Category: facility

Timely Equipment/Facility Upgrades

One of the many fascinating items in the recent Warning Letter to Sanofi is the FDA’s direction to provide a plan to perform “timely technological upgrades to the equipment/facility infrastructure.” This point drives home the point that staying current with technological advancements is crucial for maintaining compliance, improving efficiency, and ensuring product quality. Yet, I think it is fair to say we rarely see it this bluntly put as a requirement.

One of the many reasons this Warning Letter stands out is that this is (as far as I can tell) the same facility that won the ISPE’s Facility of the Year award in 2020. This means it is still a pretty new facility, and since it is one of the templates that many single-use biotech manufacturing facilities are based on, we had best pay attention. If a failure to maintain a state-of-the-art facility can contribute to this sort of Warning Letter, then many companies had best be paying close attention. There is a lot to unpack and learn here.

Establishing an Ongoing Technology Platform Process

To meet regulatory requirements and industry standards, facilities should implement a systematic approach to technological upgrades.

1. Conduct Regular Assessments

At least annually, perform comprehensive evaluations of your facility’s equipment, systems, and processes. This assessment should include:

  • Review of equipment performance and maintenance, including equipment effectiveness
  • Analysis of deviation reports and quality issues
  • Evaluation of current technologies against emerging industry standards
  • Assessment of facility design and layout for potential improvements

This should be captured as part of the FUSE metrics plan and appropriately evaluated as part of quality governance.

2. Stay Informed on Industry Trends

Keep abreast of technological advancements in biotech manufacturing at minimum by:

  • Attending industry conferences and workshops
  • Participating in working groups for key consensus standard writers, such as ISPE and ASTM
  • Subscribing to relevant publications and regulatory updates
  • Engaging with equipment vendors and technology providers

3. Develop a Risk-Based Approach

Prioritize upgrades based on their potential impact on product quality, patient safety, and regulatory compliance. Utilize living risk assessments to get a sense of where issues are developing. These should be the evolution of the risk management that built the facility.

4. Create a Technology Roadmap

Develop a long-term plan for implementing upgrades, considering:

  • Budget constraints and return on investment
  • Regulatory timelines for submissions and approvals
  • Production schedules and potential downtime
  • Integration with existing systems and processes

5. Implement Change Management Procedures

Ensure there is a robust change management process in place to ensure that upgrades are implemented safely and effectively. This should include:

6. Appropriate Verification – Commissioning, Qualification and Validation

Conduct thorough verification activities to demonstrate that the upgraded equipment or systems meet predetermined specifications and regulatory requirements.

7. Monitor and Review Performance

Continuously monitor the performance of upgraded systems and equipment to ensure they meet expectations and comply with cGMP requirements. Conduct periodic reviews to identify any necessary adjustments or further improvements. This is all part of Stage 3 of the FDA’s process validation model focusing on ongoing assurance that the process remains in a state of control during routine commercial manufacture. This stage is designed to:

  • Anticipate and prevent issues before they occur
  • Detect unplanned deviations from the process
  • Identify and correct problems

Leveraging Advanced Technologies

To stay ahead of regulatory expectations and industry trends, consider incorporating advanced technologies into your upgrade plans:

  • Single-Use Systems (SUS): Implement disposable components to reduce cleaning and validation requirements while improving flexibility.
  • Modern Microbial Methods (MMM): Implement advanced techniques used in microbiology that offer significant advantages over traditional culture-based methods
  • Process Analytical Technology (PAT): Integrate real-time monitoring and control systems to enhance product quality and process understanding.
  • Data Analytics and Artificial Intelligence: Implement advanced data analysis tools to identify trends, predict maintenance needs, and optimize processes.

Conclusion

Maintaining a state-of-the-art biotech facility requires a proactive and systematic approach to technological upgrades. By establishing an ongoing process for identifying and implementing improvements, facilities can ensure compliance with FDA requirements, align with industry standards, and stay competitive in the rapidly evolving biotech landscape.

Remember that the goal is not just to meet current regulatory expectations but to anticipate future requirements and position your facility at the forefront of biotech manufacturing excellence. By following this comprehensive approach and staying informed on industry developments, you can create a robust, flexible, and compliant manufacturing environment that supports the production of high-quality biopharmaceutical products.

Building the FUSE(P) User Requirements in an ICH Q8, Q9 and Q10 World

“The specification for equipment, facilities, utilities or systems should be defined in a URS and/or a functional specification. The essential elements of quality need to be built in at this stage and any GMP risks mitigated to an acceptable level. The URS should be a point of reference throughout the validation life cycle.” – Annex 15, Section 3.2, Eudralex Volume 4

User Requirement Specifications serve as a cornerstone of quality in pharmaceutical manufacturing. They are not merely bureaucratic documents but vital tools that ensure the safety, efficacy, and quality of pharmaceutical products.

Defining the Essentials

A well-crafted URS outlines the critical requirements for facilities, equipment, utilities, systems and processes in a regulated environment. It captures the fundamental aspects and scope of users’ needs, ensuring that all stakeholders have a clear understanding of what is expected from the final product or system.

Crafting Good User Requirements

Building Quality from the Ground Up

The phrase “essential elements of quality need to be built in at this stage” emphasizes the proactive approach to quality assurance. By incorporating quality considerations from the outset, manufacturers can:

  • Minimize the risk of errors and defects
  • Reduce the need for costly corrections later in the process
  • Ensure compliance with Good Manufacturing Practice (GMP) standards

Mitigating GMP Risks

Risk management is a crucial aspect of pharmaceutical manufacturing. The URS plays a vital role in identifying and addressing potential GMP risks early in the development process. By doing so, manufacturers can:

  • Implement appropriate control measures
  • Design systems with built-in safeguards
  • Ensure that the final product meets regulatory requirements

The URS as a Living Document

One of the key points in the regulations is that the URS should be “a point of reference throughout the validation life cycle.” This underscores the dynamic nature of the URS and its ongoing importance.

Continuous Reference

Throughout the development, implementation, and operation of a system or equipment, the URS serves as:

  • A benchmark for assessing progress
  • A guide for making decisions
  • A tool for resolving disputes or clarifying requirements

Adapting to Change

As projects evolve, the URS may need to be updated to reflect new insights, technological advancements, or changing regulatory requirements. This flexibility ensures that the final product remains aligned with user needs and regulatory expectations.

Practical Implications

  1. Involve multidisciplinary teams in creating the URS, including representatives from quality assurance, engineering, production, and regulatory affairs.
  2. Conduct thorough risk assessments to identify potential GMP risks and incorporate mitigation strategies into the URS.
  3. Ensure clear, objectively stated requirements that are verifiable during testing and commissioning.
  4. Align the URS with company objectives and strategies to ensure long-term relevance and support.
  5. Implement robust version control and change management processes for the URS throughout the validation lifecycle.

Executing the Control Space from the Design Space

The User Requirements Specification (URS) is a mechanism for executing the control space, from the design space as outlined in ICH Q8. To understand that, let’s discuss the path from a Quality Target Product Profile (QTPP) to Critical Quality Attributes (CQAs) to Critical Process Parameters (CPPs) with Proven Acceptable Ranges (PARs), which is a crucial journey in pharmaceutical development using Quality by Design (QbD) principles. This systematic approach ensures that the final product meets the desired quality standards and user needs.

It is important to remember that this is usually a set of user requirements specifications, respecting the system boundaries.

From QTPP to CQAs

The journey begins with defining the Quality Target Product Profile (QTPP). The QTPP is a comprehensive summary of the quality characteristics that a drug product should possess to ensure its safety, efficacy, and overall quality. It serves as the foundation for product development and includes considerations such as:

  • Dosage strength
  • Delivery system
  • Dosage form
  • Container system
  • Purity
  • Stability
  • Sterility

Once the QTPP is established, the next step is to identify the Critical Quality Attributes (CQAs). CQAs are physical, chemical, biological, or microbiological properties that should be within appropriate limits to ensure the desired product quality. These attributes are derived from the QTPP and are critical to the safety and efficacy of the product.

From CQAs to CPPs

With the CQAs identified, the focus shifts to determining the Critical Process Parameters (CPPs). CPPs are process variables that have a direct impact on the CQAs. These parameters must be monitored and controlled to ensure that the product consistently meets the desired quality standards. Examples of CPPs include:

  • Temperature
  • pH
  • Cooling rate
  • Rotation speed

The relationship between CQAs and CPPs is established through risk assessment, experimentation, and data analysis. This step often involves Design of Experiments (DoE) to understand how changes in CPPs affect the CQAs. This is Process Characterization.

Establishing PARs

For each CPP, a Proven Acceptable Range (PAR) is determined. The PAR represents the operating range within which the CPP can vary while still ensuring that the CQAs meet the required specifications. PARs are established through rigorous testing and validation processes, often utilizing statistical tools and models.

Build the Requirements for the CPPs

The CPPs with PARs are process parameters that can affect critical quality attributes of the product and must be controlled within predetermined ranges. These are translated into user requirements. Many will specifically label these as Product User Requirements (PUR) to denote they are linked to the overall product capability. This helps to guide risk assessments and develop an overall verification approach.

Most of Us End Up on the Less than Happy Path

This approach is the happy path that aligns nicely with the FDA’s Process Validation Model.

This can quickly break down in the real world. Most of us go into CDMOs with already qualified equipment. We have platforms on which we’ve qualified our equipment, too. We don’t know the CPPs until just before PPQ.

This makes the user requirements even more important as living documents. Yes, we’ve qualified our equipment for these large ranges. Now that we have the CPPs, we update the user requirements for the Product User Requirements, perform an overall assessment of the gaps, and, with a risk-based approach, do additional verification activations either before or as part of Process Performance Qualification (PPQ).

Preparing your BCP for Trump’s Attacks on Immigration

Time (maybe past-time) to evaluate your organization’s business continuity plan and anticipate the potential actions against immigrants, in particular the potential impact of Trump’s proposed immigration policies on the facility cleaning industry, particularly cleanrooms, which could be significant.

Labor Shortage

The cleaning industry, including cleanroom maintenance, heavily relies on immigrant labor. A mass deportation policy could lead to:

  • Significant workforce reduction: Many cleaning companies employ immigrant workers, both documented and undocumented. A large-scale deportation could severely reduce the available workforce.
  • Increased labor costs: With fewer workers available, companies may need to offer higher wages to attract and retain employees, potentially increasing operational costs.

Industry Disruption

The cleanroom industry, which requires specialized skills and training, could face particular challenges:

  • Loss of experienced workers: Cleanroom maintenance requires specific knowledge and expertise. Deporting experienced workers could lead to a skills gap in the industry.
  • Reduced productivity: As companies struggle to replace deported workers, there might be a temporary decrease in productivity and quality.
  • Increased costs for clients: Higher labor costs in the cleaning industry could be passed on to clients, potentially affecting industries that rely on cleanroom facilities, such as pharmaceuticals and electronics manufacturing.

Actions to Evaluate

Time to evaluate internal training programs to quickly upskill current and new workers, particularly for specialized cleanroom maintenance. Be prepared for the need to have your staff step in and clean, on the moment’s notice. This is a key action to have in the business continuity plan, and frankly should already be there.

Compliance and Legal Challenges

Beyond that, companies should be evaluating their other plans with broad stakeholders like HR and legal for when law enforcement comes calling as a result of heightened enforcement and audits of cleaning companies to ensure compliance with immigration laws. Remember these cleaners work side-by-side with your staff and quite frankly, are really hard to tell the difference. Are you prepared to side with law enforcement, or delay law enforcement? What is your risk tolerance for navigating the complex legal situations, particularly if long-term employees are suddenly subject to deportation?

While the full extent of the impact remains uncertain, Trump’s proposed immigration policies could significantly disrupt the facility cleaning industry, which will greatly impact every manufacturing site I know. The industry may need to adapt quickly to potential labor shortages, increased costs, and changing regulatory landscapes, while navigating the thorny ethical considerations.

No time like the present to start.

Best Practices for Managing the Life-Cycle of Single-Use Systems

Single-use systems (SUS) have become increasingly prevalent in biopharmaceutical manufacturing due to their flexibility, reduced contamination risk, and cost-effectiveness. The thing is, management of the life-cycle of single-use systems becomes critical and is an area organizations can truly screw up by cutting corners. To do it right requires careful collaboration between all stakeholders in the supply chain, from raw material suppliers to end users.

Design and Development

Apply Quality by Design (QbD) principles from the outset by focusing on process understanding and the design space to create controlled and consistent manufacturing processes that result in high-quality, efficacious products. This approach should be applied to SUS design.

ASTM E3051 “Standard guide for specification, design, verification, and application of SUS in pharmaceutical and biopharmaceutical manufacturing” provides an excellent framework for the design process.

Make sure to conduct thorough risk assessments, considering potential failure modes and effects throughout the SUS life-cycle.

Engage end-users early to understand their specific requirements and process constraints. A real mistake in organizations is not involving the end-users early enough. From the molecule steward to manufacturing these users are critical.

    Raw Material and Component Selection

    Carefully evaluate and qualify raw materials and components. Work closely with suppliers to understand material properties, extractables/leachables profiles, and manufacturing processes.

    Develop comprehensive specifications for critical materials and components. ASTM E3244 is handy place to look for guidance on raw material qualification for SUS.

    Manage the Supplier through Manufacturing and Assembly

    Implementing robust supplier qualification and auditing programs and establish change control agreements with suppliers to be notified of any changes that could impact SUS performance or quality. It is important the supplier have a robust quality management system and that they apply Good Manufacturing Practices (GMP) through their facilities. Ensure they have in place appropriate controls to

    • Validate sterilization processes
    • Conduct routine bioburden and endotoxin testing
    • Design packaging to protect SUS during transportation and storage. Shipping methods need to protect against physical damage and temperature excursions
    • Establish appropriate storage conditions and shelf-life based on stability studies
    • Provide appropriate labeling and traceability
    • Have appropriate inventory controls. Ideally select suppliers who understand the importance of working with you for collaborative planning, forecasting and replenishment (CPFR)

    Testing and Qualification

    Develop a comprehensive testing strategy, including integrity testing and conduct extractables and leachables studies following industry guidelines. Evaluate the suppliers shipping and transportation studies to evaluate SUS robustness and determine if you need additional studies.

      Implementation and Use

      End users should have appropriate and comprehensive documentation and training to end users on proper handling, installation, and use of SUS. These procedures should include how to perform pre-use integrity testing at the point of use as well as how to perform thorough in-process and final inspections.

      Consider implementing automated visual inspection systems and other appropriate monitoring.

      Implement appropriate environmental monitoring programs in SUS manufacturing areas. While the dream of manufacturing outdoors is a good one, chances are we aren’t even close yet. Don’t short this layer of control.

        Continuous Improvement

        Ensure you have appropriate mechanisms in place to gather data on SUS performance and any issues encountered during use. Share relevant information across the supply chain to drive improvements.

        Conduct periodic audits of suppliers and manufacturing facilities.

        Stay updated on evolving regulatory guidance and industry best practices. There is still a lot changing in this space.

        Validating Manufacturing Process Closure for Biotech Utilizing Single-Use Systems (SUS)

        Maintaining process closure is crucial for ensuring product quality and safety in biotechnology manufacturing, especially when using single-use systems (SUS). This approach is an integral part of the contamination control strategy (CCS). To validate process closure in SUS-based biotech manufacturing, a comprehensive method is necessary, incorporating:

        1. Risk assessment
        2. Thorough testing
        3. Ongoing monitoring

        By employing risk analysis tools such as Hazard Analysis and Critical Control Points (HACCP) and Failure Mode and Effects Analysis (FMEA), manufacturers can identify potential weaknesses in their processes. Additionally, addressing all four layers of protection helps ensure process integrity and product safety. This risk-based approach to process closure validation is essential for maintaining the high standards required in biotechnology manufacturing, including meeting Annex 1.

        Understanding Process Closure

        Process closure refers to the isolation of the manufacturing process from the external environment to prevent contamination. In biotech, this is particularly crucial due to the sensitivity of biological products and the potential for microbial contamination.

        The Four Layers of Protection

        Throughout this process it is important to apply the four layers of protection that form the foundation of a robust contamination control strategy:

        1. Process: The inherent ability of the process to prevent or control contamination
        2. Equipment: The design and functionality of equipment to maintain closure
        3. Operating Procedures: The practices and protocols followed by personnel
        4. Production Environment: The controlled environment surrounding the process

        I was discussing this with some colleagues this week (preparing for some risk assessments) and I was reminded that we really should put the Patient in at the center, the zero. Truer words have never been spoken as the patient truly is our zeroth law, the fundamental principle of the GxPs.

        Key Steps for Validating Process Closure

        Risk Assessment

        Start with a comprehensive risk assessment using tools such as HACCP (Hazard Analysis and Critical Control Points) and FMEA (Failure Mode and Effects Analysis). It is important to remember this is not a one or another, but a multi-tiered approach where you first determine the hazards through the HACCP and then drill down into failures through an FMEA.

        HACCP Approach

        In the HACCP we will apply a systematic, preventative approach to identify hazards in the process with the aim to produce a documented plan to control these scenarios.

        a) Conduct a hazard analysis
        b) Identify Critical Control Points (CCPs)
        c) Establish critical limits
        d) Implement monitoring procedures
        e) Define corrective actions
        f) Establish verification procedures
        g) Maintain documentation and records

        FMEA Considerations

        In the FMEA we will look for ways the process fails, focusing on the SUS components. We will evaluate failures at each level of control (process, equipment, operating procedure and environment).

        • Identify potential failure modes in the SUS components
        • Assess the severity, occurrence, and detectability of each failure mode
        • Calculate Risk Priority Numbers (RPN) to prioritize risks

        Verification

        Utilizing these risk assessments, define the user requirements specification (URS) for the SUS, focusing on critical aspects that could impact product quality and patient safety. This should include:

        • Process requirements (e.g. working volumes, flow rates, pressure ranges)
        • Material compatibility requirements
        • Sterility/bioburden control requirements
        • Leachables/extractables requirements
        • Integrity testing requirements
        • Connectivity and interface requirements

        Following the ASTM E2500 approach, when we conduct the design review of the proposed SUS configuration, to evaluate how well it meets the URS, we want to ensure we cover:

        • Overall system design and component selection
        • Materials of construction
        • Sterilization/sanitization approach
        • Integrity assurance measures
        • Sampling and monitoring capabilities
        • Automation and control strategy

        Circle back to the HACCP and FMEA to ensure they appropriately cover critical aspects like:

        • Loss of sterility/integrity
        • Leachables/extractables introduction
        • Bioburden control failures
        • Cross-contamination risks
        • Process parameter deviations

        These risk assessments will define critical control parameters and acceptance criteria based on the risk assessment. These will form the basis for verification testing. We will through our verification plan have an appropriate approach to:

        • Verify proper installation of SUS components
        • Check integrity of connections and seals
        • Confirm correct placement of sensors and monitoring devices
        • Document as-built system configuration
        • Test system integrity under various operating conditions
        • Perform leak tests on connections and seals
        • Validate sterilization processes for SUS components
        • Verify functionality of critical sensors and control
        • Run simulated production cycles
        • Monitor for contamination using sensitive detection methods
        • Verify maintenance of sterility throughout the process
        • Assess product quality attributes

        The verification strategy will leverage a variety of supplier documentation and internal testing.

        Closure Analysis Risk Assessment (CLARA)

        Acceptance and release will be to perform a detailed CLARA to:

        • Identify all potential points of contamination ingress
        • Assess the effectiveness of closure mechanisms
        • Evaluate the robustness of aseptic connections
        • Determine the impact of manual interventions on system closure

        On Going Use

        Coming out of our HACCP we will have a monitoring and verification plan, this will include some important aspects based on our CCPs.

        • Integrity Testing
          • Implement routine integrity testing protocols for SUS components
          • Utilize methods such as pressure decay tests or helium leak detection
          • Establish acceptance criteria for integrity tests
        • Environmental Monitoring
          • Develop a comprehensive environmental monitoring program
          • Include viable and non-viable particle monitoring
          • Establish alert and action limits for environmental contaminants
        • Operator Training and Qualification
          • Develop detailed SOPs for SUS handling and assembly
          • Implement a rigorous training program for operators
          • Qualify operators through practical assessments
        • Change Control and Continuous Improvement
          • Establish a robust change control process for any modifications to the SUS or process
          • Regularly review and update risk assessments based on new data or changes
          • Implement a continuous improvement program to enhance process closure

        Leveraging the Four Layers of Protection

        Throughout the validation process, ensure that each layer of protection is addressed:

        1. Process:
          • Optimize process parameters to minimize contamination risks
          • Implement in-process controls to detect deviations
        2. Equipment:
          • Validate the design and functionality of SUS components
          • Ensure proper integration of SUS with existing equipment
        3. Operating Procedures:
          • Develop and validate aseptic techniques for SUS handling
          • Implement procedures for system assembly and disassembly
        4. Production Environment:
          • Qualify the cleanroom environment
          • Validate HVAC systems and air filtration

        Remember that validation is an ongoing process. Regular reviews, updates to risk assessments, and incorporation of new technologies and best practices are essential for maintaining a state of control in biotech manufacturing using single-use systems.

        Connected to the Contamination Control Strategy

        Closed systems are a key element of the overall contamination control strategy with closed processing and closed systems now accepted as the most effective contamination control risk mitigation strategy. I might not be able to manufacture in the woods yet, but darn if I won’t keep trying.

        They serve as a primary barrier to prevent contamination from the manufacturing environment by helping to mitigate the risk of contamination by isolating the product from the surrounding environment. Closed systems are the key protective measure to prevent contamination from the manufacturing environment and cross-contamination from neighboring operations.

        The risk assessments leveraged during the implementation of closed systems are a crucial part of developing an effective CCS and will communicate the (ideally) robust methods used to protect products from environmental contamination and cross-contamination. This is tied into the facility design, environmental controls, risk assessments, and overall manufacturing strategies, which are the key components of a comprehensive CCS.