ISO/TS 23565 – Biotechnology – Bioprocessing – General requirements and considerations for equipment systems used in the manufacturing of cells for therapeutic use.
ISO/TS 23565 addresses an unmet need in the specification of cell processing systems. It describes the minimum requirements for the equipment, software and consumables used in the manufacturing and processing of cells for therapeutic use. The standard applies to all systems used alone or in combination with other equipment including components used for monitoring the status of manufacturing and processing equipment. It does not apply to point-of-care processing equipment, analytical devices or general equipment like biosafety cabinets.
ISO/TS 23565 is published as a Technical Specification (TS), which ISO describes as follows: A Technical Specification addresses work still under technical development, or where it is believed that there will be a future, but not immediate, possibility of agreement on an International Standard. A Technical Specification is published for immediate use, but it also provides a means to obtain feedback. The aim is that it will eventually be transformed and republished as an International Standard.
The designation as a TS acknowledges the immaturity of the current state of consensus on standard specifications for cell processing systems, yet summarizes the current thinking and applicable standards to benefit suppliers and users of equipment hardware software and consumables. The TS contains a mixture of recommendations (should statements) and requirements (shall statements).
The TS derives concepts and requirements from a number of relevant regulatory sources – standards, regulations, guidance documents, ICH documents, pharmacopeia and scientific literature. These sources are identified in the bibliography, and this listing of publications serves as a valuable index of relevant resources on its own.
Specific aspects of the TS that are relevant to the processing flow path and therefore the selection and specification of single-use components for cell processing systems include:
- General recommendation of single-use technology
- Closed systems
- Sterility and pyrogenicity
- Connection technologies
- Biocompatibility
- Extractables and leachables
- Particulates
- Impact of component materials on equipment performance (e.g., impact on cell viability, yields or quality attributes)
- Physical integrity
These attributes must be considered in the context of the entire processing system as it is used for processing cells. This includes components for all manufacturing steps, any ancillary materials used for their assembly (e.g., adhesives), and the cumulative materials in direct or indirect contact with the cells. The standard describes various attributes that are relevant to connectors and consumables used in bioprocessing equipment:
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General recommendation of single-use technology
Single-use consumables are recommended in section 4.1 as a means to maintain aseptic process conditions while allowing for a lower classification clean room process environment. Section 6.3.3 suggests single-use systems to avoid the use of chemical sterilants. -
Closed systems
The use of closed systems is recommended for each unit operation in section 4.3. -
Connection technologies
Section 4.4 recommends both sterile connectors and sterile tube welding and sealing as a way to fulfill the requirement to maintain sterility and minimize the risk of external contamination. This section also introduces the requirement to validate “consumable joint designs”. -
Extractables and leachables
Section 4.6 introduces the topic of process-related impurities with a general recommendation to “understand and acquire as much information as possible” about impurities, while also introducing the concept that in-process impurities may be cleared by downstream steps like cell washing. - Section 6.3.4 goes into much greater detail including a requirement to assess the toxicity of leachables and in-process leachables on both the patient and the therapeutic cells. Recommendations are given to assess leachables under representative conditions including “time, temperature, pH” and use a representative solution with “maximal…extraction propensities.”
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Sterility and non-pyrogenicity
Section 4.7 introduces a single requirement and several recommendations. Certification of sterility and endotoxin is required for all materials claimed to be sterile. Surprisingly, the following are only recommended: minimization of in-process connections, assessment of sampling methods for impact to sterility and pyrogenicity, pre- and post- use system integrity, post-use filter integrity, and non-endotoxin pyrogens. -
Containment and integrity
- 6.3.1 recommends integrity assessment prior to use to reduce the chances of leakage. This section also recommends secondary containment to prevent contamination of the process areas.
- 6.3.6 recommends qualifying the maintenance of integrity of the single-use systems during normal use including shipping, setup, process run and take down. This section also recommends that the supplier provide usage limits for their systems.
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Biocompatibility and impurity prevention
The biocompatibility of materials (i.e., consumable components) contacting the process material directly or indirectly should be verified (6.3.2). Indirect contact includes contact with a processing reagent but not the cells themselves. The TS recommends the use of materials “approved for direct medical use” with “documented biocompatibility.” Biocompatibility aspects to consider include the component materials, any process residuals and any substances that may leach or be extracted from the material. Any components that have not been tested independently should undergo biocompatibility testing to ensure these do not result in toxicity to the patient or the cells. -
Particulates
Section 6.3.5 provides several recommendations regarding prevention of particle contamination during processing, including the use of closed systems and air filters. It is recommended that single-use system suppliers implement controls to mitigate particle contamination. The TS acknowledges the lack of a standard test method and recommends modified compendial standard methods such as USP <788> to assess particle loads on single-use systems. It also recommends assessing if particles are generated by the normal usage of the process system. -
Shelf life
Section 6.3.6 places a requirement on suppliers of single-use components to provide validated expiration date and shelf life for sterility and “key functional properties.”
Organizations designing bioprocessing systems may be able to leverage testing and certification provided by component suppliers. Such information for components and consumables may include:
- Connection compatibility by design
- Dimensional specifications
- Process compatibility for components (e.g., compatibility with sterilization)
- Information regarding the constituent materials, certifications regarding hazardous substances, or biocompatibility reports or certifications
- Certification to relevant standards
- Performance specifications
- Shelf-life specifications for components
Qosina’s products and documentation library enable customers to identify appropriate components and consumables for bioprocessing systems and ensure compliance to ISO/TS 23565 and the safety and effectiveness of bioprocessing systems.
