A Collaborative Learning Event I Might Run

To complete a thought on community of practices I did this weekend with “A CoP is Collaborative Learning, not Lecture” and “How I would Organize a Meeting of a CoP” I’m now going to build, from the group up, a collaborative learning event I would love to organize.

A little caveat: I really burnt out on professional obligations last year and have just started to peak my head out. So, it may be a little harder to turn this mad scientist dream into a reality. However, I think it is worth putting out as a thought experiment.

Theme and Scope

I’ve written a bit about the challenges to quality, and these challenges provide a framework for much of what I think and write about.

More specifically drawing from the “Challenges in Validation” focusing on the challenges of navigating a complex validation landscape characterized by rapid technological advancements, evolving regulatory standards, and the development of novel therapies.

This event would ask, “How do we rise to the challenges of validation in the next decade, leveraging technology and a risk management approach and drawing from the best practices of ASTM E2500, GAMP5, and others to meet and exceed changing regulatory requirements.”

Intended Audience

I go to events, and there are a lot of quality people, OR risk management people, OR computer systems (IT and Q) people, OR engineers, OR analytical method folks, OR process development people. Rarely do I see an event that looks at the whole picture. And rarely do I get to attend an event where we are sharing and blurring the lines between the various silos. So let us break down the silos and invite quality, IT, engineers, and process development individuals involved in the full spectrum of pharmaceutical (and possibly medtech) validation.

This holistic event is meant to blend boundaries, share best practices, challenge ourselves, and look across the entire validation lifecycle.

Structure

Opening/Networking (1 hour)

As people arrive, they go right into a poster event. These posters are each for a specific methodology/approach of ASTM E2500, ISPE Baseline Guides, FDA’s Guidance for Process Validation: General Principles and Practices, ICH’s QbD approach, and GAMP5. Maybe some other things.

These posters would each:

Provide an overview of what it is and why it is important
Overview of methodology
What challenges it overcomes
Lessons that can be applied
Challenges/problems inherent in the approach

These posters would be fun to develop and take a good squad of experts.

After an hour of mingling, sharing, and baselining, we could move to the next step.

Fish Bowl Debate (45 minutes)

Having earlier selected a specific topic and a panel of experts, hold a fish bowl debate. This would be excellent as a mock-inspection, maybe of a really challenging topic. Great place to bring those inspectors in.

During a fish bowl, everyone not in the center is taking notes. I love a worksheet to help with this by providing things to look for to get the critical thinking going.

Future Workshop (1.5 hour)

Introduce the activity (10 min)
Ask participants to reflect on their present-day situation, write down all their negative experiences on sticky notes, and place them on the wall. (15 min)
Invite participants to list uncertainties they face by asking, “In your/our operating environment, what factors are impossible to predict or control their direction?” (5 min).
Prioritize the most critical factors by asking, “Which factors threaten your/our ability to operate successfully?” (10 min)
Based on the group’s history and experience, select the two most critical and most uncertain (X and Y). (5 min)
Create a grid with two axes—X & Y—with a “more of <— —> less of” continuum to represent the factor on each axis. For example, suppose new modalities are a critically uncertain factor for the X-axis. In that case, one end of the X-axis is many new modalities, and the other is no new modalities. Repeat for the Y factor and axis. For instance, if patent protection is a critical factor, one end of the Y axis is strong patent protection, and the other has no patent protection. Four quadrants are created. (5 min)
Break into four groups, and each group creatively names and writes a thumbnail scenario for one of the quadrants. (10 min)
The four groups share their scenarios briefly. 2 min. each
Participants fantasize about the desired future situation. How would the ideal situation be for them? At this stage, there are no limitations; everything is possible. Write on stick notes and apply them to the most likely quadrant. (10 minutes)
Do a n/3 activity to find the top ideas (enough for groups of 4-5 each) (3 min)
Explain the next activity (2 min)

Lunch (1 hour)

Open Space Solution (1 hour)

For each top idea, the participants vote with their feet and go to develop the concept. Each group is looking to come up with the challenge solved, a tool/methodology, and an example.

Review the Results of the Open Space Solutions (1 hour)

Each team presents for 5-8 minutes.

1-2-4-All (20 minutes)

Silent self-reflection by individuals on the shared challenge, framed as a question “What opportunities do YOU see for making progress on this challenge? How would you handle this situation? What ideas or actions do you recommend?” (1 min)
Generate ideas in pairs, building on ideas from self-reflection. (2 min)
Share and develop ideas from your pair in foursomes (notice similarities and differences).( 4 min)
Ask, “What is one idea that stood out in your conversation?” Each group shares one important idea with all (15 min)

Closing Commitment (5 min)

Where will this live? What comes next? Make a commitment to follow up electronically.

Networking

Spend an hour or so with drinks and food and discuss everything. Never enough socialization.

The Validation Discrepancy

I don’t like the term validation deviation, preferring to use discrepancy to cover the errors or failures that occur during qualification/validation, such as when the actual results of a test step in a protocol do not match the expected results. These discrepancies can arise for various reasons, including errors in the protocol, execution issues, or external factors.

I don’t like using the term deviation as I try to avoid terms becoming too overused in too many ways. By choosing discrepancy it serves to move them to a lower order of problem so they can be addressed holistically.

Validation discrepancies really get to the heart of deciding whether the given system/process is fit-for-purpose and fit-for-use. As such, they require being addressed in a timely and pragmatic way.

And, like anything else, having an effective procedure to manage is critical.

Validation discrepancies are a great example of building problem-solving into a process.

Subject Matter Expert in Validation

In ASTM E2500, a Subject Matter Expert (SME) is an individual with specialized knowledge and technical understanding of critical aspects of manufacturing systems and equipment. The SME plays a crucial role throughout the project lifecycle, from defining needs to verifying and accepting systems. They are responsible for identifying critical aspects, reviewing system designs, developing verification strategies, and leading quality risk management efforts. SMEs ensure manufacturing systems are designed and verified to meet product quality and patient safety requirements.

In the ASTM E2500 process, the Subject Matter Experts (SME) has several key responsibilities critical to successfully implementing the standard. These responsibilities include:

Definition of Needs: SMEs define the system’s needs and identify critical aspects that impact product quality and patient safety.
Risk Management: SMEs participate in risk management activities, helping to identify, assess, and manage risks throughout the project lifecycle. This includes conducting quality risk analyses and consistently applying risk management principles.
Verification Strategy Development: SMEs are responsible for planning and defining verification strategies. This involves selecting appropriate test methods, defining acceptance criteria, and ensuring that verification activities are aligned with the project’s critical aspects.
System Design Review: SMEs review system designs to ensure they meet specified requirements and address identified risks. This includes participating in design reviews and providing technical input to optimize system functionality and compliance.
Execution of Verification Tests: SMEs lead the execution of verification tests, ensuring that tests are conducted accurately and that results are thoroughly reviewed. They may also leverage vendor documentation and test results as part of the verification process, provided the vendor’s quality system and technical capabilities are deemed acceptable.
Change Management: SMEs play a crucial role in change management, ensuring that any modifications to the system are properly evaluated, documented, and implemented. This helps maintain the system’s validated state and ensures continuous compliance with regulatory requirements.
Continuous Improvement: SMEs are involved in continuous process improvement efforts, using operational and performance data to identify opportunities for enhancements. They also conduct root-cause analyses of failures and implement technically sound improvements based on gained product knowledge and understanding.

These responsibilities highlight the SME’s integral role in ensuring that manufacturing systems are designed, verified, and maintained to meet the highest standards of quality and safety, as outlined in ASTM E2500.

The ASTM E2500 SME is a Process Owner

ASTM E2500 uses the term SME in the same way we discuss process owners, or what is sometimes called product or molecule stewards. The term should probably be changed to reflect the special role of the SME and the relationship with other stakeholders.

A Molecule Steward has a specialized role within pharmaceutical and biotechnology companies and oversees the lifecycle of a specific molecule or drug product. This role involves a range of responsibilities, including:

Technical Expertise: Acting as the subject matter expert per ASTM E2500.
Product Control Strategies: Implementing appropriate product control strategies across development and manufacturing sites based on anticipated needs.
Lifecycle Management: Providing end-to-end accountability for a given molecule, from development to late-stage lifecycle management.

A Molecule Steward ensures a drug product’s successful development, manufacturing, and lifecycle management, maintaining high standards of quality and compliance throughout the process.

The ASTM E2500 SME (Molecule Steward) and Stakeholders

In the ASTM E2500 approach, the Subject Matter Expert (Molecule Steward) collaborates closely with various project players to ensure the successful implementation of manufacturing systems.

Definition of Needs and Requirements

Collaboration with Project Teams: SMEs work with project teams from the beginning to define the system’s needs and requirements. This involves identifying critical aspects that impact product quality and patient safety.
Input from Multiple Departments: SMEs gather input from different departments, including product/process development, engineering, automation, and validation, to ensure that all critical quality attributes (CQAs) and critical process parameters (CPPs) are considered.

Risk Management

Quality Risk Analysis: SMEs lead the quality risk analysis process, collaborating with QA and other stakeholders to identify and assess risks. This helps focus on critical aspects and consistently apply risk management principles.
Vendor Collaboration: SMEs often work with vendors to leverage their expertise in conducting risk assessments and ensuring that vendor documentation meets quality requirements.

System Design Review

Design Review Meetings: SMEs participate in design review meetings with suppliers and project teams to ensure the system design meets the defined needs and critical aspects. This collaborative effort helps in reducing the need for modifications and repeat tests.
Supplier Engagement: SMEs engage with suppliers to ensure their design solutions are understood and integrated into the project. This includes reviewing supplier documentation and ensuring compliance with regulatory requirements.

Verification Strategy Development

Developing Verification Plans: SMEs collaborate with QA and engineering teams to develop verification strategies and plans. This involves selecting appropriate test methods, defining acceptance criteria, and ensuring verification activities align with project goals.
Execution of Verification Tests: SMEs may work with suppliers to conduct verification tests at the supplier’s site, ensuring that tests are performed accurately and efficiently. This collaboration helps achieve the “right test” at the “right time” objective.

Change Management

Managing Changes: SMEs play a crucial role in the change management process, working with project teams to evaluate, document, and implement changes. This ensures that the system remains in a validated state and continues to meet regulatory requirements.
Continuous Improvement: SMEs collaborate with other stakeholders to identify opportunities for process improvements and implement changes based on operational and performance data.

Documentation and Communication

Clear Communication: SMEs ensure clear communication and documentation of all verification activities and acceptance criteria. This involves working closely with QA to validate all critical aspects and ensure compliance with regulatory standards.

System Boundary

A system boundary for equipment or utility refers to the demarcation points that define the extent of a system’s components and the scope of its operations. This boundary is crucial for managing, validating, maintaining, and securing the system.

For utilities, the last valve before the system being supplied can be used as the boundary, which can also serve as a Lock Out Tag Out (LOTO) point.
Physical connections like tri-clamp connections or flanges can define the boundary for packaged systems or skids.
For critical and non-critical systems, such as air or HVAC systems, filters can be the boundary between systems.

Defining system boundaries is crucial during the design of equipment and systems. It helps identify where the equipment starts and stops and where the breakpoints are situated. This ensures a smooth transition and handover during the commissioning process.

Early Definition: Define system boundaries as early as possible in the system’s development life cycle to reduce costs and ensure effective security controls are implemented from the start.
Stakeholder Involvement: Relevant stakeholders, such as system engineers, utility providers, and maintenance teams, should be involved in defining system boundaries to ensure alignment and a clear understanding of responsibilities.
Documentation and Traceability: To ensure consistency and traceability, document and maintain system boundaries in relevant diagrams (e.g., P&IDs, system architecture diagrams) and commissioning/qualification protocols.
Periodic Review: Regularly review and update system boundaries as the system evolves or the environment changes, using change management and configuration management processes to ensure consistency and completeness.
Enterprise-level Coordination: At an enterprise level, coordinate and align system boundaries across all major systems to identify gaps, overlaps, and seamless coverage of security responsibilities.

Applying Systems Thinking

Systems thinking and modeling techniques are essential for managing and improving complex systems. These approaches help understand the interconnected nature of systems, identify key variables, and make informed decisions to enhance performance, reliability, and sustainability. Here’s how these methodologies can be applied:

Holistic Approach

Systems thinking involves viewing the system as an integrated whole rather than isolated components. This approach acknowledges that the system has qualities that the sum of individual parts cannot explain.
When developing frameworks, models, and best practices for systems, consider the interactions between people, processes, technology, and the environment.

Key Elements:

Interconnectedness: Recognize that all parts of the utility system are interconnected. Changes in one part can affect other parts, sometimes in unexpected ways.
Feedback Loops: Identify feedback loops where outputs from one part of the system influence other parts. These can be reinforcing or balancing loops that affect system behavior over time.
Time Consideration: Understand that effects rarely ripple through a complex system instantaneously. Consider how changes will affect the system over time.

ASTM E2500 Approach to Validation

ASTM E2500, the Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment, is intended to “satisfy international regulatory expectations in ensuring that manufacturing systems and equipment are fit for the intended use and to satisfy requirements for design, installation, operation, and performance.”

The ASTM E2500 approach is a comprehensive framework for specification setting, design, and verification of pharmaceutical and biopharmaceutical manufacturing systems and equipment. It emphasizes a risk- and science-based methodology to ensure that systems are fit for their intended use, ultimately aiming to enhance product quality and patient safety.

Despite its 17-year history, it is fair to say it is not the best-implemented standard. There are still many unrealized opportunities and some major challenges. I don’t think a single organization I’ve been in has fully aligned, and ASTM E2500 can feel aspirational.

Key Principles

Risk Management: The approach integrates risk management principles from ICH Q8, Q9, and Q10, focusing on identifying and mitigating risks to product quality and patient safety throughout the lifecycle of the manufacturing system.
Good Engineering Practices (GEP): It incorporates GEP to ensure systems are correctly designed, installed, and operated.
Flexibility and Efficiency: It strives for a more flexible and efficient organization of verification activities that can be adapted to each project’s specific context.

Know your Process

Regulatory agencies expect drugmakers to persuade them that we know our processes and that our facilities, equipment, systems, utilities, and procedures have been established based on concrete data and a thorough risk assessment. The ASTM E2500 standard provides a means of demonstrating that all of these factors have been validated in consideration of carefully evaluated risks.

What the Standard Calls for

Four Main Steps

Requirements: Define the system’s needs and critical aspects. Subject Matter Experts (SMEs) play a crucial role in this phase by defining needs, identifying critical aspects, and developing the verification strategy.
Specification & Design: Develop detailed specifications and design the system to meet the requirements. This step involves thorough design reviews and risk assessments to ensure the system functions as intended.
Verification: Conduct verification activities to confirm that the system meets all specified requirements. This step replaces the traditional FAT/SAT/IQ/OQ/PQ sequence with a more streamlined verification process that can be tailored to the project’s needs.
Acceptance & Release: Finalize the verification process and release the system for operational use. This step includes the final review and approval of all verification activities and documentation.

Four Cross-Functional Processes

Good Engineering Practices (GEP): Ensure all engineering activities adhere to industry standards and best practices.
Quality Risk Management: Continuously assess and manage risks to product quality and patient safety throughout the project.
Design Review: Regularly reviews the system design to ensure it meets all requirements and addresses identified risks.
Change Management: Implement a structured process for managing system changes to ensure that all modifications are appropriately evaluated and documented.

Applications and Benefits

Applicability: The ASTM E2500 approach can be applied to new and existing manufacturing systems, including laboratory, information, and medical device manufacturing systems.
Lifecycle Coverage: It applies throughout the manufacturing system’s lifecycle, from concept to retirement.
Regulatory Compliance: The approach is designed to conform with FDA, EU, and other international regulations, ensuring that systems are qualified and meet all regulatory expectations.
Efficiency and Cost Management: By focusing on critical aspects and leveraging risk management tools, the ASTM E2500 approach can streamline project execution, reduce time to market, and optimize resource utilization.

The ASTM E2500 approach provides a structured, risk-based framework for specifying, designing, and verifying pharmaceutical and biopharmaceutical manufacturing systems. It emphasizes flexibility, efficiency, and regulatory compliance, making it a valuable tool for ensuring product quality and patient safety.

What Makes it Different?

	ASTM E2500	The more traditional approach
Testing Approach	It emphasizes a risk-based approach, focusing on identifying and managing risks to product quality and patient safety throughout the manufacturing system’s lifecycle. This approach allows for flexibility in organizing verification activities based on the specific context and critical aspects of the system.	Typically follows a prescriptive sequence of tests (FAT, SAT, IQ, OQ, PQ) as outlined in guidelines like EU GMP Annex 15. This method is more rigid and less adaptable to the specific needs and risks of each project.
Verification vs Qualification	The term “verification” encompasses all testing activities, which can be organized more freely and rationally to optimize efficiency. Verification activities are tailored to the project’s needs and focus on critical aspects.	Follows a structured qualification process (Installation Qualification, Operational Qualification, Performance Qualification) with predefined steps and documentation requirements.
Role of Subject Matter Experts	SMEs play a crucial role from the start of the project, contributing to the definition of needs, identification of critical aspects, system design review, and development of the verification strategy. They are involved throughout the project lifecycle.	SMEs are typically involved at specific points in the project lifecycle, primarily during the qualification phases, and may not have as continuous a role as in the ASTM E2500 approach.
Integration of Good Engineering Practices	Offers greater flexibility in organizing verification activities, allowing for a more efficient and streamlined process. This can lead to reduced time to market and optimized resource utilization.	While GEP is also important, the focus is more on the qualification steps rather than integrating GEP throughout the entire project lifecycle.
Change Management	It emphasizes early and continuous change management, starting from the supplier’s site, to avoid test duplication and ensure that changes are properly evaluated and documented.	It emphasizes early and continuous change management, starting from the supplier’s site, to avoid test duplication and ensure that changes are properly evaluated and documented.
Documentation	Documentation is focused on risk management and verification activities, ensuring compliance with international regulations (FDA, EU, ICH Q8, Q9, Q10). The approach is designed to meet regulatory expectations while allowing for flexibility in documentation.	quires extensive documentation for each qualification step, which can be more cumbersome and less adaptable to specific project needs.

Opinion

I’m watching to see what the upcoming update to Annex 15 will do to address the difficulties some see between an ATSM E2500 approach and the European regulations. I also hope we will see an update to ISPE Baseline® Guide Volume 5: Commissioning and Qualification to align an approach.

ISPE Baseline® Guide Volume 5	ATSM E2500
Design inputs Impact assessment Design Qualification Commissioning Multiple trial runs to get things right IQ, OQ, PQ, and acceptance criteria GEP Scope and QA Scope overlapped Focused on Documentation Deliverables Change Management	Design inputs Design Review Risk Mitigation Critical Control Parameters define Acceptance Criteria Verification Testing Performance Testing GEP Scope and QA Scope have a clear boundary Process, Product Quality and Patient Safety Quality by Design, Design Space, and Continuous Improvement

To be honest I don’t think ATSM E2500, ISPE Guide 5, or anything else has the balance just right. And your program ends up being a triangulation between these and the regulations. And don’t even bring in trying to align GAMP5 or USP <1058> or…or…or…

And yes, I do consider this part of my 3-year plan. I look forward to the challenges of a culture shift, increased SME involvement, formalization of GEPs (and teaching engineers how to write), effective change management, timely risk assessments, and comprehensive implementation planning.