ASTM E3051-16

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.
Designation: E3051 − 16
Standard Guide for
Specification, Design, Verification, and Application of
Single-Use Systems in Pharmaceutical and
Biopharmaceutical Manufacturing
This standard is issued under the fixed designation E3051; 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 2. Referenced Documents
1.1 This guide is intended as a complement to Guide E2500.
2.1 ASTM Standards:
D4169 Practice for Performance Testing of Shipping Con-
1.2 This guide is applicable to the range of manufacturing
tainers and Systems
systems described in Guide E2500, specifically all elements of
E2363 Terminology Relating to Manufacturing of Pharma-
single-use systems, or hybrids of single-use and traditional
components, used for the manufacturing of pharmaceutical and ceutical and Biopharmaceutical Products in the Pharma-
biopharmaceutical products, including: materials of ceutical and Biopharmaceutical Industry
construction, components, assembly, manifolds, supporting
E2500 Guide for Specification, Design, and Verification of
utilities, associated process monitoring and control systems,
Pharmaceutical and Biopharmaceutical Manufacturing
automation systems, and controlled environment that have the
Systems and Equipment
potential to affect product quality and patient safety.
2.2 United States Pharmacopeia:
1.3 This guide is applicable for the implementation of
USP<788> Particulate Matter in Injections
changes to manufacturing system design for existing systems.
USP<790> Visible Particulates in Injections
It may be used for continuous improvement and changes in
2.3 International Conference on Harmonization of Techni-
operation from clinical through to commercial scale.
cal Requirements for Registration of Pharmaceuticals for
1.4 For brevity, single-use systems are referred to as SUS 4
Human Use (ICH):
throughout the rest of this guide.
ICH Q7 Good Manufacturing Practice Guide for Active
1.5 The approach may be applied by the end user, the
Pharmaceutical Ingredients
supplier of SUS, and raw materials sub-suppliers further back
ICH Q8 (R2) Pharmaceutical Development
in the supply chain.
ICH Q9 Quality Risk Management
ICH Q10 Pharmaceutical Quality System
1.6 This guide is not intended to apply to the use of
single-use technology for packaging, primary containers, com-
2.4 ISO Standards:
bination products (products composed of any combination of a
ISO 13485:2003 Medical Devices—Quality Management
drug, device, or biological product) or devices.
Systems—Requirements for Regulatory Purposes
1.7 This guide does not address specific local requirements,
ISO 14644 Cleanrooms and Associated Controlled Environ-
which remain the responsibility of the end user.
ments
ISTA 3A General Simulation Performance tests
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 2
For referenced ASTM standards, visit the ASTM website, www.astm.org, or
use. It is the responsibility of the user of this standard to 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
establish appropriate safety and health practices and deter-
the ASTM website.
mine the applicability of regulatory limitations prior to use.
Available from U.S. Pharmacopeial Convention (USP), 12601 Twinbrook
Pkwy., Rockville, MD 20852-1790, http://www.usp.org.
Available from International Conference on Harmonisation of Technical
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture Requirements for Registration of Pharmaceuticals for Human Use (ICH), ICH
of Pharmaceutical and Biopharmaceutical Products and is the direct responsibility of Secretariat, 9, chemin des Mines, P.O. Box 195, 1211 Geneva 20, Switzerland,
Subcommittee E55.07 on Single Use Systems. http://www.ich.org.
Current edition approved Feb. 1, 2016. Published March 2016. DOI: 10.1520/ Available from American National Standards Institute (ANSI), 25 W. 43rd St.,
E3051-16. 4th Floor, New York, NY 10036, http://www.ansi.org.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
E3051 − 16
2.5 U.S. Food and Drug Administration (USFDA): Template for Single-Use Biopharmaceutical Manufacturing
Guidance for Industry Process Validation: General Prin- Products BioProcess Systems Alliance).
ciples and Practices
3.1.3 modular, adj—SUS can consist of assemblies of com-
Pharmaceutical cGMPs for the 21st Century, A Risk-Based
ponents or subassemblies that can be built or reconfigured or
Approach
both in a modular manner provided that connectors are
2.6 European Medicine Agency:
compatible with each other.
Commission Directive 2003/94/EC of 8 October 2003
3.1.4 subject matter experts, n—individuals with expertise
2.7 Other Publications:
in a particular area or field, which will include, but are not
PDA Technical Report No. 66 Application of Single-Use
limited to, material sciences, plastics and molding
Systems in Pharmaceutical Manufacturing
technologies, sterilization, particulate assessment, and leach-
Consensus Quality Agreement Template for Single-Use Bio-
ables and extractables.
pharmaceutical Manufacturing Products BioProcess Sys-
tems Alliance 3.1.5 verification, n—verification is a systematic approach
to verify that SUS, acting singly or in combination, are fit for
TAPPI Standard Practice T 564 sp-11
intended use, have been properly installed, and are operating
3. Terminology
correctly.
3.1.5.1 Discussion—The manufacturing process for an SUS
3.1 Definitions:
consists of multiple steps and verification activities should be
3.1.1 For definitions of terms used in this guide, refer to
appropriate for the stage of the SUS design and manufacturing
Terminology E2363, Guide E2500, and PDA Technical Report
process (for example, material selection versus component
No. 66. Terms requiring special consideration as they relate to
dimensions versus configuration) and the intended purpose of
SUS are detailed below.
the component or finished assembly or both. Verification is an
3.1.2 design reviews, n—purpose of design reviews is still to
umbrella term that encompasses all types of approaches to
evaluate design against standards and requirements, identify
assuring systems are fit for use including qualification, com-
problems, and propose corrective actions.
missioning and qualification, verification, system validation, or
3.1.2.1 Discussion—However, the scope of the review may
other and extends across the supply chain as materials and
differ depending on whether the end user is considering a
components are integrated into the completed SUS. Given that
standard design, configured variants of standard designs which
each system is partially or completely replaced after use, it is
maintain adherence to the supplier’s design space, or custom-
important to confirm that components have been assembled
ized designs, which incorporate one or more features that are
correctly, none of the critical attributes of the assembly are
outside of the supplier’s design space. Such features may
damaged during installation, and no leaks that may compro-
include components, design layout, design dimensions, or
mise the SUS are evident before use. Suppliers of SUS and
materials of construction. The end-user should first consider
their materials and components should apply similar rigor and
the requirements for any given SUS based on the application
change control procedures to their sub-suppliers to ensure
(for example, product or process contact, temperature,
consistent quality over the lifetime of the SUS (see also 8.2,
volumes, flow rates, mixing, requirements for sensors and
Change Management).
controls etc. as applicable) and define them clearly in a
document such as a user requirement specification (URS). In
the case of standard or configured designs, the review will 4. Summary of Guide
address the supplier’s criteria for selection of materials,
4.1 This guide is based on a similar risk-based and science-
components, and functional design and align these against the
based approach taken in Guide E2500 and is similar in
URS. In the case of end-user-specified custom designs, the
purpose, content, and organization.
design review should affirm that the combination of supplier-
4.2 The objective of this guide is to provide additional
and user-derived design attributes aligns with the URS.
information to support defined and controlled processes rel-
Additionally, the review should evaluate the risk taken in
evant to SUS, or hybrid traditional SUS to enable the produc-
deviating from the supplier design space, and the possible need
tion of products that consistently meet defined quality require-
for risk mitigation, which generally will be the end user’s
ments. A further objective is to support supplier manufacturing
responsibility. The risk assessment should be retained as part of
capability that meets quality requirements of SUS or User
the development history. Conditions and expectations should
Requirement Specifications (URS) or both as applicable.
be covered in a quality agreement. The quality agreement
should outline the responsibilities of the supplier and the end
4.3 The approach described within this guide supports
user with respect to the quality assurance of the system
continuous process capability improvements and facilitates
manufactured or supplied or both by the supplier to the end
incorporation of new capabilities as technology evolves.
user. Quality agreement templates are available from various
4.4 The main elements of this guide are:
industry groups (for example, Consensus Quality Agreement
4.4.1 The underlying key concepts,
4.4.2 A description of the specification, design, and verifi-
Available from U.S. Food and Drug Administration (FDA), 10903 New
cation process, and
Hampshire Ave., Silver Spring, MD 20993, http://www.fda.gov.
Available from BioProcess Systems Alliance, http://www.bpsalliance.org. 4.4.3 A description of the required supporting processes.
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5. Significance and Use 6.3.1 Product and process information, as it relates to
product quality and patient safety, remain the basis for making
5.1 Application of the approach described within this guide
science- and risk-based decision that ensure that the SUS are
is intended to satisfy international regulatory expectations in
designed and verified to be fit for their intended use.
ensuring that SUS are fit for their intended use and to satisfy
6.3.2 Examples of end-user product and process informa-
requirements for sourcing, supply, design, specification,
tion to consider include: critical quality attributes (CQAs),
installation, operation, and performance.
critical process parameters (CPPs), process control strategy
5.2 The approach described in this guide applies concepts
information, and prior production experience. For SUS, these
and principles introduced in the FDA initiative, Pharmaceutical
can include extractables information, certificates of analysis,
cGMP’s for the 21st Century – A Risk-Based Approach. It
sterilization records, change control documents, and product
supports and is consistent with the framework described in
design specifications.
FDA Guidance for Industry, Process Validation: General Prin-
6.3.3 Additional information to consider is the processing
ciples and Practices, in ICH Q7, ICH Q8 (R2), ICH Q9, and
parameters and materials for the SUS themselves. Materials
ICH Q10.
and designs should be selected and developed based on the
5.3 This guide includes concepts developed in the PDA
intended use of the SUS (for example, cell culture, buffer bag,
Technical Report No. 66.
and product container) using quality by design approaches,
such that sources of variability are understood and are managed
5.4 This guide may be used independently or in conjunction
such that they do not impact the performance of the end user’s
with other ASTM Committee E55 proposed standards to be
process or product quality.
published by ASTM International.
6.3.4 Special consideration should be given to the supplier’s
5.5 Specific standard practices about extractables,
evaluation and selection of materials of construction (for
leachables, particulate matter, and integrity testing/leak
example, films, tubing, and connectors) as related to their
detection, biocompatibility, and raw materials as available
fitness for intended use based on parameters such as physico-
should be used by suppliers and end users and applied to their
chemical properties, mechanical strength, optical properties,
own manufacturing process facilities.
and anticipated operating temperature. Materials should be
robust and compatible with product and process fluids and
6. Key Concepts
should not be excessively prone to damage, which compro-
6.1 This guide follows similar key concepts to those cov- mises structural integrity. The shedding of any materials, either
ered by Guide E2500 focusing on clarification and discussion
as solid particles or soluble leachables, that impact product
of SUS, good engineering practice, good manufacturing quality or process performance should be well characterized.
practice, and use of supplier and end user documentation. The
For SUS, this is particularly important since changes may be
concepts are listed in the following: made in the construction materials, production and sterilization
6.1.1 Risk-based approach,
processes, additives such as anti-oxidants and dyes, and
6.1.2 Science-based approach,
material origin based on their availability over the lifetime of
6.1.3 Critical aspects of SUS,
a given process. Such changes should be evaluated with the
6.1.4 Quality by design,
appropriate diligence based on the risk to the product or the
6.1.5 Good engineering/manufacturing/distribution/
process.
documentation practices,
6.3.5 Consideration should be given to the possible impact
6.1.6 Subject matter expert,
of materials of construction or in-process leachables from
6.1.7 Use of supplier documentation,
materials of construction, or both, on product quality or process
6.1.8 Continuous improvement and change management,
performance.
and
6.4 Critical Aspects of SUS:
6.1.9 Supply chain.
6.4.1 Critical aspects of SUS are typically functions,
6.2 Risk-Based Approach:
features, abilities, and performance or characteristics necessary
6.2.1 The underlying principle of risk management focuses
for the manufacturing process and systems to ensure consistent
on the issues which have the highest probability of occurring or
product quality and patient safety. They should be identified
have the greatest effect on the product quality and consequently
and documented based on scientific product and process
patient safety.
understanding for both the SUS manufacturing process and the
6.2.2 Risk management underpins the specification, design,
end-user process.
verification, and documentation activities as described in
6.4.2 SUS often consist of multiple combinations of indi-
Guide E2500 and in ICH Q9.
vidual components. Often, multiple design configurations can
6.2.3 SUS are an integral part of the drug manufacturing
be considered with varied materials and components, each of
process and it is critical that SUS suppliers provide SUS in a
which can be demonstrated as capable of meeting the critical
timely manner. Special consideration should be given to
performance requirements for a given system such as volume,
mitigating the risk of an interruption of the supply chain of
compatibility, low bioburden, freedom from leaks, and mixing
SUS, which may have an impact on the security of supply of
if required.
drug to patients.
6.4.3 Adopting a modular design approach allows for the
6.3 Science-Based Approach: interchangeable use of functionally equivalent components and
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provides flexibility, which can be used to the advantage of both materials used to make the SUS to determine any potential
end user and supplier to manage the risk to supply continuity, effects that such raw material variation may have on their
subject to the appropriate qualification of alternative suppliers, process and product quality. Variability can arise from changes
materials, components, and designs and the existence of a in sources of materials and processing conditions, both planned
well-planned connectivity strategy. and inadvertent, and should be managed by effective change
6.4.4 Critical aspects of SUS may be compromised through- management communication and transparency on the part of
the supplier.
out the lifetime of an SUS, which extends across component
manufacturing, final assembly, sterilization, transportation,
6.6 Good Engineering, Manufacturing Practices:
receiving, warehousing, installation, deployment, and use.
6.6.1 Good engineering and manufacturing practices (GXP)
6.4.5 A risk-based approach analyzing potential points and
should underpin and support the specification, design, and
types of failures through the lifetime of an SUS from
verification activities.
fabrication, shipment, installation, deployment, and operation
6.6.2 The extent to which suppliers and sub-suppliers ad-
should be used to determine the appropriate controls and
here strictly to GXP may vary. Many may also manufacture
testing to be used at each point.
medical devices and adhere to other relevant standards (for
6.4.6 Additional activities to qualify alternative components
example, ISO 13485).
and suppliers should be documented to facilitate improvements
6.6.3 The end user should engage in quality audit and
to the design or as part of change control in response to
technical due diligence activities to ensure that suppliers have
discontinuation of supply. This is detailed in following sec-
defined designs and specifications and implemented quality
tions.
management systems that are appropriate for the intended
6.4.7 Where suppliers provide standard designs for specific
purpose of the SUS.
unit operations, the supplier should provide documentation to
6.6.4 Appropriate distribution practices should be imple-
support the selection and qualification of materials,
mented and ensured throughout the entire lifecycle of the SUS
components, or functional design, or combination thereof, in
to minimize damage to assemblies. (Good manufacturing
relation to its intended use (for example, cell type, fed-batch
practice and good distribution practice compliance, European
versus perfusion, mixing and sparging, temperature shift ramp
Medicines Agency)
rates, and so forth).
6.7 Subject Matter Experts (SMEs)—The role of subject
6.4.8 Where the end user has requested a custom design
matter experts is the same in this guidance as for Guide E2500.
based on specific preferences for components, or a different
Specific areas of subject matter expertise may differ with
combination of inlets, outlets, or ports, the responsibility for
knowledge of material properties, extractables and leachables,
traceability of individual components and the performance of
and particulate generation being particularly important. Quali-
various parts of the assembly should be defined in the URS or
fied suppliers are an important source of SMEs as they have
a specific quality agreement as appropriate, along with the
industry-wide exposure to SUS performance and best prac-
supply agreement and technical diligence as appropriate.
tices.
6.4.9 SUS are susceptible to variances in appearance be-
cause of creases made throughout assembly, packing, handling,
6.8 Use of Supplier Documentation:
transit, inspection and deployment. End users and suppliers
6.8.1 Clear and comprehensive documentation between the
should establish what constitutes normal and acceptable cos-
end user and supplier is critical to define the design, specifi-
metic variances.
cation and performance of the SUS and clarify other expecta-
tions (for example, technical support).
6.5 Quality by Design:
6.8.2 The end user of SUS is considerably more dependent
6.5.1 SUS are heavily reliant on quality by design concepts.
on supplier documentation than traditional reusable systems
The degree to which post-installation verification can be
applied to SUS is limited. Quality depends upon clearly stated that are verified by the end-user. In some cases the supplier
may be the only practical source for justifying designs and
expectations defined in a URS; design specifications that match
confirming ongoing quality (for example, pre-sterilized assem-
expectations; a qualified design and manufacturing process; the
blies). Supplier documentation, including test documentation,
supplier’s quality and supply chain systems; and proper
may be used as part of the verification documentation provid-
handling, deployment, and use procedures.
ing the regulated company has assessed the supplier and has
6.5.2 The critical aspects of the design and associated
evidence of:
acceptance criteria should be documented in the URS.
6.8.2.1 An acceptable supplier quality system,
6.5.3 Assurance that manufacturing systems are fit for
intended use should not rely solely upon verification after 6.8.2.2 Supplier technical capability, and
installation but also be achieved by a planned and structured 6.8.2.3 Supplier application of appropriate practices (GXP,
verification approach applied throughout the system lifecycle. ISO) such that information obtained from the supplier will be
6.5.4 Suppliers should apply and maintain a similar level of accurate and suitable to meet the purpose of verification.
stringency and scrutiny as is applied to them to their own 6.8.3 It is incumbent on the end user to understand the
sub-suppliers to provide a higher degree of assurance that the
supplier’s product testing strategy and release criteria, as this
critical aspects of the SUS can be routinely and reliably met. technical understanding will form the basis of an overall risk
6.5.5 The end user should work with the supplier to be assessment on the use of supplier documentation. One should
knowledgeable of potential sources of variation in the raw be aware that suppliers may take different, but equally valid,
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approaches to controlling and testing for SUS critical quality 6.10.1 The supply chain for SUS is complex, starting with
attributes. The end-user assessment should focus on the desired petrochemicals, and materials undergo multiple manipulations
outcome relative to the URS or specification. and processes before becoming a completed assembly.
6.10.2 To have good assurance of quality in the overall
6.8.4 The supplier and end user should also develop a
sourcing and management of materials and components, end
shared understanding of the end-user’s acceptance criteria to
users should assure that they understand sources of product and
ensure alignment between the supplier’s capabilities, the func-
process risk that derive from their suppliers and sub-suppliers
tional requirements of the SUS, and the relevance of the testing
Such understanding will come through transparent dialog with
methods used.
suppliers and technical due diligence activities described in
6.8.5 The end user may mitigate potential inadequacies in
6.8.
quality systems or GXP by applying specific, targeted addi-
6.10.3 Special consideration should be given to the qualifi-
tional checks or other controls, which may be extended to
cation of additional suppliers and alternative designs and
sub-suppliers, rather than repeating supplier activities and
materials in the event of a supply chain failure at a single
replicating documentation.
supplier. This may be managed in part at the level of the
6.8.6 The supplier’s technical capability should be assessed
supplier who should already have qualified alternatives for
through a technical diligence exercise. Suppliers should dem-
sub-supply of materials and components.
onstrate sufficient technical capability to have control over
6.10.4 Many SUS are pre-sterilized process components or
their design, development and manufacturing processes. They
systems and often are implemented without pre-use testing by
benefit from being given an understanding of how their
the end user. Therefore, the supply chain, especially packaging
materials are used by the end user such that there is an
and transportation, should be qualified and controlled to assure
understanding of the potential impact of any changes and
that the SUS remains undamaged and that the leveraging of
ensure they are communicated, and should have sufficient
supplier activities and documentation remains relevant.
technical resources and procedures to support investigations of
6.10.5 SUS have a finite shelf life, due to materials of
complaints (Section 8). A technical diligence exercise differs
construction and the resulting stress put on such by sterilization
from a quality audit in that it is an open ended exchange of
or bioburden reduction processes. Steps should be taken
information between SME’s at the supplier and end user to
together with the supplier to ensure suitable storage conditions
provide a shared underst
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