ASTM E3244-23

This document is not an ASTM standard and is intended only to provide the user of an ASTM standard an indication of what changes have been made to the previous version. Because
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of the standard as published by ASTM is to be considered the official document.
Designation: E3244 − 20 E3244 − 23
Standard Practice for
Integrity Assurance and Testing of Single-Use Systems
This standard is issued under the fixed designation E3244; the number immediately following the designation indicates the year of
original adoption or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. A
superscript epsilon (´) indicates an editorial change since the last revision or reapproval.
1. 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), 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 (12) or medical products (21,
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.
This practice is under the jurisdiction of ASTM Committee E55 on Manufacture of Pharmaceutical and Biopharmaceutical Products and is the direct responsibility of
Subcommittee E55.04 on General Biopharmaceutical Standards.
Current edition approved Feb. 1, 2020June 1, 2023. Published April 2020August 2023. Originally approved in 2020. Last previous edition approved in 2020 as E3244 – 20.
DOI: 10.1520/E3244-20.10.1520/E3244-23.
The boldface numbers in parentheses refer to a list of references at the end of this standard.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
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2. Referenced Documents
2.1 ASTM Standards:
E3051 Guide for Specification, Design, Verification, and Application of Single-Use Systems in Pharmaceutical and Biophar-
maceutical Manufacturing
F2095E3251 Test Methods for Pressure Decay Leak Test for Flexible Packages With and Without Restraining PlatesMethod for
Microbial Ingress Testing on Single-Use Systems
F2391E3336 Test Method for Measuring Package and Seal Integrity Using Helium as the Tracer GasPhysical Integrity Testing
of Single-Use Systems
2.2 ICH Documents:
ICH Q9Q9(R1) Quality Risk Management
3. Terminology
3.1 Definitions:
3.1.1 artificial leak/representative leak, n—a leak which is applied or introduced into a SUS, a SUS’s material, or component for
the purposes of positive test controls.
3.1.1.1 Discussion—
This may or may not be a calibrated leak; however, only leaks which have been calibrated can be used to make a specific integrity
assurance claim.
3.1.1 bioprocess container (biocontainer), n—a container (bag, bottle, tank, etc.) used primarily for liquid (or frozen liquid)
storage during various stages of biopharmaceutical manufacturing processing.
3.1.2 calibrated leak, n—a hole which is characterized by its size.size (for example, artificially created into a SUS, a SUS’s
material, or component and used for creating positive controls).
3.1.2.1 Discussion—
Often, the size is a nominal size which is equivalent to a gas flow through an idealized geometry.geometry (2). A commonly used
idealized geometry is the “nominal diameter orifice size”, corresponding to the size of a perfect circular hole of negligible length
that would give the same gas flow in the calibration conditions (for example, dry air flow rate measured at 25 °C, with 1 barg inlet
pressure and 1 atm outlet pressure).
3.1.3 destructive test method, n—a test method that will alter the intended use of the tested SUS during the test and not allow
further use.use (see also non-destructive test method).
3.1.4 end user, n—a company processing (bio)pharmaceutical products.
3.1.5 integrity assurance, n—a holistic approach of risk analysis and mitigation by means of product and process robustness,
quality, and process control and integrity testing to assure that a SUS maintains its integrity prior to and during use.
3.1.6 integrity test, n—a test used to confirm the defined barrier properties of a SUS.
3.1.7 leak, n—a breach in a SUS’s material or a gap between SUS’s components through which there is a break-down of the barrier
property of interest.
3.1.8 leak test, n—a test used to identify leaks of certain sizes in not correlated to the defined barrier properties of a SUS.
3.1.9 maximum allowable leakage limit, limit (MALL), n—the greatest leakage rate (or leak size) tolerable for a given product
package that poses no to maintain its barrier properties under its use-case conditions (for example, prevent any risk to product
safety and no or inconsequential impact on product quality. safety, product quality, or operator and environmental safety).
For referenced ASTM standards, visit the ASTM website, www.astm.org, or contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM Standards
volume information, refer to the standard’s Document Summary page on the ASTM website.
Available from International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), ICH Secretariat, 9,
chemin des Mines, P.O. Box 195, 1211 Geneva 20, Switzerland, http://www.ich.org.
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3.1.9.1 Discussion—
In this document’s context, the product package is a SUS containing a (bio)pharmaceutical product, but not a final dosage form.
3.1.10 non-destructive test method, n—a test method that maintains the tested SUStest article in a condition for further use, without
impacting its quality attributes.attributes (see also destructive test method).
3.1.11 single-use components, n—parts used in single-use systems, most commonly commonly, but not limited to, bioprocess
containers, tubing, connectors, clamps, valves, sensors, and filters.
3.1.12 single-use system (SUS), n—process equipment used in (bio)pharmaceutical manufacturing, usually constructed of plastic
materials and disposed of after use.disposed of after use and usually constructed of polymer-based materials.
3.1.13 SUS supplier, n—a manufacturer that produces andand/or assembles single-use systems, also known as a system integrator.
3.1.14 tracer gas, n—a gas to be detected against the background of all other gases.
3.2 Abbreviations:
3.2.1 BPOG—Biophorum Operations Group
3.2.2 BPSA—Bio Process Systems Alliance
3.2.3 cGMP—current Good Manufacturing Practice
3.2.4 ICH—International ConferenceCouncil on Harmonization of Technical Requirements for Registration of Pharmaceuticals
for Human Use
3.2.5 LoD—limit of detection
3.2.6 MALL—maximum allowable leakage limit
3.2.7 QbD—quality by design
3.2.8 QRM—quality risk management
3.2.9 SUS—single-use system
3.2.10 SUSI(T)—single-use system integrity (testing)
3.2.11 SUT—single-use technologies
4. 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.
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5. Procedure
5.1 Quality Risk Management (QRM) and Life-Cycle Approach:
5.1.1 Introduction of Quality Risk Management (QRM):
5.1.1.1 QRM, as defined in ICH Q9, is a methodology to assess potential risk to product quality within a process. Potential risks
are managed based on their occurrence and severity in the process/product and are reviewed throughout the life cycle of the
process/product. When discussing a SUS, its integrity can be a critical attribute for maintaining product quality or protecting the
operator or environment from exposure, or both. There must be necessary controls, monitoring, and testing in place to ensure that
the integrity of the SUS is maintained throughout its life cycle. To accomplish this, the SUS supplier and end user can adopt a
life-cycle approach, where the integrity assurance of the SUS is considered from the design and production process at the SUS
supplier to its final application in the end user’s manufacturing process. Within the life cycle, the risks to SUS integrity (SUSI)
can be proactively identified and the necessary controls and testing put in place. These risks can be different for both the SUS
supplier and end user, which can necessitate differences in the test methods, testing frequency and sensitivity utilized for ensuring
SUSI.
5.1.1.2 The general approach of identifying and mitigating risks is the same regardless of the modality and the manufacturing
process for which the SUS is used, but risk rating and consequential mitigation actions can vary. As an example, a single-use
bioreactor might be considered as a low risk in a classical mAb manufacturing process, while it could be highly critical for
manufacturing cell or gene therapy products. It is important that the process and the associated risks are known and properly
identified to implement an effective risk mitigation strategy.
5.1.1.3 The end-user’s risk assessment should include the relevant aspects of the SUS life cycle related to integrity, the impact of
a potential integrity failure and whether this could be acceptable or not. This is generally done by a risk rating combining severity
(S), occurrence (O) and current mitigation control. One potential mitigation action can be to implement an in-process control (IPC),
for example, a leak/integrity test or visual inspection, in the SUS supplier’s manufacturing process and/or in the end-user’s process.
Such an implementation should be evaluated in detail, balancing the additional risks versus the benefits brought by this control,
as well as the actual sensitivity of the control. As illustration, some elements that should be included in the risk assessment are
listed below (non-exhaustive list):
(1) process step classification (low bioburden or sterile).
(2) process conditions.
(3) potential operator or environmental safety risk.
(4) risk of damages due to shipping and handling steps.
(5) market supply risks (risk of drug shortages).
5.1.2 Life-Cycle Approach for Single-Use Systems (SUSs):
5.1.2.1 When adopting a life-cycle approach for any SUS, both the supplier and end user will ensure it meets the necessary
requirements for the end product. Fig. 1 illustrates the manufacturing and use of a typical SUS, showing the necessary steps that
will be encountered at both the supplier and the end user’s sites.
5.1.2.2 The supplier will identify the critical requirements for the SUS at the start of development. The supplier will then qualify
a manufacturing process to meet those critical requirements of the design, identifying steps critical to the quality of the SUS
according to its design and intended use. Based on these critical requirements, testing and controls of the components and the SUS
will be conducted. Likewise, testing or controls, or both, will be performed on critical process steps that could impact the quality
of the SUS.
5.1.2.3 User requirements will be identified during the end user’s process development and shared with the supplier to determine
if a SUS will adequately operate in the end user’s application. These requirements will help determine critical parameters of a SUS
during processing steps at the end user’s site along with the end user’s product requirements.
5.1.2.4 Both the supplier and end user will perform risk assessments during their respective process development to identify these
critical parameters. Additionally, controls and testing will be put in place to ensure the critical quality attributes are met and quality
is assured during routine manufacturing at both the supplier and end user’s sites based on these risk assessments. Throughout the
life cycle, the supplier and end user processes will be evaluated for any modifications to improve the quality of the SUS. The
supplier and end user will need to be aware of changes in their process or SUS, or both, that have the potential to impact process
parameters (4).
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FIG. 1 SUS Life Cycle
5.1.3 Application to Integrity Assurance for a Single-Use System (SUS) within the Life Cycle:
5.1.3.1 Integrity assurance is a critical attribute of a SUS. An end-to-end risk assessment of the entire SUS’s life cycle is
recommended to ensure implementation of risk management controls that are suitable for its intended use. While end users are
ultimately accountable for SUS performance, they rely primarily on supplier controls to achieve the necessary level of integrity
assurance. Therefore, alignment between the end user’s requirements and the supplier’s capabilities is critical.
5.1.3.2 The first step for an end user is to define the requirements for the SUS and communicate these to the supplier. In compiling
the requirements, the end user should consider the application specific factors that may impact the tolerance for integrity risks (for
example, proximity to final drug product, existence of downstream filtration steps, toxicity / exposure to the operator and
environment), and key areas of the process that may impact integrity assurance (such as application details, operating conditions).
When formal user requirements are necessary, utilizing the BPOG/BPSA single-use user requirements template (3), is
recommended. This includes a mechanism for suppliers to communicate their capabilities, enabling alignment with the end user
application needs.
5.1.3.3 The end user should engage in quality audit and technical due diligence activities to evaluate how each potential supplier’s
controls contribute to the level of integrity assurance they can provide for the product. By understanding the basis of a supplier’s
qualified design space, an end user is better informed on what additional work may be required. For further discussion and
recommendations around technical due diligence activities, see Guide E3051.
5.1.4 Identifying End User Requirements That Can Impact Integrity:
5.1.4.1 The end user will define the requirements critical to the integrity assurance of the SUS based on their processing conditions
and product requirements. Additionally, the SUS supplier will determine the parameters that are critical to assure integrity of the
SUS based on their processing conditions for SUS assembly and packaging/shipping, as well as the sterilization processes. The
processing conditions at both the SUS supplier and end user identified as critical to integrity assurance will help to determine test
requirements. Some examples of these processing conditions include the temperature, pressure, and flowrates that a SUS will
experience during use at the end user’s site. The SUS supplier’s environment and handling conditions during assembly and
packaging, as well as the temperatures and pressures the SUS will experience during shipping from the supplier to receipt at the
end user along with the SUS sterilization process should also be accounted for during the risk assessment.
5.1.4.2 The constraints critical to integrity assurance during the drug manufacturing process must also be considered as part of the
risk assessment when determining user requirements. These constraints will include the intended use in the end user’s process, the
presence of (sterile) filtration steps, and impact on chemistry/biological function, toxicity of the product to the operator or
environment. All of these product constraints will be critical to determining the breach size that is acceptable for the SUS and will
not impact product quality.
5.1.5 Performing Technical Diligence:
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5.1.5.1 Suppliers may have different approaches to ensuring integrity assurance. The end user should assess a supplier’s technical
capabilities and controls. Depending on the composition of the SUS sourced from the supplier, the assessment may include how
a supplier has qualified and implemented controls for a specific component or a combination of components (for example, the
connection between tubing and hose barb, or seal between bag film layers). Understanding the scope and methods for qualification,
in-process testing, and lot release testing and how these relate to integrity assurance informs the end user how to risk assess and
align their application with the supplier’s design space.
5.1.6 Challenges for the Life-Cycle Approach:
5.1.6.1 The life-cycle approach can present different challenges to supplier and the end user in reference to SUSI assurance and
the test methods utilized at each stage of the life cycle. The magnitude of a significant integrity breach should be known for each
stage of the life cycle where testing will occur. This can lead to differences in the testing approach during the life cycle. These
differences are based on the purpose of the test (qualification versus on-going), criticality of the process step, user requirements,
and nature of the test (destructive versus non-destructive).
5.1.7 Developmental Versus On-Going Testing:
5.1.7.1 Testing as part of the development/qualification of a process step at either the SUS supplier or end user can be performed
with greater sensitivity than on-going testing. Likewise, the number of samples will have to be scientifically significant to support
integrity assurance based on the potential variability present within a given process step and the SUS. The test method chosen
should be able to quantify the integrity breach with a sensitivity aligned with the application needs. This is often referred to as the
maximum allowable leakage limit (MALL). One of the main challenges for the supplier is often that this MALL is not fully defined
given that the requirements are application driven. Because of this, additional testing of the SUS may be required by the end user
prior to implementation.
5.1.8 Stages of the Life Cycle:
5.1.8.1 Testing performed as part of the development of the SUS and the manufacturing processes at the SUS supplier factory and
the end user plant will be a factor in determining controls or testing required later in the life cycle of SUS. Understanding of
components utilized within the SUS, as well as how they are connected together, is critical to determining the potential failure
mode(s) that could lead to loss of integrity and the testing necessary for assurance of integrity of the SUSs. Likewise, the criticality
of a step to the integrity of a SUS alongside knowledge on the type and level of an integrity breach that a supplier manufacturing
step or end user operation could produce will help determine the necessary testing during on-going processing required at either
the supplier or end user sites. The auditing, release, and change controls processes by the supplier and end user will also determine
if testing is required as well as the specifics of the test that will be employed. Based on the auditing and release processes, the need
and level of testing required could change throughout the life cycle, as alignment with expectations are demonstrated and critical
parameters are met, altering the potential risks to the SUSI. Changes required within the inputs to (that is, raw materials or
components) and the manufacturing process itself could require an added level of testing in order to support the change due to a
lack of knowledge on the impact to integrity.
5.1.8.2 There will be a level of in-process controls and monitoring throughout the SUS’s life cycle by the SUS supplier and end
user to ensure its integrity. These in-process controls and monitoring will be based on critical parameters for maintenance of SUSI
throughout its life cycle. The QRM process will determine at what stages within the SUS’s life cycle in-process controls and
monitoring are needed based on how critical it is to SUSI. By reviewing in-process controls and monitoring in place prior to and
at a given stage in the life cycle, the SUS supplier or end user can then determine the acceptable level of leakage and method of
integrity assurance testing that will be required. This can also help in determining the required testing frequency for assurance of
SUSI.
5.2 Challenges:
5.2.1 The increasing uptake of SUSs in more critical current Good Manufacturing Practice (cGMP) processes and applications,
especially the development of larger and complex, multi-component systems has made integrity assurance a critical attribute of
the system (5). SUSI assurance is not easily solved as challenges exist for both groups, end users work to inform the application
requirements and SUS suppliers act to meet these specifications. The challenges include practical aspects, test methodology with
appropriate sensitivity, and result interpretation. Furthermore, economics of testing is a separate challenge, for example, the method
cannot be cost-prohibitive to either the end user or supplier.
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5.2.2 In terms of practical aspects, a consensus testing standard should ideally be applicable to all types of SUSs, regardless of
components or design. Unfortunately, due to physical constraints (for example, pressure resistance, permeability) or characteristics
to be tested (for example, filters versus containers), such ideal one-size-fits-all testing standard does not exist currently. More,
requirements might be different depending on the application (for example, storage and shipping in non-controlled environment
versus transfer made in a controlled environment like a cleanroom). For multi-component or large volume systems, or both, which
can be more complex, guidance should be available allowing these systems to be divided into smaller units to accommodate the
testing standard. Furthermore, the controls performed to verify SUSI are likely to differ, for practical reasons, between the Design,
Validation or Qualification, and Commercial Productiondesign, validation or qualification, and commercial production phases. The
requirements and how these are met should be phase appropriate and correlated to the application’s risk level. An end user may
require destructive testing of representative lot samples from the SUS supplier during Design and Validation or Qualificationdesign
and validation or qualification phases, and potentially during manufacture of the SUS on a per sample basis. When 100 % integrity
testing is required during production of the SUS, non-destructive testing must be applied. Additionally, end users may decide to
perform leak/integrity testing at the point-of-use to mitigate risks associated with shipping, handling and installation during
Commercial Production.commercial production. Time, cost, and potential risks with handling the SUS during point-of-use
leak/integrity testing must be balanced against the test’s benefits. From a technical perspective, there may be masking effects due
to contact of bag film with the supporting hardware of the SUS. Devices that prevent this masking effect should not alter the heat
transfer during (bio)pharmaceutical manufacturing beyond what is acceptable to the process if these remain with the hardware.
5.2.3 Aside from practical aspects, there are numerous challenges associated with developing testing methodology for a consensus
standard. The ideal consensus standard should cover the vast majority of process conditions. These process conditions can vary
so much that defining conditions to cover most of them would likely lead to an over-challenge: as example, conditions to combine
temperatures for frozen conditions at –80°C–80 °C up to hot conditions at +60°C,+60 °C, mechanical stress from various side
loading, from transfer with peristaticperistaltic pumps, diaphragm pumps, or air pressure, would be both difficult to implement but
also lead to a very harsh, non-representative challenge for most of the process conditions taken separately. During Design and
Validation or Qualificationdesign and validation or qualification phases, additional or specific tests may be performed in worst-case
or failure mode conditions. These qualification tests are not in the scope of this practice.
5.2.4 A SUS is typically comprised of components which have different pressure ratings. Polymeric materials are flexible and
prone to deformation under pressure, which can impact the test result (particularly upon repeat testing) and interpretation.
Furthermore, pressure decay test results depend on environmental conditions; such as temperature and pressure; as discussed in
later sections. Finally, the pre-treatment condition, for example, steam sterilization, gamma irradiation, or ethylene oxide, should
be accounted for to ensure determination of integrity assurance is as representative as possible. In each instance, the test
methodology challenges place considerable cost and time burden on the SUS supplier.
5.2.5 Finally, interpretation of test results presents challenges to both the SUS supplier and end user and must be agreed between
both parties to prevent misinterpretations. SUS suppliers are generally coming with data demonstrating that their systems are
passing successfully their integrity test, in their testing conditions (for example, at a defined pressure) and according their
acceptance criteria. While this is valuable information, having results of tests-to-failure (for example, at what pressure the systems
are failing) would be much more informative to the end users, and help them to better judge in what process conditions they can
use the SUS.
5.2.6 Integrity testing is used to confirm the SUS’s barrier properties; it verifies functional performance, taking into consideration
the process environment and considerations (5). The required level of integrity assurance will depend on how critical the
application is and can be interpreted in different ways, such as microbial ingress risk, operator safety, or liquid leaks.
5.2.7 Employing a quality-by-design (QbD) approach may eliminate testing in Qualification phase if different SUS designs are
considered functionally equivalent under a bracketing approach, allowing to leverage previous Qualification phase results. This
would require a strong dialog between the supplier and end user to get adequate understanding to justify appropriately such
functional equivalent. In-depth dialog is also required when implementing point-of-use testing performed by the end user in a
Commercial Production application. If planned, point-of-use testing should be incorporated in the user requirement specification
(URS) with required sensitivity, in order for the SUS supplier to design the appropriate system and provide input on the test
procedure. Alignment between SUS supplier and end user is crucial with point-of-use testing to ensure test results are correctly
interpreted, avoiding false test failures which could lead to improper SUSs or batch discards for pre- or post-use testing,
respectively.
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6. Test Method Overview
6.1 The following sections are intended to give an overview about existing microbial and physical testing method to evaluate the
integrity of various flexible SUS configurations. Standard test setups are shown and standard procedures briefly described. Test
parameter sets and result interpretation are not discussed.
MICROBIAL SINGLE-USE SYSTEM INTEGRITY TEST (SUSIT) METHODS
6.2 More detailed explanation for microbial test methods is provided in Test Method E3251, and for physical test methods in Test
Method E3336. This includes:
6.2.1 Specific test method principles, procedures and apparatus adapted to test SUS.
6.2.2 Interference and their mitigation strategies.
6.2.3 Test method validation principles.
6.2.4 Calibration and conditions needs.
6.2.5 Calculation and interpretation of results.
MICROBIAL SINGLE-USE SYSTEM INTEGRITY TEST (SUSIT) METHODS
6.3 Introduction:
6.3.1 Ultimately QbD principles, leak tests, operator training, visual inspections and a thorough initial validation of the process
and handling are the best steps in protecting SUSs from microbial contamination. However, in addition to the above steps,
implementation of a microbial ingress test as part of a SUS’s initial validation may be necessary. This test can either be done on
negative test articles only to prove the microbial barrier property of the integral SUS, or on positive control test articles,
intentionally compromised with calibrated defects to determine the MALL. Applying analytical validation principles from ICH
Q2(R1), the detection limit of the microbial ingress test method must be determined to fulfill the requirements for test method
validation. This is especially important, when using the determined MALL as a reject criterion for a non-destructive, deterministic
integrity test to prove the inherent microbial integrity of an individual SUS.
6.3.2 A microbial challenge study by immersion exposure is a common microbial ingress test. Tests by aerosol exposure can also
be performed. It is important to point out that, with these studies, results are dependent on the conditions under which the test is
performed, and they are not suitable for routine checking of containers due to the test’s destructive nature. They are also technically
challenging for large systems and very labor-intensive to perform. Note that any breach larger than 0.2 μm may be forced to fail
under sufficiently aggressive conditions (including sufficiently large sample size, high differential pressure, or high hydrostatic
pressure, for example). Thus, one must clearly define relevant conditions for the test through a risk assessment of both the actual
SUS claims and final use. “Relevant conditions” refers to the worst case actual most severe use conditions but does not mean a
SUS must be tested under theoretically absolute (extreme) “worst-case” conditions. Testing may be performed on individual
components or entire systems. For example, a large SUS used to hold an in-process material, may be subjected to a microbial
challenge test under conditions that simulate relevant worst-case pharmaceutical manufacturing conditions. However, when testing
a small SUS where the primary container is intended for a sterile final drug product, more rigorous microbial test challenge
conditi
...