E55.07 - Single Use Systems

SIGNIFICANCE AND USE
4.1 This practice provides:  
4.1.1 A holistic approach to evaluate risks associated with an integrity breach in a SUS, considering its life cycle from development to disposal.  
4.1.2 An overview of physical and microbial test methods that could be applicable to SUS testing, for qualification and validation purposes, as well as for routine testing.  
4.1.3 Information on the main challenges faced when testing SUSs for integrity.  
4.2 This practice can be used by SUS suppliers and SUS end users to define an integrity assurance strategy for SUSs, with the relevant tests when appropriate.
SCOPE
1.1 This practice uses quality risk management (QRM) and life-cycle approach to establish integrity assurance of single-use systems (SUSs), such as but not limited to bag assemblies and liquid transfer sets for processing, storage, and shipping of (bio)pharmaceutical products. It gives recommendations to identify failure modes and risks associated with such systems and their use-cases and how to identify the relevant leak(s) of concern. Integrity assurance in this context is limited to the barrier properties of the SUS, linked to microbial integrity and bioburden control (product quality) and liquid product loss (operator and environmental contamination). The required level of integrity assurance will depend on how critical the application is and can be interpreted in different ways. It can also vary between processes and applications used for different modalities (for example, advanced therapies). Other package barrier properties different from that, such as but not limited to gas barrier properties for gas headspace preservation, as well as porous barrier packages are not considered. Specific aspects how to address the contamination control strategy (CCS) for SUS are also described in chapters 8.131ff of the new Revision of Annex 1 (1),2 including chapter 8.137 regarding SUS integrity.  
1.2 The test method overview provides descriptions that focus on the standard test setup and the identification of challenges in combination with SUSs. Details, including specific test setups, test parameter, and result interpretation, are not discussed. For more detailed information refer to Test Method E3251 for microbial test methods, and to Test Method E3336 for physical test methods.  
1.3 This practice is not intended to apply to the use of single-use technology for primary containers, combination products (products composed of any combination of a drug, device, or biological product), or devices. Appropriate procedures related to these products are discussed in documents covering the integrity assurance for primary containers (2) or medical products (1, 3).  
1.4 Techniques and procedures for complaint management and root cause analysis related to integrity failures are also not discussed.  
1.5 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.  
1.6 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety, health, and environmental practices and determine the applicability of regulatory limitations prior to use.  
1.7 This international standard was developed in accordance with internationally recognized principles on standardization established in the Decision on Principles for the Development of International Standards, Guides and Recommendations issued by the World Trade Organization Technical Barriers to Trade (TBT) Committee.

SIGNIFICANCE AND USE
4.1 Single-use systems (SUSs) used for biopharmaceutical manufacturing must maintain sterility and product quality of the fluid inside. Such articles or systems should therefore be validated as providing an effective barrier against microbial ingress. The microbial barrier properties of a SUS may be demonstrated using deterministic physical tests that have been correlated to microbial integrity. Such physical test methods are described in Test Method E3336. Two microbial test methods (aerosol exposure and immersion exposure) are described in this test method that can be used to demonstrate microbial integrity of a SUS or determine the MALL, the maximum defect size that does not allow microbial ingress, into a SUS.  
4.2 It is important to note that the results of microbial ingress tests are heavily dependent on the conditions under which the test is performed and are not suitable for routine checking of a SUS due to the test’s destructive nature.  
4.2.1 Any size defect may be forced to fail under sufficiently aggressive conditions (including a large enough sample size, high differential pressure, or high hydrostatic pressure, for example) that would not ordinarily reflect normal use conditions. Thus, it is necessary to clearly define the relevant conditions for a test through a risk assessment of both the actual SUS claims and its final use (Practice E3244). Once that is established, the size of defect that can be detected under those conditions can be determined, if required, using defined defects.  
4.2.2 “Relevant conditions” refers to worse-case actual use conditions but does not mean that a SUS must be tested under theoretically absolute (extreme) “worst-case” conditions.  
4.2.3 Testing may be performed on individual components or entire systems. Considerations for defining “relevant conditions” and testing design should be based on a risk assessment for the SUS intended use and should include:
4.2.3.1 A channel created by a defect or breach through the...
SCOPE
1.1 The microbial test method outlined in this test method applies to microbial ingress risk assessment of a single-use system (SUS) or its individual components that require integrity testing either by the assembly supplier or the end user of the assembly based on a potential risk of a breach to the product or manufacturing process.  
1.2 The aim of microbial ingress testing of sterile SUSs used in biopharmaceutical manufacturing is two-fold:  
1.2.1 Firstly, it is used to evaluate the ability of a SUS fluid path to remain sterile after a SUS has been challenged by microbial exposure. Microbial exposure is achieved either by directly placing a SUS into a container of microbial challenge solution, or by delivering an aerosolized microbial challenge onto a SUS that is placed inside a test chamber designed to generate and deliver the aerosol. The choice of the test challenge organism should be justified based on a risk assessment of the SUS and conditions of use.  
1.2.2 Additionally, microbial ingress testing can be used to determine the maximum allowable leakage limit (MALL) that does not allow microbial ingress under specific test conditions. The defect size that can be detected by specific physical integrity testing methods (see Test Method E3336) can be correlated to this MALL in order to claim microbial integrity. Test articles bearing calibrated defects over a range of dimensions, including up to a defect size expected to consistently allow microbial ingress as a positive control (defect-based positive control), may be tested to determine the MALL.  
1.3 Both purposes for microbial ingress testing as described in 1.2.1 and 1.2.2 can either be conducted by liquid immersion or aerosol exposure. For the purpose described in 1.2.2, the type of exposure should be determined according to the SUS’s use-case conditions and a risk assessment.  
1.4 The method used to create a breach, hole or defect in single-use film or...

SIGNIFICANCE AND USE
4.1 The test methods outlined in this standard allow for suppliers and end users of SUSs in (bio)pharmaceutical manufacturing processes to detect a leak and/or confirm the barrier properties of empty, clean, and dry SUSs. Performing integrity testing can be a significant contribution to the overall integrity assurance of SUSs.  
4.2 The two types of physical test methods outlined in this standard are:  
4.2.1 Section 5, Pressure-Based Test Methods.  
4.2.2 Section 6, Tracer Gas-Based Test Methods.
Note 3: Other test methods are currently being adapted for robust, reliable, and reproducible testing SUS, for example, Vacuum Decay Test Method as described in Test Method F2338.  
4.3 Pressure-based test methods are generally less sensitive compared to tracer gas-based test methods but have a lower complexity and cost. To assist in selecting a method that will fit an application, refer to Table 1 in Practice E3244 for a more detailed comparison of the two methods.  
4.4 Both types of test methods can be used to detect leaks of any sizes in a SUS (referred to as leak testing) or confirm the barrier properties of the SUS (referred to as integrity testing).  
4.5 To ensure that integrity testing performed on SUSs is effective and accurate, the properties of the SUS (pressure capabilities, volume, material properties, etc.) must be considered. Also, a validation should be performed on the chosen test method as further described in 5.11 and 6.11.  
4.6 Practice E3244 should be referenced to determine the maximum allowable leakage limit for a SUS, along with the routine testing requirements that are suitable for each application.  
4.7 The purpose of the described test methods is not to stress the SUS until a potential defect occurs. The testing parameters, mainly test pressure, are independent from the use-case conditions. The robustness of the SUS under use-case conditions should be proven during product qualification.  
4.8 This standard test method describes the...
SCOPE
1.1 The test methods described in this standard are applicable for single-use manufacturing equipment, further called Single-use Systems (SUSs), used for (bio)pharmaceutical products.  
1.2 The test methods described in this standard are not intended to be used on single-use technology for primary containers, combination products (products composed of any combination of a drug, device, or biological product), or devices. Appropriate procedures related to these products are discussed in documents covering the integrity assurance for primary containers (1)2 or medical products (2-4).  
1.3 The test methods and their validation are described to only cover testing of empty and dry SUSs. Residual liquid in the SUS can impact the test reliability and reproducibility.  
1.4 The test methods are intended to be used to confirm the barrier properties of the test article, further called integrity testing, or test the SUS for leaks of certain sizes, further called leak testing.
Note 1: To verify that an integrity test can confirm the intended barrier properties of the SUS, its detection limit must be equal or better than the respective maximum allowable leakage limit.  
1.5 The physical test methods covered by this standard are:  
1.5.1 Pressure-based test methods.  
1.5.2 Tracer gas-based test methods.  
1.6 The physical test methods described are in general non-destructive and allow further use of the SUS.
Note 2: Some variations can be used in a destructive way, for example, to perform root cause analysis of the leak.  
1.7 The standard describes the test apparatuses, operation procedures, environment requirements, and discusses specific challenges with testing SUSs, as well as how to perform robust validation of the test method.  
1.8 This standard does not include methods to determine the maximum allowable leakage limit for maintaining the barrier properties of the SUS. For that, refer to Practice E3244 and Test Me...

SIGNIFICANCE AND USE
4.1 Conventional stainless-steel process equipment for biopharmaceutical manufacturing require cleaning and sterilization prior to implementation. Single-use systems (SUS), stand-alone equipment typically composed of plastic components and assemblies, are usually assembled in cleanrooms and are usually not cleaned or rinsed prior to implementation (with the exception of filters, which are often rinsed prior to use). SUS cleanliness with respect to particulate matter depends upon the quality of the SUS manufacturing process, and also upon the care and handling of the SUS upon implementation by the end-user.  
4.2 In the process of manufacturing single-use components or assemblies, particulate matter may adhere to the interior (fluid contacting) or exterior surfaces of SUS (BPSA). Visual inspection of SUS components and assemblies for particulate matter is often limited by translucent or opaque materials which inhibit visualization, especially of interior fluid-contacting surfaces. Also in some cases, the large size of single-use assemblies significantly reduces the effectiveness of visual inspections. A more complete assessment of particulate matter load requires a method to extract particulate matter from the surfaces of single-use components or assemblies using a test liquid, which makes the particles readily available for analytical characterization using counting, sizing and chemical/physical identification methods.  
4.3 Pharmaceutical manufacturers use a wide variety of configurations and sizes of single-use components and assemblies, such as bioreactors, bioprocess containers, tubing, connectors, clamps, valves, sensors and filters. Extraction of particulate matter may be relatively easy from small components with readily accessible surfaces, however, extraction of particulate matter from large and complex assemblies with less readily accessible interior surfaces may require significantly more effort.  
4.4 The wide variety of single-use components and asse...
SCOPE
1.1 This practice describes the requirements for development, qualification, and routine application of a procedure for the effective liquid extraction of particulate matter from the surfaces of single-use components and assemblies designed for use in biopharmaceutical manufacturing processes. The extraction generates a suspension of particulate matter in liquid which makes the particulate matter readily available for analytical characterization.  
1.2 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.  
1.3 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety, health, and environmental practices and determine the applicability of regulatory limitations prior to use.  
1.4 This international standard was developed in accordance with internationally recognized principles on standardization established in the Decision on Principles for the Development of International Standards, Guides and Recommendations issued by the World Trade Organization Technical Barriers to Trade (TBT) Committee.

SIGNIFICANCE AND USE
5.1 A risk-based approach must be used to determine the cell lines, test articles, and materials used for testing. An evaluation of relevant factors should be made to determine if a test article is representative of the intended use.  
5.2 Cell culture compatibility should be assessed if the material is in direct contact with cell culture medium regardless of duration of contact. Test articles can be of a single material or assembled from a multitude of materials.  
5.3 Two perspectives to single-use material cell culture compatibility assessments are the supplier and the end user perspectives. It is understood that the supplier may have better access to single-use materials and material manufacturing processes, while having limited access to representative cell lines. Supplier assessment of materials are best tested using cell lines available that have shown known material sensitivity. The end users may have more limited access to materials but access to more representative cell lines and processes. Therefore assessment of compatibility of material with a specific cell line in a process is best evaluated by the end user.  
5.4 This guide outlines best practices to establish test procedures. Appendix X1 outlines an example test procedure for a commercially available CHO cell line.
SCOPE
1.1 This guide outlines best practices to consider when setting up a representative leachable test method to detect if a material is compatible with cell culture media or manufacturing processes. This guide does not replace or supersede cell growth tests like USP , USP  (plastic/elastomeric materials), or ISO 10993 (medical device materials), that are used in assessing biological reactivity in humans. Polymeric materials that have passed these tests have been found to leach compounds under normal process conditions that can inhibit cell culture growth for some cell lines. See Refs (1-5).2 Test methods that are representative of the manufacturing conditions will help identify materials that are appropriate for use during manufacturing.  
1.2 This guide may be relevant to biopharmaceutical manufacturing, cell-based therapeutics, vaccines, cell-based diagnostics, and other areas.  
1.3 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.  
1.4 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety, health, and environmental practices and determine the applicability of regulatory limitations prior to use.  
1.5 This international standard was developed in accordance with internationally recognized principles on standardization established in the Decision on Principles for the Development of International Standards, Guides and Recommendations issued by the World Trade Organization Technical Barriers to Trade (TBT) Committee.

SIGNIFICANCE AND USE
5.1 Application of the approach described within this guide is intended to satisfy international regulatory expectations in ensuring that SUS are fit for their intended use and to satisfy requirements for sourcing, supply, design, specification, installation, operation, and performance.  
5.2 The approach described in this guide applies concepts and principles introduced in the FDA initiative, Pharmaceutical cGMP’s for the 21st Century – A Risk-Based Approach. It supports and is consistent with the framework described in FDA Guidance for Industry, Process Validation: General Principles and Practices, in ICH Q7, ICH Q8 (R2), ICH Q9, and ICH Q10.  
5.3 This guide includes concepts developed in the PDA Technical Report No. 66.  
5.4 This guide may be used independently or in conjunction with other ASTM Committee E55 proposed standards to be published by ASTM International.  
5.5 Specific standard practices about extractables, leachables, particulate matter, and integrity testing/leak detection, biocompatibility, and raw materials as available should be used by suppliers and end users and applied to their own manufacturing process facilities.
SCOPE
1.1 This guide is intended as a complement to Guide E2500.  
1.2 This guide is applicable to the range of manufacturing systems described in Guide E2500, specifically all elements of single-use systems, or hybrids of single-use and traditional components, used for the manufacturing of pharmaceutical and biopharmaceutical products, including: materials of construction, components, assembly, manifolds, supporting utilities, associated process monitoring and control systems, automation systems, and controlled environment that have the potential to affect product quality and patient safety.  
1.3 This guide is applicable for the implementation of changes to manufacturing system design for existing systems. It may be used for continuous improvement and changes in operation from clinical through to commercial scale.  
1.4 For brevity, single-use systems are referred to as SUS throughout the rest of this guide.  
1.5 The approach may be applied by the end user, the supplier of SUS, and raw materials sub-suppliers further back in the supply chain.  
1.6 This guide is not intended to apply to the use of single-use technology for packaging, primary containers, combination products (products composed of any combination of a drug, device, or biological product) or devices.  
1.7 This guide does not address specific local requirements, which remain the responsibility of the end user.  
1.8 This guide does not address employee health and safety, environmental, nor other good engineering and manufacturing practices (GXP) requirements. This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety and health practices and determine the applicability of regulatory limitations prior to use.