Fine-Tuning Regulatory Compliance: A Human Performance Approach

When it comes to manufacturing life-saving biologics and CGT (cell and gene therapy) products, compliance is the core of market authorization and sustained operational success. However, beyond the regulations themselves, it is the human factors—the intricacies of human performance—that often determine the fate of compliance efforts. This article explores the regulatory landscape of biotech manufacturing, focusing on the critical stages of applying for Biologics Licensing Application (BLA) or New Drug Application (NDA) and securing approval to reach and benefit more patients in need. We will examine three points in this journey where human performance is most critical and offer solutions for integrating improvements to bolster compliance.

The Regulatory Landscape

The biotech industry operates under a complex and continually evolving regulatory framework designed to ensure the safety, efficacy, and quality of its products. Regulatory bodies such as the FDA (Food and Drug Administration) in the United States, the EMA (European Medicines Agency) in Europe, and their global counterparts set rigorous standards for every aspect of the manufacturing process. Key regulatory requirements include:

1. Current Good Manufacturing Practices (CGMP): Established to ensure products are consistently produced and controlled according to quality standards.
2. Documentation and Record-Keeping: Accurate and comprehensive documentation is essential for traceability and accountability.
3. Quality Control (QC) and Quality Assurance (QA): Responsible for continuous monitoring and verification of processes to maintain product quality.
4. Regulatory Submissions: Comprised of detailed dossiers that demonstrate compliance with regulatory requirements, submitted to obtain and maintain market authorization.

The Keystone of Compliance

Before we consider the regulatory affairs process, let’s first start with a crash course in human performance.

Human performance encompasses the behaviors and actions of individuals within an organization that influence its overall functioning and outcomes. It encourages organizations to understand the factors that influence how employees perform, so as to implement strategies for optimization. Incorporating Safety I and Safety II perspectives enhances these concepts. Safety I focuses on minimizing adverse events by identifying and eliminating errors and hazards. It views safety as the absence of negatives. Safety II, on the other hand, emphasizes ensuring that things go right by understanding everyday performance variability and enhancing system resilience. This dual approach promotes not only error reduction but also the ability to adapt and succeed under varying conditions, fostering a culture of safety, continuous improvement, and high reliability. Some key concepts include:

• Cognitive Functions: These are the mental processes that enable individuals to perform tasks, make decisions, and solve problems. In biotech manufacturing, workers must accurately follow complex procedures, identify, and mitigate potential errors, and ensure precise documentation. Poorly written and haphazardly formatted documents lead to a greater risk for human error; however, the document generation process is often rushed in an effort to meet production timelines. This can lead to rework and subsequent document revisions after gaps are uncovered during execution.
• Human Factors Engineering: This involves designing systems, processes, and equipment that accommodate human abilities and limitations. Effective human factors engineering reduces the likelihood of errors and enhances efficiency by creating user-friendly interfaces and work environments. The main point here is that an effort is in managing a system or environment, not people.
• Organizational Culture: Changing the way an organization views “errors” from being rare and serious problems to normal and manageable events is tough. However, this shift can have a huge impact. It moves the focus away from just fixing workers’ mistakes to improving how we manage risks and learn from operations. This approach helps us better understand and improve our processes overall. (Wilkes, Berry, Wilson, & Morris, 2020).

Integrating Human Performance (HuP)

From beginning to end, each phase of the regulatory process presents unique challenges. We will look at three areas where human performance principles can be applied to enhance compliance, improve efficiency, and ensure the safety and efficacy of the products. At the end of the article, there is a list of questions to help evaluate the current state of human performance controls within an organization.

Pre-Authorization Phase (Application for BLA/NDA)

• Error Reduction in Documentation: Utilizing user-friendly documentation practices, error-proof forms, and automated systems can significantly reduce manual entry errors and ensure compliance with regulatory requirements. The FDA’s guidance on data integrity highlights the importance of using technological solutions to minimize human error and enhance data accuracy (FDA, 2020). Automated documentation systems can help maintain consistency and accuracy, which are critical for successful regulatory submissions.
• Review and Oversight: Implementing robust review processes to catch and correct errors before submission is essential. This includes independent checks and balances to minimize the risk of regulatory rejections. According to James Reason’s Swiss Cheese Model, multiple layers of defense can prevent errors from leading to adverse outcomes (Reason, 2000). Moreover, as part of the review process, the regulatory agencies may inspect manufacturing facilities to assess adherence to Current Good Manufacturing Practices (CGMPs) and relevant Public Health Service regulations (Rossello, 2023). Oversight is crucial in this context to prevent poor GMP habits, which can lead to serious quality and safety issues. Effective oversight ensures that facilities maintain high standards of operation. Without rigorous mock inspections and compliance coaching, there is a risk that shortcuts or lapses in procedures could become normalized, leading to compromised product quality and delays in approval.

Post-Authorization Phase (Commercialization)

Manufacturing and Quality

• Process Design: Ensuring that manufacturing processes are designed with human factors in mind can reduce the likelihood of operator error through intuitive controls, clear instructions, and ergonomic workstations. According to the Chartered Institute of Ergonomics and Human Factors (CIEHF), well-designed processes that consider human capabilities and limitations can significantly enhance performance and reduce errors (CIEHF, 2023). Additionally, when creating SOPs, batch records, and other processing documentation, applying cognitive load reduction principles can significantly improve usability and compliance. Use clear, concise language and break down complex tasks into manageable steps. Incorporate visual aids like diagrams and checklists and ensure a consistent format across all documents. Modular sections and standardized templates help users quickly find relevant information, while only essential details are included and provide context for each step. The use of interactive digital tools can also keep information current and relevant. These practices help reduce errors and enhance overall efficiency and accuracy.
• Learning and Development: Human error traps are conditions or situations that increase the likelihood of mistakes during execution of a task. These can include distractions, time-pressures, and inadequate training. Cognitive load refers to the amount of mental effort required to perform a task. When cognitive load is too high, it can overwhelm the working memory, leading to errors. According to cognitive load theory, reducing unnecessary cognitive load can enhance learning and task performance (Sweller, 1988). This also pertains to the format and layout of documents, which can impact the user. When designing training and documentation, we must consider the impact on cognitive load. Our memory has two parts: working memory and long-term memory. When we process new info, it puts a “cognitive load” on our working memory, impacting how well we learn. By easing this load, we help users quickly and easily grasp new information (Hudson, 2021). This is especially important at sites where training is being conducted during live processing versus in a simulated environment, which is preferable.
• Automation and Error Detection: Incorporating automated systems for monitoring and controlling manufacturing processes can detect and correct errors in real-time, reducing reliance on human intervention and increasing process reliability. As highlighted by Deming’s principles of quality management, automation can enhance precision and reduce variability (Deming, 1986). By leveraging advanced technologies, biotech companies can ensure that their manufacturing processes are robust and compliant with regulatory requirements.

Sustained Operational Success

Organizational Culture and Continuous Improvement

• Leadership Commitment: Leadership must demonstrate a commitment to human performance principles, fostering a culture that values safety, quality, and continuous improvement. Regular communication, engagement, and coaching of staff at all levels reinforces the importance of adherence to procedures and the role of human performance in achieving operational excellence. Effective communication, as emphasized by Edgar Schein, is essential for building a strong organizational culture (Schein, 2010). Implementing feedback loops where staff can provide input on procedures and processes helps identify potential improvements and areas where errors are likely to occur. Listening and acting on the feedback also boosts retention. According to the employee engagement blog Engage, 90% of employees state they are more likely to stay with an organization that listens to and acts on their feedback. However, only 12% feel their managers are effective at soliciting feedback. While giving feedback to employees is essential for guiding their work, it’s equally important for managers to collect input from employees to address issues and steer initiatives effectively (Quilici, 2021).
• Root Cause Analysis: Employing systematic root cause analysis for any deviations to identify underlying issues related to human performance ensures that CAPAs address the root causes and not just the symptoms. According to James Reason, understanding the root causes of errors is crucial for developing effective solutions (Reason, 2000). Encouraging an open culture where staff feel comfortable reporting near-misses and potential issues without fear of reprisal is crucial. The FDA advocates for a transparent reporting culture to improve quality and safety (FDA, 2020). This openness helps companies address issues early and prevent them from escalating into major compliance problems.

Human performance controls are essential in preventing regulatory compliance failures in the biotech manufacturing industry. Embracing the human element leads to reframing potential pitfalls into opportunities for growth and innovation, ensuring a place at the forefront of the industry.

HuP Assessment for Regulatory Compliance

This set of questions is designed to help organizations evaluate the strength of their human performance controls in place to support regulatory compliance. Each section includes a brief explanation of why the questions are important and how they apply to maintaining compliance and operational efficiency.

Documentation

Training Programs

• Why: Regular training ensures that employees are familiar with documentation standards and regulatory requirements, reducing errors and ensuring compliance.
  • Are all employees regularly trained on documentation standards?
  • Is the training content updated regularly to reflect current regulatory requirements and best practices?
  • Are assessments conducted to ensure employees understand the training material?

Collaborative Tools

• Why: Collaborative tools enhance communication and real-time editing, which helps maintain accurate and up-to-date documentation, crucial for compliance.
  • Are collaborative document platforms being used for real-time editing and tracking?
  • Are all relevant employees trained on how to use these platforms effectively?
  • Is there a system in place for notifying employees of document updates?

Standard Operating Procedures (SOPs)

• Why: SOPs provide a clear and consistent framework for operations, ensuring all employees follow the same standards and procedures, which is critical for compliance.
  • Are SOPs easily accessible to all relevant employees?
  • Are SOPs reviewed and updated regularly?
  • Is there a process for employees to provide feedback on SOPs?

Review and Approval Processes

• Why: Structured review processes ensure that documents are thoroughly vetted for accuracy and compliance before finalization, preventing regulatory issues.
  • Are clear review and approval workflows established for all documents?
  • Is version control implemented and monitored?
  • Are review and approval timelines adhered to?

Audit Trails

• Why: Maintaining detailed audit trails ensures transparency and traceability, which are essential for regulatory audits and investigations.
  • Are detailed audit trails maintained for all documents?
  • Is there a process for regularly reviewing audit trails for compliance?
  • Are discrepancies or issues identified in audit trails promptly addressed?

Quality Control (QC) & Quality Assurance (QA)

Error Prevention and Detection

• Why: Regular assessments and robust tracking systems help identify and prevent errors, ensuring product quality and regulatory compliance
  • Are regular assessments conducted to keep QC skills sharp?
  • Is there a robust system for tracking and analyzing QC errors?
  • Are preventive measures implemented based on QC data analysis?

Cross-Functional Teams

• Why: Cross-functional teams bring diverse perspectives and expertise, enhancing the identification and resolution of quality issues.
  • Are cross-functional teams established for QC and QA processes?
  • Do these teams meet regularly to discuss and resolve quality issues?
  • Is there a clear process for team collaboration and communication?

Standardization of Processes

• Why: Standardized processes ensure consistency and reliability, which are critical for maintaining high-quality standards and compliance.
  • Are QC and QA processes standardized and documented?
  • Are these processes regularly reviewed and updated?
  • Are employees trained on the standardized processes?

Continuous Monitoring and Improvement

• Why: Real-time monitoring systems and a culture of continuous improvement help maintain high quality and compliance standards.
  • Are real-time monitoring systems in place to track quality metrics?
  • Is there a culture of continuous improvement within the organization?
  • Are employees encouraged to suggest and implement quality improvements?

Root Cause Analysis

• Why: Conducting thorough root cause analyses for quality issues helps develop effective corrective actions, preventing recurrence and ensuring compliance.
  • Are thorough root cause analyses conducted for quality issues?
  • Are corrective and preventive actions (CAPAs) developed and implemented based on root cause analyses?
  • Is the effectiveness of CAPAs regularly reviewed and assessed?

Regulatory Submissions

Attention to Detail

• Why: Meticulous review and attention to detail ensure that submissions meet regulatory requirements, preventing delays and rejections.
  • Are submissions reviewed multiple times to ensure accuracy and completeness?
  • Is there a detailed checklist used to verify that all regulatory requirements are met?
  • Are submission documents formatted and structured according to regulatory guidelines?

Comprehensive Knowledge Management

• Why: Keeping regulatory information up-to-date and accessible ensures compliance with current regulations and guidelines.
  • Is there a knowledge management system in place to track and update regulatory information?
  • Are employees regularly trained on changes in regulations and guidelines?
  • Is there a process for disseminating updated regulatory information to all relevant departments?

Collaboration and Communication

• Why: Effective collaboration and communication ensure that all necessary data and documents are compiled accurately for regulatory submissions.
  • Are cross-functional teams established to contribute to the regulatory submission process?
  • Is there a clear communication plan to ensure all departments provide the necessary information?
  • Are regular meetings held to review progress and address any issues in the submission process?

Structured Review Processes

• Why: Structured review processes ensure that submissions are thoroughly vetted, reducing the risk of errors and non-compliance.
  • Are internal reviews conducted by regulatory affairs teams before finalizing submissions?
  • Are cross-functional team reviews implemented to ensure all aspects of the submission are covered?
  • Is there a process for external reviews or audits, if necessary, to validate the submission?

Mentorship and Expertise Development

• Why: Developing expertise in regulatory affairs through mentorship and continuous professional development ensures high-quality submissions and compliance.
  • Are mentorship programs established to develop expertise in regulatory affairs?
  • Are less experienced employees paired with seasoned professionals for guidance?
  • Is continuous professional development encouraged and supported through training programs and workshops?

Process Design and Implementation

Ergonomic Assessments

• Why: Ergonomic assessments help design efficient workspaces that minimize errors and improve employee well-being, which is essential for compliance.
  • Have ergonomic assessments been conducted to design efficient workspaces?
  • Are workspaces regularly reviewed and updated based on ergonomic principles?
  • Are employees trained on ergonomic best practices to minimize errors and injuries?

Process Simplification

• Why: Simplifying processes reduces complexity, making it easier to maintain compliance and reduce errors.
  • Are processes regularly reviewed for complexity and simplified where possible?
  • Is there a feedback mechanism for employees to suggest process improvements?
  • Are process changes documented and communicated effectively to all relevant employees?

Regular Review and Improvement

• Why: Regular reviews and updates of processes ensure they remain effective and compliant with current best practices and regulations.
  • Are processes and procedures regularly reviewed and updated to reflect current best practices and regulatory requirements?
  • Is there a system in place for continuous monitoring and improvement of processes?
  • Are employees encouraged to participate in process improvement initiatives?

Continuous Improvement and Training

Comprehensive Training Programs

• Why: Regular training ensures that employees are knowledgeable about regulatory requirements, quality standards, and best practices, which is crucial for compliance.
  • Are regular training sessions conducted on regulatory requirements, quality standards, and best practices?
  • Are training materials regularly updated to reflect changes in regulations and industry standards?
  • Are training sessions interactive and designed to engage employees effectively?

Feedback Mechanisms

• Why: Feedback loops help identify training needs and process improvements, ensuring continuous improvement and compliance.
  • Are feedback loops established to identify training needs and process improvements?
  • Are employees encouraged to provide feedback on training programs and processes?
  • Is feedback regularly reviewed and used to make improvements?

Mentorship and Professional Development

• Why: Mentorship and continuous professional development build regulatory expertise, ensuring high-quality compliance and operational excellence.
  • Are mentorship programs in place to guide less experienced employees?
  • Is continuous professional development supported through training programs, workshops, and conferences?
  • Are employees encouraged to pursue certifications and advanced training in their fields?

References

1. Chartered Institute of Ergonomics and Human Factors (CIEHF). (2023). Ergonomics in Manufacturing. Retrieved from https://www.ergonomics.org.uk
2. Deming, W. E. (1986). Out of the Crisis. MIT Press.
3. FDA. (2020). Guidance on Data Integrity and Compliance With Drug CGMP. Retrieved from https://www.fda.gov/media/119267/download.
4. Hudson, N. (2021, January 12). Design principles for reducing cognitive load. Distinction. Retrieved from https://distinction.studio/journal/design-principles-for-reducing-cognitive-load
5. Quilici, E. (2021, April 13). Acting on Employee Feedback Integral to Manager Growth. Pharmaceutical Executive, 41(4). Retrieved from https://www.pharmexec.com/view/acting-on-employee-feedback-integral-to-manager-growth.
6. Reason, J. (2000). Human error: models and management. BMJ, 320(7237), 768-770.
7. Rossello, J. (2023, December 26). What is a BLA (Biologics License Application)? Essential Guide for Professionals. Pharmacovigilance Analytics. https://www.pharmacovigilanceanalytics.com/regulations/what-is-a-bla-biologics-license-application-essential-guide-for-professionals/
8. Schein, E. H. (2010). Organizational Culture and Leadership. Jossey-Bass.
9. Sweller, J. (1988). Cognitive Load Theory. Cognitive Science, 12(2), 257-285.
10. Wilkes, J., Berry, C., Wilson, A. D., & Morris, J. (2020, November 9). Human Performance in Biopharma Operations — Your Problem Isn’t Error. Pharmaceutical Online. Retrieved from https://www.pharmaceuticalonline.com/doc/human-performance-in-biopharma-operations-your-problem-isn-t-error-0001.

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About The Author:

Sarah Boynton is a consultant on the Quality Executive Partners (QxP) team. She has extensive experience in the biopharmaceutical/cell and gene therapy space, with a particular focus on cGMP training, human performance/error prevention, downstream processing, and non-conformance investigations. Prior to joining QxP, Boynton worked for Catalent Pharma Solutions, KBI Biopharma, AstraZeneca, Med Immune, and GlaxoSmithKline.

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