Tag: leachable

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.

        The Importance for USP <665> for E&L

        The United States Pharmacopeia (USP) General Chapter <665> focuses on the plastic components and systems used in the manufacturing of pharmaceutical drug products and biopharmaceutical drug substances and products and is one the fundamental documents for manufacturers, especially in the age of single use.

        Key Changes in USP <665>

        1. Effective Date Extension

        The official effective date for USP <665> has been extended to May 1, 2026. This extension is intended to give stakeholders enough time to follow the new requirements and to align with the development of the ICH Q3E guideline for extractables and leachables (E&Ls).

        2. Mandatory Compliance

        Previously, USP <665> was informational and not mandatory for compendial compliance. The revisions will make it a mandatory chapter, meaning that compliance will be required for regulatory purposes.

        3. Risk-Based Assessments

        The revised chapter emphasizes risk-based assessments for the qualification of plastic components. This approach aligns with modern regulatory expectations and provides a structured methodology for evaluating the safety and compatibility of materials used in pharmaceutical manufacturing.

        4. Scope and Applicability

        USP <665> will cover single-use systems (SUS) and container closure systems used in the storage and processing of pharmaceutical and biopharmaceutical products. This includes guidance on the characterization and qualification of these systems to ensure they do not adversely affect product quality.

        5. No Grandfathering of Existing Products

        The revisions explicitly state that there will be no grandfathering of existing products. All products, including those already on the market, will need to comply with the new requirements by the effective date.

        6. Alignment with USP <1665>

        USP <665> is closely related to USP <1665>, which provides guidance on the characterization and qualification processes. Together, these chapters offer a comprehensive framework for managing the risks associated with plastic components in pharmaceutical manufacturing.

        7. Stakeholder Engagement

        The USP has planned to engage with stakeholders throughout the revision process to ensure that the new requirements are practical and achievable. This includes public notices, comment periods, and collaboration with industry experts.

        Implications for Manufacturers

        Preparation and Compliance

        Manufacturers are advised to start preparing for the changes now to avoid potential backlogs and delays. Early compliance will help make sure a smooth transition and keep product quality.

        Global Considerations

        While the USP is a U.S.-based standard, its guidelines are often adopted globally. Manufacturers should consider the potential for international regulatory bodies to require equivalency to USP <665> compliance in the future.

        What do I need a Toxicologist for in the GMPs

        Working on a job description for a toxicologist. Here’s what I have so far: what am I missing on the GMP side (not the GCP, GVP, or GLP sides).

        A toxicologist plays several important roles in GMP activities, including in cleaning validation and extractable/leachable (E&L) studies for pharmaceutical manufacturing:

        For cleaning validation:

        1. Establishing safety thresholds: Toxicologists help determine the Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE) limits for residual substances. These limits are crucial for setting acceptance criteria in cleaning validation.
        2. Risk assessment: They evaluate the potential health risks associated with residual substances that may remain after cleaning processes.
        3. Determining safety factors: Toxicologists apply appropriate safety factors when calculating acceptable residue limits, considering factors like route of administration and patient population.
        4. Reviewing toxicological data: They analyze available toxicity data on active ingredients, excipients, and cleaning agents to inform safety assessments.

        For extractable and leachable studies:

        1. Toxicological evaluation: Toxicologists assess the potential health impacts of identified extractables and leachables from packaging materials or manufacturing equipment.
        2. Setting thresholds: They help establish Safety Concern Thresholds (SCT) and Analytical Evaluation Thresholds (AET) for E&L studies.
        3. Risk characterization: Toxicologists evaluate the toxicological significance of detected leachables in relation to patient exposure.
        4. Providing expertise on regulatory guidelines: They ensure studies comply with regulatory expectations regarding toxicological risk assessment.
        5. Interpreting study results: Toxicologists help interpret the significance of E&L findings in the context of patient safety.

        Toxicologists provide critical expertise in assessing the potential health impacts of trace contaminants or leached substances. They also ensure that cleaning processes and packaging materials do not introduce unacceptable risks to patient safety. Their input is essential for developing scientifically sound and regulatorily compliant approaches to these critical pharmaceutical quality and safety aspects.