiring active management.

Bias mitigation integration embeds cognitive bias awareness and countermeasures into standard risk assessment procedures. This includes systematic use of devil’s advocate processes, structured approaches to challenging assumptions, and requirements for evidence-based justification of conclusions.

Structured decision processes ensure consistent application of comprehensive risk assessment methodologies with clear requirements for documentation, evidence, and review. Teams follow standardized approaches that promote systematic consideration of relevant risk factors while providing flexibility for situation-specific analysis.

Quality characteristics include more consistent risk assessment performance across different teams and situations, systematic documentation that enables effective review and learning, and better integration of risk assessment activities with broader quality system objectives.

Level 4: Integrated – Cultural Transformation

Level 4 organizations achieve cross-functional teams, systematic training, and continuous improvement processes with bias mitigation embedded in quality culture. Cognitive excellence becomes an organizational capability rather than a set of procedures, supported by culture, training, and systematic reinforcement.

Knowledge management integration fully integrates knowledge management with risk assessment processes and supports these with technology platforms. Knowledge flows seamlessly between different organizational functions and activities, with systematic approaches to maintaining currency and relevance of organizational knowledge assets.

Cultural integration creates organizational environments where systematic, evidence-based decision-making is expected and rewarded. Personnel at all levels understand the importance of cognitive rigor and actively support systematic approaches to risk assessment and decision-making.

Systematic training and development builds organizational capabilities in both technical risk assessment methodologies and cognitive skills required for effective application. Training programs address not just what tools to use, but how to think systematically about complex risk assessment challenges.

Continuous improvement mechanisms systematically analyze risk assessment performance to identify opportunities for enhancement and implement improvements in methodologies, training, and support systems.

Level 5: Optimizing – Predictive Intelligence

Organizations at the optimizing level implement predictive analytics, real-time bias detection, and adaptive systems that learn from assessment performance. These organizations leverage advanced technologies and systematic approaches to achieve exceptional performance in risk assessment and management.

Predictive capabilities enable organizations to anticipate potential risks and bias patterns before they manifest in assessment failures. This includes systematic monitoring of assessment performance, early warning systems for potential cognitive failures, and proactive adjustment of assessment approaches based on accumulated experience.

Adaptive learning systems continuously improve organizational capabilities based on performance feedback and changing conditions. These systems can identify emerging patterns in risk assessment challenges and automatically adjust methodologies, training programs, and support systems to maintain effectiveness.

Industry leadership characteristics include contributing to industry knowledge and best practices, serving as benchmarks for other organizations, and driving innovation in risk assessment methodologies and cognitive excellence approaches.

Implementation Strategies: Building Cognitive Excellence

Training and Development Programs

Cognitive bias awareness training must go beyond simple awareness to build practical skills in bias recognition and mitigation. Effective programs use case studies from pharmaceutical manufacturing to illustrate how biases can lead to serious consequences and provide hands-on practice with bias recognition and countermeasure application.

Critical thinking skill development builds capabilities in systematic analysis, evidence evaluation, and structured problem-solving. These programs help personnel recognize when situations require careful analysis rather than intuitive responses and provide tools for engaging systematic thinking processes.

Risk assessment methodology training combines technical instruction in formal risk assessment tools with cognitive skills required for effective application. This includes understanding when different methodologies are appropriate, how to adapt tools for specific situations, and how to recognize and address limitations in chosen approaches.

Knowledge management skills help personnel contribute effectively to organizational knowledge capture, validation, and sharing activities. This includes skills in documenting decision rationales, participating in knowledge networks, and using knowledge management systems effectively.

Technology Integration

Decision support systems provide structured frameworks that prompt systematic consideration of relevant factors while providing access to relevant organizational knowledge. These systems help teams engage appropriate cognitive processes while avoiding common bias traps.

Knowledge management platforms support effective capture, organization, and retrieval of organizational knowledge relevant to risk assessment activities. Advanced systems can provide intelligent recommendations for relevant expertise, historical assessments, and validated approaches based on assessment context.

Performance monitoring systems track risk assessment effectiveness and provide feedback for continuous improvement. These systems can identify patterns in assessment performance that suggest systematic biases or knowledge gaps requiring attention.

Collaboration tools support effective teamwork in risk assessment activities, including structured approaches to capturing diverse perspectives and managing group decision-making processes to avoid groupthink and other collective biases.

Technology plays a pivotal role in modern knowledge management by transforming how organizations capture, store, share, and leverage information. Digital platforms and knowledge management systems provide centralized repositories, making it easy for employees to access and contribute valuable insights from anywhere, breaking down traditional barriers like organizational silos and geographic distance.

Organizational Culture Development

Leadership commitment demonstrates visible support for systematic, evidence-based approaches to risk assessment. This includes providing adequate time and resources for thorough analysis, recognizing effective risk assessment performance, and holding personnel accountable for systematic approaches to decision-making.

Psychological safety creates environments where personnel feel comfortable challenging assumptions, raising concerns about potential risks, and admitting uncertainty or knowledge limitations. This requires organizational cultures that treat questioning and systematic analysis as valuable contributions rather than obstacles to efficiency.

Learning orientation emphasizes continuous improvement in risk assessment capabilities rather than simply achieving compliance with requirements. Organizations with strong learning cultures systematically analyze assessment performance to identify improvement opportunities and implement enhancements in methodologies and capabilities.

Knowledge sharing cultures actively promote the capture and dissemination of expertise relevant to risk assessment activities. This includes recognition systems that reward knowledge sharing, systematic approaches to capturing lessons learned, and integration of knowledge management activities with performance evaluation and career development.

Conducting a Knowledge Audit for Risk Assessment

Organizations beginning this journey should start with a systematic knowledge audit that identifies potential vulnerabilities in expertise availability and access. This audit should address several key areas:

Expertise mapping to identify knowledge holders, their specific capabilities, and potential vulnerabilities from personnel changes or workload concentration. This includes both formal expertise documented in job descriptions and informal knowledge that may be critical for effective risk assessment.

Knowledge accessibility assessment to evaluate how effectively relevant knowledge can be accessed when needed for risk assessment activities. This includes both formal systems such as databases and informal networks that provide access to specialized expertise.

Knowledge quality evaluation to assess the currency, accuracy, and completeness of knowledge used to support risk assessment decisions. This includes identifying areas where assumptions may be outdated or where knowledge gaps may compromise assessment effectiveness.

Cognitive bias vulnerability assessment to identify situations where systematic biases are most likely to affect risk assessment conclusions. This includes analyzing past assessment performance to identify patterns that suggest bias effects and evaluating current processes for bias mitigation effectiveness.

Designing Bias-Resistant Risk Assessment Processes

Structured assessment protocols should incorporate specific checkpoints and requirements designed to counter known cognitive biases. This includes mandatory consideration of alternative explanations, requirements for external validation of conclusions, and systematic approaches to challenging preferred solutions.

Team composition guidelines should ensure appropriate cognitive diversity while maintaining technical competence. This includes balancing experience levels, functional backgrounds, and thinking styles to maximize the likelihood of identifying diverse perspectives on risk assessment challenges.

Evidence requirements should specify the types and quality of information required to support different types of risk assessment conclusions. This includes guidelines for evaluating evidence quality, addressing uncertainty, and documenting limitations in available information.

Review and validation processes should provide systematic quality checks on risk assessment conclusions while identifying potential bias effects. This includes independent review requirements, structured approaches to challenging conclusions, and systematic tracking of assessment performance over time.

Building Knowledge-Enabled Decision Making

Integration strategies should systematically connect knowledge management activities with risk assessment processes. This includes providing risk assessment teams with structured access to relevant organizational knowledge and ensuring that assessment conclusions contribute to organizational learning.

Technology selection should prioritize systems that enhance rather than replace human judgment while providing effective support for systematic decision-making processes. This includes careful evaluation of user interface design, integration with existing workflows, and alignment with organizational culture and capabilities.

Performance measurement should track both risk assessment effectiveness and knowledge management performance to ensure that both systems contribute effectively to organizational objectives. This includes metrics for knowledge quality, accessibility, and utilization as well as traditional risk assessment performance indicators.

Continuous improvement processes should systematically analyze performance in both risk assessment and knowledge management to identify enhancement opportunities and implement improvements in methodologies, training, and support systems.

Excellence Through Systematic Cognitive Development

The journey toward cognitive excellence in pharmaceutical risk management requires fundamental recognition that human cognitive limitations are not weaknesses to be overcome through training alone, but systematic realities that must be addressed through thoughtful system design. The PIC/S observations of unjustified assumptions, incomplete risk identification, and inappropriate tool application represent predictable patterns that emerge when sophisticated professionals operate without systematic support for cognitive excellence.

Excellence in this context means designing quality systems that work with human cognitive capabilities rather than against them. This requires integrating knowledge management principles with cognitive science insights to create environments where systematic, evidence-based decision-making becomes natural and sustainable. It means moving beyond hope that awareness will overcome bias toward systematic implementation of structures, processes, and cultures that promote cognitive rigor.

Elegance lies in recognizing that the most sophisticated risk assessment methodologies are only as effective as the cognitive processes that apply them. True elegance in quality system design comes from seamlessly integrating technical excellence with cognitive support, creating systems where the right decisions emerge naturally from the intersection of human expertise and systematic process.

Organizations that successfully implement these approaches will develop competitive advantages that extend far beyond regulatory compliance. They will build capabilities in systematic decision-making that improve performance across all aspects of pharmaceutical quality management. They will create resilient systems that can adapt to changing conditions while maintaining consistent effectiveness. Most importantly, they will develop cultures of excellence that attract and retain exceptional talent while continuously improving their capabilities.

The framework presented here provides a roadmap for this transformation, but each organization must adapt these principles to their specific context, culture, and capabilities. The maturity model offers a path for progressive development that builds capabilities systematically while delivering value at each stage of the journey.

As we face increasingly complex pharmaceutical manufacturing challenges and evolving regulatory expectations, the organizations that invest in systematic cognitive excellence will be best positioned to protect patient safety while achieving operational excellence. The choice is not whether to address these cognitive foundations of quality management, but how quickly and effectively we can build the capabilities required for sustained success in an increasingly demanding environment.

The cognitive foundations of pharmaceutical quality excellence represent both opportunity and imperative. The opportunity lies in developing systematic capabilities that transform good intentions into consistent results. The imperative comes from recognizing that patient safety depends not just on our technical knowledge and regulatory compliance, but on our ability to think clearly and systematically about complex risks in an uncertain world.

Reflective Questions for Implementation

How might you assess your organization’s current vulnerability to the three PIC/S observations in your risk management practices? What patterns in past risk assessment performance might indicate systematic cognitive biases affecting your decision-making processes?

Where does critical knowledge for risk assessment currently reside in your organization, and how accessible is it when decisions must be made? What knowledge audit approach would be most valuable for identifying vulnerabilities in your current risk management capabilities?

Which level of the cognitive bias mitigation maturity model best describes your organization’s current state, and what specific capabilities would be required to advance to the next level? How might you begin building these capabilities while maintaining current operational effectiveness?

What systematic changes in training, process design, and cultural expectations would be required to embed cognitive excellence into your quality culture? How would you measure progress in building these capabilities and demonstrate their value to organizational leadership?

Transform isolated expertise into systematic intelligence through structured knowledge communities that connect diverse perspectives across manufacturing, quality, regulatory, and technical functions. When critical process knowledge remains trapped in departmental silos, risk assessments operate on fundamentally incomplete information, perpetuating the very blind spots that lead to unjustified assumptions and overlooked hazards.

Bridge the dangerous gap between experiential knowledge held by individual experts and the explicit, validated information systems that support evidence-based decision-making. The retirement of a single process expert can eliminate decades of nuanced understanding about equipment behaviors, failure patterns, and control sensitivities—knowledge that cannot be reconstructed through documentation alone

Not all Non-Compliance Reports are Equal

When engaged in regulatory/quality intelligence you should have a program in place to monitor for non-compliance reports, evaluate the internal quality system against those reports, and take appropriate preventative action. This is a fundamental risk management activity.

I tend to post about interesting 483s and Warning Letters fairly often, but one thing you won’t see me do is often delve deep into non-compliance reports from countries like India and China. For a manufacturer based in the US, this can often be a fair bit of noise, as the general state of the GMPs is different between the regions. The level of quality intelligence valuable to me if I was in India is different when I only support US and European sites.

I tend to follow a mode that looks like this:

I apply two different urgency levels between regulatory intelligence (preventive action) and supplier management (ensuring baseline is compliant).

Focusing on regulatory intelligence, I ensure we evaluate each and every noncompliance report coming from pharma and medical device for companies in the US, Europe, Canada, Japan. Each one of those is evaluated to see if a similar issue could potentially be found.

OTC and similar manufacturers from those markets end up in the trending evaluation. Might not drive immediate action, but trends should.

Noncompliances from developing regions, like China and India I rarely give much thought to in regulatory intelligence. They will end up in trending, such as a yearly look at 483s, but in themselves there is usually little that is actionable.

As a consumer, there is a different, and unfortunately, worse story.

Understanding the Distinction Between Impact and Risk

Two concepts—impact and risk — are often discussed but sometimes conflated within quality systems. While related, these concepts serve distinct purposes and drive different decisions throughout the quality system. Let’s explore.

The Fundamental Difference: Impact vs. Risk

The difference between impact and risk is fundamental to effective quality management. The difference between impact and risk is critical. Impact is best thought of as ‘What do I need to do to make the change.’ Risk is ‘What could go wrong in making this change?'”

Impact assessment focuses on evaluating the effects of a proposed change on various elements such as documentation, equipment, processes, and training. It helps identify the scope and reach of a change. Risk assessment, by contrast, looks ahead to identify potential failures that might occur due to the change – it’s preventive and focused on possible consequences.

This distinction isn’t merely academic – it directly affects how we approach actions and decisions in our quality systems, impacting core functions of CAPA, Change Control and Management Review.

AspectImpactRisk
DefinitionThe effect or influence a change, event, or deviation has on product quality, process, or systemThe probability and severity of harm or failure occurring as a result of a change, event, or deviation
FocusWhat is affected and to what extent (scope and magnitude of consequences)What could go wrong, how likely it is to happen, and how severe the outcome could be
Assessment TypeEvaluates the direct consequences of an action or eventEvaluates the likelihood and severity of potential adverse outcomes
Typical UseUsed in change control to determine which documents, systems, or processes are impactedUsed to prioritize actions, allocate resources, and implement controls to minimize negative outcomes
MeasurementUsually described qualitatively (e.g., minor, moderate, major, critical)Often quantified by combining probability and impact scores to assign a risk level (e.g., low, medium, high)
ExampleA change in raw material supplier impacts the manufacturing process and documentation.The risk is that the new supplier’s material could fail to meet quality standards, leading to product defects.

Change Control: Different Questions, Different Purposes

Within change management, the PIC/S Recommendation PI 054-1 notes that “In some cases, especially for simple and minor/low risk changes, an impact assessment is sufficient to document the risk-based rationale for a change without the use of more formal risk assessment tools or approaches.”

Impact Assessment in Change Control

  • Determines what documentation requires updating
  • Identifies affected systems, equipment, and processes
  • Establishes validation requirements
  • Determines training needs

Risk Assessment in Change Control

  • Identifies potential failures that could result from the change
  • Evaluates possible consequences to product quality and patient safety
  • Determines likelihood of those consequences occurring
  • Guides preventive measures

A common mistake is conflating these concepts or shortcutting one assessment. For example, companies often rush to designate changes as “like-for-like” without supporting data, effectively bypassing proper risk assessment. This highlights why maintaining the distinction is crucial.

Validation: Complementary Approaches

In validation, the impact-risk distinction shapes our entire approach.

Impact in validation relates to identifying what aspects of product quality could be affected by a system or process. For example, when qualifying manufacturing equipment, we determine which critical quality attributes (CQAs) might be influenced by the equipment’s performance.

Risk assessment in validation explores what could go wrong with the equipment or process that might lead to quality failures. Risk management plays a pivotal role in validation by enabling a risk-based approach to defining validation strategies, ensuring regulatory compliance, mitigating product quality and safety risks, facilitating continuous improvement, and promoting cross-functional collaboration.

In Design Qualification, we verify that the critical aspects (CAs) and critical design elements (CDEs) necessary to control risks identified during the quality risk assessment (QRA) are present in the design. This illustrates how impact assessment (identifying critical aspects) works together with risk assessment (identifying what could go wrong).

When we perform Design Review and Design Qualification, we focus on Critical Aspects: Prioritize design elements that directly impact product quality and patient safety. Here, impact assessment identifies critical aspects, while risk assessment helps prioritize based on potential consequences.

Following Design Qualification, Verification activities such as Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ) serve to confirm that the system or equipment performs as intended under actual operating conditions. Here, impact assessment identifies the specific parameters and functions that must be verified to ensure no critical quality attributes are compromised. Simultaneously, risk assessment guides the selection and extent of tests by focusing on areas with the highest potential for failure or deviation. This dual approach ensures that verification not only confirms the intended impact of the design but also proactively mitigates risks before routine use.

Validation does not end with initial qualification. Continuous Validation involves ongoing monitoring and trending of process performance and product quality to confirm that the validated state is maintained over time. Impact assessment plays a role in identifying which parameters and quality attributes require ongoing scrutiny, while risk assessment helps prioritize monitoring efforts based on the likelihood and severity of potential deviations. This continuous cycle allows quality systems to detect emerging risks early and implement corrective actions promptly, reinforcing a proactive, risk-based culture that safeguards product quality throughout the product lifecycle.

Data Integrity: A Clear Example

Data integrity offers perhaps the clearest illustration of the impact-risk distinction.

As I’ve previously noted, Data quality is not a risk. It is a causal factor in the failure or severity. Poor data quality isn’t itself a risk; rather, it’s a factor that can influence the severity or likelihood of risks.

When assessing data integrity issues:

  • Impact assessment identifies what data is affected and which processes rely on that data
  • Risk assessment evaluates potential consequences of data integrity lapses

In my risk-based data integrity assessment methodology, I use a risk rating system that considers both impact and risk factors:

Risk RatingActionMitigation
>25High Risk-Potential Impact to Patient Safety or Product QualityMandatory
12-25Moderate Risk-No Impact to Patient Safety or Product Quality but Potential Regulatory RiskRecommended
<12Negligible DI RiskNot Required

This system integrates both impact (on patient safety or product quality) and risk (likelihood and detectability of issues) to guide mitigation decisions.

The Golden Day: Impact and Risk in Deviation Management

The Golden Day concept for deviation management provides an excellent practical example. Within the first 24 hours of discovering a deviation, we conduct:

  1. An impact assessment to determine:
    • Which products, materials, or batches are affected
    • Potential effects on critical quality attributes
    • Possible regulatory implications
  2. A risk assessment to evaluate:
    • Patient safety implications
    • Product quality impact
    • Compliance with registered specifications
    • Level of investigation required

This impact assessment is also the initial risk assessment, which will help guide the level of effort put into the deviation. This statement shows how the two concepts, while distinct, work together to inform quality decisions.

Quality Escalation: When Impact Triggers a Response

In quality escalation, we often use specific criteria based on both impact and risk:

Escalation CriteriaExamples of Quality Events for Escalation
Potential to adversely affect quality, safety, efficacy, performance or compliance of product– Contamination – Product defect/deviation from process parameters or specification – Significant GMP deviations
Product counterfeiting, tampering, theft– Product counterfeiting, tampering, theft reportable to Health Authority – Lost/stolen IMP
Product shortage likely to disrupt patient care– Disruption of product supply due to product quality events
Potential to cause patient harm associated with a product quality event– Urgent Safety Measure, Serious Breach, Significant Product Complaint

These criteria demonstrate how we use both impact (what’s affected) and risk (potential consequences) to determine when issues require escalation.

Both Are Essential

Understanding the difference between impact and risk fundamentally changes how we approach quality management. Impact assessment without risk assessment may identify what’s affected but fails to prevent potential issues. Risk assessment without impact assessment might focus on theoretical problems without understanding the actual scope.

The pharmaceutical quality system requires both perspectives:

  1. Impact tells us the scope – what’s affected
  2. Risk tells us the consequences – what could go wrong

By maintaining this distinction and applying both concepts appropriately across change control, validation, and data integrity management, we build more robust quality systems that not only comply with regulations but actually protect product quality and patient safety.

The Pre-Mortem

A pre-mortem is a proactive risk management exercise that enables pharmaceutical teams to anticipate and mitigate failures before they occur. This tool can transform compliance from a reactive checklist into a strategic asset for safeguarding product quality.


Pre-Mortems in Pharmaceutical Quality Systems

In GMP environments, where deviations in drug substance purity or drug product stability can cascade into global recalls, pre-mortems provide a structured framework to challenge assumptions. For example, a team developing a monoclonal antibody might hypothesize that aggregation occurred during drug substance purification due to inadequate temperature control in bioreactors. By contrast, a tablet manufacturing team might explore why dissolution specifications failed because of inconsistent API particle size distribution. These exercises align with ICH Q9’s requirement for systematic hazard analysis and ICH Q10’s emphasis on knowledge management, forcing teams to document tacit insights about process boundaries and failure modes.

Pre-mortems excel at identifying “unknown unknowns” through creative thinking. Their value lies in uncovering risks traditional assessments miss. As a tool it can usually be strongly leveraged to identify areas for focus that may need a deeper tool, such as an FMEA. In practice, pre-mortems and FMEA are synergistic through a layered approach which satisfies ICH Q9’s requirement for both creative hazard identification and structured risk evaluation, turning hypothetical failures into validated control strategies.

By combining pre-mortems’ exploratory power with FMEA’s rigor, teams can address both systemic and technical risks, ensuring compliance while advancing operational resilience.


Implementing Pre-Mortems

1. Scenario Definition and Stakeholder Engagement

Begin by framing the hypothetical failure, the risk question. For drug substances, this might involve declaring, “The API batch was rejected due to genotoxic impurity levels exceeding ICH M7 limits.” For drug products, consider, “Lyophilized vials failed sterility testing due to vial closure integrity breaches.” Assemble a team spanning technical operations, quality control, and regulatory affairs to ensure diverse viewpoints.

2. Failure Mode Elicitation

To overcome groupthink biases in traditional brainstorming, teams should begin with brainwriting—a silent, written idea-generation technique. The prompt is a request to list reasons behind the risk question, such as “List reasons why the API batch failed impurity specifications”. Participants anonymously write risks on structured templates for 10–15 minutes, ensuring all experts contribute equally.

The collected ideas are then synthesized into a fishbone (Ishikawa) diagram, categorizing causes relevant branches, using a 6 M technique.

This method ensures comprehensive risk identification while maintaining traceability for regulatory audits.

3. Risk Prioritization and Control Strategy Development

Risks identified during the pre-mortem are evaluated using a severity-probability-detectability matrix, structured similarly to Failure Mode and Effects Analysis (FMEA).

4. Integration into Pharmaceutical Quality Systems

Mitigation plans are formalized in in control strategies and other mechanisms.


Case Study: Preventing Drug Substance Oxidation in a Small Molecule API

A company developing an oxidation-prone API conducted a pre-mortem anticipating discoloration and potency loss. The exercise revealed:

  • Drug substance risk: Inadequate nitrogen sparging during final isolation led to residual oxygen in crystallization vessels.
  • Drug product risk: Blister packaging with insufficient moisture barrier exacerbated degradation.

Mitigations included installing dissolved oxygen probes in purification tanks and switching to aluminum-foil blisters with desiccants. Process validation batches showed a 90% reduction in oxidation byproducts, avoiding a potential FDA Postmarketing Commitment