Using consolidated data for single-use system component selection
The fundamental principles of quality by design (QbD) focus on consistent and controlled processes based on data and a thorough understanding of process parameters in the design, development, and manufacture of products to manage risks by ensuring products are consistently fit for purpose.
A central part of how Cytiva manages quality in designing single-use systems is controlled by our proprietary online quality, design, and business information advanced central management system (ACMS).
The ACMS contains fully controlled and traceable data on validated and tested assembled components and configurations by uniting end-user application information, quality, supply chain, technical support, engineering, and project management departments. From the point we receive an inquiry for a single-use system until it leaves the factory, the project is executed through the ACMS. If a new configuration is requested for which data is not available, the system will block progress and require immediate testing for validation.
When developing new single-use solutions, using ACMS information, you can choose to use only prequalified and preferred components, each supported by an array of data and testing to help standardize design and accelerate delivery while minimizing the risk of mechanical or physiochemical incompatibility.
Check out this podcast on the benefit of single-use technologies for gene therapy manufacturing and considerations for system design, assembly, and how the ACMS can be used to streamline these steps.
Robust extractables and leachables characterization data
Standardization of the approach to risk assessments for product contact surfaces for systems used in biopharmaceutical production from BPOG (1, 2) and potential United States Pharmacopeia (USP) USP <665> (3) places an increased importance on the use of relevant, high-quality, validated supplier data for extractables and leachables (E&L).
- An extractable is a chemical that is extracted from a component into a solvent under controlled conditions that are usually more aggressive than normal operating conditions.
- A leachable is a chemical that comes from systems or components during normal use and therefore has the potential to be present in the final drug product.
Minimum requirements for E&L for fluid-contact, plastic components, and systems will be specified by USP <665> (3). The expectation is that manufacturers of plastic components used in cGMP pharmaceutical manufacturing will generate extractables data in compliance with USP and make these data available to end users to aid in component selection and qualification.
We recognize the need for standardized extractables data and have, for many years, committed extensive resources to the execution of extractable testing on our single-use components according to the BioPhorum recommendations. Risks and risk assessments can be reduced by designing systems using preferred components that are supported by comprehensive data packages. These are stored within our ACMS and can be supplied as part of the documentation pack. Where needed we can also provide the consultancy to interpret this data, and where the process conditions are not adequately bracketed by the existing data, we can perform process specific extractables and leachables testing.
The BioPhorum Leachables Working Group Best Practice Guide for Leachables is composed of three parts:
- The risk assessment model
- Leachable study design
- Analytical methods
This on-demand webinar provides insight into the application of the best practices for leachables study design by end users, with an example case study.
Control of particulates in single-use system manufacture and operation
Minimizing particulates in drug products is essential to reduce the risk of harm to patients. US FDA cGMP for Biologicals, CFR 600.11 states: “All surfaces that come in contact with products shall be clean and free of surface solids, leachable contaminants, and other materials that will hasten the deterioration of the product or otherwise render it less suitable for the intended use…” (4).
Control of particulates in the application of single-use systems is especially important for those that are used for final formulation and filling downstream of final filtration, or for aseptic manufacturing of vaccines and therapies that cannot be filtered. The Bio-Process Systems Alliance (BPSA) has published specific recommendations for testing, evaluation, and control of particulates for single-use process equipment (5).
Processes that minimize the potential introduction of particulates are built into the manufacturing of our Allegro™ single-use technologies. In a case study where we were involved in implementation of single-use technologies in a clinical-scale filling system in partnership with Merck & Co., Inc. (Kenilworth, NJ), our process qualification data included evaluation of the presence of particulates (6). Merck manufacturing department’s strategic goal was to achieve broader implementation of single-use technologies to meet requirements of a pipeline of diverse and evolving sterile products that would require a filling line capable of supporting multiple dosing technologies and other configurations. In order to ensure that all critical performance parameters established for an existing stainless steel process were fulfilled, the single-use system was evaluated using an engineering batch of sterile product. Only one to three fibers showed up in each test sample. The detected fibers (polycarbonate, cellulose, and polyethylene terephthalate) are common in the laboratory environment, and it was concluded that they did not originate from the biocontainer itself. About 7500 syringes were filled with a dosing accuracy meeting the user-requirement specification (URS) and no visible particles.
Read the full article: A Single-Use, Clinical-Scale Filling System: From Design to Delivery
Junction and component leak and integrity data
Our quality by design principles prevent the use of combinations of components and tubing that are untested. Where there are no viable alternatives to untested junctions, testing is initiated. Designs can be finalized and put into production if all junctions have been validated. Some component types are individually tested prior to release into the system build. These include sterilizing grade and virus filter capsules, our Kleenpak™ Presto sterile connectors and all biocontainer chambers.
Our Kleenpak Presto sterile connector is the only connector that has 100% quality inspection linked to unit traceability. Our vision system automatically checks the connector peel strip and weld, and stores the results for each unit for full traceability.
Read the whitepaper: Genderless Sterile Connection Technology , A Quality By Design (QbD) Approach For Greater Sterility Assurance From Manufacturing To Use.
Regulatory resources
We have developed a comprehensive regulatory portal to support customers in navigating the requirements of risk management, regulatory, and quality support when adopting single-use systems. You will find access to a range of 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 our regulatory portal.
References
- BioPhorum. Disposables: Extractables testing of polymeric single-use components used in biopharmaceutical manufacturing. 2020. Accessed February 23, 2023.
- BioPhorum Operations Group (BPOG) Leachables: Best practices guide for evaluating leachables risk from polymeric single-use systems. 2017. Accessed February 23, 2023.
- Hathcock J. Extactables and Leachables: Ready for USP 665? Document Number: RPSCEL_01 Revision Number: 1.0 2019. Accessed February 23, 2023.
- U.S. Food and Drug Administration. CFR - Code of Federal Regulations Title 21. (21CFR600) 2019. Accessed February 23, 2023.
- Bio-Process Systems Alliance (BPSA) Recommendations for Testing, Evaluation, and Control of Particulates from Single-Use Process Equipment. 2014 Accessed February 23, 2023.
- Camposano D, Mills A, Piton C. A Single-Use, Clinical-Scale Filling System: From Design to Delivery. BioProcess International 14(6) 2016. Accessed February 23, 2023.