Author: Jeremiah Genest

Quality professional with over 20 years of experience. Gamer and storyteller with forty years of practice.

What is Ahead for US Pharma?

It has been a wild ride this past week. I know my family and I have been on an emotional rollercoaster, and I bet many of you are feeling the same way. One question that keeps popping up in our household (and probably yours too) is: “What does this mean for my job, and should I be freaking out?”

Short-term outlook: Keep calm and carry on

First things first, take a deep breath. In the immediate future, it’s unlikely that we’ll see any massive shifts in pharma world. Most of us can probably continue our daily grind without too much disruption. So, for now, it’s business as usual, folks! Unfortunately that business has been pretty tough the last two years.

Long-term forecast: Cloudy with a chance of uncertainty

Now, here’s where things get a bit murky. The long-term outlook? Well, it’s like trying to predict the weather a year from now – pretty darn tricky. What we do know is that this situation has cranked up the uncertainty dial, and let’s face it, uncertainty in the pharmaceutical world is very unwelcome.

We already have a hefty dose of uncertainty due to the 2024 Supreme Court decisions, which are slowly starting to have impact but the boundaries are really unknown. Add to that an incoming administration with a noted dislike (and a set of vendettas) against the HHS and FDA, and government employees. And on top of that we have the wild card of Robert F. Kennedy Jr. being able to “go wild on health” – whatever that ends up meaning but my fear is nothing good.

But I also need to be pragmatic, and as a quality individual involved in risk management and managing uncertainty, I need to start evaluating impacts. Here are the things I am looking at.

On-Shoring

On-Shoring has been a growing conversation for years. We are an incredibly global industry and have been hard hit by a variety of supply disruptions:

  1. Global Pandemic: COVID-19 threw a massive wrench into our well-oiled supply chain machine.
  2. Geopolitical Tensions: The ongoing trade tiffs between major economies have kept us on our toes.
  3. Natural Disasters: Mother Nature hasn’t exactly been playing nice lately.
  4. Labor Shortages: Finding skilled workers has become a bit like searching for a needle in a haystack.

Add to this cocktail the ongoing GMP issues with sites in key manufacturing countries like India and China, and you’ve got a recipe for some serious supply chain headache,

Add to that we have a whole lot of talk of tariffs. The incoming Trump administration is practically drooling to raise tariffs which will have some serious implications:

  • Market Access Issues: Suddenly, selling your products in certain countries becomes a whole lot trickier.
  • Higher Costs: Tariffs often mean higher prices for imported goods.
  • Retaliation Risks: When one country imposes tariffs, others tend to follow suit.

The Critical Component Conundrum

Here’s where things get scary. We are seeing an increase in both price and availability issues for critical raw materials and components. And it is not just about overseas suppliers – even our domestic suppliers are feeling the heat. Remember the great plastics shortage that hit our Single-Use System (SUS) component suppliers? That is potentially just the tip of the iceberg.

The Ripple Effect

Now, let’s connect the dots:

  1. Supply Chain Vulnerability: Our global supply chains are showing their weak spots.
  2. Critical Item Shortages: There’s a growing concern about shortages of essential items.
  3. Price Hikes: As supplies tighten and tariffs kick in, prices are heading north.
  4. Market Access Challenges: A potential trade war could make it tough to serve international markets from the U.S. And remember, we are a very global industry.

Risk Management Approach

  1. Diversify Supply Sources: Don’t put all your eggs in one basket (or country).
  2. Build Resilience: Create buffer stocks of critical components.
  3. Explore On-Shoring Options: Look into bringing some production closer to home.
  4. Stay Flexible: Be ready to pivot your strategy as the global situation evolves.
  5. Plan for multi-country impact: Evaluate what happens when other countries start retaliating and it becomes difficult to get clinical or commercial supply into a country.

Regulatory Changes

Here are my fears where RFK Jr can really do damage. He may push for less stringent approval processes for certain drugs or treatments he favors, potentially allowing more alternative or “natural” products to enter the market. Conversely, he could impose stricter regulations on vaccines and other pharmaceutical products he views skeptically (which is all of them).

There may be efforts to roll back regulatory controls that currently protect public health, potentially allowing unproven treatments to reach consumers more easily. All of this uncertainty is going to be difficult and will impact company’s ability to raise funds. Which will impact the job market. And it has been a bad couple of years for layoffs.

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.

        AI/ML – In-Process Monitoring

        I’m often asked where we’ll first see the real impact of AI/ML in GMP. I don’t think I’ve hidden my skepticism on the topic in the past, but people keep asking, so here’s one of the first places I think it will really impact our field.

        In-Process Monitoring

        AI algorithms, coupled with advanced sensing technology, can detect and respond to minute changes in critical parameters. I can, today, easily imagine a system that not only detects abnormal temperatures but also automatically adjusts pressure and pH levels to maintain optimal conditions to a level of responsiveness not possible in today’s automation system, with continuous monitoring of every aspect of the production process in real-time. This will drive huge gains in predictive maintenance and data-driven decision making for improved product quality through early defect detection, especially in continuous manufacturing processes.

        AI and machine learning algorithms will more and more empower manufacturers to analyze complex data sets, revealing hidden patterns and trends that were previously undetectable. This deep analysis will allow for more informed decision-making and process optimization, leading to significant improvements in manufacturing efficiency. Including:

        • Enhancing Equipment Efficiency
          • Reduce downtime
          • Predict and prevent breakdowns
          • Optimize maintenance schedules
        • Process Parameter Optimization
          • Analyze historical and real-time data to determine optimal process parameters
          • Predict product quality and process efficiency
          • Adapt through iterative learning
          • Suggest proactive adjustments to production parameters

        There is a lot of hype in this area, I personally do not see us as close as some would say, but we are seeing real implementations in this area, and I think we are on the cusp of some very interesting capabilities.

        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.