A process boundary is the clear definition of where a process starts and where it ends. It sets the parameters for what is included in the process and, just as importantly, what is not. The boundary marks the transition points: the initial trigger that sets the process in motion and the final output or result that signals its completion. By establishing these boundaries, organizations can identify the interactions and dependencies between processes, ensuring that each process is manageable, measurable, and aligned with objectives.
Why Are Process Boundaries Important?
Defining process boundaries is essential for several reasons:
Clarity and Focus: Boundaries help teams focus on the specific activities, roles, and outcomes that are relevant to the process at hand, avoiding unnecessary complexity and scope creep.
Effective Resource Allocation: With clear boundaries, organizations can allocate resources efficiently and prioritize improvement efforts where they will have the greatest impact.
Accountability: Boundaries clarify who is responsible for each part of the process, making it easier to assign ownership and measure performance.
Process Optimization: Well-defined boundaries make it possible to analyze, improve, and optimize processes systematically, as each process can be evaluated on its own terms before considering its interfaces with others.
How to Determine Process Boundaries
Determining process boundaries is both an art and a science. Here’s a step-by-step approach, drawing on best practices from process mapping and business process analysis:
1. Define the Purpose of the Process
Before mapping, clarify the purpose of the process. What transformation or value does it deliver? For example, is the process about onboarding a new supplier, designing new process equipment, or resolving a non-conformance? Knowing the purpose helps you focus on the relevant start and end points.
2. Identify Inputs and Outputs
Every process transforms inputs into outputs. Clearly articulate what triggers the process (the input) and what constitutes its completion (the output). For instance, in a cake-baking process, the input might be “ingredients assembled,” and the output is “cake baked.” This transformation defines the process boundary.
3. Engage Stakeholders
Involve process owners, participants, and other stakeholders in boundary definition. They bring practical knowledge about where the process naturally starts and ends, as well as insights into handoffs and dependencies with other processes. Workshops, interviews, and surveys can be effective for gathering these perspectives.
4. Map the Actors and Activities
Decide which roles (“actors”) and activities are included within the boundary. Are you mapping only the activities of a laboratory analyst, or also those of supervisors, internal customers who need the results, or external partners? The level of detail should match your mapping purpose-whether you’re looking at a high-level overview or a detailed workflow.
5. Zoom Out, Then Zoom In
Start by zooming out to see the process as a whole in the context of the organization, then zoom in to set precise start and end points. This helps avoid missing upstream dependencies or downstream impacts that could affect the process’s effectiveness.
6. Document and Validate
Once you’ve defined the boundaries, document them clearly in your process map or supporting documentation. Validate your boundaries with stakeholders to ensure accuracy and buy-in. This step helps prevent misunderstandings and ensures the process map will be useful for analysis and improvement.
7. Review and Refine
Process boundaries are not set in stone. As the organization evolves or as you learn more through process analysis, revisit and adjust boundaries as needed to reflect changes in scope, objectives, or business environment.
Common Pitfalls and How to Avoid Them
Scope Creep: Avoid letting the process map expand beyond its intended boundaries. Stick to the defined start and end points unless there’s a compelling reason to adjust them7.
Overlapping Boundaries: Ensure that processes don’t overlap unnecessarily, which can create confusion about ownership and accountability.
Ignoring Interfaces: While focusing on boundaries, don’t neglect to document key interactions and handoffs with other processes. These interfaces are often sources of risk or inefficiency.
Conclusion
Defining process boundaries is a foundational step in business process mapping and analysis. It provides the clarity needed to manage, measure, and improve processes effectively. By following a structured approach-clarifying purpose, identifying inputs and outputs, engaging stakeholders, and validating your work-you set the stage for successful process optimization and organizational growth. Remember: a well-bounded process is a manageable process, and clarity at the boundaries is the first step toward operational excellence.
In manufacturing circles, “First-Time Right” (FTR) has become something of a sacred cow-a philosophy so universally accepted that questioning it feels almost heretical. Yet as continuous manufacturing processes increasingly replace traditional batch production, we need to critically examine whether this cherished doctrine serves us well or creates dangerous blind spots in our quality assurance frameworks.
The Seductive Promise of First-Time Right
Let’s start by acknowledging the compelling appeal of FTR. As commonly defined, First-Time Right is both a manufacturing principle and KPI that denotes the percentage of end-products leaving production without quality defects. The concept promises a manufacturing utopia: zero waste, minimal costs, maximum efficiency, and delighted customers receiving perfect products every time.
The math seems straightforward. If you produce 1,000 units and 920 are defect-free, your FTR is 92%. Continuous improvement efforts should steadily drive that percentage upward, reducing the resources wasted on imperfect units.
This principle finds its intellectual foundation in Six Sigma methodology, which can tend to give it an air of scientific inevitability. Yet even Six Sigma acknowledges that perfection remains elusive. This subtle but crucial nuance often gets lost when organizations embrace FTR as an absolute expectation rather than an aspiration.
First-Time Right in biologics drug substance manufacturing refers to the principle and performance metric of producing a biological drug substance that meets all predefined quality attributes and regulatory requirements on the first attempt, without the need for rework, reprocessing, or batch rejection. In this context, FTR emphasizes executing each step of the complex, multi-stage biologics manufacturing process correctly from the outset-starting with cell line development, through upstream (cell culture/fermentation) and downstream (purification, formulation) operations, to the final drug substance release.
Achieving FTR is especially challenging in biologics because these products are made from living systems and are highly sensitive to variations in raw materials, process parameters, and environmental conditions. Even minor deviations can lead to significant quality issues such as contamination, loss of potency, or batch failure, often requiring the entire batch to be discarded.
In biologics manufacturing, FTR is not just about minimizing waste and cost; it is critical for patient safety, regulatory compliance, and maintaining supply reliability. However, due to the inherent variability and complexity of biologics, FTR is best viewed as a continuous improvement goal rather than an absolute expectation. The focus is on designing and controlling processes to consistently deliver drug substances that meet all critical quality attributes-recognizing that, despite best efforts, some level of process variation and deviation is inevitable in biologics production
The Unique Complexities of Continuous Manufacturing
Traditional batch processing creates natural boundaries-discrete points where production pauses, quality can be assessed, and decisions about proceeding can be made. In contrast, continuous manufacturing operates without these convenient checkpoints, as raw materials are continuously fed into the manufacturing system, and finished products are continuously extracted, without interruption over the life of the production run.
This fundamental difference requires a complete rethinking of quality assurance approaches. In continuous environments:
Quality must be monitored and controlled in real-time, without stopping production
Deviations must be detected and addressed while the process continues running
The interconnected nature of production steps means issues can propagate rapidly through the system
Traceability becomes vastly more complex
Regulatory agencies recognize these unique challenges, acknowledging that understanding and managing risks is central to any decision to greenlight CM in a production-ready environment. When manufacturing processes never stop, quality assurance cannot rely on the same methodologies that worked for discrete batches.
The Dangerous Complacency of Perfect-First-Time Thinking
The most insidious danger of treating FTR as an achievable absolute is the complacency it breeds. When leadership becomes fixated on achieving perfect FTR scores, several dangerous patterns emerge:
Overconfidence in Automation
While automation can significantly improve quality, it is important to recognize the irreplaceable value of human oversight. Automated systems, no matter how advanced, are ultimately limited by their programming, design, and maintenance. Human operators bring critical thinking, intuition, and the ability to spot subtle anomalies that machines may overlook. A vigilant human presence can catch emerging defects or process deviations before they escalate, providing a layer of judgment and adaptability that automation alone cannot replicate. Relying solely on automation creates a dangerous blind spot-one where the absence of human insight can allow issues to go undetected until they become major problems. True quality excellence comes from the synergy of advanced technology and engaged, knowledgeable people working together.
Underinvestment in Deviation Management
If perfection is expected, why invest in systems to handle imperfections? Yet robust deviation management-the processes used to identify, document, investigate, and correct deviations becomes even more critical in continuous environments where problems can cascade rapidly. Organizations pursuing FTR often underinvest in the very systems that would help them identify and address the inevitable deviations.
False Sense of Process Robustness
Process robustness refers to the ability of a manufacturing process to tolerate the variability of raw materials, process equipment, operating conditions, environmental conditions and human factors. An obsession with FTR can mask underlying fragility in processes that appear to be performing well under normal conditions. When we pretend our processes are infallible, we stop asking critical questions about their resilience under stress.
When FTR becomes dogma, teams may become reluctant to report or escalate potential issues, fearing they’ll be seen as failures. This creates a culture of silence around deviations-precisely the opposite of what’s needed for effective quality management in continuous manufacturing. When perfection is the only acceptable outcome, people hide imperfections rather than address them.
Magical Thinking in Quality Management
The belief that we can eliminate all errors in complex manufacturing processes amounts to what organizational psychologists call “magical thinking” – the delusional belief that one can do the impossible. In manufacturing, this often manifests as pretending that doing more tasks with less resources will not hurt the work quality.
This is a pattern I’ve observed repeatedly in my investigations of quality failures. When leadership subscribes to the myth that perfection is not just desirable but achievable, they create the conditions for quality disasters. Teams stop preparing for how to handle deviations and start pretending deviations won’t occur.
The irony is that this approach actually undermines the very goal of FTR. By acknowledging the possibility of failure and building systems to detect and learn from it quickly, we actually increase the likelihood of getting things right.
Building a Healthier Quality Culture for Continuous Manufacturing
Rather than chasing the mirage of perfect FTR, organizations should focus on creating systems and cultures that:
Detect deviations rapidly: Continuous monitoring through advanced process control systems becomes essential for monitoring and regulating critical parameters throughout the production process. The question isn’t whether deviations will occur but how quickly you’ll know about them.
Investigate transparently: When issues occur, the focus should be on understanding root causes rather than assigning blame. The culture must prioritize learning over blame.
Implement robust corrective actions: Deviations should be thoroughly documented including details about when and where it occurred, who identified it, a detailed description of the nonconformance, initial actions taken, results of the investigation into the cause, actions taken to correct and prevent recurrence, and a final evaluation of the effectiveness of these actions.
Learn systematically: Each deviation represents a valuable opportunity to strengthen processes and prevent similar issues in the future. The organization that learns fastest wins, not the one that pretends to be perfect.
Breaking the Groupthink Cycle
The FTR myth thrives in environments characterized by groupthink, where challenging the prevailing wisdom is discouraged. When leaders obsess over FTR metrics while punishing those who report deviations, they create the perfect conditions for quality disasters.
This connects to a theme I’ve explored repeatedly on this blog: the dangers of losing institutional memory and critical thinking in quality organizations. When we forget that imperfection is inevitable, we stop building the systems and cultures needed to manage it effectively.
Embracing Humility, Vigilance, and Continuous Learning
True quality excellence comes not from pretending that errors don’t occur, but from embracing a more nuanced reality:
Perfection is a worthy aspiration but an impossible standard
Systems must be designed not just to prevent errors but to detect and address them
A healthy quality culture prizes transparency and learning over the appearance of perfection
Continuous improvement comes from acknowledging and understanding imperfections, not denying them
The path forward requires humility to recognize the limitations of our processes, vigilance to catch deviations quickly when they occur, and an unwavering commitment to learning and improving from each experience.
In the end, the most dangerous quality issues aren’t the ones we detect and address-they’re the ones our systems and culture allow to remain hidden because we’re too invested in the myth that they shouldn’t exist at all. First-Time Right should remain an aspiration that drives improvement, not a dogma that blinds us to reality.
From Perfect to Perpetually Improving
As continuous manufacturing becomes the norm rather than the exception, we need to move beyond the simplistic FTR myth toward a more sophisticated understanding of quality. Rather than asking, “Did we get it perfect the first time?” we should be asking:
How quickly do we detect when things go wrong?
How effectively do we contain and remediate issues?
How systematically do we learn from each deviation?
How resilient are our processes to the variations they inevitably encounter?
These questions acknowledge the reality of manufacturing-that imperfection is inevitable-while focusing our efforts on what truly matters: building systems and cultures capable of detecting, addressing, and learning from deviations to drive continuous improvement.
The companies that thrive in the continuous manufacturing future won’t be those with the most impressive FTR metrics on paper. They’ll be those with the humility to acknowledge imperfection, the systems to detect and address it quickly, and the learning cultures that turn each deviation into an opportunity for improvement.
The first 100 days of President Trump’s second term have been nothing short of seismic for the Food and Drug Administration (FDA). Sweeping layoffs, high-profile firings, and a mass exodus of experienced staff have left the agency reeling, raising urgent questions about the safety of drugs, devices, and food in the United States.
Unprecedented Layoffs and Firings
Mass Layoffs and Restructuring
On April 1, 2025, the Department of Health and Human Services (HHS) executed a reduction in force that eliminated 3,500 FDA employees. This was part of a larger federal downsizing that saw at least 121,000 federal workers dismissed across 30 agencies in Trump’s first 100 days, with health agencies like the FDA, CDC, and NIH particularly hard hit. Security guards barred entry to some FDA staff just hours after they received termination notices, underscoring the abruptness and scale of the cuts.
The layoffs were not limited to support staff. Policy experts, project managers, regulatory scientists, and communications professionals were let go, gutting the agency’s capacity to write guidance documents, manage application reviews, test product safety, and communicate risks to the public. Even before the April layoffs, industry had noticed a sharp decline in FDA responsiveness to routine and nonessential queries-a problem now set to worsen.
High-Profile Departures and Forced Resignations
The leadership vacuum is equally alarming. Key figures forced out or resigning under pressure include:
Dr. Peter Marks, CBER Director and the nation’s top vaccine official, dismissed after opposing the administration’s vaccine safety stance.
Dr. Robert Temple, a 52-year FDA veteran and regulatory pioneer, retired amidst the turmoil.
Dr. Namandjé N. Bumpus, Deputy Commissioner; Dr. Doug Throckmorton, Deputy Director for regulatory programs; Celia Witten, CBER Deputy Director; Peter Stein, Director of the Office of Drugs; and Brian King, head of the Center for Tobacco Products, all departed-some resigning when faced with termination.
Communications, compliance, and policy offices were decimated, with all FDA communications now centralized under HHS, ending decades of agency independence.
The new FDA Commissioner, Martin “Marty” Makary, inherits an agency stripped of much of its institutional memory and scientific expertise. Add to this very real questions about about Makary’s capabilities and approach:
1. Lack of FDA Institutional Memory and Support: Makary steps into the role just as the FDA’s deep bench of experienced scientists, regulators, and administrators has been depleted. The departure of key leaders and thousands of staff means Makary cannot rely on the usual institutional memory or internal expertise that historically guided complex regulatory decisions. The agency’s diminished capacity raises concerns about whether Makary can maintain the rigorous review standards and enforcement practices needed to protect public health.
2. Unconventional Background and Public Persona: While Makary is an accomplished surgeon and health policy researcher, his career has been marked by a willingness to challenge medical orthodoxy and criticize federal health agencies, including the FDA itself. His public rhetoric-often sharply critical and sometimes inflammatory-contrasts with the FDA’s traditionally cautious, evidence-based communication style. For example, Makary has accused government agencies of “lying” about COVID-19 boosters and has called the U.S. food supply “poison,” positions that have worried many in the scientific and public health communities.
3. Alignment with Political Leadership and Potential Conflicts: Makary’s views align closely with those of HHS Secretary Robert F. Kennedy Jr., particularly in their skepticism of certain mainstream public health measures and their focus on food additives, pesticides, and environmental contributors to chronic disease. This alignment raises questions about the degree to which Makary will prioritize political directives over established scientific consensus, especially in controversial areas like vaccine policy, food safety, and chemical regulation.
4. Contrarianism and a Tendency Towards Conspiracy: Makary’s recent writings, such as his book Blind Spots, emphasize his distrust of medical consensus and advocacy for challenging “groupthink” in health policy. Critics worry this may lead to the dismissal of well-established scientific standards in favor of less-tested or more ideologically driven policies. As Harvard’s Dr. Aaron Kesselheim notes, Makary will need to make decisions based on evolving evidence, even if that means occasionally being wrong-a process that requires humility and openness to expert input, both of which could be hampered by the loss of institutional expertise.
5. Immediate Regulatory and Ethical Challenges: Makary inherits unresolved, high-stakes regulatory issues, such as the controversy over compounded GLP-1 drugs and the agency’s approach to ultra-processed foods and food additives. His prior involvement with telehealth companies and outspoken positions on food chemicals could present conflicts of interest or at least the appearance of bias, further complicating his ability to act as an impartial regulator.
Impact on Patient Health and Safety
Reduced Oversight and Enforcement
The loss of thousands of staff-including scientists and specialists-means fewer eyes on the safety of drugs, devices, and food. Despite HHS assurances that product reviewers and inspectors were spared, the reality is that critical support staff who enable and assist reviews and inspections were let go. This has already resulted in:
Delays and unpredictability in drug and device approvals, as fewer project managers are available to coordinate and communicate with industry.
A likely reduction in inspections, as administrative staff who book travel and provide translation for inspectors are gone, forcing inspectors to take on additional tasks and leading to bottlenecks.
The pausing of FDA’s unannounced foreign inspection pilot program, raising the risk of substandard or adulterated imported products entering the U.S. market.
Diminished Public Communication
With the elimination of FDA’s communications staff and the centralization of messaging under HHS, the agency’s ability to quickly inform the public about recalls, safety alerts, and emerging health threats is severely compromised. This loss of transparency and direct communication could delay critical warnings about unsafe products or outbreaks.
Loss of Scientific Capacity
The departure of regulatory scientists and the decimation of the National Center for Toxicological Research threaten the FDA’s ability to conduct the regulatory science that underpins product safety and efficacy standards. As former Commissioner Robert Califf warned, “The FDA as we’ve known it is over, with most leaders who possess knowledge and deep understanding product development safety no longer in their positions… I believe that history will regard this as a grave error”.
Impact on Clinical Studies
Oversight and Ethical Safeguards Eroded
FDA oversight of clinical trials has plummeted. During Trump’s previous term, the agency sent far fewer warning letters for clinical trial violations than under Obama (just 12 in Trump’s first three years, compared to 99 in Obama’s first three), a trend likely to worsen with the latest staff cuts. The loss of experienced reviewers and compliance staff means less scrutiny of trial protocols, informed consent, and data integrity, potentially exposing participants to greater risk and undermining the credibility of U.S. clinical research.
Delays and Uncertainty for Sponsors
With fewer staff to provide guidance, answer questions, and manage applications, sponsors of clinical trials and new product applications face longer wait times and less predictable review timelines. The loss of informal dispute resolution mechanisms and scientific advisory capacity further complicates the regulatory landscape, making the U.S. a less attractive environment for innovation.
Impact on Good Manufacturing Practices (GMPs)
Inspections and Compliance at Risk
While HHS claims inspectors were not cut, the loss of support staff and administrative personnel is already affecting the FDA’s inspection regime. Inspectors now must handle both investigative and administrative tasks, increasing the risk of missed deficiencies and delayed responses to manufacturing problems. The FDA may increasingly rely on remote, paper-based inspections, which proved less effective during the COVID-19 pandemic and could allow GMP violations to go undetected.
Global Supply Chain Vulnerabilities
The rollback of foreign inspection programs and diminished regulatory science capacity further expose the U.S. to risks from overseas manufacturers, particularly in countries with less robust regulatory oversight. This could lead to more recalls, shortages, and public health emergencies.
A Historic Setback for Public Health
The Trump administration’s first 100 days have left the FDA a shell of its former self. The mass layoffs, firings, and resignations have gutted the agency’s scientific, regulatory, and communications capacity, with immediate and long-term consequences for patient safety, clinical research, and the integrity of the U.S. medical supply. The loss of institutional knowledge, the erosion of oversight, and the retreat from global leadership represent a profound setback for public health-one that will take years, if not decades, to repair.
As former FDA Commissioner Califf put it, “No segment of FDA is untouched. No one knows what the plan is”. The nation-and the world-are watching to see if the agency can recover from this unprecedented upheaval.
Engineering runs (ERs) represent a critical yet often underappreciated component of modern biopharmaceutical validation strategies. Defined as non-GMP-scale trials that simulate production processes to identify risks and optimize parameters, Engineering Runs bridge the gap between theoretical process design and manufacturing. Their integration into the ASTM E2500 verification framework creates a powerful synergy – combining Good Engineering Practice (GEP) with Quality Risk Management (QRM) to meet evolving regulatory expectations.
When aligned with ICH Q10’s pharmaceutical quality system (PQS) and the ASTM E2500 lifecycle approach, ERs transform from operational exercises into strategic tools for:
Design space verification per ICH Q8
Scale-up risk mitigation during technology transfer
Specification & Design The standard mandates “right-sized” documentation – detailed enough to ensure product quality without unnecessary bureaucracy.
Verification This phase provides a unified verification approach focusing on:
Critical process parameters (CPPs)
Worst-case scenario testing
Leveraging vendor testing data
Acceptance & Release Final review incorporates ICH Q10’s management responsibilities, ensuring traceability from initial risk assessments to verification outcomes.
Engineering runs serve as a critical bridge between design verification and formal Process Performance Qualification (PPQ). ERs validate critical aspects of manufacturing systems by confirming:
Equipment functionality under simulated GMP conditions
Process parameter boundaries for Critical Process Parameters (CPPs)
Facility readiness through stress-testing utilities, workflows, and contamination controls
Demonstration/ Training Run prior to GMP area
Shakedown. Demonstration/Training Run in GMP area
Engineering Run
cGMP Manufacturing
Room and Equipment
Room
N/A
IOQ Post-Approval
Released and Active
Process Gas
Generation and Distribution Released Point of use assembly PQ complete
Process utility
Process Equipment
Functionally verified or calibrated as required (commissioned)
IOQ Approved
Full released
Analytical Equipment
Released
Alarms
N/A
Alarm ranges and plan defined
Alarms qualified
Raw Materials
Bill of Materials
RM in progress
Approved
Suppliers
Approval in Progress
Approved
Specifications
In Draft
Effective
Release
Non-GMP Usage decision
Released
Process Documentation
Source Documentation
To be defined in Tech Transfer Plan
Engineering Run Protocol
Tech Transfer closed
Batch Records and product specific Work Instructions
Draft
Reviewed Draft
Approved
Process and Equipment SOPs
N/A
Draft
Effective
Product Labels
N/A
Draft Labels
Approved Labels
QC Testing and Documentation
BSC and Personnel Environmental Monitoring
N/A
Effective
Analytical Methods
Suitable for use
Phase Appropriate Validation
Stability
N/A
In place
Certificate of Analysis
N/A
Defined in Engineering Protocol
Effective
Sampling Plan
Draft
Draft use as defined in engineering protocol
Effective
Operations/Execution
Operator Training
Observe and perform operations to gain hands on experience with SME observation
Process specific equipment OJT Gown qualifiedBSC OJT Aseptic OJT Material Transfer OJT (All training in eQMS)
Training in Use
Process Lock
As defined in Tech Transfer Plan
6-week prior to execution
Approved Process Description
Deviations
N/A
N/A
Process – Per Engineering Run protocol FUSE – per SOP
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.
Aspect
Impact
Risk
Definition
The effect or influence a change, event, or deviation has on product quality, process, or system
The probability and severity of harm or failure occurring as a result of a change, event, or deviation
Focus
What 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 Type
Evaluates the direct consequences of an action or event
Evaluates the likelihood and severity of potential adverse outcomes
Typical Use
Used in change control to determine which documents, systems, or processes are impacted
Used to prioritize actions, allocate resources, and implement controls to minimize negative outcomes
Measurement
Usually 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)
Example
A 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
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.
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 Rating
Action
Mitigation
>25
High Risk-Potential Impact to Patient Safety or Product Quality
Mandatory
12-25
Moderate Risk-No Impact to Patient Safety or Product Quality but Potential Regulatory Risk
Recommended
<12
Negligible DI Risk
Not 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:
An impact assessment to determine:
Which products, materials, or batches are affected
Potential effects on critical quality attributes
Possible regulatory implications
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 Criteria
Examples 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
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:
Impact tells us the scope – what’s affected
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.
Investigations of a Dog 