Viral Controls in Facility Design

Facility design and control considerations for mitigating viral contamination risk is a holistic approach to facility design and controls, considering all potential routes of viral introduction and spread. A living risk management approach should be taken to identify vulnerabilities and implement appropriate mitigation measures.

Facility Considerations

Segregation of areas: Separate areas for cell banking, small-scale and large-scale upstream cell culture/fermentation, downstream processing, media/buffer preparation, materials management, corridors, and ancillary rooms (e.g. cold rooms, freezer rooms, storage areas).
Traffic flow: Control and minimize traffic flow of materials, personnel, equipment, and air within and between areas and corridors. Implement room segregation strategies.
Air handling systems: Design HVAC systems to maintain appropriate air quality and prevent cross-contamination between areas. Use HEPA filtration where needed.
Room Classifications
- For open operations:
  - Open sterile and aseptic operations must be performed in an environment where the probability of contamination is acceptably low, i.e. an environment meeting the bioburden requirements for a Grade A space.
  - Open bioburden-controlled processing may be performed in an ISO Grade 8/EU Grade C or EU Grade D environment as appropriate for the unit operation.
  - Open aseptic operations require a Grade A environment. Maintaining a Grade A cleanroom for large bioreactors is not feasible.
- For closed operations:
  - Closed systems do not require cleanroom environments. ICH Q7 states that closed or contained systems can be located outdoors if they provide adequate protection of the material.
  - When all equipment used to manufacture a product is closed, the surrounding environment becomes less critical. The cleanroom requirements should be based on a business risk assessment and could be categorized as unclassified.
  - Housing a closed aseptic process in a Grade C or Grade B cleanroom would not mitigate contamination risk compared to an unclassified environment.
  - For low bioburden closed operations, the manufacturing environment can be unclassified.

Equipment Considerations

Closed vs. open processing: Utilize closed processing operations where possible to prevent introduction/re-introduction of viruses. Implement additional controls for open processing steps.

Closure Level	Description
Closed Equipment	Single use, never been used, such as irradiated and autoclaved assembles; connections are made using sterile connectors or tube wielders/sealers
Functionally closed equipment: cleaned and sterilized	Open vessels or connections that undergo cleaning and sterilization prior to use and are then aseptically connected. The connection is then sterilized after being closed and remains closed during use.
Functionally closed equipment: cleaned and sanitized	Open vessels or connections that are CIPed including bioburden reducing flushes, but not sterilized before use and remain closed during use
Open	Connections open to the environment without subsequent cleaning, sanitization or sterilization prior to use

Operational Practices

Personnel controls: Implement rigorous training programs, safety policies and procedures for personnel working in critical areas.
Cleaning and sanitization: Establish frequent and thorough cleaning protocols for facilities, equipment, and processing areas using appropriate cleaning agents effective against viruses.
Material and equipment flow: Define procedures for disinfection and transfer of materials and equipment between areas to prevent contamination spread.
Storage practices: Implement proper storage procedures for product contact materials, intermediates, buffers, etc. Control access to cold rooms and freezers.

Additional Controls

Pest control: Implement comprehensive pest control strategies both inside and outside facilities, including regular treatments and monitoring.
Water systems: Design and maintain water systems to prevent microbial growth and contamination.
Process gases: Use appropriate filtration for process air and gases.
Environmental monitoring: Establish environmental monitoring programs to detect potential contamination early.

Risk Management Addresses Uncertainty

The ICH Q9 guideline on Quality Risk Management (QRM), including its revised version ICH Q9(R1), addresses the concept of uncertainty as a critical component in risk management within the pharmaceutical industry.

Understanding Uncertainty in ICH Q9

Uncertainty in the context of ICH Q9 refers to the lack of complete knowledge about a process and its expected or unexpected variability. This uncertainty can stem from various sources, including gaps in knowledge about pharmaceutical science, process understanding, and potential failure modes.

Key Points on Uncertainty from ICH Q9(R1)

Sources of Uncertainty:

Knowledge Gaps: Incomplete understanding of the scientific and technical aspects of processes.
Process Variability: Both expected and unexpected changes in process performance.
Failure Modes: Unidentified or poorly understood potential points of failure in processes or systems.

Managing Uncertainty:

Risk-Based Decision Making: The guideline emphasizes that decisions should be made based on the level of uncertainty, importance, and complexity of the situation. This means that more formal and structured approaches should be used when uncertainty is high.
Formality in QRM: ICH Q9(R1) introduces the concept of formality as a spectrum, suggesting that the degree of formality in risk management activities should be commensurate with the level of uncertainty. Less formal methods may be appropriate for well-understood processes, while highly structured methods are necessary for areas with high uncertainty.

Reducing Subjectivity:

The guideline acknowledges that subjectivity can impact the effectiveness of risk management. It recommends strategies to minimize subjectivity, such as using well-recognized risk assessment tools and involving cross-functional teams to provide diverse perspectives.

Continuous Improvement:

ICH Q9(R1) stresses the importance of continual improvement in risk management processes. This involves regularly updating risk assessments and control measures as new information becomes available, thereby reducing uncertainty over time.

Practical Implementation

In practice, managing uncertainty within the framework of ICH Q9 involves:

Conducting thorough risk assessments to identify potential hazards and their associated risks.
Applying appropriate risk control measures based on the level of uncertainty and the criticality of the process.
Documenting and reviewing risk management activities to ensure they remain relevant and effective as new information is obtained.

Conclusion

The ICH Q9 approach to uncertainty underscores the importance of a structured, knowledge-based approach to risk management in the pharmaceutical industry. By addressing uncertainty through rigorous risk assessments and appropriate control measures, organizations can enhance the reliability and safety of their processes and products, ultimately safeguarding patient health and safety.

Build Key Risk Indicators

We perform risk assessments; execute risk mitigations; and we end up with four types of inherent risks (parenthesis is opportunities) in our risk register:

Mitigated (or enhanced)
Avoided (or exploited)
Transferred (or shared)
Accepted

We’ve built a set of risk response plans to ensure we are continuing to treat these risks. And now we need to monitor the effectiveness of our risk plan and to ensure that the risks are behaving in the manner anticipated during risk treatment.

The living risk assessment is designed to conduct reassessment of risks after treatment and continuously throughout the life cycle. However, not all systems and risks need to be reassessed continually, and the organization should prioritize which systems should be reassessed based on a schedule.

Identify indicators that inform the organization about the status of the risk without having to conduct a full risk assessment every time. The trending status of these indicators can act as a flag for investigations, which may result in complete risk assessments.

This risk indicator is then a metric that indicates the state of the level of risk. It is important to note that not all indicators show the exact level of risk exposure, instead providing a trend of drivers, causes or intermediary effects of risk.

The most important risks can be categorized as key risks and the indicators for these key risks are known as key risk indicators (KRIs) which can be defined as: A metric that provides a leading or lagging indicator of the current state of risk exposure on key objectives. KRIs can be used to continually assess current and predict potential risk exposures.

These KRIs need to have a strong relationship with the key performance indicators of the organization.

KRIs are monitored through Quality Management Review.

A good rule of thumb is as you identify the key performance indicators to assess the performance of a specific process, product, system or function you then identify the risks and the KRIs for that objective.

Strive to have leading indicators that measure the elements that influences the risk performance. Lagging indicators will measure they actual performance of the risk controls.

These KRIs qualitatively or quantitatively present the risk exposure by having a strong relationship qirh the risk, its intermediate output or its drivers.

Let’s think in terms of a pharmaceutical supply chain. We’ve done our risk assessments and end up with a top level view like this:

For the risk column we should have some good probabilities and impacts and mitigations in place. We can then chose some KRIs to monitor, such as

Nonconformance rate
Supplier score card
Lab error rate
Product Complaints

As we develop, our KRIs can get more specific and focused. A good KRI is:

Quantifiable
Measurable (accurately and precisely)
Can be validated (have a high level of confidence)
Relevant (measuring the right thing associated with decisions)

In developing a KRI to serve as a leading indicator for potential future occurrences of a risk, it can be helpful to think through the chain of events that led to the event so that management can uncover the ultimate driver (i.e., root cause(s)) of the risk event. When KRIs for root cause events and intermediate events are monitored, we are in an enviable position to identify early mitigation strategies that can begin to reduce or eliminate the impact associated with an emerging risk event.

These KRIs will help us monitor and quantify our risk exposure. They help our organizations compare business objectives and strategy to actual performance to isolate changes, measure the effectiveness of processes or projects, and demonstrate changes in the frequency or impact of a specific risk event.

Effective KRIs can provide value to the organization in a variety of ways. Potential value may be derived from each of the following contributions:

Risk Appetite – KRIs require the determination of appropriate thresholds for action at different levels within the organization. By mapping KRI measures to identified risk appetite and tolerance levels, KRIs can be a useful tool for better articulating the risk appetite that best represents the organizational mindset.
Risk and Opportunity Identification – KRIs can be designed to alert management to trends that may adversely affect the achievement of organizational objectives or may indicate the presence of new opportunities.
Risk Treatment – KRIs can initiate action to mitigate developing risks by serving as triggering mechanisms. KRIs can serve as controls by defining limits to certain actions.

Level of Effort for Planning

In the post “Design Lifecycle within PDCA – Planning” I laid out a design thinking approach to planning a change.

Like most activities, the level of effort is commensurate with the level of risk. Above I provide some different activities that can happen based on the risk inherent in the process and problem being evaluated.

This is a great reason why Living Risk Assessments are so critical to an organization.

Pandemics and the failure to think systematically

As it turns out, the reality-based, science-friendly communities and information sources many of us depend on also largely failed. We had time to prepare for this pandemic at the state, local, and household level, even if the government was terribly lagging, but we squandered it because of widespread asystemic thinking: the inability to think about complex systems and their dynamics. We faltered because of our failure to consider risk in its full context, especially when dealing with coupled risk—when multiple things can go wrong together. We were hampered by our inability to think about second- and third-order effects and by our susceptibility to scientism—the false comfort of assuming that numbers and percentages give us a solid empirical basis. We failed to understand that complex systems defy simplistic reductionism.
Zeynep Tufekci, “What Really Doomed Americas Coronovirus Response” published 24-Mar-2020 in the Atlantic

On point analysis. Hits many of the themes of this blog, including system thinking, complexity and risk and makes some excellent points that all of us in quality should be thinking deeply upon.

COVID-19 is not a black swan. Pandemics like this have been well predicted. This event is a different set of failures, that on a hopefully smaller scale most of us are unfortunately familiar with in our organizations.

I certainly didn’t break out of the mainstream narrative. I traveled in February, went to a conference and then held a small event on the 29th.

The article stresses the importance of considering the trade-offs between resilience, efficiency, and redundancy within the system, and how the second- and third-order impacts can reverberate. It’s well worth reading for the analysis of the growth of COVID-19, and more importantly our reaction to it, from a systems perspective.