EPA targets cancer-causing emissions from medical sterilization facilities

Ethylene oxide has long been linked to cancers of the breasts, lymph nodes, and lungs.
Sterilizing medical equipment is essential for modern healthcare, but the process generates a
substantial public health risk. The key culprit is the chemical ethylene oxide, which is both a
highly effective fumigator and a potent carcinogen. The Environmental Protection Agency
revealed the shocking extent of the pollutant’s toxicity in 2016, but it has not proposed
comprehensive regulation of the chemical until now.
This week, the EPA proposed a rule that promises to reduce annual ethylene oxide emissions
by at least 19 tons a year — an 80 percent reduction from current levels. The proposal builds
on a separate set of rules that the agency passed earlier this month to curb ethylene oxide
releases from certain types of chemical plants.
Environmental advocates called the news an important but belated response to the cancer risk
that communities near these facilities have endured, in some cases, for decades. The Clean
Air Act directs the EPA to update its pollution standards for medical sterilization facilities
every eight years, but the agency has repeatedly missed these deadlines. The rules proposed
this week come after the environmental nonprofit Earthjustice filed a lawsuit over the
agency’s failure to issue the rules by April of last year. In that case, the court ruled that the
EPA must publish the rules by this spring.
“Today’s proposals are an important first step in remedying an injustice that affects far too
many communities,” said Earthjustice attorney Marvin Brown in a press release. “Too many
workers and community members have gotten cancer from facilities that are supposed to
make sure that our medical equipment is safe.”

Brown and other advocates argued that the EPA should go further to protect residents living
near sterilization facilities by requiring companies to install air quality monitors at the
facilities’ borders and regularly post the collected data to a public site.
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According to the EPA, there are 86 medical sterilization facilities currently operating across
the U.S., 23 of which generate levels of cancer risk that the agency considers unacceptable.
They operate quietly in nondescript buildings, sometimes mere feet from schools and
residential neighborhoods. It is impossible for residents of these areas to understand their
exposure to ethylene oxide without special monitoring technology, since it is colorless and
odorless.
Medical sterilization facilities came under scrutiny in 2016 when the EPA published an
assessment finding ethylene oxide to be 30 times more toxic to adults and 60 times more
toxic to children than previously known. Numerous studies had linked the chemical to
cancers of the breasts, lymph nodes, and lungs. Research also found that it is a mutagen,
meaning it can alter DNA.
The EPA directed its regional offices to inform communities near the biggest polluters of the
risks they faced. In response, elected officials and residents in Georgia and Illinois filed
lawsuits against medical sterilization companies, leading to settlement deals and the closure
of a major plant in a suburb of Chicago, Illinois.
But news did not travel as fast for other residents. In Laredo, Texas, where the most toxic
industrial sterilizer in the nation is located, residents were not informed of their exposure
until 2021. That plant continues to operate today.
“Here in Laredo, a South Texas border community that is 95% Latinx, our children attend
schools with some of the worst air quality in the country because of ethylene oxide
pollution,” said Tricia Cortez, co-founder of the Clean Air Laredo Coalition, in a press
release.

During a press conference on Tuesday, EPA Deputy Assistant Administrator Tomás

Carbonell said that the agency’s proposed rules, if implemented as written, will help protect
residents in places like Laredo. They require that 86 commercial sterilization facilities install
equipment that better captures ethylene oxide and reduces emissions of the chemical by 80
percent. To ensure that the facilities are meeting these standards, the rule requires that
facilities monitor for ethylene oxide releases and report to the agency twice a year.

While the EPA invoked the Clean Air Act to protect residents near sterilization facilities, it
also leaned on a different environmental law to protect workers within those plants. The
Federal Insecticide, Fungicide, and Rodenticide Act gives the EPA the authority to assess
whether chemicals used as pesticides are safe. Since ethylene oxide has antimicrobial
properties and is used for sterilization, the EPA used its authority under that law to require
that workers wear protective equipment like respirators if ethylene oxide levels exceed 10
parts per billion in the air.

As part of the proposal, the EPA conducted a risk assessment and found that the chemical
posed as much as a 1 in 10 lifetime cancer risk for workers. That means that, if 10 workers
are exposed to current workplace levels of the chemical over the course of their lifetimes, one
of them would be expected to develop cancer from the exposure.

The proposal also requires facilities to not use more than 500 milligrams of ethylene oxide
per liter of solvent for one sterilization cycle. EPA officials said that some facilities are
already meeting that requirement, but that others are using twice as much. In cases where
alternatives to ethylene oxide exist — such as in some cosmetics manufacturing and in
museum work — the EPA is prohibiting the chemical’s use.
Ethylene oxide manufacturers and sterilizers have long been opposed to stricter rules for
governing ethylene oxide emissions. Industry groups like the American Chemistry Council
have taken issue with the EPA’s 2016 finding that ethylene oxide is 30 times more toxic for
adults than previously understood. In response to EPA’s announcement last week, the
Council said in a press release that it opposes any rule-making that uses the EPA’s “flawed”
assessment of ethylene oxide’s toxicity.
Scott Whitaker, president and CEO of AdvaMed, a trade group representing medical
technology companies, also raised concerns about this week’s rules. The EPA is requiring the
companies comply with the rule in 18 months — a shorter time frame than is typical due to
the chemical’s toxicity and potential for harm. Whitaker said the timeline for compliance “is
much too short” and that it could take many months to procure emissions reductions
equipment. “Supply chains and manufacturing are still recovering from the pandemic,” he
said in a press release.

Whitaker noted that ethylene oxide is used to sterilize half of all medical technology — about
20 billion devices — in the U.S. each year. Many medical devices cannot be sterilized
through other methods, and shuttering even a few sterilization facilities could adversely affect
patients, he claimed.

Still, Whitaker appeared confident about the industry’s ability to comply with the rules
overall.
“If we have careful coordination with the EPA, we are confident we can deliver for all
interests as these regulations are refined and finalized,” he said.
Editor’s note: Earthjustice is an advertiser with Grist. Advertisers have no role in Grist’s
editorial decisions.

Validating sterilization processes by ethylene oxide
October 18, 2015 By MDO Editor
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This process challenge device is a strip holding bacteria enclosed in a capped tube. If the
PCD can be deactivated or sterilized, then a device of lesser resistance would also be
considered sterile.

Paul Dvorak | Founding Editor | Medical Design & Outsourcing

The FDA’s expectation is that validating a sterilization process follows the traditional
validation and verification model, commonly referred to as “V&V.” An installation
qualification verifies that the sterilization equipment has been installed to manufacturer’s
specification, while the operational qualification verifies that the machinery is working as
intended. The final step in a validation process is a performance qualification, which
validates that products exposed to the sterilization process meet the required sterility
assurance level.

“That’s it in a nutshell,” said Paul Littley, a consulting manager at Nelson Laboratories.

“When we talk about V&V, the installation qualification, more of a verification, is making
sure the equipment is installed correctly, for example electrical and plumbing is correctly
installed.”

“An operation qualification ensures the chamber is functional for a generic process,” said
Littley, noting that operation and performance qualifications are a bit more in-depth. “Once
we get to performance qualification, you are looking for repeatability and reproducibility of
the cycle for a particular process challenge.”

The common approach for ethylene oxide sterilization (EO sterilization) validation is referred
to as the “Overkill Approach,” in which a biological indicator, placed in the most resistant
location of the device, is deactivated or killed in one-half the time of the routine sterilization
cycle. The half cycle’s lethality must be demonstrated a minimum of three times to be
considered adequate or validated. Additionally, a full cycle is performed to demonstrate that
the defined cycle is capable of maintaining the process parameters for the entirety of the
routine production cycle.

The equipment and process

EO chambers are basically pressure vessels which work under sub-atmospheric conditions
(i.e., below atmospheric pressure). Some EO sterilization processes which use a gas blend,
such as carbon dioxide, are performed at a positive pressure, but most proesses are 100% EO
and are sub-atmospheric due to flamibility concerns.

“The chambers will pull a particular vacuum, commonly referred to as deep or shallow
vacuum. A deep vacuum is typically below six psia, pounds per square inch absolute,”
said Littley.

Most sterilization processes are batch operations. Some of the smaller test chambers are in
the 9-ft³ range, but larger industrial units handle 30 pallets, a full load for a tractor trailer.

EO sterilization proceeds through a three-phase process. The first phase, preconditioning,

conditions the load to an even temperature and relative humidity, often for 24 hours at 115° F
and 65% RH.

“This does several things. Because the product is in packages, the heat and humidity
condition the packaging material so the gas can penetrate easier,” he said. “The actual sterile
barrier is typically Tyvek, a breathable layer that provides a difficult pathway for
microorganisms to enter, yet it lets EO and other gases through. EO’s penetration is unique in
that it is a small molecule which can diffuse through plastics quite readily.”

EO chambers come in a variety of sizes from smaller than this one to those that hold palletts
of products. Validating a process requires killing a sample of bacteria placed in the most
difficult to reach nooks in a package or product.
The second purpose is to condition the microorganisms on the device, as well as the
Biological Indicator (BI) used to measure the process, for gassing. Humidity helps condition
the cellular wall and reduces the organism’s resistance to sterilization. The BI contains a
minimum of one million organisms of the EO sterilization indicator organism Bacillus
atrophaeus, a spore-forming organism.

“These spore-forming organisms exist in two states. One is a dormant state in which they are
called endospores. The organism forms a shell-like structure to protect itself until a nutrient-
rich environment becomes available, at which time it can sporulate, grow and reproduce,”
said Littley. “When the organism is in this second state of growth and reproduction, we call it
the vegetative state. Endospores are so durable some have been pulled off of ancient
mummies making them at least 4,000 years old. Spore-forming microorganisms are used as
the indicator because they are difficult to kill.”

After the pre-conditioning phase, operators quickly load the product into the sterilization
chamber so as to not lose heat from preconditioning.

“Once in the chamber, the system pulls a vacuum to evacuate the air. Typical cycles pull deep
vacuums down to 1 psia. EO in air raises an issue, because it is flammable at about 10%
oxygen concentration, so it is important to remove the air from the chamber and the product,”
he said. “Depending on the cycle and product, there might be a few nitrogen washes during
the initial stages to flush the residual oxygen. This is more common in shallow vacuums of 6
psia or greater. Next the EO gas is injected and it is absorbed into the nooks and crannies of
the devices, referred to as restricted pathways or mated surfaces which are void of air.”

From there, the process goes into a dwell state, typically 3 to 5 hours, of static conditions in
which the gas is allowed to penetrate deep into the load and devices.

“When the dwell period ends, it is important to exhaust the EO out of the load and devices
due to the flammability as well as because it is a carcinogen,” said Littley.

To remove most of the EO gas before opening the chamber, the load is washed with an inert
gas such as nitrogen or steam, until most of the EO is out. Once below flammable
concentrations, air is typically used for additional washes. Finally, the product goes into a
heated aeration chamber where it dwells at approximately 110° to 115° F with air circulation,
to further reduce the residual EO absorbed into the product.

In general, sterilization validation is required to demonstrate that the devices are free of
viable microorganisms. As a first step in the validation process, the resistance of the device
must be determined. According to Littley, there are two ways to verify the resistance.

“One is direct innoculation of the product, where a BI is placed in the most difficult-to-
sterilize location of the device, such as restricted pathways, mated surfaces or long narrow
lumens,” Littley said. “In theory, the process should kill a given population of that organism.
The biological indicator, with a minimum of one million organisms on a paper strip, is our
‘meter stick’ for determining the sterility-assurance level. Naked, by themselves, the
organisms are not difficult to kill. But placing the BI inside a device relatively compares to
how other microbes may or might not survive during EO exposure.”

Another approach to validating the process is through a process-challenge device (PCD),

which provides an additional avenue for products which are expensive or not easily
accessible. In these cases, the manufacturer would prefer not to destroy a $5,000 product, for
example.

Instead, an easy-to-handle, inexpensive PCD, like a coupon, is qualified for use in the
sterilization validation to simulate the product. Common PCD configuration might be a
sealed a polybag, sealed tubing, or 5 to 10cc capped non-vented syringe, with a BI placed
inside. The average cost of a PCD is in the $10 to $15 range. The PCD is then used in the
validation process instead of the inoculated device. If the PCD can be deactivated or
sterilized, then a device of lesser resistance would also be considered sterile.

How often to revalidate a product?

Revalidation would not always be necessary for a design change. For example, if a design
change increases an inner diameter, making a pathway easier for a gas to infiltrate, a
requalification would not be required.

“But if the pathway or inner diameters are reduced in size and made more restrictive, that
would call for a revalidation. Also, as production ramps up and loads become larger or
perhaps more dense, or if the packaging significantly changes, that would also require a
revalidation,” said Littley.

However, once the validation process is defined and the device and sterilization process does
not change, there is no reason to revalidate.

Nevertheless, annual requalification of the sterilization process is required by ISO and the
FDA. This can be a pen-and-paper-change assessment or actual testing.

“During requalification it is not uncommon for the device manufacturer to reach out to the
contract sterilization facility and ask if anything has changed with the process, paying special
attention to unscheduled maintenance or equipment changes,” Littley said. “At minimum,
there should be some level of testing every two years, say a half cycle with a full cycle to be
conservative.”

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ISO 11135: Requirements for sterilisation with ethylene oxide

ByQualityMedDev
OCT 24, 2021 ISO 11135
The ISO 11135 defines the requirements associated to the development, validation and
routine control of the process of sterilization with ethylene oxide.

The sterilization of medical device products with ethylene oxide or mixture of gases
containing variable amount of ethylene oxide is one of the most important methods for
sterilization. We have already been talking on different occasions about the requirements for
sterile products, for example in the article related to ISO 11137 related to gamma sterilization
or to ISO 11167, linked to the packaging requirements for terminally sterilised medical
devices.

In this article we will go through the main requirements associated to ISO 11135, including
the steps to be performed for the validation of the ethylene oxide sterilization as well as
qualification of the equipment linked to this process.

QMS Requirements as per ISO 11135

In order to properly keep under control the sterilization process, it is necessary to address
specific requirements within the quality management system.
First of all, it is important to have dedicated procedure for the design, validation, routine
control and product release for the sterilization process; it is also necessary that all the
documentation related to the ethylene oxide sterilization process is approved by personnel
with a specific level of training and experience. `

Management responsibilities are also essential. It is necessary that authorities and

responsibilities in relation to the sterilization process are properly defined and that dedicated
contract agreement (quality agreement) are up and running in case sterilization activities are
performed by external parties.

In a context of product realisation, the ISO 11135 requires the presence of a dedicated
procedure purchasing, identification and traceability; the standard procedure aligned with the
requirements of ISO 13485 would be sufficient. Moreover, Ian adequate management of the
equipment in terms of calibration and maintenance is essential to ensure to have a reliable
sterilisation process that can ensure quality safety and efficacy of the sterilization process.

Last point, an efficient method for the management of CAPA and non-conformities is
needed, as it is essential in order to manage the deviations in the sterilization process and
implement appropriate corrections.

Validation of Sterilization Process according to ISO 11135

The validation activities of the ethylene oxide sterilization process follow the standard
approach based on the so-called IQ/OQ/PQ, meaning Installation Qualification, Operational
Qualification and Performance Qualification. In this section we will go through the main
requirements for validation activities according to ISO 11135.

Installation Qualification

In the context of Installation Qualification, it is necessary to ensure that sterilisation’s

equipment is compliant with their related specification at the location where the equipment is
used. All the specifications related to the used equipment need to be established and
documented

Specific user manual detailing the related procedures for the main activities to be performed
with the equipment such as, for example, step by step instructions manual, a list of error and
actions to be taken to resolve it, instructions for maintenance and calibration and information
on contact and technical support.

It is also necessary, always in the framework of Installation Qualification, to have detail

specifications for any type of customer services and for all the preventive maintenance and
actions to be performed on the equipment at the installation site.

Moreover, instructions concerning any actions to be performed in relation to the health care
and safety of the personnel working with the specific equipment.
Operational Qualification

The goal of the operational qualification is to establish specific tolerance for the process and
ensure that the installed equipment is able to performed the specified process within that
tolerances.

Attention should also be paid to the calibration of the equipment to ensure that, in this phase
of the validation effort, all the calibration and maintenance is performed.

Performance Qualification

Based on the ISO 11135, performance qualification (PQ) for the process of sterilization with
ethylene oxide consists of two different parts:

a. Microbial Performance Qualification (MPQ)

b. Physical Performance Qualification (PPQ)

The microbial performance qualification is aiming at finding the appropriate minimum

process parameters in order to ensure product bioburden is killed. More specifically, the
microbial performance qualification uses half sterilization cycle (meaning a cycle lasting half
of a normal time in the sterilization chamber) with the goal to demonstrate a sterility
assurance level (SAL) equal to 10-6. This test is typically performed in at least three cycles
and the requirement is to have a sterile product in all the cycles.

This method is called the “overkilled” methodology, because during standard operations the
full cycle will then be used, which indeed is considered an overkill.

The physical performance qualification (PPQ) typically consists of three full cycles and
measurement of EO residuals in accordance with ISO 10993-7:2008.

Moreover, it is necessary to show, in the context of a PPQ, that after the product has been
sterilized, it remains fully functional with no specific effects on quality, safety and
functionality of the device.

Sometimes in the context of the PPQ it is possible to add a second cycle to confirm that the
product can be sterilized a second time, with no specific impact on the safety and the
performance of the product. This allows the validate a second sterilization cycle that can be
used in case a first cycle went wrong, without the need for additional process validation
activities.

It is very important to highlight that the Performance Qualifation phase shall be repreated
every time there is a change in the product, packaging, loading con- figuration, equipment,
process parameters.
A deep dive into Microbiological Performance Qualification (MPQ)

One of the critical aspect of the ethylene oxide sterilization process for the MPQ phase is the
collection of evidences that the cycle is indeed killing all the microorganisms, ensuring thus
an adequate assurance of sterility. In fact, during the MPQ, the so called “Process Challenge
Devices” (PCD’s) are placed inside and outside the load. the PCD’s contains what is usually
refer as biological indicators, basically a strip with a million bacteria, of a species which is
relatively resistant against ethylene oxide gas.

The challenge during the MPQ phase is to demonstrate that the biological indicator’s in the
Internal PCD are killed more easily than the BI’s in the External PCD. This is checked
during a separate “sub-lethal” cycle in which the sterilization cycle is too short to kill all of
the million bacteria of the biological indicator’s. When the percentage of kill is larger for the
Internal PCD’s than for the External PCD’s, the monitoring of routine production cycles can
be performed with External PCD’s only.

ETO STERILIZATION

By following a structured method, process engineers can design and validate safe and
efficacious EtO steilization cycles.

Among the sterilization technologies currently available to the medical device industry, 100%
ethylene oxide (EtO) gas remains one of the most popular. Validated EtO processes can be
run in sterilizers ranging from BIER vessels of a few cubic feet to industrial-sized vessels
exceeding 4500 cu ft. Typically, the EtO process can be broken down into four basic phases,
each of which needs careful planning to ensure a safe and efficacious process. The four
phases are: (1) air removal, (2) steam injection and conditioning dwell, (3) EtO injection and
gas dwell, and (4) gas purge and air inbleed.

Mid-infrared gas spectrometer measures EtO and water

vapor during sterilization. Photo courtesy Spectros
Instruments, Inc. (Whitinsville, MA)

This article is intended to guide the reader through the

components of each phase of two hypothetical 100% EtO
with nitrogen processes. The following assumptions were
made for the purpose of explaining the rationale behind the design of the cycles and the
options available:
  Water vapor and process nitrogen are the only inert gases considered in the
flammability calculations performed during the air-elimination and gas-purge phases.
 There is no stratification of process gases.
 All process gases are presumed to behave as ideal gases.
 Preconditioning and aeration are performed externally to the sterilizer.
 Atmospheric and barometric pressure are constant, with atmospheric pressure at 14.7
psia.

An effective EtO process can be properly designed for almost every type of medical device
and permeable packaging configuration, provided that all variables are assessed through
thorough process design and development. It is here, in fact, that one notices how EtO
processes possess a greater number of variables in comparison with other sterilization
technologies. However, by following a structured method that systematically examines and
considers each of these variables, the process engineer can design, validate, and routinely
sterilize with a safe and efficacious process.

The critical parameters of an EtO sterilization cycle are typically given as temperature,
pressure, humidity, EtO concentration, and gas dwell time. However, the process engineer
must also identify and evaluate relationships that may exist between any given process
parameter(s), the product being sterilized, and the equipment used.

The sterilization process must consistently deliver all critical process parameters to each and
every component contained within the load, to a degree that will ensure a 10-6 sterility
assurance level (SAL) without causing any deleterious effect to the product or its sterile
barrier packaging. In addition, this process must occur under controlled conditions that will
protect the sterilization personnel monitoring the operation, the equipment employed, and
ultimately the end-user.

Each product component contained in the load must be examined for the following
characteristics: natural bioburden, physical configuration, raw-material composition,
sensitivity to both negative and positive pressure changes, maximum heat tolerance, and
chemical reaction to water vapor and ethylene oxide. For example, surgical sutures may
present an extreme sensitivity to what are often considered even moderate temperature levels.
Other materials, especially those containing salts, may react strongly with EtO to form
ethylene chlorohydrin (ECH), a residual chemical produced during the EtO process. Some
materials may bind, through a positive reaction, large quantities of EtO molecules, presenting
the problem of excessively high postprocess levels of EtO and ethylene glycol (EG), another
process residual.1 Those components presenting the greatest challenge to the process—due
either to physical configuration (obstruction of gas permeation) or high bioburden (natural
fibers, for example)—should be selected for the microbiological challenge. Other product
sensitivities should also be noted, as they will determine maximum ramp rates and set points
employed in the cycle. For the validation of the process, a reference load must be selected
that will represent the most difficult combination to heat, humidify, sterilize, and aerate.

Each level of packaging, from master cartons to the unit package (the primary sterile barrier),
must be examined and evaluated for its ability to allow heat, moisture, and sterilant to
permeate. Gas delivery to and permeation within the product, in addition to aeration of the
gas from the product, are all important considerations. Data obtained from fractional studies
can provide the basis for the calculation of the dwell times for the conditioning and gas
exposure. The process engineer must be cautious of excessively long gas-exposure dwells or
high gas concentrations, as they can result in the need for long multiple evacuations and/or
aeration times that will delay product release. The objective is to decide whether to adopt a
cycle using a long gas-exposure time with low EtO concentration or one with brief gas
exposure and a high EtO concentration. Naturally, if gas is easily aerated from the product,
production times are improved by a short exposure to a high concentration of sterilant.

Before a preliminary cycle plan can be drafted, the process engineer must have a thorough
knowledge of the process equipment, including the minimum and maximum operating ranges
of the preconditioning facility, the sterilizer and ancillary equipment, and the aeration facility.
The sterilizer control system must be able to perform all evacuations and gas injections
(nitrogen, steam, EtO, and air) at steady, preprogrammed rates. Accurately calibrated
proportional valves facilitate the delivery of these rates. The objective is to perform each
process ramp at gradual (linear) rates.
Both in the first part of the sterilization cycle (air removal) and in the final stage (sterilant
removal), the safety of the facility and personnel are paramount issues. During the air-
removal phase, the sterilizer is evacuated and then backfilled with nitrogen. After each
vacuum/nitrogen sequence, a calculated amount of air is displaced. Depending on the depth
of each vacuum and the final pressure achieved by the nitrogen addition, the process engineer
must determine the minimum number of sequences necessary to bring the air content of the
sterilizer atmosphere to a composition at which there is insufficient oxygen left to pilot a
combustible reaction. EtO is flammable and can ignite in the presence of static electricity. 2 It
is, therefore, essential to know, prior to EtO injection, the volume percentage of air (%vol air)
left in the chamber before deciding upon the maximum amount of sterilant to be used. Later,
when the volume percentages of air, of the inert gases (%volsteam and %volnitrogen), and of EtO
(%volEtO) are known, they can be plotted on a flammability chart to confirm the
nonflammability of the cycle.3

Following gas contact, the EtO must be displaced from the load and removed from the
chamber. In planning this segment of the cycle, the same routine—postvacuums followed by
nitrogen flushes—is followed. A volumetric calculation of the percentage of EtO left in the
sterilizer after each vacuum/nitrogen sequence will determine when the level of EtO has been
brought down to an acceptable level. Usually, after the final evacuation is performed, the
sterilizer is backfilled with ambient air instead of nitrogen. In the final stage of the cycle, the
sterilizer rear exhaust is activated while fresh air is allowed into the sterilizer either through a
dedicated vent or by partially opening the door. Sufficient time must be allotted to flushing
the sterilizer headspace so that the EtO concentration is brought to a safe level before the
sterilizer is unloaded. Some workers wear industrial respirators with catalytic filter canisters
rated for atmospheres containing not more than 50 ppm of EtO.

Flammability is not the only factor that determines the number of evacuations. In most cases,
increasing the number of evacuations will also lower the EtO residuals left on the product,
thus decreasing the amount of time the load must be quarantined for aeration. Although in
this case "more is better," limitations are imposed by product and packaging tolerances as
well as by equipment demands. A greater number of evacuations will subject the load to
increased physical stress, which, when combined with EtO, heat, and humidity, could have a
negative effect on product and packaging constructions such as, for example, glues or seals.
Time spent for additional postvacuums also reduces the overall productivity of the sterilizer,
which can affect facility profitability.

AIR REMOVAL

Before 100% EtO can be introduced into the sterilizer, the original air content (%volair =
100% of the initial sterilizer atmosphere) must be displaced and substituted with an inert gas
such as nitrogen (N2). The physical parameters for the air-removal phase are determined by
the tolerances of the most sensitive products or packaging (e.g., nonpermeable foil pouches or
sealed cavities). If data are not available from the respective component or product
manufacturers, they can be generated by conducting preliminary studies during which
samples are exposed to different ramp rates (i.e., change in pressure per unit time) and
vacuum set points. Each set of samples is then tested (both product and packaging) for
conformity to original manufacturing specifications until the fastest permissible ramp rate
and deepest acceptable evacuation set point are determined and recorded in the sterilization
process design history record.

The initial pressure inside the sterilizer at the moment the door is closed is equivalent to
atmospheric pressure (14.7 psia at sea level). The first evacuation will remove a quantifiable
amount of air. For example, an initial evacuation from Pinitial = 14.7 psia to a depth of Pfinal =
7.35 psia will eliminate 50% of the original air content in the sterilizer. While the volume
percentage of air is still 100%, the partial pressure of air is reduced in direct proportion to the
pressure change:

The sterilizer is programmed to backfill with nitrogen to a set point of 14.7 psia. The
resulting sterilizer atmosphere is now 50% air and 50% nitrogen. After this first
vacuum/nitrogen sequence, the volume percentages of air and nitrogen are represented as:

After the second vacuum/nitrogen sequence, the amount of air in the sterilizer reduces again
by half (%volair = 25%), while the nitrogen increases by half (%volnitrogen = 75%). This
sequence is repeated as many times as necessary, until the %volair is reduced to a safe level.
Ethylene oxide requires oxygen to ignite. The term safe level is intended to mean that the air
originally contained in the sterilizer at the beginning of the process has been reduced to the
point that there remains insufficient oxygen to allow a reaction to occur should a source of
ignition be available.4 Here it should be easy for the reader to see the relationship between the
final set point of each vacuum/nitrogen sequence and the total number of sequences that will
be required to render the cycle safe.

In selecting the ramp rates and set points for the vacuum/nitrogen sequences of an EtO
process, there are various options. In general, a deep vacuum set point is preferred because it
allows the air-removal process to be completed more efficiently. As stated earlier,
determination of a maximum vacuum set point is a function of product/packaging tolerance
as well as equipment limitations. Once the maximum ramp rate tolerances are determined for
the vacuum and nitrogen sequences, the process engineer must decide what rate is best for the
given product configuration. While the air-removal phase ensures that the sterilizer
atmosphere is almost void of air, a consequence of these purges is loss of product moisture.
The goal of process design is to displace air as efficiently as possible while minimizing load
desiccation.

Deeper vacuums can complete air removal with fewer sequences. When dealing with a
vacuum-resistant product, one vacuum from atmospheric (14.7 psia) to 2.0 psia, followed by
a nitrogen backfill to 14.7 psia, will quickly reduce the %volair to 13.6% (Table I). Products
that can withstand this rate and depth of vacuum will usually tolerate an equally rapid
nitrogen injection. Fast ramp rates for nitrogen backfilling also minimize product-level
moisture loss.
 Process Cycle Set Set Ramp Segme Cumulati
Phase Segment Poin Poin Rate nt ve Cycle
t t (psi/mi Time Time
(in. (psia n) (min) (min)
HgA )
)

Cycle start 29.9 14.7 N/A N/A 0.0

Air removal Evacuation 1 4.1 2.0 1.00 12.7 12.7

Nitrogen 29.9 14.7 1.00 12.7 25.4

purge 1

Evacuation 2 4.1 2.0 1.00 12.7 38.1

Humidificati Steam 6.3 3.1 0.02 55.0 93.1

on injection

EtO inject EtO 17.9 8.8 0.20 28.5 121.6

injection

Nitrogen 29.5 14.5 0.20 28.5 150.1

overlay

Gas contact 29.5 14.5 0.00 480.0 630.1

EtO removal Postevacuati 4.1 2.0 1.00 12.5 642.6

on #1

Nitrogen 29.9 14.7 1.00 12.7 655.3

flush #1

Postevacuati 4.1 2.0 1.00 12.7 668.0

on #2

Nitrogen 29.9 14.7 1.00 12.7 680.7

flush #2

Postevacuati 4.1 2.0 1.00 12.7 693.4

on #3

Final air 29.9 14.7 1.00 12.7 706.1

inbleed

Total cycle 706.1 706.1

time (min)
 Process Cycle Partial Partial Partial Total
Phase Segment Pressur Pressure Pressur Partial
e Inerts e Pressure
Air (psi) (psi) EtO s
(nitroge (psi) (psia)
n
and
steam)

Cycle start 14.70 0.00 0.00 14.70

Air removal Evacuation 1 2.00 0.00 0.00 2.00

Nitrogen 2.00 12.70 0.00 14.70

purge 1

Evacuation 2 0.27 1.73 0.00 2.00

Humidificatio Steam 0.27 2.83 0.00 3.10

n injection

EtO inject EtO injection 0.27 2.83 5.70 8.80

Nitrogen 0.27 8.53 5.70 14.50

overlay

Gas contact 0.27 8.53 5.70 14.50

EtO removal Postevacuatio 0.04 1.18 0.79 2.00

n #1

Nitrogen 0.04 13.88 0.79 14.70

flush #1

Postevacuatio 0.01 1.89 0.11 2.00

n #2

Nitrogen 0.01 14.59 0.11 14.70

flush #2

Postevacuatio 0.00 1.98 0.01 2.00

n #3

Final air 12.70 1.98 0.01 14.70

inbleed

Total cycle
time (min)
 Process Cycle %Volu %Volume %Volume %Volume
Phase Segment me Inerts EtO Total
Air (nitrogen
and
steam)

Cycle start 100.00 0.00 0.00 100.00

Air removal Evacuation 1 100.00 0.00 0.00 100.00

Nitrogen purge 1 13.61 86.39 0.00 100.00

Evacuation 2 13.61 86.39 0.00 100.00

Humidification Steam injection 8.78 91.22 0.00 100.00

EtO inject EtO injection 3.09 32.14 64.77 100.00

Nitrogen overlay 1.88 58.81 39.31 100.00

Gas contact 1.88 58.81 39.31 100.00

EtO removal Postevacuation #1 1.88 58.81 39.31 100.00

Nitrogen flush #1 0.26 94.40 5.35 100.00

Postevacuation #2 0.26 94.40 5.35 100.00

Nitrogen flush #2 0.03 99.24 0.73 100.00

Postevacuation #3 0.03 99.24 0.73 100.00

Final air inbleed 86.40 13.50 0.10 100.00

Total cycle time

(min)

Table I. Process calculations for cycle 1—deep-vacuum type.

In the case of a vacuum-sensitive product, such as a kit containing multiple devices, the air-
removal phase could require multiple slow vacuums—down to 7.0 psia, for example. The
first vacuum/nitrogen sequence will only bring the %volair from 100% down to 47.62%
(Table II). In this case, the process engineer must consider that the desiccating effect inherent
in this process is further amplified. Multiple vacuum/nitrogen injections coupled with slow
ramp rates mean that there is more time for moisture to be driven out of the load by the
induced pressure gradient. Water becomes more volatile as temperature is increased and
pressure is decreased. In these circumstances, one must begin the steam-injection phase as
soon as possible in order to replace some of the moisture lost during the multiple slow-
vacuum phases.
 Process Cycle Set Set Ramp Segme Cumulati
Phase Segment Point Poin Rate nt ve Cycle
(in.Hg t (psi/mi Time Time
A) (psia n) (min) (min)
)

Cycle start 29.9 14.7 N/A N/A 0.0

Air removal Evacuation 14.3 7.0 0.25 30.8 30.8

1

Nitrogen 29.9 14.7 0.25 30.8 61.6

purge 1

Evacuation 14.3 7.0 0.25 30.8 92.4

2

Nitrogen 29.9 14.7 0.25 30.8 123.2

purge 2

Evacuation 14.3 7.0 0.25 30.8 154.0

3

Nitrogen 29.9 14.7 0.25 30.8 184.8

purge 3

Evacuation 14.3 7.0 0.25 30.8 215.6

4

Nitrogen 29.9 14.7 0.25 30.8 246.4

purge 4

Evacuation 14.3 7.0 0.25 30.8 277.2

5

Humidificati Steam 16.5 8.1 0.02 55.0 332.2

on injection

EtO inject EtO 28.1 13.8 0.20 28.5 360.7

injection

Nitrogen 29.5 14.5 0.20 3.5 364.2

overlay

Gas contact 29.5 14.5 0.00 480.0 844.2

EtO removal Postevacuati 14.3 7.0 0.25 30.0 874.2

on #1

Nitrogen 29.9 14.7 0.25 30.8 905.0

flush #1

Postevacuati 14.3 7.0 0.25 30.8 935.8

on #2

Nitrogen 29.9 14.7 0.25 30.8 966.6

flush #2
 Process Cycle Partial Partial Partial Total
Phase Segment Pressur Pressure Pressur Partial
e Inerts e Pressure
Air (psi) (psi) EtO s
(nitroge (psi) (psia)
n
and
steam)

Cycle start 14.70 0.00 0.00 14.70

Air removal Evacuation 1 7.00 0.00 0.00 7.00

Nitrogen 7.70 0.00 14.70 47.62

purge 1

Evacuation 2 3.33 3.67 0.00 7.00

Nitrogen 3.33 11.37 0.00 14.70

purge 2

Evacuation 3 1.59 5.41 0.00 7.00

Nitrogen 1.59 13.11 0.00 14.70

purge 3

Evacuation 4 0.76 6.24 0.00 7.00

Nitrogen 0.76 13.94 0.00 14.70

purge 4

Evacuation 5 0.36 6.64 0.00 7.00

Humidificatio Steam 0.36 7.74 0.00 8.10

n injection

EtO inject EtO injection 0.36 7.74 5.70 13.80

Nitrogen 0.36 8.44 5.70 14.50

overlay

Gas contact 0.36 8.44 5.70 14.50

EtO removal Postevacuatio 0.17 4.07 2.75 7.00

n #1

Nitrogen 0.17 11.77 2.75 14.70

flush #1

Postevacuatio 0.08 5.61 1.31 7.00

n #2

Nitrogen 0.08 13.31 1.31 14.70

flush #2

Postevacuatio 0.04 6.34 0.62 7.00

n #3
 Process Cycle %Volum %Volum %Volum %Volum
Phase Segment e e e e
Air Inerts EtO Total
(nitroge
n
and
steam)

Cycle start 100.00 0.00 0.00 100.00

Air removal Evacuation 1 100.00 0.00 0.00 100.00

Nitrogen 52.38 0.00 100.00 7.00

purge 1

Evacuation 2 47.62 52.38 0.00 100.00

Nitrogen 22.68 77.32 0.00 100.00

purge 2

Evacuation 3 22.68 77.32 0.00 100.00

Nitrogen 10.80 89.20 0.00 100.00

purge 3

Evacuation 4 10.80 89.20 0.00 100.00

Nitrogen 5.14 94.86 0.00 100.00

purge 4

Evacuation 5 5.14 94.86 0.00 100.00

Humidificatio Steam 4.44 95.56 0.00 100.00

n injection

EtO inject EtO injection 2.61 56.09 41.30 100.00

Nitrogen 2.48 58.21 39.31 100.00

overlay

Gas contact 2.48 58.21 39.31 100.00

EtO removal Postevacuati 2.48 58.21 39.31 100.00

on #1

Nitrogen 1.18 80.10 18.72 100.00

flush #1

Postevacuati 1.18 80.10 18.72 100.00

on #2

Nitrogen 0.56 90.52 8.91 100.00

flush #2

Postevacuati 0.56 90.52 8.91 100.00

on #3
Table II. Process calculations for cycle 2—shallow-vacuum type.

Packaging Validation for Medical Devices

ByQualityMedDev
JUL 10, 2021 packaging validation
For medical devices that have to be provided sterile, packaging validation plays an extremely
important role.

The validation of the packaging processes might involve different players, not only the
manufacturer, but also the health care facilities and sterilisation subcontractors. The ISO
11607, for which we already discussed within QualityMedDev – explicitly calls for
validation of all type of packaging. The present article deals with the following packaging
processes:

 pouch, reel, or bag sealing

 sterilization sheets folding and wrapping
 filling, and closing of reusable sterilization containers

Likewise, packaging processes not dealt with here must also be validated as per ISO 11607-2.

In this post, we will go through the main requirements associated with packaging validation,
taking into consideration three main different regulations:

 ISO 11607-1:2019 — Packaging for terminally sterilized medical devices — Part 1:

Requirements for materials, sterile barrier systems, and packaging systems
 ISO 11607-2:2019 — Packaging for terminally sterilized medical devices — Part 2:
Validation requirements for forming, sealing, and assembly processes
 European GMP guideline.

Aspects of Packaging, Packaging Materials, and Closures

When performing the activity of packaging validation, different aspects shall be taken in
consideration, such as:
  the functions of packaging;
 the selection of packaging material;
 the testing of the material selected;
 filling, and assembling;
 sterilization;
 storage, and stability.

The materials that can be used for medical device packaging could be of different types, and
they are summarised in the table below.

Type of Material Packaging-related Application

Boxes
Cardboard
Display units

Labels
Paper
Leaflets

Ampules
Bottles
Glass Vials
Syringes
Cartridges

Closures
Bottles
Plastic Bags
Tubes
Laminates with paper, or foil

Collapsible tubes
Rigid cans
Foils
Metal, Alluminium, etc
Needles
Gas cylinders
Pressurized containers

Rubber Closures, including plungers

Packaging validation has surely a critical role for the safety of patients and ensuring an
appropriate sterile barrier will reduce the number of infections that happen due to lost barrier,
or bad aseptic presentation. In fact, the primary package is a minimum package that prevents
ingress of microorganisms and allows aseptic presentation at the point of use. Only intact
packaging can serve as a sterile barrier.
ISO 11607 – 2 states that there needs to be a documented validation program in all healthcare
facilities where medical devices are packed and sterilized. The validation has as well the goal
to prove that the sealer makes a proper seal and that the sealed package can serve as a sterile
barrie and that packaging perfectly works in the environment it is supposed to be used.

Responsibilities of the Manufacturer for Packaging Validation Material conformance.

The manufacturer has multiple responsibilities related to packaging validation. First of all
only virgin medical-grade materials can be used. No recycled paper, or recycled plastics. The
printing process shall be safe (outside of packing area), including the inks that are used to
include specific contents on the packaging.

Huge importance for packaging validation standpoint is a clean environment; in this context a
quality systems in place as per ISO 13485, ISO 9001, ISO 14001, ISO 22000, could further
help the organization. Moreover the manufacturer shall own a declaration of conformity and
studies for material compatibility, microbial properties, double pouching validation, etc.

Finally, packaging validation is directly linked with the sterilization method used. Validation
of the sterilisation shall be performed and IFU and technical specifications shall be prepared
accordingly.

ISO Standards related to Packaging Validation

Different standards provide official guidelines on the activities related to packaging

validation. Excluding the ISO 11607-1 and 2 that we have already mentioned earlier, we have

 EN 868 (parts 2 10) related to packaging for terminally sterilised medical devices
 ISO 11140 – 1 : Sterilization of health care products — Chemical indicators — Part 1:
General requirements

The Process for Packaging Validation

In principle, a documented process must be available for validation. The general strategy for
packaging validation could be the standard IQ/OQ/PQ process. This process comprises:

Drafting a Validation Plan

The validation plan should contain, at least, the following details:

 Responsibilities and Competences

 Description of the packaging process
 Description of the materials /equipment
 Description of the sterilization processes
 Qualification steps (IQ, OQ, and PQ)

Installation Qualification (IQ)

The technical equipment should be properly installed, and users trained. In general, the
packing processes involving sterilization sheets as well as reusable sterilization containers are
purely manual processes, which is why proof of IQ is based on documentation of training of
staff. It is recommended that the corresponding checklists be used to conduct installation
qualification (IQ).

Operational Qualification
In principle, a distinction must be made here between automated, and manual processes and
the OQ phases varies a lot based on the subject type of packaging under validation. In
general, the typical approach is to take in consideration the worst case process parameters and
ensure adequate functionality of the packaging even using this worst case scenario.

Performance Qualification
During performance qualification, proof must be provided after sterilization that the process
is under control, and produces optimally sealed, or closed sterile barrier systems.

Validation Report
The validation procedures and results must be documented in a summary report. The
checklists, protocols, and any photographic documentation used to serve as evidence and
must be enclosed in an annex to the report. The report must contain, at least, the following
information:

 Validation plan
 Evidence of implementation of the validation plan (IQ, OQ, and PQ checklists
completed as per Annex)
 Evaluation of the results
 Photographic documentation for manual packing processes
 Details, and explanation of any deviations from validation plan
 Formal approval of validation
 Process control, and monitoring
 Process changes, and revalidation

Approval of the Validation Documentation

Validation should be formally approved, and fully documented, by the authorized person
appointed by the operator. If all validation results are not accepted, this must be documented,
including an assessment of any remaining risks.

Process Control and Monitoring

The established routine tests used during the validation should be documented in the standard
operating procedure. This is intended as a means of ensuring that changes in the packaging
process are detected on time before they compromise the sterile barrier systems, and the
requirements are no longer met. These include;

 Visual inspection
 Peelability
 Seal integrity test
 Seal integrity indicator
 Tensile strength of seal seam
 Stepwise opening of packaging (in the case of sterilization sheets, or reusable
sterilization containers).
Intervals (e.g., daily, weekly, monthly, yearly), and acceptance values must be defined for the
routine tests needed, including the action to be taken if a test result is not satisfactory. The
routine test results must be documented. This procedure must be set out in the quality
management system.

Process Changes and Revalidation

Processes must be revalidated:

 Unscheduled revalidation,
o in the event of changes to materials, processes, including changes to
equipment, or occurring during sterilization (revalidation)
 Scheduled revalidation,
o at regular intervals, i.e., in general after one year if no changes were made to
materials, sealing process, or sterilization (performance requalification).
o Provides evidence that the packaging process continues to be within the limits
defined at the time of initial validation (IQ, OQ, and PQ). That no changes
were made to materials, processes, or sterilization compared to the previous
validation must be confirmed in the revalidation report. If changes are made to
materials, processes, or sterilization, how such changes will affect the
packaging process results must be elucidated. Based on the documented
results, an individual revalidation plan must be drafted.

Conclusions

In conclusion, we have been through the main requirements associated with the Packaging
validations, and related topics. Specifically, we went through the requirements associated
with ISO 11607-1, 11607-2, and GMP.

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What precautions should be taken when sterilizing ethylene oxide?

When working near liquid ethylene oxide, maintenance personnel must wear protective
gloves and splash goggles. Any other area of the body which could come in contact with
liquid EO should be covered with protective clothing. area when an EO sterilizer is in the
exhaust phase of its cycle.

Exposure to ETO can cause eye pain, sore throat, difficulty breathing and blurred vision.
Exposure can also cause dizziness, nausea, headache, convulsions, blisters and vomiting and
coughing. In a variety of in vitro and animal studies, ETO has been demonstrated to be
carcinogenic.

What is the sterilization control for ethylene oxide?

ETO should be considered a known human carcinogen. The basic ETO sterilization cycle
consists of five stages (i.e., preconditioning and humidification, gas introduction,
exposure, evacuation, and air washes) and takes approximately 2 1/2 hrs excluding aeration
time.
What are the regulations for ethylene oxide?
What should employers know about ethylene oxide? Employee exposure is limited to one
part EtO per million parts of air (1 ppm) measured as an 8-hour time-weighted average
(TWA). Employee exposure may not exceed the short-term excursion limit of 5 ppm EtO
averaged over any 15-minute sampling period.

Toxicokinetics

Ethylene oxide is rapidly absorbed through the respiratory tract. Due to its high solubility in
blood, uptake is largely dependent on the ventilation rate and the concentration of ethylene
oxide in the inspired air. Studies in mice indicate that at ∼0.5 ppm, ∼100% of the inspired
ethylene oxide is absorbed. At higher concentrations, the percentage absorbed decreases from
90% (10 ppm) to 68% (100 ppm) and falls to 36% at 1000 ppm. Humans exposed to ethylene
oxide at levels ranging from ∼0.1 to 10 ppm absorb 75–80% of the inspired ethylene oxide.

Absorbed ethylene oxide is rapidly distributed throughout the body. In mice exposed by
inhalation to radiolabeled ethylene oxide, distribution was immediate, with the highest
concentrations of ethylene oxide or its metabolites in the lungs, liver, and kidneys. After 4 h,
levels in the liver and kidney had decreased and were comparable to those detected in the
lungs, testes, spleen, and brain.

Ethylene oxide is metabolized by either conjugation with glutathione or hydrolysis by

epoxide hydrolase. Metabolites from both pathways are excreted primarily in the urine,
although some are further metabolized to CO2 and exhaled via the lungs along with a small
amount of unmetabolized ethylene oxide. While metabolism of ethylene oxide is qualitatively
similar among species, the glutathione pathway appears to predominate in mice and rats
while the epoxide hydrolase is the primary metabolic pathway in larger species, including
man. The half-life of ethylene oxide in the blood of mice (3–12 min), rats (9 min), and
humans (42 min) is relatively short.
Disposition

Ethylene oxide is readily taken up by the lung. At steady state, 20–25% of inhaled ethylene
oxide reaching the alveolar space is exhaled as unchanged compound and 75–80% is taken up
by the body and metabolized. Aqueous ethylene oxide solutions can penetrate human skin.

Ethylene oxide is rapidly and uniformly distributed throughout the body. It is eliminated
metabolically by hydrolysis and by conjugation with glutathione and glycol. The half-life has
been estimated at 14 minutes to 3.3 hours [5–8]. It is excreted mainly in the urine as
thioethers; at higher doses, the proportion of thioethers is reduced, while the proportion of
ethylene glycol increases.

Ethylene oxide alkylates nucleophilic groups in biological macromolecules. Hemoglobin

adducts have been used to monitor tissue doses of ethylene oxide [9].

Women exposed to EtO during pregnancy may have a higher rate of spontaneous abortion
(miscarriage). EtO damages the sperm and testicles of test animals, reducing their
fertility.6 May 2008
After inhaling ethylene oxide it takes about 45 to 60 minutes for half of it to break down and
be exhaled back out of the body (the “half-life”). That means that ethylene oxide will be
completely eliminated from the body within 1-2 days to a week after being exposed.
However, ethylene is easily removed from the body through exhalation, which limits the
amount of EtO produced. Signs of toxicity occurring after short-term exposure to ethylene
oxide include eye and upper respiratory tract irritation, nausea, vomiting, diarrhea,
headache, dizziness, malaise, fatigue, muscle weakness, and signs and symptoms of
peripheral neuropathy.
Ethylene Oxide may polymerize (self-react) violently. OSHA: The legal airborne permissible
exposure limit (PEL) is 1 ppm averaged over an 8-hour workshift and 5 ppm, as an
excursion limit, averaged over a period of 15-minutes.
Ethylene oxide reacts with water to form ethylene glycol and with ethanol to form 2-
ethoxyethanol.

How to safely work with ethylene oxide?

Eye/Face Protection: Wear chemical safety goggles. A face shield (with safety goggles) may
also be necessary. Skin Protection: Wear chemical protective clothing e.g. gloves, aprons,
boots. In some operations: wear a chemical protective, full-body encapsulating suit and self-
contained breathing apparatus (SCBA).
Can ethylene oxide be used on skin?
Skin/Eye Contact Skin contact with concentrated solutions of ethylene oxide, liquid
ethylene oxide, or high vapor concentrations may cause chemical burns. Contact with
liquefied ethylene oxide may result in frostbite. Exposure to high levels of the gas may cause
corneal burns and cataracts.
The ability of ethylene oxide to damage DNA makes it an effective sterilizing agent but also
accounts for its cancer-causing activity
xposure can cause headaches, nausea, diarrhea, difficulty breathing and other problems.
Long-term exposure can cause cancer in humans. Gas coming from power ..

The main disadvantages associated with ETO are the lengthy cycle time, the cost, and its
potential hazards to patients and staff; the main advantage is that it can sterilize heat- or
moisture-sensitive medical equipment without deleterious effects on the material used in the
medical devices (Table 6).

Disadvantages of Ethylene Oxide

The main disadvantages associated with ETO are the lengthy cycle time, the cost, and its
potential hazards to patients and staff; the main advantage is that it can sterilize heat- or
moisture-sensitive medical equipment without deleterious effects on the material used in the
medical devices (Table 6). Acute exposure to ETO may result in irritation (e.g., to skin, eyes,
gastrointestinal or respiratory tracts) and central nervous system depression.859-862 Chronic
inhalation has been linked to the formation of cataracts, cognitive impairment, neurologic
dysfunction, and disabling polyneuropathies.860, 861, 863-866 Occupational exposure in healthcare
facilities has been linked to hematologic changes 867 and an increased risk of spontaneous
abortions and various cancers318, 868-870. ETO should be considered a known human
carcinogen.871

The basic ETO sterilization cycle consists of five stages (i.e., preconditioning and
humidification, gas introduction, exposure, evacuation, and air washes) and takes
approximately 2 1/2 hrs excluding aeration time. Mechanical aeration for 8 to 12 hours at 50
to 60°C allows desorption of the toxic ETO residual contained in exposed absorbent
materials. Most modern ETO sterilizers combine sterilization and aeration in the same
chamber as a continuous process. These ETO models minimize potential ETO exposure
during door opening and load transfer to the aerator. Ambient room aeration also will achieve
desorption of the toxic ETO but requires 7 days at 20°C. There are no federal regulations for
ETO sterilizer emission; however, many states have promulgated emission-control
regulations.814

ETO is absorbed by many materials. For this reason, following sterilization the item must
undergo aeration to remove residual ETO. Guidelines have been promulgated regarding
allowable ETO limits for devices that depend on how the device is used, how often, and how
long in order to pose a minimal risk to patients in normal product use.814

ETO toxicity has been established in a variety of animals. Exposure to ETO can cause eye
pain, sore throat, difficulty breathing and blurred vision. Exposure can also cause dizziness,
nausea, headache, convulsions, blisters and vomiting and coughing.873 In a variety of in vitro
and animal studies, ETO has been demonstrated to be carcinogenic. ETO has been linked to
spontaneous abortion, genetic damage, nerve damage, peripheral paralysis, muscle weakness,
and impaired thinking and memory.873 Occupational exposure in healthcare facilities has been
linked to an increased risk of spontaneous abortions and various cancers.318 Injuries (e.g.,
tissue burns) to patients have been associated with ETO residues in implants used in surgical
procedures.874 Residual ETO in capillary flow dialysis membranes has been shown to be
neurotoxic in vitro.875 OSHA has established a PEL of 1 ppm airborne ETO in the workplace,
expressed as a TWA for an 8-hour work shift in a 40-hour work week. The “action level” for
ETO is 0.5 ppm, expressed as an 8-hour TWA, and the short-term excursion limit is 5 ppm,
expressed as a 15-minute TWA814. For details of the requirements in OSHA’s ETO standard
for occupational exposures, see Title 29 of the Code of Federal Regulations (CFR) Part
1910.1047.873 Several personnel monitoring methods (e.g., charcoal tubes and passive
sampling devices) are in use.814 OSHA has established a PEL of 5 ppm for ethylene
chlorohydrin (a toxic by-product of ETO) in the workplace.876
Source:-https://www.cdc.gov/infectioncontrol/guidelines/disinfection/sterilization/ethylene-
oxide.html#:~:text=The%20main%20disadvantages%20associated%20with,medical
%20devices%20(Table%206).