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Risk Management in Single-Use Systems

Manage quality and mitigate risks in single-use system design and operation

Streamline Adoption of Single-Use Systems by Partnering with a Trusted Supplier

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scientist with bioreator

Single-use technologies have enabled significant flexibility and efficiency in biopharmaceutical manufacturing in recent years as their implementation has expanded from single-use components to complete end-to-end process solutions. With any evolution of technology comes the requirement to reassess risks and implement appropriate risk management strategies. In the absence of specific regulations regarding the implementation of single-use systems, the implications for drug and patient safety have led industry groups to develop best practice guidance in order to ensure current Good Manufacturing Practice (cGMP) and critical quality attributes (CQA) are maintained, particularly in relation to extractables, leachables and system integrity. 

 

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Shared Responsibility for Quality Risk Management

 

The quality of a drug product can potentially be impacted by the quality and integrity of the single-use system, not only at commissioning but during the whole life cycle life of the process. The adoption of single-use technology in commercial manufacturing necessitates a partnership between supplier and customer, with greater emphasis on a shared responsibility for quality risk management when compared to traditional multi-use systems. Trust and transparency between customer and supplier are essential. Sharing expertise to mitigate risks, adopting a quality by design (QbD) approach, advanced process testing methods, and robust supply chain management are fundamentals to increase process reliability and compliance.

 

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Developing a Risk Management Strategy for Single-Use Systems

 

European Medicines Agency1 and Food and Drug Administration (FDA)2 cGMP guidance provides the principles for identifying and assessing risk, and implementing appropriate risk management measures within the supply chain and throughout a pharmaceutical manufacturing process, to safeguard critical quality attributes. The guidelines apply irrespective of the technology used. To comply with cGMP requirements, manufacturers must undertake risk assessments for the use of single-use technologies in their applications and put in place a risk mitigation strategy.

 

The BioPhorum Operations Group (BPOG), a global cross industry collaboration between developers, suppliers, and manufacturers in the biopharmaceutical industry, has worked to issue best practice for assessing and mitigating risks when adopting single-use systems.3, 4 Similarly, the Bio-Process Systems Alliance (BPSA) guide on ‘Design, Control, and Monitoring of Single-Use Systems for Integrity Assurance5 recommends a risk-based approach to support manufacturers. 

 

In practice, layers of risk management can be applied based on risk assessment recommendations, with each application dictating an optimal level of control required to maintain the assurance of CQA. These include:

 

  • Core supplier controls: Robust quality management systems and a quality by design approach to ensure integrity: material controls, design controls, component testing, documentation and data packages, gamma irradiation, and robust supply chain agreements for components, along with validated transport protocols from manufacturing site to point of use.
  • System-level testing: Helium integrity testing for highly critical applications.
  • In-operation integrity testing: Pre- and post-use filter integrity and system leak testing.
  • Training: Operator training programs for unpacking, installing and operation to ensure system integrity is maintained on an ongoing basis.

 

 

risk management process flow chart

Figure 1 shows an example of the layers of risk management for single-use system design, manufacture, transfer and deployment at the end-user site.

 

Pall, Your Partner in Quality Risk Management

 

Pall has partnered with our biopharmaceutical customers for many years to develop new technologies, improved systems and robust data resources to ensure success.  Pall Biotech is a member of two BPOG working groups: Technology Roadmapping (TR) and Supply Partner (SP) phorums, collaborating to drive technological advancement and continuous improvements in business. Core to our approach to managing quality and mitigating risk in single-use system design and operation are:

 

  • Comprehensive data-driven quality by design processes
  • High-sensitivity helium integrity testing services for critical applications
  • Fast and accurate point-of-use filter integrity testing and leak testing solutions

 

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Pall’s Quality by Design Approach for Single-Use Technologies

 

 

Quality by design (QbD) provides a risk-management tool for integrity assurance. It demands an understanding of the risks and potential defects associated with each stage of the single-use technology life cycle. Building quality into the design and construction of every single-use system requires a combination of documented component quality, optimized system design and strong assembly validation process.

 

Core to the way Pall Biotech manages quality in designing single-use systems is Pall’s proprietary online quality, design and business information advanced central management system  (ACMS).

 

Learn more about Pall’s data-driven approach to single-use system design

 

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High Sensitivity Integrity Testing Service for Critical Applications

 

 

While a quality by design approach is essential to establish the best component selection, testing and system assembly procedures to design a secure, sterile and leak free system, there are circumstances when an additional level of testing sensitivity may be desirable.

 

Pall’s Helium Integrity Test method (using HIT™ technology) provides the highest level of control of integrity for single-use systems that are incorporated into the most critical steps in aseptic processing, or drug substance or drug product bulk storage for enhanced patient safety.

 

The test can be requested for Allegro™ biocontainer systems, Allegro mixer biocontainer systems and single-use filling sets and transfer lines.

 

The helium integrity test occurs at the Pall site during the manufacturing of Allegro single-use systems. The test offers the highest level of sterility assurance by measuring any trace leakage of helium from an assembly.

 

Learn more about Pall’s Helium Integrity Test for Allegro™ Single-Use Systems

 

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charlotte masy

On-Demand Webinar: Ensuring Integrity of Single-Use Systems for Sterile Processing

 

Charlotte Masy of GlaxoSmithKline plc presents a case study on GSK’s strategic approach to ensure the highest level of sterility assurance when applying single-use technologies in sterile vaccine manufacture.

 

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Fast and Accurate Point-of-Use Leak and Integrity Testing Solutions

 

For critical processes where risk assessment requires an additional level of control to assure product quality or operator safety, a point-of-use test immediately prior to use may be performed.  While now common place for confirming the integrity of critical filters prior to use, a similar technology can be applied to confirming the absence of leaks in the processing system fluid pathway.

 

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flowstar lgr test instrument

Fast Fully Traceable System Leak Testing of Single-Use Systems

 

For risk management in the biopharmaceutical industry, the absence of leaks can be confirmed prior to single-use system use. The availability of an easy and reliable point-of-use leak test provides end users with the confidence that the single-use system they are going to use is leak-free and has not been damaged during  transportation, unpacking or installation.


The Palltronic® Flowstar LGR test instrument enables point-of-use leak testing of single-use systems up to 200 L nominal volume, and provides the ability to test the integrity of the filters within single-use systems.

 

Learn more about the Palltronic Flowstar LGR Test Instrument

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palltronic flowstar iv filter integrity test instrument

Reliable Filter Integrity Testing for Single-Use Systems

 

Critical filters such as those used for virus removal and for aseptic processing must be integrity tested to confirm performance.  Pre-use, post-sterilization integrity testing, can be performed in-line with appropriate design additions. Filter integrity test requirements are highlighted at the system design stage.

 

The Palltronic Flowstar IV instrument enables users to reliably and reproducibly test filters quickly, saving time and money, with minimal training of operators, while being compatible with 21CFR part II regulations and data integrity. The Palltronic Flowstar IV supports filter integrity testing by diffusive flow (forward flow), bubble point, pressure decay and water intrusion methods.

 

Learn more about the Palltronic Flowstar IV Filter Integrity Test Instrument

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Regulatory Resource for End Users

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Pall has developed a comprehensive regulatory portal to support biomanufacturers in navigating the requirements of risk management when adopting single-use systems. You will find access to technical information including: regulatory documents, validation protocols, quality certificates and policies, expert opinions on regulatory affairs and quality assurance topics, and other helpful resources. Visit the regulatory portal

 

References:

 

1.        European Medicines Agency ICH guideline Q9 on quality risk management. 2015 Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-3.pdf [Accessed 5 June 2020]

2.        Food and Drug Administration. Current Good Manufacturing Practice (CGMP) Regulations. Available at: https://www.fda.gov/drugs/pharmaceutical-quality-resources/current-good-manufacturing-practice-cgmp-regulations [Accessed 5 June 2020]

3.        BioPhorum Extractables testing of polymeric single-use components used in biopharmaceutical manufacturing. 2020 Available at: https://www.biophorum.com/download/extractables-testing-of-polymeric-single-use-components-used-in-biopharmaceutical-manufacturing/ [Accessed May 2020]

4.        BioPhorum Operations Group (BPOG) Leachables: Best practices guide for evaluating leachables risk from polymeric single-use systems. 2017 Available at: https://www.biophorum.com/download/best-practices-guide-for-evaluating-leachables-risk-from-polymeric-single-use-systems/ [Accessed May 2020]

5.        Bio-Process Systems Alliance (BPSA). Design, Control, and Monitoring of Single-Use Systems for Integrity Assurance. 2017 Available at: https://bpsalliance.org/pdf-download-form-11/ [Accessed 5 June 2020]