ASTM F3206-17
(Guide)Standard Guide for Assessing Medical Device Cytocompatibility with Delivered Cellular Therapies
Standard Guide for Assessing Medical Device Cytocompatibility with Delivered Cellular Therapies
SIGNIFICANCE AND USE
4.1 This guide is designed to assist medical device manufacturers as they develop new devices or qualify existing devices (e.g., catheters, needles) for delivering clinical cell therapies. Cytocompatibility considers the impact of the delivery device on the cells passing through the device during the delivery procedure. The biological safety of the device (e.g., the device’s cytotoxicity) should be addressed via other methods, such as ISO 10993-5. It is understood that this guide does not address testing of specific cellular products with specific delivery devices. Such testing may be required by regulatory authorities prior to clinical trial of cellular product or marketing applications. This guide outlines considerations to make the product qualification procedures more likely to succeed and more cost effective.
4.2 The key aspects of assessing device cytocompatibility include selecting a test cell line or cell lines and determining the cell physiology parameters that will be measured to make a determination of cytocompatibility. Acceptance criteria for designating a device as cytocompatible are not detailed here. It will be up to the delivery device end user to determine if the results of a cytocompatibility assessment are sufficient to consider that device cytocompatible. Delivery device lot to lot variability may impact cytocompatibility, therefore validated manufacturing processes should be considered when producing devices for cytocompatibility assessments.
SCOPE
1.1 This guide outlines the parameters to consider when designing in vitro tests to assess the potential impact of a delivery device on a cellular product being dispensed. This guide does not provide specific protocols, but rather suggests what should be considered the minimum characterization necessary to assess device cytocompatibility. Topics discussed include selecting an appropriate cell line(s), cell physiology parameters to measure, and relevant test procedure variables. Only cells suspended in liquid and infused through a device are considered. Cell therapies paired with scaffolds, suspended in hydrogels, or administered via other methods (e.g., tissue grafting) are not included in the scope of this document. This document does not address physical characterization of delivery devices, such as mechanics, composition, or degradation.
1.2 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.
1.3 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.
General Information
Relations
Standards Content (Sample)
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: F3206 − 17
Standard Guide for
Assessing Medical Device Cytocompatibility with Delivered
Cellular Therapies
This standard is issued under the fixed designation F3206; 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 F2739 Guide for Quantifying Cell Viability within Bioma-
terial Scaffolds
1.1 This guide outlines the parameters to consider when
F2809 Terminology Relating to Medical and Surgical Mate-
designing in vitro tests to assess the potential impact of a
rials and Devices
delivery device on a cellular product being dispensed. This
2.2 ISO Standard:
guide does not provide specific protocols, but rather suggests
ISO 10993-5 Biological evaluation of medical devices – Part
what should be considered the minimum characterization
5: Tests for in vitro cytotoxicity
necessary to assess device cytocompatibility. Topics discussed
include selecting an appropriate cell line(s), cell physiology
3. Terminology
parameters to measure, and relevant test procedure variables.
3.1 Definitions:
Only cells suspended in liquid and infused through a device are
3.1.1 cell line, n—a generic term that includes primary,
considered. Cell therapies paired with scaffolds, suspended in
stem, and immortalized cells.
hydrogels, or administered via other methods (e.g., tissue
3.1.2 cytocompatible, adj—referringtothelackofunaccept-
grafting) are not included in the scope of this document. This
document does not address physical characterization of deliv- able impact on a cellular product from interaction with a
medical device used for delivery or interaction with manufac-
ery devices, such as mechanics, composition, or degradation.
turing components. For example, a cytocompatible device does
1.2 This standard does not purport to address all of the
not unacceptably impact the cells passing through it as to
safety concerns, if any, associated with its use. It is the
compromise the potency of the cell therapy product.
responsibility of the user of this standard to establish appro-
3.1.3 immortalized cell, n—a primary cell that has been
priate safety and health practices and determine the applica-
bility of regulatory limitations prior to use. transformed or otherwise altered to provide an extended
1.3 This international standard was developed in accor- replication capacity beyond that of the originating primary cell.
dance with internationally recognized principles on standard- An immortalized cell may be naturally isolated (e.g., cancer
ization established in the Decision on Principles for the cell) or purposely transformed in the laboratory.
Development of International Standards, Guides and Recom-
3.1.4 primary cell, n—a cell with a finite replication poten-
mendations issued by the World Trade Organization Technical
tial that has not been biologically altered to promote extended
Barriers to Trade (TBT) Committee.
survival. A primary cell may be frozen or freshly isolated but
the passage history must be known and display demonstrable
2. Referenced Documents
senescence.
2.1 ASTM Standards:
3.1.5 senescence, n—the property attributable to finite cell
F813 Practice for Direct Contact Cell Culture Evaluation of
cultures; namely, their inability to grow beyond a finite number
Materials for Medical Devices
of population doublings. F2809
F2394 Guide for Measuring Securement of Balloon Expand-
3.1.6 stem cells, n—progenitor cells capable of self-
able Vascular Stent Mounted on Delivery System
replication, proliferation, and differentiation. F2809
3.1.7 viable cell, n—a cell capable of sustaining metabolic
This test method is under the jurisdiction ofASTM Committee F04 on Medical activity that is structurally intact with a functioning cell
and Surgical Materials and Devices and is the direct responsibility of Subcommittee
membrane. F2739
F04.43 on Cells and Tissue Engineered Constructs for TEMPs.
Current edition approved March 1, 2017. Published June 2017. DOI: 10.1520/ 3.2 Definitions of Terms Specific to This Standard:
F3206–17.
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 Available from International Organization for Standardization (ISO), ISO
Standards volume information, refer to the standard’s Document Summary page on Central Secretariat, BIBC II, Chemin de Blandonnet 8, CP 401, 1214 Vernier,
the ASTM website. Geneva, Switzerland, http://www.iso.org.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
F3206 − 17
3.2.1 ancillary equipment, n—equipment to be paired with bility during passaging, acceptable passage number, and simi-
the delivery device (e.g., fittings, syringes, etc.) to facilitate in lar parameters should all be well established. Delivered cells
vitro testing through which the cells will pass but are not part may be assayed for viability or function as part of the
of the delivery device as used in the clinic. cytocompatibility evaluation. It is vital that the baseline viabil-
ity and functionality of the cells is established and tracked over
3.2.2 delivery device, n—a medical device designed to
time in order to detect any adverse device impacts.
deliver therapeutic cells into the body.
5.3 Animal cell lines may be a possibility for use in
4. Significance and Use
cytocompatibility testing; however, human cell data is prefer-
4.1 This guide is designed to assist medical device manu-
able. Animal cells offer an advantage given that the in vitro
facturers as they develop new devices or qualify existing
testing can be supplemented by delivering cells directly into
devices (e.g., catheters, needles) for delivering clinical cell
established animal models for further characterization;
therapies. Cytocompatibility considers the impact of the deliv-
however, that is outside the scope of this guide.
ery device on the cells passing through the device during the
delivery procedure. The biological safety of the device (e.g.,
6. Test Method Design
the device’s cytotoxicity) should be addressed via other
6.1 Determining the device impact on delivered cells neces-
methods, such as ISO 10993-5. It is understood that this guide
sitates careful characterization of the chosen cell line(s). The
does not address testing of specific cellular products with
appropriate cell morphology and harvest density for use in an
specific delivery devices. Such testing may be required by
assay must be established. The potential impact of the disso-
regulatory authorities prior to clinical trial of cellular product
ciation method if using adherent cells (e.g., trypsin versus
or marketing applications. This guide outlines considerations
non-enzymatic dissociation) may also need to be considered. It
to make the product qualification procedures more likely to
is assumed that cells in culture will be used for purposes of
succeed and more cost effective.
expediency and throughput, but using freshly thawed cell
4.2 The key aspects of assessing device cytocompatibility
aliquots to mimic a clinical application is also suitable. If this
include selecting a test cell line or cell lines and determining
method is selected, the baseline physiology of the cells after
the cell physiology parameters that will be measured to make
thawing must be established. Consideration should be given to
a determination of cytocompatibility. Acceptance criteria for
how the liquid chosen for suspension of the cells, or other
designating a device as cytocompatible are not detailed here. It
suspension liquids, may interact with the delivery device
will be up to the delivery device end user to determine if the
materials (e.g., degrade the materials, extract leachables) and
results of a cytocompatibility assessment are sufficient to
impact cytocompatibility.
consider that device cytocompatible. Delivery device lot to lot
6.2 Positive and negative assay controls will be included
variability may impact cytocompatibility, therefore validated
whenever possible.The negative control will be cells harvested
manufacturingprocessesshouldbeconsideredwhenproducing
and assayed having never touched the delivery device. Nega-
devices for cytocompatibility assessments.
tive control cells should be prepared as if being passed through
5. Cell Selection
the device (e.g., at the set density, added to any ancillary
equipment required). The positive control will be cells that
5.1 The cellular response to delivery device contact will
show diminished viability and/or function. Producing a posi-
comprise the readout for the cytocompatibility characteriza-
tive control can be accomplished by different approaches. A
tions considered in this guide. Given this, selection of the test
specific delivery device known to impair cells by impacting
cell line to be used is critical. Selecting a cell line that
cell viability or function would be an ideal positive control.
represents the intended use of the delivery device is
Alternatively, chemical or mechanical treatments known to
encouraged, but not required. A single cell line or a panel of
impair cell line viability and/or function will suffice to dem-
lines, whether stem cells, primary cells, immortalized cells, or
onstrate that the cell line is sensitive enough to report these
a mixture thereof, may be necessary to characterize the device.
aspects of physiology. Processing agents used in device manu-
Regardless of the approach selected, the cell line(s) chosen
facture or known to be present in the manufacturing environ-
must demonstrate sensitivity to one or more evaluation param-
ment may make suitable positive controls. If using chemical or
eters being used to characterize cytocompatibility. The identity
mechanical treatments, a dose-response relationship should be
of selected cell lines should be authenticated by appropriate
evident to demonstrate the sensitivity of the chosen cell to
means. Be mindful that some cell lines have licensing fees or
impairment. Different treatments may be used on separate
patent protection which must be addressed. Also consider the
positive control samples in the same assay to perturb specific
available supply and potential issues with obtaining additional
functions (i.e., multiple positive controls are acceptable).
cell stocks which may introduce unacceptable variability.
Ideally, as the field develops further, a reference cell line or
6.3 Akey aspect of testing will be selecting device delivery
panel of lines may be established for the purpose of device
flow rates that approximate clinical use rates. At a minimum,
cytocompatibility testing.
delivery should be assessed at both a minimum and a maxi-
5.2 It is critical that the chosen cells are well characterized. mum approximated clinical use flow rate. Syringe pumps or
Cell and culture condition variables such as growth rate, similar calibrated equipment should be used to ensure delivery
handling protocols, media requirements, culture vessel coating, consistency. Since the delivery flow rate will determine intra-
dissociation methods (if adherent), typical morphologies, sta- device forces and the impact on delivered cells, when possible,
F3206 − 17
the ancillary equipment required to use the device being tested impact cytocompatibility. If so, simulated deployment prior to
(e.g., syringes, adapter fittings, needles, etc.) should be kept delivery should be included in the test method.
constant for all testing. Different device sizes may necessitate
multiple groups of ancillary equipment. The chosen cell line(s)
7. Cell Physiology Assessment Post Device Delivery
andintendedclinicaluseofthedeliverydevicemaydictatethat
7.1 A multitude of characteristics could be considered in
additional delivery rates besides the minimum and maximum
evaluatingthecytocompatibilityofthedeliverydevicewiththe
should be part of the assessment.
test cell. For the simplest assessment, three key measures of
6.4 Cell density in the test sample delivered through the
cytocompatibility will be discussed and should be the mini-
device may also be important as different cell lines show
mum required in any report on device cytocompatibility.
density effects. As with delivery rates, careful characterization
Additional parameters may be added at the discretion of the
of the chosen cell line during assay development will deter-
user. The technical methods used to quantify the three key
mine if a range of densities should be part of the protocol or if
measures should be well characterized in their use with the
a single standard density is sufficient. The volume of liquid
chosen test cell line.
suspension to deliver should be sufficient to account for any
7.2 Total Cell Recovery—One component of a device cyto-
dead space that the device will hold and still yield enough
compatibility assessment is determining recovery of cells
sample volume for all subsequent characterization. The meth-
ods used to determine recovery and viability may dictate an passed through a device relative to the input population. Cells
may adhere to the delivery device or become trapped in device
acceptable cell density range to use in order to provide
confidence with the selected method. geometry and be lost to the recoverable population. Cells may
also clump leading to clogging of the device or force the
6.5 Delivery devices should be evaluated in their finished
delivered cells into unintended aggregates. Cell recovery can
form as they would be offered for clinical use (i.e., not
be determined by counting the number of intact input cells that
modified to facilitate cytocompatibility testing). If testing a
pass through the delivery device. Methods to determine recov-
range of devices (e.g., an infusion catheter available in a range
ery should be able to distinguish intact individual cells from
of French sizes and lengths), it is acceptable to select the
debris and aggregates. Manual or automated cell counting
largest and smallest for each parameter as representative of the
methods are both acceptable; provided the error associated
range as long as the delivery rates, cell densities, and any
with a given method is known. In addition, visual inspection of
required ancillary equipment does not change. Smaller devices
the used delivery device may help identify potential recovery
designed to hold and deliver minimal volum
...
Questions, Comments and Discussion
Ask us and Technical Secretary will try to provide an answer. You can facilitate discussion about the standard in here.