Technical

Information
Report

AAMI TIR42:
2021
Evaluation of particulate
associated with vascular
medical devices

Advancing Safety in Health Technology

AAMI Technical Information Report AAMI TIR42:2021

Evaluation of particulate associated with vascular

medical devices

Approved 31 March 2021 by

AAMI

Abstract: This document provides information for defining appropriate test methods, determining the source of
particulate, assessing the clinical risk of particulate, and establishing product particulate limits.
Particulate could arise from many sources including materials, environment, and clinical use. This
TIR is intended to offer guidance to the medical device industry when evaluating the tendency for
medical devices to release particulate, identifying particulate sources, applying analytical methods
for particulate testing, and developing particulate limits based on clinical risk.

Keywords: acute, coating, emboli, hydrophilic, light microscopy, light obscuration, literature review, medical
device, particle, particle counting, particulate limits, particulate matter, risk, simulated use, test
method, validation
AAMI Technical Information Report

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Published by
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© 2021 by the Association for the Advancement of Medical Instrumentation

All Rights Reserved

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Printed in the United States of America

ISBN 978-1-57020-787-7
Contents Page

Committee representation ............................................................................................................................................. iv

Foreword ........................................................................................................................................................................ v
Introduction ................................................................................................................................................................... vi
1 Scope .................................................................................................................................................................... 1
2 Normative references ............................................................................................................................................ 1
3 Definitions ............................................................................................................................................................. 1
4 Introduction ........................................................................................................................................................... 2
5 Key characteristics for evaluation of particulate .................................................................................................... 2
6 Sources of particulate ........................................................................................................................................... 3
7 Particulate evaluation test methods ...................................................................................................................... 7
8 Literature review.................................................................................................................................................. 12
9 Considerations for establishing quantitative limits for product particulate ........................................................... 22
Annex A Summary of particulate characterization technologies .................................................................................. 30
Bibliography ................................................................................................................................................................. 34

Tables

Table A.1—Primary particulate quantitation and sizing technologies ........................................................................... 30

Table A.2—Additional particulate quantitation and sizing technologies ....................................................................... 31

Table A.3—Particulate chemical identification technologies ........................................................................................ 32

Committee representation

Association for the Advancement of Medical Instrumentation

Medical Device Particulates Committee
This technical information report (TIR) was developed by the AAMI Medical Device Particulates Committee. Approval
of the TIR does not necessarily imply that all committee members voted for its approval.

At the time this document was published, the AAMI Medical Device Particulates Committee had the following
members:

Cochairs: Terry Irwin, MBA, CMQ/OE

Dinesh Patwardhan, PhD
Project Leader: Eleni Whatley, PhD
Members: Susanne Anderson, NAMSA
August Baur, Centurion Sterilization Services
Kendahl Bennis, Boston Scientific
Martin Boehm, Shire/Takeda Pharmaceuticals
Lindsey Borton, MPH, Smiths Medical
Carolyn Braithwaite-Nelson, Spectranetics/Philips
Alina Bridges, Mayo Clinic
Amitabh Chopra, Camarillo, CA
James Conti, PhD, Dynatek Labs
Lydia Edgewater, W.L. Gore & Associates
Paul Fioriti, B. Braun Medical
Dan Floyd, CISS-EO, DuPont Tyvek Medical and Pharmaceutical Protection
Doug Harbrecht, Sterility Assurance Ltd.
Stephanie Hsia, Medtronic Neurovascular
Yin Hu, MD, University Hospitals of Cleveland
Terry Irwin, Edwards Lifesciences
Allan Kimble, DuPuy Synthes USA/Johnson & Johnson
Stan Lam, PhD, Stryker Neurovascular
Rashi Mehta, West Virginia University Hospitals
Rupal Mehta, Rush University Medical Center
Tonya Morris, BS, Nelson Laboratories/Sotera Health
Dinesh Patwardhan, U.S. Food and Drug Administration/CDRH
Christin Pawleski-Hoell, Raumedic Inc.
Sandi Schaible, WuXi Apptec Inc.
Kyle Timme, Cook Research
Craig Weinberg, PhD, Biomedical Device Consultants & Laboratories
Neal Zupec, Baxter Healthcare Corporation
Alternates: Brian Choules, PhD, Biomedical Device Consultants & Laboratories
Robert John Evjen, Boston Scientific
Siddharth Loganathan, Stryker Neurovascular
Gerald McDonnell, PhD, Johnson & Johnson
Nicholas Packet, DuPont Tyvek Medical and Pharmaceutical Protection
Elaine Strope, PhD, Dynatek Laboratories
Carl Swanson, NAMSA
Eleni Whatley, PhD, U.S. Food and Drug Administration/CDRH
Preston Zook, Nelson Laboratories/Sotera Health

NOTE Participation by federal agency representatives in the development of this technical information report does
not constitute endorsement by the federal government or any of its agencies.

iv © 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021

Foreword

This technical information report was developed by the AAMI Medical Device Particulates Committee. The objective is
to provide technical information that will assist medical device manufacturers in determining acceptable levels of
particulate on medical device products used to deliver or implant into the vasculature, or both.

The following verbal forms are used within AAMI documents to distinguish requirements from other types of provisions
in the document:

 “shall” and “shall not” are used to express requirements;

 “should” and “should not” are used to express recommendations;

 “may” and “may not” are used to express permission;

 “can” and “cannot” are used as statements of possibility or capability;

 “might” and “might not” are used to express possibility;

 “must” is used for external constraints or obligations defined outside the document; “must” is not an alternative
for “shall.”

Suggestions for improving this recommended practice are invited. Comments and suggested revisions should be sent
to Standards, AAMI, 901 N Glebe Road, Suite 300, Arlington, VA 22203 or standards@aami.org.

NOTE This foreword does not contain provisions of the AAMI TIR42, Evaluation of acute particulate generation
associated with vascular medical devices (AAMI TIR42:2021), but it does provide important information about the
development and intended use of the document.

© 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021 v

Introduction

This Technical Information Report (TIR) addresses the particulate matter on limited duration and implantable medical
devices, and on accessory devices used in the vascular system during the delivery and implantation or exposure and
removal of such devices. Unintentional particulate matter on medical devices can be a quality control issue because of
the manufacturing environment or a device design–related issue. Sources of particulate in the manufacturing
environment might include glove powders, lint and other fibers, paper particles, packaging materials, paint particles,
and many other materials. Release of particulate during use is a characteristic of medical devices that may be
addressed in product development. Particulate consisting of device materials can arise because of friction, abrasion,
or dissolution, and can have significant effects on patient outcome.

vi © 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021

AAMI Technical Information Report AAMI TIR42:2021

Evaluation of particulate associated with vascular

medical devices
1 Scope
1.1 General
This document addresses particulate released from intravascular medical devices that have direct contact with
circulating blood. It is intended to assist intravascular medical device manufacturers in defining appropriate test
methods, determining the source of particulate, assessing the clinical risk of particulate, and establishing product
particulate limits.

1.2 Inclusions
This document specifically includes particulate that could be acutely released into the vasculature from intravascular
medical devices and accessories used with the devices. This might include particulate as a result of manufacturing,
packaging, materials, coatings, and acute device use. This document only addresses particulate that might be released
during acute intravascular device use, i.e., from introduction to device and accessory withdrawal.

1.3 Exclusions
This document does not address particulate released after removal of a non-implantable device or after removal of an
implant’s delivery system and accessories, i.e., chronic particulate release from an implanted device such as due to
wear. It excludes intentional therapies in the form of particulate, for example drug coatings on balloons and embolization
microspheres or beads, though their delivery systems are included.

This document specifically excludes particulate arising from the operating room or clinical environment in which the
device is used.

This document does not address patient-generated particulate, such as those originating from plaque, that might be
produced before, during, or following an acute device procedure. Liquids, such as lubricating fluids, are not considered
to be particulate in the context of this document.

Routine monitoring of particulate levels on the device due to unintended changes in the manufacturing process or
environment are not discussed in this document.

2 Normative references
There are no normative references in this document.

3 Definitions
For the purposes of this technical information report, the following terms and definitions apply.

3.1
acute application
time frame during device delivery, or exposure to the device, up until all accessories have been removed during typical
procedures

NOTE Typical acute procedures usually last 2 hours or less. However, for the purposes of this document, acute procedures can
last up to 24 hours.

© 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021 1

3.2
fiber
minute piece of matter with defined physical boundaries and a length to width ratio (i.e., aspect ratio) of at least 10:1

3.3
particle
minute piece of matter with defined physical boundaries

[SOURCE: ISO 16197 [1] and ISO 14644

3.4
particulate
3.5
particulate matter
mobile particles and/or fibers present on or arising from the use of a medical device

NOTE Liquids and gas bubbles, whether miscible or immiscible, are not considered particulate. Hydrogels or other highly solvated
materials, which consist primarily of solvent in a polymer matrix, are included.
3.6
visible particulate
particulate matter 100 microns or larger

4 Introduction
In presentation of a medical device to patients, it is important to minimize the unintentional particulate matter present
on the device or released from the device during clinical use that can interact with the patient during therapy. Extraneous
particulate matter from a device has been indicated to present a safety risk to patients, in some instances, as described
in Sections 8 and 9 of this document.

Due to the absence of comprehensive and definitive clinical safety data, generally accepted particulate size ranges and
particulate count limits that aid patient safety have yet to be established for intravascular devices. This is due to the
fact that setting specific limits is complicated by varied patient thresholds to emboli due to a broad array of medical
conditions and comorbidities, the vast array of vascular beds with different sizes in the human anatomy, and the
benefit(s) of the device to the patient. This TIR has not overcome this obstacle but recommends general approaches
to generate limits based on benefit/risk principles. These approaches require assumptions with appropriate rationale
by the device manufacturer to set particulate limits.

5 Key characteristics for evaluation of particulate

5.1 Identity
The chemical composition of particulate might be an important consideration when investigating and characterizing
potential sources of the particulate matter. The identification of particulate matter is usually conducted through analytical
techniques as discussed in Section 7 and Annex A below. It might be important to consider the identity (e.g., material
type, chemical composition, etc.), source, and potential toxicity of each type of particulate. It is not expected that all
particulate need to be identified, but efforts at identification should be undertaken when appropriate (e.g., when
particulate levels have exceeded limits, large or atypical particulate, such as in color, shape, or morphology, is found,
or as necessary to better derive the source of particulate).

5.2 Size
The size of particulate can be important because particulate can block blood vessels, however criticality of size might
vary depending on vasculature and risk. Manufacturers should determine what sizes are appropriate based on their
device considerations and the vascular area for which a device will be used. It is often useful to describe particulate
size ranges (generally three or more) to quantify the number of particulate falling into these specified groupings.

2 © 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021

5.3 Shape
The shape of particulate matter can have important effects. Understanding particulate shape is important not only to
determine the source, but to also understand added risks posed by the introduction of these particulate to the vascular
system. For example, fibers might be a unique concern because the three dimensions will be very different (fibers are
defined as having an aspect ratio of ≥ 10:1). Counting and characterization methods might not distinguish fibers in the
same way, and the biological effects of fibers can be different from round particles having the same surface area or
dimension. If the presence of fibers is suspected, it might be useful to employ multiple characterization methods.
Appropriate methods (e.g., microscopy) should be used to characterize the shape of particulate shed by intravascular
medical devices in order to ensure particulate counting methods are appropriate.

5.4 Quantity
The allowable quantity of particulate matter depends on a variety of factors including chemical composition, potential
toxicity, shape, and size. Particulate count limits are not recommended in this TIR because of the absence of
comprehensive and definitive clinical data and the benefits of the device should be weighed with the particulate risks.
See Section 9 for more detail on strategies for establishing particulate limits.

6 Sources of particulate
6.1 Baseline identification of particulate contaminants
Effective control of particulate matter starts early in the product and manufacturing development process. As a result,
initial characterization of particulate matter released from the device should be performed as early as possible in the
product development process and compared to the proposed particulate limits for the device. When the device design
reaches a state of maturity where human use is being considered or if the device is already available for human use, a
program should be initiated to measure and identify the burden of particulate matter on the device. It can be helpful for
this program to include development of a list of all materials associated with the device as well as possible contaminants
from the manufacturing process and environment, by documenting and identifying, when needed, (e.g., by Fourier
transform infrared spectroscopy):

a) materials used in the device;

b) materials used during manufacturing, such as gowns, gloves, hair covers, and shoe covers;

c) materials of manufacture for machine parts such as valves, gaskets, and belts;

d) reagents used, such as lubricants, cleaning agents, and processing agents;

e) packaging materials and processes;

f) environmental contaminants.

This list is an important tool that can be used later to help identify sources of particulate matter.

Based on the risk assessment, if potentially harmful particulate matter is found (e.g., large quantities of particulate,
large-sized particulate, or particulate of a harmful material/chemical composition), and the related risk cannot be
appropriately mitigated, the device design, manufacturing process, cleaning, and/or preparation processes might need
to be modified to reduce particulate levels. If the characterization data demonstrates acceptable levels of particulate
when compared to the proposed device particulate limits, then product and manufacturing control limits (a.k.a. alert
and action limits) may be established using the available data.

6.2 Control of particulate sources

Unintended particulate matter can originate from a variety of sources that include the medical device itself, its
packaging, and the manufacturing environment. The table below provides an overview of common particulate sources
and typical methods that are applied to evaluate, reduce and/or control the particulate source.

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 Particulate Source Evaluation and Control Method
6.2.1 Product Design

The control or minimization of particulate matter starts during device design and development. This TIR does not
address particulate released by wear or degradation after implantation of a device, though this risk should be
considered in the design of a device.
6.2.1.1 Materials and Coatings 6.2.1.2 Evaluation and Control Method

Materials During device design, consideration should be given to

the particulate levels associated with device materials or
Particulate can be released from the materials used in components. These considerations may include:
the device. Consideration should also be made for wear
of those materials during use. a) requirements for cleanliness of the materials or
components from the selected supplier;
Coatings
b) ease of cleaning materials and components;
In addition, coated devices (e.g., hydrophilic,
hydrophobic, antithrombotic, polymer, etc.) can shed c) tendency of the material to shed particulate,
more particulate than uncoated devices. The amount of such as when flexed, heated, aged, or rubbed
particulate released from a coating depends on its against packaging materials or against another
physical and chemical properties, such as chemical device in use;
composition, structure, and coating/attachment method.
Hydrophilic coatings have been reported to delaminate d) tendency of the material (if the material easily
and/or shed particulate [2]-[8]. Hydrophilic and/or becomes statically charged, or if it is tacky) to
hydrophobic coatings can separate (e.g., peel, flake, attract particulate from the environment;
shed, delaminate, slough off) from medical devices and e) composition and amount (thickness, length) of
potentially cause serious patient injury. coatings and how they might relate to particulate
generation when used intravascularly and in
challenging clinical scenarios;
6.2.1.3 Design Configuration 6.2.1.4 Evaluation and Control Method

The number of parts in the device and the way those Generation of particulate can be reduced by
parts interact with each other during use can have a
large effect on the number and size of particulate a) minimizing the use of surfaces that rub together,
released during use. Parts that rub together or interfere such as o-ring seals and threaded connections;
with each other are more likely to release particulate b) minimizing complexity of the design;
than those with no contact. In addition, the complexity of
a single part in the design can affect how easily that part c) designing for ease of cleaning;
can be cleaned to remove particulate prior to and during d) ensuring appropriate labeled dimensions.
assembly.
A vascular device’s interaction with accessory devices
(e.g., guidewires, introducer sheaths, etc.) can also
contribute to particulate generation and shedding.
Inappropriate labelled sizing or mismatch of accessories
during use can result in high frictional forces which can
increase the likelihood of particulate generation.
6.2.1.5 Packaging 6.2.1.6 Evaluation and Control Method

Because packaging is either in direct contact with the The potential of each packaging component to transfer
device or in close proximity to the device, there is particulate should be considered during package design.
potential for transfer of particulate matter to the device. Particulate contribution from packaging should be
This potential is especially true of the following: minimized. Control of particulate matter should include
the packaging materials.
a) paper packaging;
b) chipboard backing cards, forms, or holders;
c) instructions for use;
d) rough edges on polymeric containers;
e) elastomeric fixtures;

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 Particulate Source Evaluation and Control Method
f) hinged packaging; and
g) hypo-tubes or other components designed with
a snug fit to the device.
6.2.1.7 Shelf Life 6.2.1.8 Evaluation and Control Method

Most medical devices have a shelf life claim. The level Assessment of device particulate should be considered
of particulate released by the device can be affected by for accelerated and real-time shelf life studies. These
the amount of time that elapses between manufacture studies should also incorporate samples exposed to the
and use. Changes in material properties occurring maximum number of allowed sterilization exposures (e.g.,
during the aging process can lead to increased double sterilization). Discussion of aging protocols can be
particulate release during use. Examples are found in AAMI TIR17, ASTM F1980, and ANSI/AAMI/ISO
11607-1.
a) environmental stress cracking of embrittled
parts;
b) environmental stress cracking of molded parts
with residual stress;
c) oxidative and drying effect on materials,
especially films and coatings; and
d) delamination of material layers.
6.2.2 Manufacturing

Manufacturing controls should manage five areas of concern: component or raw materials, manufacturing processes,
manufacturing equipment, manufacturing personnel, and manufacturing environment. The effect of particulate should
also be considered during changes in manufacturing processes or materials.
6.2.2.1 Components and Raw Materials 6.2.2.2 Evaluation and Control Method

Components and raw materials might be a significant The integration of the components into the manufacturing
source of particulate. process should take into consideration the amount of the
components’ particulate burden and the steps
implemented to reduce it. Components and raw materials
that present a high potential source of particulate should
be cleaned before being introduced into a clean
manufacturing environment. Material and component
cleaning should be validated to ensure particulate levels
are acceptable. Examples of component cleaning include
sonication and agitating with detergents or soaps.
6.2.2.3 Manufacturing Processes 6.2.2.4 Evaluation and Control Method

Consideration should be given to manufacturing steps The manufacturing process should have adequate
that might generate or increase the level of particulate controls to ensure particulate matter that will
such as inappropriately affect the finished product, either directly
or indirectly, is not released during the process or is
a) grinding; removed as part of the manufacturing process. Such
b) polishing; processes should be segregated from other
manufacturing operations and followed by adequate
c) cutting; cleaning procedures. Optimization of manufacturing steps
d) stamping; can be considered to reduce particulate matter, when
possible.
e) spraying;
For devices with coatings, optimization of coating
f) sonication; processes can help improve coating adhesion and overall
integrity to help reduce the amount of particulate
g) surface modification (e.g., coatings, etchings);
shedding.
h) drying;

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 Particulate Source Evaluation and Control Method
i) packaging, transport, and storage of
subassemblies;
j) hand operations.
6.2.2.5 Manufacturing Equipment 6.2.2.6 Evaluation and Control Method

In addition to the manufacturing operation performed by Equipment that generates large quantities of airborne
equipment, the equipment itself and related utilities can particulate in a clean manufacturing environment should
generate particulate. Equipment used in the be vented or otherwise mitigated (e.g., filtered) to ensure
manufacturing operation should be appropriate for the the manufacturing environment does not become
environment in which it is used. contaminated. Micro-controlled environments can be
used to control the environments in which molded
components are manufactured. Compressed gases used
in the manufacturing process that vent into the
manufacturing areas should meet the quality
requirements for particulate of the manufacturing areas.
Equipment that sheds particulate such as those with
moveable parts that contact each other and shed material
should be avoided in clean manufacturing environments.
6.2.2.7 Manufacturing Personnel 6.2.2.8 Evaluation and Control Method

Sources of particulate from personnel include, for Gowning and other personnel practices should be
example, skin cells, hair, cosmetics, clothing fibers, and established and maintained to ensure that personnel are
soil from clothing and shoes. not contributing particulate to the product or
manufacturing environments. These practices may
include, for example, gowns, gloves, sleeve covers, hair
covers, beard covers, face covers, shoe covers, smocks,
or complete jumpsuits and face shields. The use of
cosmetics is not recommended in manufacturing areas.
The number of personnel in a given area can be restricted
to reduce the contribution of particulate from personnel.
See ISO 14644-5 for personnel operations
considerations.
6.2.2.9 Manufacturing Environment 6.2.2.10 Evaluation and Control Method

There is the potential for the manufacturing environment If it is required that the manufacturing environment be
to introduce particulate to the medical device. The controlled, refer to the ISO 14644 series. As
manufacturing environment should be adequate to recommended in these documents, action and alert levels
control the levels and type of particulate and to prevent should be established. AAMI TIR52 can also be
the generation of product particulate matter. The referenced.
cleanliness level of the manufacturing environment
depends on the requirements of the device.
6.2.3 Sterilization 6.2.4 Evaluation and Control Method

Effects of sterilization on particulate generation will differ The potential effect of the sterilization process on the
by the modality used. The following are potential generation of particulate should be considered in the
physical effects of sterilization on the device: selection of sterilization method, materials, components,
and packaging.
a) moist heat, ethylene oxide, or chemical vapor-
sterilization parameters (e.g., temperature,
humidity and pressure) might result in material
changes such as deformation, corrosion or
liberation of particulate;
b) irradiation–scission of polymer chains might
result in embrittlement, cracking, or oxidative
stress.

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 Particulate Source Evaluation and Control Method
6.2.5 Shipping and Distribution 6.2.6 Evaluation and Control Method

The amount of particulate released by a device can be Evaluation of particulate on devices in their finished
significantly affected during transit of the packaged carton configuration after environmental conditioning and
device from the manufacturer to the end user. Vibration shipping simulation should be conducted. See ASTM
and effects caused by stacking and/or dropping can be D4169, ASTM D7386 and/or International Safe Transit
anticipated during transit. Additionally, potential Association (ISTA) 2A and 3A. The impact of package
pressure stress can occur during airborne transport. and carton configuration should be considered when
Anticipation of these effects will account for movement determining appropriate testing.
and rubbing of parts in the package. Each of these
factors can affect the amount and type of particulate
released from the device and from the device packaging
onto the device. Temperature extremes might also affect
particulate generation and should be considered.
6.2.7 Clinical Application and Use 6.2.8 Evaluation and Control Method

During clinical use of the device, particulate matter can Evaluation of particulate generation from the device is
be released from the device or due to interactions of the recommended to be performed under conditions
device with ancillary components (e.g., guiding catheter, representative of the clinical use (i.e., simulated use
guidewire). conditions and at physiological temperature of 37 ± 2 °C)
unless a suitable justification can be made. Refer to
Section 7 for further details.

6.3 In-process visual inspection for particulate

In-process visual inspections can be used to limit visible particulate matter present on the medical device. These
inspections should be performed with the naked eye or 2.5X magnification, with appropriate justification. If visible
particulate matter is detected, it might be appropriate to remove particulate matter as part of the validated manufacturing
process. Other validated methods to ensure visible particulate matter is limited on the device can be appropriate.

7 Particulate evaluation test methods

7.1 General considerations for particulate evaluation
Appropriate evaluation of the quantity, sizing, and identification of particulate shed from vascular medical devices is a
systematic process that requires multiple steps. The first step is to generate an appropriate simulated use model for
testing. Once complete, various counting and sizing methods can be employed as well as analytical techniques for
determination of source. The sections below outline these steps along with considerations for testing.

7.1.1 Test environment controls

Particulate testing should be carried out in a controlled environment (e.g., a class 100 laminar flow cabinet) that limits
the introduction of extraneous particulate matter. The analyst should gown with the appropriate clothing (e.g., hair nets,
non-shedding polyester coats, and particle-free gloves) to reduce the risk of particulate contamination. All equipment
and supplies used in the evaluation should be reasonably free of contaminants, as appropriate. Glassware should be
washed with a detergent solution, followed by a thorough rinse using particle free or filtered fluid.

Collection of particulate matter at one facility while performing primary sizing and counting at another facility is not
recommended due to the potential for introduction of test artifacts (e.g., due to settling, agglomeration, or breaking up
of particulate matter). If this approach is employed, the validation should account for all aspects of this process (e.g.,
shipping, time from collection to analysis, packaging, collection container, temperature variation).

7.1.2 Test article

The test article should be representative of the finished device, as intended for clinical use and should undergo all
manufacturing processes including single or multiple sterilization cycles (as applicable). When sampling, a product
should be contained in its usual packaging and tested after removal from its packaging. If the device comes in multiple
sizes, testing should be conducted on various device sizes to ensure that the testing is representative of the entire

© 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021 7

product matrix, or a justification of a worst-case size with regards to particulate should be provided. Testing devices
from multiple lots, when appropriate (e.g., process or design validation), can be important in order to ensure lot-to-lot
variability of particulate is controlled. Since particulate generation can be affected by aging, testing should be conducted
on both unaged devices and devices aged to the device’s proposed shelf life. If testing on aged devices is not
conducted, it should be justified. Shipping and environmental simulations should also be considered.

7.1.3 Sample size

A sufficient number of devices should be assessed in order to ensure the data are representative. Principles outlined
in ASTM F3172 may be utilized. Particulate testing is known to be a highly variable test, so this should be considered
when determining sample size. A justification should be provided for the sample size chosen.

7.1.4 Simulated use model

Particulate testing should be conducted in a tortuous pathway that simulates challenging clinical anatomy in accordance
with device indications. The pathway should be filled with particle free fluid (static or with flow) at physiological
temperatures (i.e., 37 °C), including all tracking and deployment locations within the model. The model pathway should
be made of a non-particulate shedding material. If the device can be used in multiple vasculatures, the most challenging
(e.g., tortuosity, tracking path length) anatomy should be used. When evaluating devices that are deployed, the
attributes of the deployment site (e.g., diametric compliance, dimensions, geometry) should be considered. Detailed
recommendations regarding the simulated model are not provided in this document. Please see applicable standards
for more in-depth recommendations. A rationale should be provided for the simulated use model chosen.

7.1.5 Simulated use method

The test method employed for particulate testing should simulate challenging clinical use, including the use of all
accessory devices (e.g., guiding catheter, guidewire, guide sheath) and conditioning steps outlined in the instructions
for use (IFU). The challenging clinical use should take into consideration tracking time, deployment time (if applicable),
deployment pressure (if applicable), and device use time. The test method and flushing procedures should be validated
to accurately characterize and detect particulate that might be shed from the device. Particulate count bin sizes should
be appropriately set, as described in Section 9.4.

Prior to evaluation of the first test article, after the pathway and test environment have been prepared and the particle
free or filtered fluid are allowed to stabilize at temperature (i.e., 37 ± 2 °C), performing a calibration check or monitoring
sample can be helpful in establishing test system suitability for use. The baseline number and size of particulate from
the test apparatus should be determined prior to evaluating each test article to establish system noise from background
sources and document performance in absence of a test article. The baseline particulate count should be sufficiently
low to enable accurate enumeration of test article particulate counts during assessment. As outlined in the device
instructions for use and with the appropriate accessories and any preparation / conditions steps, the device should be
introduced, advanced, deployed (if applicable), and withdrawn within the pathway model. After the simulated use
procedure, flush the anatomical model with particle free fluid or continue in-line flow, until achieving the level of baseline
particulate count, or other test termination criteria to prevent cross contamination of samples. All fluid containing the
shed particulate should be collected or counted in-line, as applicable, and evaluated for the entire simulated use activity
until baseline particulate counts are achieved. Secondary analyses of shed particulate (e.g., chemical characterization,
shape) should also be considered for additional particulate characterization of the particulate source or sizes outside
the particle counter measurement range, when appropriate.

7.1.5.1 Considerations for beaker capture measurement

The beaker capture method can be used to collect particulate samples either with or without having continuous flow
during the procedure. The device is tracked through a simulated model pathway filled with particle-free/filtered fluid
which is captured in a clean container. Successive flushes after device removal should be performed until a baseline
particulate count is achieved. These successive flushes should be collected as a separate aliquot from the sample to
determine baseline conditions. If desired, particulate can be captured at each procedural step with an associated flush.

Care should be taken not to introduce any air bubbles or other contamination which might affect the study results.
Solutions that retain air bubbles or that can produce gas bubbles should be avoided or sonicated before analysis to

8 © 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021

remove the gas bubbles. The samples may remain undisturbed for a period of time to allow for degassing of the sample
but should be mixed (e.g., stirred, inverted, rolled, swirled) to ensure that particulate is suspended in the sample while
being analyzed. Time, method, and rate of mixing should be considered and controlled to allow for degassing while
maintaining particulate suspension and minimizing particulate agglomeration or degradation (e.g., breaking up of large
particulate).

7.1.5.2 Considerations for in-line flow measurement

Some systems allow for in-line particulate size/quantity detection during an active simulated use test, which counts the
amount of particulate in real time during simulated use. Circulated test fluid should be appropriately filtered before
introduction to the tracking pathway. Connections and features downstream of the pathway, prior to the particulate
counting and sizing, should be minimized to increase the accuracy of the assessment and reduce the likelihood of
particulate degradation (e.g., breaking up of large particulate) and particle captured in local eddies. The flow rate
through the counter(s) should be consistent with the flow rate of the particle counter calibration.

7.1.6 Calibration and validation

7.1.6.1 Counting and sizing equipment calibration

The instruments used for particulate sizing and counting should be calibrated or certified against a calibrated reference
(e.g., if using microscopic method for size determination). Additional critical measurement equipment (e.g., temperature
probe, flow meter) should also be calibrated.

7.1.6.2 Simulated use system validation

Test methods should be validated to ensure that they are capable of accurately detecting the size and quantity of
particulate that were released during simulated use. This typically involves “spike and recovery,” e.g., releasing a known
quantity of particulate matter of a known size into the vascular model and determining the fraction recovered. A proper
spike and recovery activity should include practices to keep particulate in suspension both in the reference particle
standard and sample aliquots, as well as within the syringe prior to injecting the sample into the pathway model. The
validation should also assess repeatability over multiple particle sizes through spike and recovery analysis.

In general, the method should be able to demonstrate recovery of greater than or equal to 90 % for the particulate sizes
of 10 and 25 microns. For particulate sizes that are reported above 25 µm, greater than or equal to 75 % recovery
should be obtained. At a minimum, the largest particulate size of at least 50 µm should be validated at 75 % recovery.
An upper limit for percent recovery should be established, as well since accuracy levels that are too high can indicate
an inaccurate validation. The upper limit for accuracy should be determined by the tolerance supported by the reference
particle standard (e.g., 105-110 %). Particle standards that have too wide of an accuracy/tolerance (i.e., >10 %) should
be avoided. It is pertinent to conduct the validation within the simulated use model and full test apparatus, and not just
the particle counter, in order to ensure the system is suitable. Full details regarding the method validation are not
included in this document. Reference standards such as ASTM F2743, USP 1788, and USP 788 for further details and
recommendations regarding particulate counting methods and validations, as these are good resources for these
applications.

7.1.6.3 Considerations

Due to the limitations of particle measurement systems, it might be pertinent to use two different methods (i.e., light
obscuration and microscopic). Other limitations for counting larger particulate should also be considered, including the
potential for loss of these particulate in the simulated use model.

7.1.6.3.1 Reference particle standards

When using reference particle standards, care should be taken to follow the manufacturer’s instructions. Specifically,
any instructions related to mixing of the reference particle standard to make sure settling does not occur while also
ensuring that bubbles are not introduced.

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Larger size National Institute of Standards & Technology (NIST) traceable reference particle standards in excess of
100 µm are not readily commercially available. If it is determined that quantitation of larger size particulate is necessary,
then it is understood that although the size is outside the validated range that the information is still valuable.

7.1.6.3.2 Recovery

Recovery rates can be affected by various aspects of the test system, including:

 model geometry/dimensions;

 settling;

 model material;

 test fluid concentration;

 test system orientation;

 test fluid interference;

 In-line flow rate or model flush rate.

These parameters should be considered when designing the test system, performing the validation, and interpreting
results.

7.2 Test methods for determination of size and quantity of particulate

Enumeration of particulate matter is commonly conducted using light obscuration (LO) and/or microscopic examination.

Details are provided below. Additional details are provided in Annex A as well as alternate methods.

7.2.1 Light Obscuration (LO)

The most common instrumental method of particulate sizing and enumeration in the medical device industry is LO. LO
uses the principle of light blockage which allows a determination of the size of particulate and the number of particulates
according to size. A volume of liquid is passed through a sample chamber that contains a photodetector. The
photodetector is illuminated by a monochromatic light source (such as a laser) positioned at a right angle to solution
flow. As particulate passes through the light beam, it reduces the amount of light impinging on the detector, causing a
change in voltage. The change in voltage can be correlated to the number and size of particulate by calibration of the
sensor with particles of a known size and shape (e.g., polystyrene-divinylbenzene spheres). Circumstances that are
not suitable for LO analysis include solutions having reduced clarity or increased viscosity (e.g., emulsions, syrups,
whole blood).

Light obscuration methods provide number and size data only; they give no information about the shape or identity of
the particulate being counted. Therefore, before routinely applying LO as the sole counting method, it is important to
characterize with microscopy to ensure that all particulates are appropriately enumerated. Since the particulate size is
based on the profile of the particulate presented to the instrument’s detector, particulate with a large aspect ratio (e.g.,
fibers) might not be sized accurately.

In cases where the light obscuration instrument samples only a portion of the liquid being tested (i.e., beaker method),
that portion of the liquid counted is assumed to be representative of the bulk. See Section 7.1.5.1 for techniques to
ensure adequate suspension. If only a portion of the liquid is sampled, the amount of particulate enumerated should be
multiplied in order to extrapolate how many particulates were shed from the entire device (i.e., if only 10 % of the total
volume was sampled, multiply the final counts by 10 to report the particulate count per device).

The LOC method has several advantages, namely speed and ease of validation, as well as disadvantages, namely the
inability to provide any shape or morphological information. A full listing of the advantages and disadvantages of this
method are provided in Annex A.

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7.2.2 Light microscopy using manual or automated counting

Another accepted method to measure particulate for particulate sizing and enumeration is light microscopy following
isolation of the particulate matter by filtration. The microscopic method involves manually using the microscope to
directly observe the particulate. This inherently makes the method extremely flexible because the investigator can
customize the sample preparation, illumination, and measurement technique. In the most common and simplest form,
particulate is captured and dried by filtering the suspension. Complex statistical sampling methods, different
illumination, dyes, and sizing methods can also be introduced as needed.

Poor sample preparation is a major source of error in all microscopy. If the sample measured does not represent the
true particulate load, then all conclusions based on this test might be invalid. Although there are numerous variations
of how samples are prepared, some fundamental aspects are universal. Subsampling should be representative of the
sample and should be well mixed to avoid particulate sedimentation or creaming. Care should be taken to ensure the
analysis does not lose existing particulate nor become contaminated by any new particulate. For this reason, samples
are often in a laminar flow hood.

An advantage of the microscopic method is the ability for a trained analyst to directly observe the particulate. This
enables particulate with unique shapes, such as fibers, or large or irregular sizes to be analyzed. This also means that
the process can be time consuming and labor intensive. A full listing of the advantages and disadvantages of this
method are provided in Annex A.

7.3 Test methods for chemical identification of particulate and source determination
The chemical composition of isolated particulate matter is also a valuable characteristic to describe. Understanding the
chemical composition of the particulate will allow for the determination of the potential source. There are no standard
definitions in place to describe the difference between heterogeneous and homogeneous distributions; the description
is based on the variety of composition of particulate matter isolated. However, by combining an understanding of
particulate numbers with the heterogeneity of the composition of the particulate, a manufacturer is able to focus efforts
for continuous improvement.

The particulate sample can be captured in conjunction with the testing described above or separately. Particulate should
be captured and separated from collection liquid (e.g., filtered, centrifuged) prior to characterization of chemical
identification. If the entire sample is not tested, it is recommended that a sufficient sample is tested and that the samples
are taken from representative locations of the filter or collection vessel in order to ensure that the data are representative
of the entire sample.

The method used should allow actual determination of chemical composition. This will allow for identification of possible
sources of the particulate matter. Once the particulate matter is identified, the manufacturer can review sources of that
particulate matter in the manufacturing process, determine root cause, and implement corrective and preventive action,
if necessary. It is recommended to use another independent approach to confirm the identity of particulate.

A variety of instrumental techniques may be applied to the chemical identification of particulate matter. The main
methods include Fourier transform infrared (FTIR) spectroscopy, Raman spectroscopy, and X-ray spectroscopy. Other
less-frequently used surface analytical methodologies might be appropriate. Bulk analysis, such as methods that
require dissolution or vaporization might not be appropriate since they only provide information on the bulk properties.
Additional information regarding these methods, including advantages and disadvantages can be found in Annex A.

7.4 Additional considerations and limitations of particulate quantitation and sizing methods
7.4.1 Size/shape

Automated counting methods might not accurately identify the size of a fiber or larger particulate, thus potentially
underestimating the clinical significance. Microscopic methods should be employed, in addition to an automated
counting method, ensure the method is appropriate to detect such particulate. It can be helpful to conduct this
characterization before establishing the final particulate counting method, or during particulate quantitation. If
microscopic analysis indicates the shedding of a significant quantity of fibrous or larger particles on a given device, or
on devices manufactured in a given environment, test methods that are capable of identifying and counting fibrous or
larger particles should be used.

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7.4.2 Composition

The composition, e.g., hydrophilic coatings, can result in particulate that are hard to count due to index of refraction
from test medium. Considerations should be taken such as dyeing the coating prior to testing, as long as the dye does
not affect the chemical structure or the potential for shedding particulate (i.e., changes its lubricity). Further, for these
types of coatings, counting and sizing in a non-aqueous environment (i.e., microscopic method) can result in incorrect
sizing information. Thus, consideration for any potential changes to the particulate shape or size should be considered
when determining the appropriate method.

7.4.3 Agglomeration

Particulate can agglomerate after collection and result in inaccurate counts (i.e., too low) or inaccurate sizes (i.e., too
large). Consideration should be taken to immediately test the sample in order to avoid agglomeration. Other
considerations, for example, the use of surfactants could be considered if they do not interfere with the test method.

7.5 Other test method considerations

There are numerous tests that can be conducted in addition to particulate assessments that can provide supplementary
information that elucidates if any particulate sheds from the device. These include coating integrity testing, coating
lubricity/durability testing, and flow reduction testing, among others. Though these methods are important
supplementary techniques, they are outside of the scope of this document and thus, recommendations are not provided.

8 Literature review
8.1 Introduction and scope
The clinical risk of particulate matter introduced from medical devices has been described extensively within literature
and is discussed here (Section 9.1). This literature review focuses on the specific consequences related to particulate
matter, and associated attributes, when it is delivered to various organs through the neurovascular, cardiovascular,
pulmonary vascular, and peripheral vascular systems. The scope of this literature review is, thus, limited because few
available references provide information pertaining to particle information (i.e., attributes such as composition, size,
quantity, shape), and those that do not were excluded. How these attributes can relate to the clinical outcome is also
discussed and recommendations for how particulate matter can be evaluated and controlled are given. While this
approach eliminates a lot of risk-based information that does not include specific information regarding the particulate,
extensive information regarding risks in each organ system and vascular bed is discussed in Section 9.1 of this
document. More comprehensive literature reviews with broader scopes (e.g., [8]) can provide additional beneficial
information and guidance.

The literature review here is intended to provide some context to the resulting recommendations made regarding the
importance of controlling the amount and size of particulate matter, as well as how to better understand clinical risk
related to composition and shape of particulate matter. In order to reduce the cumbersome nature of such a literature
review, and to make it most useful to the reader, only the most relevant articles were considered. Information from both
animal studies and clinical information is included, as these studies have strengths and limitations in their utility
regarding outcomes related to particulate matter shed in the vasculature. A discussion regarding the limitations of this
review, including limitations of the data sources, is presented in the section below. In addition to the animal and clinical
study, information from bench testing assessments of particulate matter is provided, as these types of studies too can
be informative.

The vasculatures that are included below are organized by end organ as this is the location that will most often suffer
the clinical consequence of the particulate matter. For instance, if a procedure is conducted in the carotid artery, the
vasculature of the brain will most likely be affected rather than the local vasculature. Therefore, review of particulate
matter introduced from devices implanted in the carotid artery would be discussed in the neurovasculature section.
However, understanding the procedural use locations and the potential consequences (in regard to the end organs) is
also important since the risk of a device intended for a certain location is directly related to all organs it might affect.
Consequently, manufacturers should always consider where the device will be used and all locations that could have
undesired consequences from the introduction of particulate matter as part of their risk assessment.

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8.2 Neurovasculature
Within the neurovasculature, the presence of particulate emboli has been associated with partial or total occlusion of
small and medium sized arteries, accompanied by ischemia, infarct and sometimes hemorrhage [8]. Histological
evaluations of targeted biopsy, autopsy or resected tumors also highlight scattered multinucleated giant cells and
granulomas surrounding the emboli. Patient symptoms include focal weakness, sensory and visual deficits, seizures,
and constitutional symptoms (tiredness, headaches, fever, chills, and loss of concentration) [9]-[12]. In some cases,
neurologic decline has been followed by death [5]. In these events, occlusion of blood vessels was accompanied with
inflammation and hemorrhage. Even though symptoms vary based on the location of particulate emboli and patient
comorbidities, magnetic resonance imaging is fairly consistent, i.e., showing the presence of round enhancing lesions
with surrounding vasogenic edema. Patient symptoms are often delayed and range from 1 day to 1 year post
interventional procedure ([8], [13]). Oral corticosteroids have proven useful for addressing vasogenic edema and patient
symptoms. Notably however, in some cases, round brain lesions persist, and the symptoms return, making the patient
dependent on medications for extended periods of time. In few cases focal brain lesions disappeared on follow-up
imaging [8]. A review of select assessments in animal models and well as observations in patients can be found below.

A. Pre-clinical assessments

1) An animal study in 24 healthy Yucatan miniswine (Stanley et al. [3]) observed hydrophilic coating from a
90cm, hydrophilic coated sheath embolized to the brain in 12 of 19 (63 %) animals accessed via the right
common carotid artery and in 1 of 5 (20 %) animals accessed using the right femoral artery. The study
was performed using a 90 cm, hydrophilic-coated sheath to access the right common carotid artery or the
right femoral artery in a stent placement procedure. Since femoral access was used in 18 animals, carotid
access was used in 3 animals, and carotid and femoral access was used in 2 animals, the study suggests
that the increased incidence of coating in the brain from carotid access is not statistically significant and
might be due to the small number of animals treated using only femoral access. However, the observed
difference in embolization rate based on access site, highlights an important consideration when
determining access locations for interventional procedures.

2) There are few animal studies that have correlated particle sizes with sequelae within the brain. Swank et
al [14]. conducted an animal study showing that smaller emboli (4 to 17 μm in diameter) produce lesions
in the white matter of the brain of dogs while larger emboli (35 to 60 μm in diameter) produce lesions in
the grey matter of the brain (or in both white and grey matter areas). The study also suggests that
regardless of size or quantity, considerable vessel dilation occurs, and particulate is captured and
secreted by the kidneys into urine.

3) Rapp et al [15] observed via ex-vivo analysis in rats that calcific plaques ranging from 60 to 200 μm in
size and fibrotic plaques 100 to 200 μm in size that are released during balloon angioplasty correlated
with cerebral infarctions when n=100 plaque particles were injected into the carotid artery. However,
fibrotic plaques in the 60 to 100 μm size range showed a lesser correlation with infarction. Notably, larger
sized plaque (100 to 200 μm) also resulted in one death. Regardless of plaque composition, ischemia
was more common than infarction for plaque sizes between 60 and 100 μm.

B. Clinical observations

1) Particulate emboli within the neurovasculature originate from neurovascular procedures as well as
cardiovascular, structural heart and peripheral vascular procedures [8]. Within the neurovascular bed,
particulate emboli flow downstream from areas of treatment and can become lodged in smaller
downstream vessels. Among available reports, the affected downstream vessels in the neurovasculature
ranged in size from 13 μm to 600 μm in diameter [12].

2) In available literature, particles of sizes between 50 μm and 647 μm were found in the neurovasculature
or collected debris ([16] [17] [18]). Accumulation of particulate was associated with vascular occlusion
and intraparenchymal hemorrhage leading to death [13].

3) In a study by Frerker et al [17], particles with diameters ranging from 56 to 647 μm were found in cerebral
protection devices post mitral valve repair procedures. Since the debris was removed, no correlation with

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 neurologic function was possible. While embolic debris was found in all patients, 85.7 % of the patients
had small fragments of foreign material likely originating from the device hydrophilic- coating.

4) Blazek et al [19], in a study of patients undergoing mitral valve procedures, reported an 85 % incidence
rate of cerebral lesions. Various risk factors (degree of mitral insufficiency, number of clips needed,
operation time, body mass index, and device time) impact the presence of device related particulate
emboli in the brain. There was a statistically significant correlation between cerebral lesions post mitral
valve repair procedure and device time in vivo. The studies by Frerker et al [17] and Blazek et al [19]
suggest particulate emboli shed from a device may potentially cause cerebral lesions.

5) Vermeer et al [20] studied the association between “silent” brain infarcts and the risk of dementia and
cognitive decline in healthy elderly people. Brain infarcts were defined as areas of focal hyperintensity on
T2-weighted MRI images that were at least 3 mm in diameter. The presence of silent brain infarcts more
than doubled the risk of dementia and was associated with worse performance on neuropsychological
tests and a steeper decline in global cognitive function. While clinical studies often characterize such
infarcts seen after a procedure as silent, current data suggest there might be longer-term deleterious
effects that are not as well understood.

6) The studies by Blazek [19] and Astarcip [21] suggest a higher rate of cerebral lesions post structural heart
procedures (87 % & 91 % respectively) compared to surgical valve replacement (control) with a 7 % rate
of embolism. More data is required to quantify the number and long-term impact of cerebral lesions from
neurovascular and peripheral vascular procedures.

The preceding reviews lacked sufficient data to draw definitive relationships between the type, amount, or size of
particulate matter and clinical outcomes. It has been demonstrated, however, that patients exposed to particulate in
this high-risk tissue bed have had catastrophic effects. This emphasizes the importance of controlling of particulate
matter when designing devices for use in vasculatures that are upstream of this tissue bed.

8.3 Cardiovasculature
The coronary vascular system is vital for supplying oxygenated blood to and returning deoxygenated blood from the
heart muscle. Particulate that enters the cardiovascular system provide a direct insult to the system itself which is why
the coronary vasculature is considered a higher risk vasculature system when it comes to particulate matter exposure.
Several pre-clinical studies as well as clinical case studies were evaluated using different sizes, shapes, and types of
particulate in the coronary vascular system. These details are further discussed in detail by each identified risk category.

A. Pre-clinical assessments

Controlled animal studies, while somewhat limiting, can be a valuable indication of cause and effect regarding
particulate matter introduction and its effect on the cardiovascular system. Specific details of these studies can be found
below.

1) Akiyama et al [22]. evaluated 16 dogs by comparing the effects of 9 µm and 500 µm particles. The
particles were injected into the left anterior descending coronary artery until the artery flow rate was
reduced to less than 30 %. Results from this study suggest that the smaller particles created a transmural
perfusion defect at maximal embolization whereas the 500 µm sized particles revealed that the tributaries
of the epicardial coronary arteries were involved with embolism.

2) In another study, Hori et al [23] determined that when evaluating canine coronary blood flow, there was
actually a hyperemic flow response of coronary blood flow in the embolized area. They further showed
that the maximal increase in coronary blood flow after 100 µm microsphere embolization was significantly
less as compared to 15 µm microspheres. In addition, 300 µm microspheres minimally increased the
resting coronary blood flow. The authors conclude that the results suggest that “embolization with
microspheres less than 300 microns in diameter, hyperemic response of coronary blood flow occurs,
probably due to the hyperemia of nonoccluded vessels in the adjacent area of ischemic foci to adenosine
released from the ischemic myocardium.”

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 3) A porcine model study performed by Babcock et al [24], evaluated the effects of hydrogel coated catheters
and coating thickness using a 2-micron (“micron”) coating vs. a 0.5-micron coating (“sub-micron”). The
study demonstrated that the sub-micron coating released 5 x fewer particles in the sizes of 10 µm, 25 µm,
50 µm and 100 µm. The thicker coated catheter (2 µm) released up to 25,180 particles ≥10 µm with 93 %
<25 µm. Results were read 28 days post experiment; the animal was euthanized, and the hearts dissected
to identify agglomeration and/or occlusion. The results indicated no adverse effect.

4) In a canine model, Dorge et al [25] evaluated particulate levels by introducing 42 µm sized microspheres,
at a rate of 3,000 microspheres per milliliter per minute, specifically, to induce microembolism. The study
confirmed perfusion contraction matching with coronary inflow restriction but also demonstrated a
progressive loss of regional myocardial function with no decrease in regional myocardial blood flow after
coronary microembolization.

5) Skyschally et al [26] investigated the impact of controlled coronary microembolization on coronary and
inotropic reserves in anesthetized dogs in vivo. Embolisms were induced by repeat injections of 30,000
microspheres of 42 µm size, into the left coronary artery. In eight anesthetized dogs, left circumflex
coronary blood flow (CBF), regional blood flow (RBF), and posterior systolic wall thickening were
measured. The amount of microspheres injected was 158,000 ± 48,000. CBF and RBF remained
unchanged. The authors concluded that coronary microembolization, caused by a significant number of
42 µm microspheres, reduced coronary and inotropic reserves.

6) In a rotational atherectomy study by Zacca et al [27] particles were captured and then injected into pigs.
The majority (90 %) of the particles were < 10 µm, 5 % were from 200 to 250 µm, though the quantity of
particles was not reported. The results indicated no evidence of compromise to microcirculation with these
sizes of particles.

While the pre-clinical studies reviewed above had differences in the overall outcome, a trend in the size of particulate
and clinical effects could be observed. In many cases, larger sized particulate was found to adversely impact the
performance of the coronary vascular system.

B. Clinical observations

There is limited data regarding controlled particulate studies in human patients as the majority of the data are collected
from postmortem evaluations. Due to this, it is difficult to make conclusions as the different variables cannot be
controlled.

1) Orenstein et al [28] reported that refractile foreign particles were observed in capillaries of many organs
from 17 autopsied patients that died after being exposed to antifoaming agents and polyvinyl chloride
(PVC) tubing particulate during cardiopulmonary bypass surgery. The approximate maximal diameter of
the individual particles was 10 µm and that of the vacuoles 60 µm. The particle-droplet complexes showed
affinity for hydrophobic stains. In all 17 cases, the kidneys were involved in combination with several other
organs. In two patients, the emboli were associated with microinfarcts in one or more organs. Scanning
electron microscopy (SEM) of the PVC tubing indicated spallation and shredding of the luminal surface
of the tubing where exposed to the roller pump. However, another possible source was the antifoam
agent. A strong positive response to silicon but not chlorine was observed within capillaries, consequently,
the morphologic finding indicated antifoam microembolization to be the potential cause of the
postoperative morbidity. The consequence of the fragments of PVC tubing released into the circulation
remained to be established at the time of the article.

2) Limbruno et al [29] describes a situation that demonstrates a prevalence of embolization during primary
percutaneous coronary interventions (PCIs). Embolic material was recovered in 41 of the 46 cases. The
mean debris was 1.2 ± 2.2 cubic mm and consisted of 47 % thrombus, 29 % fresh thrombus and 24 %
plaque fragments.

3) In another study, Grames et al [30] evaluated the safety of radiolabeled 300,000-800,000 albumin
particles ranging in size of 10 – 80 µm that were injected into the coronary arteries of up to 800 patients
with no adverse clinical effects.

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 4) An additional study Parodi et al [31], assessing patients with critical coronary lesions, injected 800,000
albumin particles sized 12 – 20 µm into the left ventricle to evaluate left ventricular function. No adverse
effects or arrythmias were noted.

5) In two cases, hydrophilic polymer coating was found to cause embolism as described by Schipper et al
[4] and Sequeira et al [32]. In one instance, a 43-year old patient had a total of 32 PTCA procedures and
the hydrophilic coating might have caused damage in the downstream intracardial arteries. In the second,
3 cases of hydrophilic polymer embolization are described.

6) In another clinical case involving polymer coating. Hickey et al [33] describes a retrospective autopsy
analysis of 110 individuals who had undergone endovascular procedures. They found histologic evidence
of hydrophilic polymer emboli (HPE) in 23 % of all cases. In 9 of the cases, this complication directly
contributed to the death of the patients. HPE were found in various organs, including the brain, heart,
lung, kidney, and spleen.

7) Analysis of the material captured by an embolic containment catheter system designed to retrieve
particulate matter was described by Webb et al [34] post vein graft intervention. Analyses of the material
from 27 procedures retrieved particulate matter consisting of soft acellular atheromatous material,
typically found under the fibrous cap. The particle sizes ranged from 22 µm -3,427 µm. According to the
authors, embolic atherothrombotic particulate matter is commonly liberated during angioplasty and
stenting of saphenous vein grafts. This particulate matter might play a role in the pathogenesis of distal
embolization, no-reflow and infarction following vein graft intervention.

The literature review of the clinical aspects of the coronary vascular system further supports several of the identified
risk factors associated with particulate on medical devices in this TIR: namely that size, quantity, and composition of
particulate matter can have an effect on clinical outcomes. Although limits and absolute determinations cannot be
determined based on this literature, it is clear that the effects of these three parameters related to particulate contribute
to the potential adverse effect of the emboli.

8.4 Pulmonary vasculature

The pulmonary vasculature is a high-risk region vulnerable to particulate introduction as blockage of these arteries (i.e.,
pulmonary embolism) can result in cutoff of blood supply to the lungs, leading to lack of oxygenated blood normally
supplied to other organs. Numerous types of data sources are available to examine effects of particulate, including
prospective animal studies, human perfusion studies, but also case studies relating to clinical observations of
pulmonary embolism related to particulate matter. A discussion of this information, as it relates to size, quantity, and
composition of the particulate matter, as well as associated outcomes, is discussed below.

A. Pre-clinical assessments

While there are inherent limitations of animal studies, they often provide useful information given that the studies can
be prospectively designed and allow for complete evaluation of affected tissues after necropsy. While small animal
models (e.g., rats) have examined particulate effects on pulmonary vasculature, larger models (e.g., canine, or porcine)
are more similar in size to the human vasculature and can provide more valuable information to correlate to human
effects. Specific examples are provided below.

1) A study by Glenny et al [35] assessed pulmonary perfusion and vascular resistance when injecting 15 µm
polystyrene microspheres in rats and provides great insight into sizes and tolerable limits of particulate in
this small animal model. Vascular resistance, or obstruction of capillaries changed minimally with
introduction of 100,000 15 µm particulate. The authors estimated 6x106 of 15 µm microspheres would
need to be injected in order to obstruct half of the capillary bed. Further, 15 µm particulate mostly lodge
in 7 to 8 µm diameter capillaries, highlighting the compliant nature of the capillary bed.

2) Liu et al [36] studied the effects of injecting 13, 20, 45, and 75 µm polyvinyl chloride particles in the right
atrium of twenty dogs during cardiopulmonary bypass. The authors determined that particulate matter
greater than 20 µm caused damage to the pulmonary ultrastructure. Notably, larger particulate sizes
correlated with a higher severity of damage.

16 © 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021

 3) Yokel et al [37] administered various sizes of latex microspheres in dogs and rats to determine the impact
of particulate size on vessel obstruction or occlusion. The studies demonstrated that 3 µm particulate
rapidly cleared from the canine lung whereas 8 to 25 µm particulate remained in the lung for at least one
month. The study also showed that three out of four dogs injected with 8x104 of 3 µm particles per gram
body weight died from acute respiratory failure, suggesting that a higher dose of smaller particulate might
be lethal. Similar results were observed in rats, with rapid clearance of 3 µm spheres from the lungs. The
animals that died exhibited acute dyspnea. The investigators used LD50 values to predict toxicity of the
microspheres and determined that toxicity due to vascular occlusion is a function of total volume of
microspheres injected.

4) Davis et al [38] evaluated the minimum lethal dose (MLD) of polystyrene microparticles in rats and mice
and extrapolated these values for human use (per body weight). Based on 1 million particles administered
to a 70 kg man, the MLD estimated a safety factor of 36 to 401 for 45 to 90 µm particulates, 1663 for 25
to 28 µm particulate, 3360 for 15 µm particulate, and 6283 for 13 µm particulate. Clinical outcomes were
dependent on size and not chemical composition of particulate.

From this small subset of studies, differences in outcomes were noted for various sizes and amounts of particulate.
While some studies highlighted adverse effects for large particulate, others showed that even 3 µm particulates in large
quantities can have an adverse effect.

B. Clinical observations

Some information is available for patients that were injected with particulate matter (e.g., microspheres) to study
perfusion or for therapeutic occlusion of blood vessels (e.g., for tumor treatment or for arteriovenous malformations).
Some notable evaluations are discussed below.

1) Selwyn et al [39] injected 2 to 3 million 15 to 20 µm microspheres into the left ventricle of ten patients with
previous myocardial infarction in order to assess regional blood flow in various organs. For the lungs, no
significant difference was noted in flow in the left and right lung providing evidence that recirculation is
not significant. Further, no adverse effects were reported with this size and quantity of particulate.

2) Lovering et al [40] demonstrated that 50 µm macro aggregated albumin (MAA) particles were not able to
pass through pulmonary capillaries (typically 3 to 7 µm in diameter) at rest, but during exercise, large
diameter intrapulmonary arteriovenous conduits open and were able to accommodate the 50 µm particles
in seven human patients. The authors concluded that recruitment of these pathways can divert blood flow
away from pulmonary capillaries during exercise and compromise the lung’s function as a biological filter.

3) Burdine et al [41] studied 115 patients who had a clinical indication for lung scanning (e.g., pneumonia,
COPD, etc.). 45,000 to 270,000 of 15 to 30 µm human albumin microspheres (HAM) were injected and
assessed for cardiopulmonary function. The authors concluded that no significant changes occurred in
any of the parameters measured. Rapid pulmonary clearance through the liver and spleen was attained
(within 30 minutes). The authors also made some conclusions regarding composition of the microspheres.
They note that ceramic and carbonized microspheres cleared very slowly (if at all) from the pulmonary
circulation and can produce permanent damage (e.g., pulmonary fibrosis). The clearance data presented
by the authors suggests that it can vary based on composition of the particles and is dependent upon
biodegradation and absorption of the particles.

4) Wijeyaratne et al [42] studied the outcome of a single case of intentional infusion of 6 mL of 300-500 µm
PVA particles for treatment of an arteriovenous malformation in the cheek. The patient became hypoxic
after treatment and had repeated cardiorespiratory arrests. The patient died 24 hours later. A postmortem
autopsy confirmed pulmonary embolism with “widespread thrombosis and PVA particles in the pulmonary
microvasculature.” The authors conclude that particles injected arterially pass through to the venous
system and have the ability to eventually lodge in the lungs and cause pulmonary embolism and eventual
death.

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Current data sources suggest that controlled delivery of small microspheres intended for human use might not have
adverse effects, even in the lungs. However, as highlighted by Wijeyaratne et al [42], larger particulate in the size range
of 300 to 500 µm have the potential to migrate to the lungs and can cause pulmonary embolism.

Select case reports and autopsy studies confirming the presence of particulate matter post interventional procedures
are available.

1) Allan et al [5] reported multiple cavitary lung lesions which mimicked granulomatous vasculitis after use
of a hydrophilic-coated central venous catheter. Biopsies revealed multiple cavitary nodules up to 0.8 cm
in diameter with central purulent material. H&E stain demonstrated the material was amorphous, non-
refractile, nonpolarizable, and colored pink-purple to blue-gray. The appearance was consistent with
hydrophilic polymer, as previously described.” The authors describe the material to be “ill-defined” and
easily overlooked as artifact, thus requiring keen awareness in recognizing iatrogenic complications.

2) Mehta et al [6] retrospectively analyzed the results of 136 autopsies and reported 13 % of cases with
histological evidence of hydrophilic polymer embolism, mostly in the lungs. Associated histopathologic
changes included occlusive intravascular or perivascular inflammation (89 %), intravascular fibrous
response (56 %), micro thrombus formation (44 %), vasculitis (28 %), and/or pulmonary microinfarction
(28 %). In regard to clinical symptoms, the authors noted a greater incidence of suspected pulmonary
embolism in patients that had hydrophilic polymer embolism than those that did not. Patients with
hydrophilic polymer emboli had undergone significantly greater number of percutaneous vascular
procedures with polymer-coated devices. While the size range of the particulate is not discussed, it is
evident that particulate shed from use of coated vascular devices targets the lung with clinical
consequences.

3) Mehta et al [7] evaluated 9 cases of foreign body emboli in patients undergoing vascular procedures with
hydrophilic-coated medical devices. Five patients that had cardiac catheterization or central venous
catheterization placement had hydrophilic coating in the lungs. In two cases, the authors determined the
affected arteries were between 25 to 950 µm in diameter.

Literature suggests that particulate matter migrates into the lungs from interventional devices used in structural heart
procedures or placed in the venous system. Occlusion of smaller pulmonary vessels is typically accompanied with
intense inflammation i.e., formation of giant cells or granulomas, and/or presence of neutrophils and histocytes. This
response is reported to be most intense in the lungs and noted to mimic granulomatosis with polyangiitis [43]. Notably,
particulate emboli can contribute to patient morbidity and mortality, however, are not typically a primary cause of death.
In reported cases, particulate matter was incidentally found on autopsy within days to several months (and sometimes
years) of prior interventional procedure [43]-[45]. No definitive conclusion regarding the type, amount, or size of
particulate matter that has clinical consequences in the pulmonary vasculature. The pulmonary vasculature is a high-
risk vascular bed, as obstruction of pulmonary blood vessels has the potential to disrupt oxygenated blood supply to
vital organs. Thus, when designing and validating a medical device that is used upstream from the lungs, it is extremely
important to minimize the introduction of particulate matter. If a large quantity or sizes of particulate are expected, then
pre-clinical safety studies should be included in device assessments.

8.5 Other/peripheral vasculature

Non-absorbable particulate matter in the peripheral vasculature can result in cutoff of blood supply to the feet, spleen,
liver, kidneys, pancreas, bowels, and other peripheral organs leading to clinical effects, such as ischemia, necrosis,
other organ related conditions, or additional interventions, such as amputation and need for dialysis. Literature related
to pre-clinical assessments and clinical observations related to particulate matter in the peripheral vasculature are
summarized below. Limited literature with detailed information related to size, quantity, and composition of the
particulate matter as correlated to potential clinical events was able to be identified.

A. Pre-clinical assessments

While there are inherent limitations of animal studies, they can provide useful information given that the studies can be
prospectively designed and allow for complete evaluation of affected tissues after necropsy. The following article
provides useful information regarding size and quantity of particulate in pre-clinical evaluation of peripheral tissues:

18 © 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021

 1) Harringer et al [46] studied physiologic effects of 15 µm radiolabeled-microsphere injections in the
pancreas using a canine model. The injections were used to quantify pancreatic blood flow. They found
50 million 15 µm spheres resulted in an acute transient decrease in pancreatic and renal blood flow that
returned back to baseline values within 2 minutes. A cumulative injected dose of 150 million 15 µm
spheres were also found to return to baseline flow levels. Chronic effects were not studied.

B. Clinical observations

Foot and toes:

Several clinical cases were prevalent in which the authors conclude that patients suffered from hydrophilic polymer
embolization resulting from vascular devices containing such materials. In two of the cases, toes were required to be
amputated. Timing of symptoms were reported to vary from the initial instrumentation to late complications presenting
up to 6 years later. No definitive information regarding the size or quantities of particulate matter was reported. A
summary of the most relevant findings is included below:

1) Komatsu et al [47] provide a case of a patient after TAVR procedure via the left femoral artery. After the
procedure, a skin rash appeared on the left foot sole and worsened over the next 20 days. A biopsy of
the rash was performed, and the results were consistent with those previously reported as hydrophilic
polymer embolization. The rash gradually healed 6 days later. No details regarding the particulate matter
was presented.

2) Gottesman et al [48] provide a case of a patient that had undergone a left heart catheterization via the
right femoral artery approach. A stent was implanted which contained a hydrophilic polymer. Amputation
of the patient’s toe was required 6 years later because of chronic dry gangrene. The autopsy revealed
occluded capillaries with basophilic, amorphous, whirled foreign body material with no evidence of
atherosclerotic disease. The largest convoluted ball of foreign body material at the dermal-subcutaneous
junction was found to have a diameter of 500.08 μm and an estimated unraveled length of 8.836 mm.

3) French et al [49] provide a case of a patient who underwent cardiac catheterization with stenting and
defibrillator placement. A non-healing ulcer of the toe resulted 4 months later requiring amputation.
Pathology showed scattered amorphous basophilic emboli, which is compatible with previous pathology
reports of emboli from hydrophilic coating of intravascular sheaths and catheters. No information
regarding the size of the emboli was provided.

Arteriovenous Malformations (AVM) and tumors:

Some information is available for patients that were purposely injected with particulate matter (e.g., microspheres) to
study perfusion or to specifically block blood vessels (e.g., treatment of tumors or arteriovenous malformations).

1) Beaujeux et al [50], used supple, hydrophilic, and calibrated trisacryl gelatin micro-spheres embolization
in 105 patients with tumors, facial AVMs, spinal cord AVMs, cerebral AVMs, and 6 miscellaneous
diseases. The diameter for facial AVMs was found to be 200 to 400 µm with 50-100 spheres needed. For
the spinal cord AVMs, the diameter was found to be 500 to 700 µm with between 10 to 50 spheres used
clinically. In cases of cerebral AVMs, the optimal size seemed to be larger than 1000 µm, with 100 to 500
spheres used clinically. For the tumors, the diameter was found to be 600 µm with between 100 to 300
spheres used clinically.

Various peripheral organs (kidney, liver, pancreas, spleen, bowels):

1) Sasaki et al [51] provided a case where a patient received transcatheter aortic valve implantation. Two
days after the procedure, the patient presented with purpura on the soles and toes and reduced renal
function. Skin biopsy showed evidence of polymer emboli. Hemodialysis was required for four days until
renal function recovered.

2) Chopra et al [43] summarized clinical effects of polymer embolization from polymer-coated devices in
various organs and with varied resulting clinical sequelae. Regarding skin and dermal vessels, patients

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 typically complain of pain from ulcers or parethesias and do not require pharmacologic intervention and/or
additional surgeries. Regarding kidneys, bowels, liver and related arteries, case reports intra-arteriolar
emboli in the kidney with surrounding giant cell reaction, possibly inducing downstream ischemic
glomerular collapse and the presence of polymer emboli in interlobular arteries. Polymer emboli were
observed in submucosal vessels of the bowels, affiliated with ischemic enterocolitis. Polymer emboli in
the liver were found. No particulate size or quantity data related to the clinical effects were discussed.

3) Hickey et al [33] conducted a retrospective autopsy analysis and found histologic evidence of polymer
embolization in 23 % (25/110) cases. Endovascular aortic repair was associated with the greatest
density/distribution of hydrophilic polymer emboli. Organs identified with hydrophilic polymer emboli were
the heart, kidney, spleen, lung, stomach, rectum, liver, pancreas, adrenal gland, skeletal muscle, and
brain. The three most prevalent sites were kidneys (13/25), lung (8/25) and heart (7/25).

4) Selwyn et al [39] injected 2-3 million 15-20 µm biodegradable human albumin microspheres into the left
ventricle of 10 patients in order to assess regional blood flow in various organs. No significant difference
was noted in flow in the liver, spleen, or kidneys. These microspheres were reported to degrade within 6
to 12 hours after administration.

5) Febres-Aldana and Howard [52] presents a case of patient with sickle cell disease who suffered fatal
splenic failure resulting from foreign body pulmonary and systemic embolization due to intravenous
administration of hydromorphone pills. Three different types of foreign particulate were identified
microscopically on stained tissue sections, which were in clusters of greater than or equal to 15 μm. The
most abundant particulate consisted of elongated, rod-like, and pleomorphic crystalline structures
concluded to be microcrystalline cellulose. A second type of particulate consisted of non-refractile, deeply
basophilic, irregular, coral-like formations concluded to be crospovidone. Finally, a third type of particulate
consisted of amorphous light blue structures that were concluded to be related to devices coated with
hydrophilic polymer gel. The particulate accumulated in all organs.

As summarized in the review of peripheral literature above, there is no definitive conclusion regarding what type,
amount, or size of particulate matter that can have clinical consequences when introduced into the peripheral
vasculature. The literature focused on embolism related to polymers which are commonly used to coat endovascular
devices. Polymers related to endovascular devices were reported to end up in various peripheral organs including
kidney, liver, pancreas, spleen, bowels, and feet. Clinical effects ranged from rash, pain, necessity of hemodialysis, to
amputation. Particle sizes of 15 µm did not result in pancreatic and renal flow after 2 minutes in canines. Polymeric
strands 8.836 mm long resulted was found present in a toe that was amputated. Ideal sizes of trisacryl gelatin micro-
spheres for embolization were found to have diameters ranging between 200 and 1000 µm depending on the organ. 2-
3 million 15-20 µm biodegradable human albumin microspheres had no perceivable clinical effects. Particles greater
than or equal to 15 μm were found in all organs of a patient that undertook intravenous administration of hydromorphone
pills through a polymeric catheter.

8.6 In vitro characterization

Several benchtop or in vitro evaluations have been conducted that provide direct insight to the types or quantities of
particulate that patients can tolerate, as shown in the first two references below, or how a medical device can perform
when used in vivo, as shown in the third reference.

1) Several investigators have published their findings to better understand the inherent daily patient
particulate load in intravascular injectable solutions for large volume parenteral (LVP) and small volume
parenteral (SVP) as well as parenteral nutrition. Backhouse [53] used light obscurations to characterize
39 commercially available SVP and 7 LVP. After conducting informal surveys in the ICU with 20 patients,
they determined the average SVP dosed in a 24-hour period was 24 doses of SVP with a range of 17 to
33 doses. This data was used to back calculate the daily particulate load. The daily particulate load was
estimated to be 3.6 x 106 particles greater than 2 µm and 8400 particles greater than 25 μm. The number
of particles greater than 10 μm would be 2.4 x 105 by extrapolation of the data. This finding indicates that
SVP contributes more to daily patient particulate load than LVP. This also suggests that the product
design and manufacturing processes are critical to how particulate enters the final product.

20 © 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021

 2) A second paper from Madsen et al [54] explored the impact of establishing normal flow in intravenous
sets using the stripping method. This method consists of bending the tube proximally near the drop
chamber and compressing the tubing between the finger and scissor and stripping the tube towards the
cannula. This results in a pressure drop in the tube and reestablishes IV fluid flow. This was found to be
a common practice with 70 % of the 144 nurses surveyed. The authors counted the particulate left on the
filter after two flushes with no stripping and then a final third flush right after stripping. Results indicated
significantly higher particulate counts (3X and beyond) after stripping the IV tubing.

3) An in vitro study by Stanley et al confirms the time-dependent shedding of particulate from an

interventional device [3]. This study found avulsions of hydrophilic coating in as little as 15 minutes with
separation of particulate in 1 hour for a hydrophilic coated sheath immersed in 0.9 % saline solution.

Though there were limited publications available that could directly correlate in vitro evaluations to clinical impacts,
these studies discuss particulate loads that can be experienced by clinical patients.

8.7 Limitations
There is no perfect meth

od or model to predict the impact of the introduction of particulate matter into the vasculature. Pre-clinical models are
useful in that they allow for accurate and precise introduction of particulate and complete evaluation of each organ
system at the appropriate time point afterwards. However, these animals are typically non-diseased and differences in
size of the vasculature and end organs of the animal models might not be similar to human anatomy (e.g., rat model).
Thus, the outcomes might not correlate with human use. Clinical information is sometimes available after particulate
were inadvertently introduced into a human body, however, full details regarding the outcomes might not be available.
If a clinical event occurs due to particulate matter, it might go undetected due to the presence of numerous
comorbidities. The ability to detect particulate in vivo in human patients is generally not possible with the available
imaging and detection techniques. One way to assess for particulate matter (i.e., whether particulate matter was
introduced, and if so, the type, size, and quantity) in a patient is by pathological evaluation and application of ex vivo
analyses after death. Thus, given that both pre-clinical and clinical information is limited, as described above,
information pertaining to both assessment types was included in this review in order to provide a better picture for the
potential consequences.

While various characteristics of particulate matter and associated outcomes were reported, these are all case-by-case
examples. The relationship between particulate-induced thrombosis and patient outcomes is not well-established or
understood. Patients could experience a clinical outcome due to one small particulate and in other cases, millions of
particulates can be introduced with no adverse effects noted. Thus, while not ideal, given that there is no known
correlation between size, shape, amount, and composition for particulate matter that will have definitive clinical adverse
effects, it is important to be cautious in this regard. The information provided above provides guidance for a risk-based
analysis to ultimately determine the type, size, and quantity of particulate that might be acceptable for a given
application.

8.8 Conclusions
Intravascular particulate generation from medical devices has gained attention as a result of a specific product failure
that led to numerous negative clinical observations and it subsequently being recalled [55]. As described in the sections
above, although there is limited specific chemical, size, or number data there is evidence that negative clinical events
might be associated with their release into the vasculature. The control of particulate matter is more relevant in higher
risk vascular beds, such as the neurovascular, cardiovascular, and certain peripheral vasculature, because of the
organs served. Literature reporting on clinical cases lack details on the particulate (number, size, and chemistry) which
makes it impossible to assess its dose response. Higher particulate loading from some devices (sheaths) has been
associated with clinical issues while even higher particulate loads of smaller particulate (e.g., from small volume
parenteral solution with 10x the USP<788> limits) [56] have been shown to be well tolerated [53]. In some cases, large
volumes of small particulates have been well tolerated as highlighted by Yokel et al [37]. This observation reinforces
the concept that the relative risk to the patients could depend on the patient condition and comorbidities, device
indication, and method of use. The relative risk to benefit assessment should be made for each device: weighing the
potential implications of the particulate to the patient versus the treatment options and potential outcomes.

© 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021 21

9 Considerations for establishing quantitative limits for product particulate
The total particulate load potentially delivered into the vasculature of the patient should be characterized and limits
established. Since the total particulate load is comprised of the additive effects of particulate from multiple sources
(reference Section 6 for more information), separate limits may be established for each source. Special consideration
should be given to devices made of materials that have a greater potential to form or shed particulate (i.e., devices with
coatings, materials more susceptible to wear). Rationale should be provided for the selected device particulate limits
including the approach that was used and the factors that were considered (e.g., potential clinical risks, standards,
regulatory guidance, benefits of the medical device).

9.1 Clinical risk and need for limits

Any time the vascular system is accessed there is a risk of introducing particulate into the blood stream, which might
cause potential adverse reactions such as vein irritation, local tissue infarction, anaphylactic shock, emboli, and even
death. The clinical risk associated with the use of intravascular devices due to particulate shedding depends on several
different variables, including the route of administration, the intended use location, particulate size, size distribution,
shape, the number of particulates, particulate composition, and the intended patient population. As such, risk-based
approaches and tools should be implemented to address these variables and ultimately be used to establish product
particulate limits, if needed. The table below provides a summary of some potential acute and subacute or delayed
events that can be caused by particulate in specific anatomical locations.

Cardiovascular System Potential Adverse Effects [57]

 Focal neurological deficits
Meningismus/headache
 Coma/mental status change
 Cerebral vasculitis
 Cerebral granulomas
 Cerebral abscesses
 Cerebral thrombosis
Neurovasculature
 Cerebral white matter loss
 Seizure/involuntary movements
 Secondary hydrocephalus
 Hemorrhagic stroke
 Ischemic stroke
 Anoxic brain injury
 Death
 Arrhythmia
 Cardiac thrombosis
 Cardiac granulomas
Cardiovasculature  Myocardial hemorrhage
 Cardiac vasculitis
 Myocardial infarction
 Death
 Acute pulmonary embolism
 Pulmonary infarction
 Pulmonary granulomas
 Pulmonary vasculitis
Pulmonary Vasculature  Pulmonary thrombosis
 Pulmonary abscesses
Pulmonary/mediastinal
lymphadenopathy
 Death
Other Vasculature
 Acute renal failure
 Oliguric renal failure
Kidney
 Renal abscesses
 Hematuria

22 © 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021

 Cardiovascular System Potential Adverse Effects [57]
 Acute hepatic hemorrhage
 Hepatic vasculitis
Liver  Hepatic granulomas
 Hepatic infarction
 Hepatic abscesses
 Acute gastrointestinal hemorrhage
Ischemic colitis
 Colonic granulomas
 Colonic vasculitis
Colon
 Colonic abscesses
 Delayed gastrointestinal
hemorrhage
 Retroperitoneal lymphadenopathy
 Purpura, dermal hemorrhage
 Induration/ulceration
 Deep vein thrombosis
Skin/Extremities  Livedo reticularis
 Ecchymoses
 Panniculitis
 Gangrene
 Pancreatic granulomas
 Patchy pancreatic necrosis
Pancreas
 Scattered chronic pancreatitis
 Pancreatic abscesses
Spleen  Splenic granulomas
Muscle  Muscle granulomata
 Patchy myositis
 Multifocal hemorrhage
 Multifocal vasculitis
 Systemic lymphadenopathy
 Multiple organ failure
Systemic Effects  Multifocal embolic infarcts
 Multifocal thrombosis and
hemorrhage Disseminated
intravascular coagulation Systemic
inflammatory response syndrome
 Death

9.2 Approaches for determining allowable limits for particulate on an intravascular device
Since particulates released from intravascular devices can pose significant risks to the patient, particulate limits are
established during product development. Because of the absence of comprehensive and definitive clinical safety data,
generally accepted particulate size ranges and particulate count limits that ensure patient safety have yet to be
established for intravascular devices. Setting specific limits is complicated by varied patient thresholds to emboli due
to a broad array of medical conditions and comorbidities, the vast array of vascular beds with different sizes in the
human anatomy, and the benefit(s) of the device to the patient. As a result, different approaches may be used to set
particulate limits. Suggested approaches to establish appropriate particulate limits for intravascular devices are
discussed below. Use of one or more approach might be appropriate.

9.2.1 Use of established standards and regulatory guidance documents to justify and establish limits

Generally speaking, there are no acceptance limits established specifically for intravascular medical devices in
standards or regulatory documents. Historically, limits established in USP 788 [56] have been applied to medical
devices due to no other standard being available.

© 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021 23

Similar particulate limits for injectables are captured in British Pharmacopeia [58] and United States Pharmacopoeia
[56] and were initially focused on large volume parenteral (LVP) greater than or equal to 100 ml. This was based on
legacy products and was later expanded to small volume parenteral (SVP) less than 100 ml. In order to ensure the
particle load for SVP was less, the assumption was made that the ratio of SVP to LVP should be 5:1 in USP XXI in
1984 [59]. These values are commonly cited as 6000 particles at ≥ 10 microns and 600 particles at ≥ 25 microns for
small volumes parenteral which was update in USP XXIII in 1995 [60].

Although not deliberately intended or specifically required for intravascular devices, these standards have historically
been adapted to intravascular devices.

When applying these standards to a vascular medical device, manufacturers should be mindful of the following:

a) None of these standards provide guidance or limits on particles in larger ranges (e.g., ≥ 50 microns. Additional
sizes should be included to align with those potentially generated by or released from the device.

b) The test methods used might not be aligned with the manner in which particles would be released from the
vascular device in circulating blood (e.g., counting particles released from the entire device or healthcare
product versus particles released from the patient contact portions and the fluid pathway).

c) The potential risks of the products referenced in the standard might be different than the specific risks of the
vascular device and its intended use.

9.2.1.1 Active implantable medical devices

Specified Limits
Standard
≥ 5 µm ≥ 10 µm ≥ 25 µm
ISO 14708-2, Part 2: Cardiac Pacemakers [61]
ISO 14708-4, Part 4: Implantable Infusion ≤ 100 Particles/mL N/A ≤ 5 Particles/mL
Pumps [62]
ISO 14708-1 General Requirements [63]
ISO 14708-3 Implantable Neurostimulators [64]
≤ 6,000 ≤ 600
ISO 14708-5 Circulatory Support Devices [65] N/A
Particles/Device Particles/Device
ISO 14708-6 Medical Devices Intended to Treat
Tachyarrhythmia [66]
When considering these standards, note that:

a) The devices they describe are implanted in body tissue instead of being directly used in the vasculature. For
example, implantable pacemakers are placed in the thoracic cavity and are not placed directly in circulating
blood.

b) The test methods rely on counting particles residing on the exterior of the device that are rinsed into a fluid
media and do not include other device interactions such as deployment, actuation, interaction with
accessories, etc.

9.2.1.2 USP <788> particulate matter in injections

Specified Limits
Standard Test Method
≥ 10 µm ≥ 25 µm
USP <788> [56] Large Volume (> 100 mL),
≤ 25 Particles/mL ≤ 3 Particles/mL
Light Obscuration
Small Volume (≤ 100 mL),
≤ 6,000 Particles/Container ≤ 600 Particles/Container
Light Obscuration
Large Volume (> 100 mL),
≤ 12 Particles/mL ≤ 2 Particles/mL
Microscopic
Small Volume (≤ 100 mL),
≤ 3,000 Particles/Container ≤ 300 Particles/Container
Microscopic

24 © 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021

When considering application of this standard, note that:

a) The recommended USP limits have been used by some intravascular medical device manufacturers, but the
intended scope is solutions for injections and parenteral infusion and the limits specified in liquid volume do
not align with evaluation of particulate from an intravascular device.
b) These are historical limits and the rationale behind the assigned limits for clinical relevance and safety is not
well documented. The limits were first determined in the 1980’s and are generally considered sufficiently low
since they have been used without significant reported adverse events.
c) Since they are considered sufficiently low, the specified limits are generally accepted for verification and
routine monitoring for many applications.
9.2.1.3 Infusion sets and transfusion sets for single use, gravity feed

Standard Specified Limit

ISO 1135-4, Part 4: Transfusion sets for single use, gravity feed [67]
≤ 90 Particles/Device
ISO 8536-4, Part 4: Infusion sets for single use, gravity feed [68]
When considering application of this standard, note that:

a) The specified limit is termed a contamination index and is determined by subtracting the total count of particles
≥ 25 µm flushed from blank controls from the total count of particles ≥ 25 µm flushed from the fluid pathway
of the device. Particles are counted microscopically.

b) The test methods count particles released from the fluid path into a gravity fed fluid media and do not include
other device interactions such as deployment, actuation, interaction with accessories, etc.

c) Similar to intravascular devices, the limit considers particulate that is introduced intravascularly.

d) The rationale for the contamination limit is not clearly stated.

9.2.1.4 ANSI/AAMI AT6 autologous transfusion devices

Specified Limits
Standard
> 10 µm ≥ 25 µm Fibers
ANSI/AAMI AT6 [69] ≤ 50 Particles/mL ≤ 5 Particles/mL ≤ 6.5 Particles/mL
When considering application of this standard, note that:

a) Particles released from the fluid path into fluid media by gravity or by assistance from normally operating
electromechanical apparatus are counted microscopically.

b) The test method does not include other device interactions such as deployment, actuation, interaction with
accessories, etc.

c) Similar to intravascular devices, the limit considers particulate that is introduced intravascularly.

d) The specified limits are based on limits established for blood transfusion microfilters (ANSI/AAMI BF7 [70]).

9.2.2 Basing limits on comparison to comparable commercially available product

Comparative testing to a comparable commercially available product can be an acceptable method to use when
establishing particulate limits. The basis for this approach is that if the commercially available device is similar (i.e., the
same or similar intended use, used in the same anatomical area, similar patient risk profile, etc.) and has a history of
safe clinical use, then it can be assumed that the proposed device would have a similar risk profile if the particulate
levels are similar or below those of the comparative device. If this approach is used, simulated use testing should be
conducted in a side-by-side manner comparing the new device to the commercial product without relying on historical
data or data reported elsewhere since test conditions can drastically affect the test results. In many instances, it is

© 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021 25

feasible to develop a benchtop simulated use model based on the appropriately challenging anatomy in clinical use,
identified by clinical risk assessment. Then, this model may be employed in the simulated use method described in
Section 7.1.5. to capture and count particulate released from each device during simulated clinical use. Once testing
is conducted, a full discussion and rationalization of the results should be provided, including if/how it was determined
that the data are comparable (e.g., statistical analysis) and how the limits were determined from the dataset (e.g., use
of comparative device’s reported limits, use of maximum values, etc.).

A limitation of this approach is that adverse events related to particulate in the vasculature can go undetected or be
attributed to the disease being treated, comorbidities or other causes.

9.2.3 Based on correlation to safety in animal study

If animal studies are conducted with the device, and an appropriately challenging assessment is conducted (e.g., longer
duration than expected clinically more devices than expected clinically), a safety factor for particulate exposure can be
generated and used to establish particulate specifications. The animal study should include a full assessment of
downstream organs and tissues should be evaluated for embolic observations.

Steps for how these limits can be determined, or supported, are summarized below:

i. Conduct appropriately challenging simulated use studies for the device based on the device risk assessment
(entry route, duration, model parameters, etc.).

ii. Count and analyze the size and amount of particulate released during the studies.

iii. Assess the device(s) in an appropriate animal model. If a sufficient safety factor is needed, larger sizes or
multiple devices may be used. Determine the maximum particulate values, as assessed on the bench for each
particulate bin size from the lots used in the animal study, that were theoretically introduced into the animal
model.

iv. Determine the maximum particulate values that could be theoretically introduced into patients based on the
worst-case device use (sizes, multiple devices, maximum lesion length, etc.).

v. Determine appropriate specifications based on the theoretical safety margin provided by your animal study
based on above calculations (animal use divided by simulated clinical use). Justification for the safety margin
should be provided and should be based on clinical risk.

Limitations of this approach need to be considered and justified. An animal model is never perfect and will never fully
replicate what will happen clinically in patients. For example, use of the device in an animal might not be able to replicate
physical attributes of use such as tracking length, vessel size or tortuosity. In addition, animal models are typically
healthy which can lead to differences in particulate generation, different clinical sequelae and confound the perceived
safety factors. If devices are used in extreme conditions (e.g., longer duration than expected clinically more devices
than expected clinically), it can help correct for some of these limitations.

9.2.4 Basing limits on literature review

A survey of available literature on medical and scientific studies can provide some insight into particulate incidence
rates and the relative safety associated with those rates. Literature can be evaluated for studies with similar disease
states, anatomical locations, and routes of access for similar devices. Some investigations might provide information
on particulate burden with particulate count, size, and shape information along with associated clinical impacts.
Comparing this information with particulate data from the test device can assist in extrapolating potential risks. The
device treatment benefits can be compared with extrapolated risks to assess particulate limits for the device.

Advantages of this approach include establishment of limits based on clinical investigations with real-world patient
disease conditions, anatomical variations, and procedural parameters. A disadvantage of this approach is the limited
availability of clinical investigations with demonstrated procedural controls, a limited number of devices used in an
individual study, unknown quantity and size of particulate released from the device, and uncertainty around the
treatment and/or test parameters that were used when gathering the data. In addition, there might be no indication of

26 © 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021

the repeatability of the findings. For example, there have been reports in literature connecting related polymer emboli
with clinical sequelae, but these reports are limited and cannot be connected to a single cause or clinical outcome (as
noted in Section 8 above). As such, caution should be adopted when setting particulate limits with this approach. This
approach might be more useful in the future as additional studies are conducted and reported.

Published literature can have the ability to provide information about the number and size of particulate and the related
clinical sequelae, especially with increased scrutiny in this area and if more studies are conducted to address this issue
in the future. If this approach is used, this information should be considered through a benefit-risk assessment to
establish acceptable particulate limits for the device and related medical therapy. Then, the particulate data from a
simulated use test can be compared to these limits to establish the relative safety of the device relative to particulate
generated or released during use.

9.3 Applying benefit/risk principles to particulate limit setting

As discussed above, there are many variables that affect the clinical risk associated with particulate including intended
patient population, the route of administration, the intended use location, and the particulate size, shape, number,
composition, and size distribution. As highlighted in the table above, the risks can vary in severity from mild to very
severe (e.g., infarct leading to death). However, it is also pertinent to discuss the benefits that can be achieved with
using medical devices that pose the risk of shedding particulate. Many intravascular medical devices that are included
within the scope of this TIR treat life threatening or irreversibly debilitating diseases. For some patients or indications,
relevant treatment options might be limited in effectiveness, or perhaps not available. Therefore, the risk of a potential
safety event related to particulate relative to the potential benefits that might be realized for the patient should be
considered (i.e., a higher risk of shedding particulate may be rationalized in some instances). Weighing of benefits of
the device with risks of the device (including risks associated with shedding of particulate) should be part of the
particulate limit determination process. Refer to ISO 14971:2012 Medical Devices – Application of Risk Management
to Medical Devices [71] for further information.

9.4 Determining appropriate particulate size ranges for evaluation

When determining appropriate particulate size ranges to use for particulate counting, consider the effect of particulate
sizes on the patient. Risks associated with the size and shape of the particulate should be thoroughly evaluated and
should include an evaluation of the intended use of the device, quantity delivered, route of administration, intended
anatomical location, intended patient population, as well as the techniques used during clinical use.

Commonly validated bin sizes include ≥ 10 µm, ≥ 25 µm, and ≥ 50 µm. Larger bin sizes, such as ≥ 70 µm and ≥ 100
µm, can be validated if appropriate. However, though these values were likely based on recommendations provided in
USP 788 (reference Section 9.2.1.2) [66], the basic and clinical relevance for these values are unknown for
intravascular applications. The need for assessment of more particulate bin sizes, both smaller and larger is likely
justified in order to fully characterize the particulate shed from an intravascular medical device. For instance, the clinical
risk associated with a device that is intended for use in the neurovascular arterial system or intended for use in a child
or neonatal patient should consider an evaluation of a smaller particulate size

When considering larger size bins, think carefully about how grouping of particulate sizes will affect the results. For
instance, if ≥ 50 µm is used as the largest bin size, then a 2 mm particulate would be grouped together with the ≥ 50
µm particulate count, though they pose significantly different risks. Therefore, it is more appropriate to characterize and
include limits for particulate bin sizes based on test method and equipment capabilities as well as validated particle
recovery limits (i.e., the ability to retrieve and identify particulate of different sizes that are introduced into the test
apparatus). Commonly validated bin sizes include ≥ 10 µm, ≥ 25 µm, and ≥ 50 µm. Larger bin sizes, such as ≥ 70 µm
and ≥ 100 µm, can be validated if appropriate.

When evaluating clinical risk to determine appropriate particulate size ranges, a review of literature on clinical
significance of particulate matter size for similar vascular applications, as well as vasculature size, can be helpful. Size
ranges can also be established based on comparative testing to similar devices.

Despite the limitations of the test systems and available traceable particulate reference standards, as discussed in
Section 7.1.6, it might still be necessary to evaluate and report larger sizes even though recovery cannot be validated.

© 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021 27

9.5 Maintenance of particulate limits
Change control is an important element of the device lifecycle that helps ensure the benefits derived from a vascular
device outweigh its risks. When considering the effects of changes to the intended use, design and/or manufacturing
of a vascular device, the particulate limits applied to the design and manufacturing processes should be reviewed to
assure the composition, size, and quantity of particulate potentially released into the vasculature are maintained at safe
levels.

9.5.1 Re-evaluation of overall device particulate limits

The cumulative acceptable particulate limits established for the device should be reviewed periodically and revised as
needed. This review can be performed independent of other activities but will most often be tied to post-market
surveillance. Although the overall allowable level of particulate from the device will generally remain unchanged, the
following should be considered after a device has been commercialized:

9.5.1.1 Change in intended vascular location or use

The intended vascular location in the anatomy and the treatment provided by the device are key considerations that go
into determining the benefit-risk profile of the device. If the device is used in a location that is different than the original
intent, it can have the unintended consequence of exposing different downstream organs to particulate released from
the device. A change in intended location may be directly related to expanding the intended use of the device such as
adding marketing indications. For example, a device intended to be used in the peripheral vasculature might later be
indicated for use in coronary regions. Particulate seen as acceptable in the extremities and venous system might cause
serious harm in the coronary arterial system.

9.5.1.2 New clinical data

Advances in medicine lead to new discoveries as the medical community learns about and studies new therapies and
treatments. New clinical data might be discovered over time that provides further insights into the pathological impact
of particulate burden in the vasculature. As an example, hydrophilic and hydrophobic coatings were once thought to be
harmless. Although it is generally accepted that the benefits of these coatings outweigh the risks, new data suggests
that coatings can separate from the device leading to unexpected adverse events.

9.5.1.3 Post-market surveillance trends

Medical device companies gather clinical device data through complaints analysis and post-market surveillance. Trends
in this data over time might show an increase in Medical Device Reports (MDR), complaints and/or recalls related to
adverse events that can suggest current particulate limits are not adequate. Since particulate related adverse events
can be masked by vascular disease complications that often lead to the same vascular issues, it can be difficult to
determine if the issues are particulate related which can also make it difficult to determine if the acceptable limits should
be adjusted. Nonetheless, if post-market data suggests that particulate is linked to an increase in events, it should be
investigated.

9.5.1.4 Changes in standards, device guidance and/or regulatory requirements

Current standards and regulatory guidance for medical device particulate limits were discussed earlier in this section.
Although specific guidance for vascular devices is limited and/or does not exist, standards bodies and regulatory
authorities might introduce guidance and/or regulations that limit the particulate burden that a single device might
introduce into the body. Revisions to existing standards can also result in changes to generally accepted limits already
in place.

9.5.1.5 Changes or improvements in technology

Changes and improvements in technology (e.g., automation, modified coating application, improved cleanroom
technologies, etc.) can assist in lowering particulate levels even further which could lead to the need to re-evaluate the
risk profile of the device. In line with the principal of “state of the art,” new technologies should be adopted by
manufacturers to reduce device particulate release as far as possible.

28 © 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021

9.5.1.6 Particulate reassessment for design and manufacturing changes

A change in particulate can be experienced when modifications are made to the device design, materials, or
manufacturing processes. When changes are made to an attribute that could potentially affect particulate generation,
particulate levels should be re-evaluated. Attributes that can affect particulate generation include changes to:

 Product design (e.g., length, coating coverage, coating thickness)

 Packaging design (e.g., using an inner package that sheds more particulate)

 Manufacturing sequence, methods, and location

 Shipping and distribution methods

 Storage conditions

 Shelf life (i.e., increasing the amount of time a device might age before use can lead to material embrittled,
flaking, etc.)

Changes to the product and/or manufacturing process should be reviewed to determine whether they are likely to alter
particulate levels considering the purpose for which particulate data is to be used.

Re-assessment of product changes should also include evaluation of elements that might impact the particulate test
method, including introduction of new materials, processing steps, product configuration changes, or a different product
manufacturing site. This assessment should also include evaluation of the effect of the change on the outcome of the
test. If the test method is changed, the particulate method should be assessed to evaluate the effect of the change on
the results of the test. The results of this assessment should be recorded, and a new test method validation study
should be performed.

© 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021 29

 Annex A

Summary of particulate characterization technologies

This table provides a quick overview of the advantages and disadvantages of each of the primary technologies that are
discussed above that are used to quantify and size particulate matter shed from vascular medical devices. For
additional information, refer to listed references.

Table A.1—Primary particulate quantitation and sizing technologies

Technology Advantages Disadvantages Method Summary
Light 1. Light obscuration can 1. There are This is the most common
obscuration be easily automated limitations for method of sizing and
to perform counting accurate counting particulate matter
and sizing quickly. detection of for medical devices. This
2. Method is easily larger particulate method uses laser
validated. (e.g., 150-300 obscuration technology to
3. The method is simple microns and determine particulate size
and requires greater, distribution based on the
minimum operator depending on signal from a photodetector
training. equipment). produced when particulate in
4. LOC counts all 2. No information is a solution are exposed to a
particulate, including captured on beam of monochromatic light
immiscible liquids. color, shape, or [56] [58] [72] [73]. This
other visual method enables the
characteristics. assessment of samples
3. Unintended quickly and easily.
particulate might
be counted, such
as gas bubbles.
Light 1. Light microscopes 1. Manual Sizing and counting of
Microscopy are readily available. quantitation is particulate matter are
2. It allows the time consuming conducted using light
investigator to directly and labor microscopy after being
observe the intensive. collected on a microporous
particulate, including 2. The potential for membrane filter. This method
size and visual human error enables the assessment of
characteristics. requires careful visual characteristics, which
3. A wide range of training to allows for determination of
particulate sizes can mitigate physical features and
be measured variability. properties (e.g., color, size,
accurately with NIST 3. If using shape) [56] [58] [68] [72] [74]
calibration automated - [76].
traceability. sizing/counting, it
4. Larger particulate, can be difficult to
which might not be set parameters to
able to be sized and distinguish
counted accurately particulate
with other methods, agglomerates
might be able to be and edges.
sized and counted 4. The method is
more accurately with only suitable for
light microscopy. solid particulate.
5. Agglomerates can be 5. There is a lower
distinguished and threshold for the
evaluated. need to sample
6. Specific particulate of (and
interest can be further extrapolation of
data) for high

30 © 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021

 Technology Advantages Disadvantages Method Summary
analyzed with other particulate
methods. counts which
7. The method is introduces
suitable for fluids that uncertainty.
are not compatible
with the light
obscuration particle
counters.
8. The method can
distinguish between
bubbles, immiscible
liquid mixtures, and
solid particulate.
Technologies listed in Table A.1 are the most commonly used methods, however based on the device and particulate
being measured, additional particulate methods may be considered. This list is not exhaustive but captures several
additional methods. For additional information, refer to listed references. There are a multitude of other surface analysis
techniques such as TOF-SIMS, XPS, AES. These highly specialized methods require extensive expertise and
significant equipment. These methods require special sample preparation and expertise running the studies and are
outside of the scope of this document.

Table A.2—Additional particulate quantitation and sizing technologies

Technology Advantages Disadvantages Method Summary
Electrical Zone Sensing 1. Measures the 1. Each orifice The electrical zone sensing
(Coulter Principle) number of has a size method measures the change in
particulate and range. The impedance as particulate travels
the volume method might through an orifice. The size of
average of each require the signal is related to the
particulate. multiple volume of the particulate. This
2. Method lends orifices to method lends itself to
itself to span a highly automation to measure
validation and polydisperse particulate count and size [58]
requires population. [77] [78]..
minimum 2. Requires
operator diluent to be
training. low viscosity
electrolyte.
Scanning Electron 1. Ability to 1. It is labor SEM permits the observation
Microscopy (SEM) measure intensive. and characterization of materials
particulate 2. Challenging to on a nanometer (nm) to
shape, size and sample a micrometer (μm) scale. The
surface large number area to be examined is
morphology with of irradiated with a finely focused
very high particulates. electron beam raster scanned to
resolution. 3. Requires form images in the magnification
skilled range of approximately 10–
operator to 10,000x. This method also
avoid allows for detailed
artifacts. morphological analysis, which
4. Particulate allows for determination of
might require physical features and properties
conductive (e.g., size, shape, texture) [79]
coating prior [80].
to imaging,
which would
make further
analysis
difficult.

© 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021 31

This table provides a quick overview of the advantages and disadvantages of various commonly used technologies
that can be used to chemically identify particulate matter.

Table A.3—Particulate chemical identification technologies

Technology Advantages Disadvantages Method Summary
Fourier 1. Robust 1. Requires skill to FTIR spectroscopy is an
transform analytical setup equipment analytical technique used to
infrared method to and test. identify organic materials. This
spectroscopy identify 2. Labor intensive to technique measures the
(FTIR) composition of identify particulate absorption of specific frequency
organic and acquire of infrared radiation by the
materials. spectra. Not sample. The specific frequencies
2. Able to focus on practical to test of adsorption uniquely identify
individual every particulate. the structure of the molecules
particulate as 3. Dried samples are providing a fingerprint of the
small as 10 µm. required. Water composition. Micro-FTIR can
3. Libraries of has a strong broad obtain infrared spectra of
compounds are absorbance hiding particulate as small as 10 µm in
readily available. other functional size.
The database is groups.
extensive for The unique spectrum can be
FTIR. compared to potential reference
4. Complements samples or chemical libraries to
Raman. FTIR find a match. [81] - [83]
absorption
strength is
strong when
Raman is weak.
5. Readily available
and more
familiarity with
use.
Raman 1. Robust 1. Requires skill to Raman spectroscopy is a
Spectroscopy analytical setup equipment complementary technique to
method to and test. infrared spectroscopy. Like FTIR,
identify 2. Labor intensive to this method is able to uniquely
composition of identify particulate identify the composition of
organic and acquire matter, however, the absorption
materials. spectra. Not intensities differ. This is
2. Able to focus on practical to test particularly useful when FTIR
individual every particulate. results in a poor spectrum
particulate as because of the functional groups
small as 1 µm. have low absorption (e.g., C-S)
3. Libraries of or extremely broad absorption
compounds (e.g., Water). Micro-Raman
readily available. spectrometers have the ability to
4. Complements collect spectra from particulate
FTIR. Raman as small as 1 µm.
absorption
strength is The “identification” of a Raman
strong when spectrum can be performed by
FTIR is weak comparison of the test sample
5. Sample does not spectrum to a reference
need to be dried. spectrum of a known compound
The presence of or material or by comparison to
water in a chemical libraries of compounds.
sample does not [82] [83]
interfere with the
spectrum.
Energy 1. Method often 1. Elemental analysis With EDX, the energy excites the
Dispersive X- available on is limited to electrons of the individual atoms

32 © 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021

 Technology Advantages Disadvantages Method Summary
Ray scanning inorganic and which generates x-rays as the
Spectroscopy electron metals. electron relaxes back to the
(EDX) microscopes. 2. Method performs ground state. This enables the,
2. Use of SEM and elemental mapping relative quantities of each
EDX determines only and does not element present to be accurately
both the size provide molecular determined. This method
and shape as information. enables semi- quantitative
well as 3. Method is semi- elemental analysis of surfaces
elemental quantitative and but is restricted to elements with
information on provides relative higher atomic numbers. This
the same amounts of each makes the method suitable for
particulate. element but not inorganics and metals but less
3. Enables absolute useful for organics.
elemental quantification.
mapping of EDX units are commonly
specific areas of integrated into electron
a single microscopes which facilitates
particulate. elemental mapping as well as
imaging. The electrons source of
the electron microscope is used
to excite the electrons of the
elements and generate x-rays as
the electrons relax back to the
ground state.
Polarized Light 1. Simple method 1. Does not provide Polarized light microscopy
Microscopy that is available actual composition measures the interaction of
for many information, so polarized light by the sample as
microscopes. should be used as it passes through two polarizing
2. Provides a supporting lenses oriented at 90 degrees to
molecular analysis only. one another.
structural data.
If the sample is isotropic, the
image will remain black as the
two polarizing lenses filter out all
the light. As the anisotropy
increases, more light will be able
to pass through the filters. This
simple yet powerful method is
useful for characterizing
particulate that have molecular
orientation [84].

© 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021 33

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For further reading:

AAMI TIR17: 2017. Compatibility of materials subject to sterilization

AAMI TIR52:2014 (R2017). Environmental monitoring for terminally sterilized healthcare products

ANSI/AAMI/ISO 10993-1, Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk
management process

ANSI/AAMI/ISO 11607-1:2019. Packaging for terminally sterilized medical devices - Part 1: Requirements for materials,
sterile barrier systems and packaging systems

ASTM D4169-16. Standard Practice for Performance Testing of Shipping Containers and Systems

ASTM D7386-16. Standard Practice for Performance Testing of Packages for Single Parcel Delivery Systems. ASTM
International, West Conshohocken, PA, 2016, www.astm.org

ASTM F1980-16, Standard Guide for Accelerated Aging of Sterile Barrier Systems for Medical Devices, ASTM
International, West Conshohocken, PA, 2016, www.astm.org

ASTM F2743-11, Standard Guide for Coating Inspection and Acute Particulate Characterization of Coated Drug-Eluting
Vascular Stent Systems

Ball P.A., et al (2001). Particulate contamination in parenteral nutrition solutions: Still a cause for concern? Nutrition.
17(11). 2001: 926–29

FDA Guidance “Certain Percutaneous Transluminal Coronary Angioplasty (PTCA) Catheters - Class II Special Controls
Guidance for Industry and FDA” issued September 8, 2010

FDA Guidance “Guidance for Industry and FDA Staff Non-Clinical Engineering Tests and Recommended Labeling for
Intravascular Stents and Associated Delivery Systems” issued April 18, 2010

ISO 14644 (series), Cleanrooms and associated controlled environments

ISO 14644-1:2015. Cleanrooms and associated controlled environments — Part 1: Classification of air cleanliness by
particle concentration

ISO 14644-5:2004. Cleanrooms and associated controlled environments — Part 5: Operations

Institute of Environmental Sciences and Technology (IEST): IEST-STD-CC1246D, Product cleanliness levels and
contamination control program

ISTA 2A Series: Partial Simulation Performance Test Procedure. Procedure 2A: Packaged-Products weighing 150 lb
(68 kg) or Less. 2011. International Safe Transit Association.

38 © 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021

ISTA 3 Series: General Simulation Performance Tests. Procedure 3A: Packaged-Products for Parcel Delivery System
Shipments 70kg (150 lb) or Less (standard, small, flat or elongated). 2018. International Safe Transit Association.

USP <1788>, Methods for Determination of Particulate Matter in Injections

© 2021 Association for the Advancement of Medical Instrumentation ■ AAMI TIR42:2021 39