bioprocess equipment x -ray sterilization of single -use
TRANSCRIPT
2021
X-RAY STERILIZATION OF SINGLE-USE
BIOPROCESS EQUIPMENT PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT: PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
1
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
AUTHORS and CONTRIBUTORS
James Hathcock, Pall Biotech (subcommittee lead)
Samuel Dorey, Sartorius (subcommittee lead)
Monica Cardona, MilliporeSigma
Sean Lynch, AdvantaPure/NewAge Industries
Nick Troise, PendoTECH
CD Feng, Broadley James
Kirsten Strahlendorf, Sanofi Pasteur (Scientific Advisory Board)
Amit Bhatt, Merck & Co.
Timo Neumann, MilliporeSigma
John Murphy, Merck & Co.
Michael Allard, Venair
Bhuvnesh Sharma, Pall Biotech
Noel Long, Cytiva
Etienne Durant, GSK
Jeffrey Noyes, Steris
Marisa Caliri, Cytiva
Dennis Annarelli, PendoTECH
Rafael Rodriguez, Cytiva
Stephen Hodder, Pall Biotech
Larry Nichols, Steri-tek
Helene Pora, Pall Biotech (sponsor)
CONTRIBUTORS
Jeff Carter, Cytiva
Sade Mokuolu, WMFTG Biopure
John Benson, PendoTECH
Mary Marcus, AdvantaPure/NewAge Industries
Emily S. Alkandry, Saint-Gobain
Max Blomberg, Meissner
Olivia Butterfield, Meissner
Ken Baker, AdvantaPure/NewAge Industries
Mark Petrich, Merck & Co.
Mike Smet, Cytiva
Clive Wingar, Thermo Fisher Scientific
Paul Calverley, Sterigenics
Gabrielle McIninch, Saint-Gobain
Janmeet Anant, MilliporeSigma
Dominic Moore, Sanofi Pasteur
Brian McEvoy, Steris
Acknowledgements
We kindly thank John Logar, Thomas Kroc, and Mark Murphy for their incredible expertise and guidance.
2
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
Table of Contents
1 EXECUTIVE SUMMARY .......................................................................................................................... 4
2 OVERVIEW............................................................................................................................................. 4
3 SUPPLY-CHAIN RISKS ASSOCIATED WITH GAMMA IRRADIATION ........................................................ 5
3.1 Growing Demand for Gamma-Irradiation in a Highly Consolidated Market ................................ 5
3.2 Production and Resupply Challenges with 60Co ............................................................................ 5
3.3 Off-Switch Not Included (Always On, Always Irradiating) ............................................................ 6
3.4 Regulatory, Government, and Security Pressures ........................................................................ 6
3.5 Market Plans to Support Future Irradiation Capacity ................................................................... 6
3.6 Urgency, Timelines, and Need for Action ..................................................................................... 6
4 ALTERNATIVES TO GAMMA IRRADIATION ............................................................................................ 7
4.1 TECHNICAL EVALUATION OF X-RAY AS COMPARED TO GAMMA ................................................. 8
4.1.1 Irradiation Beam Characteristics .................................................................................... 8
4.1.2 Product Impact Characteristics ...................................................................................... 9
4.2 ISO11137 REQUIREMENTS TO TRANSITION FROM GAMMA TO X-RAY ...................................... 10
4.2.1 Requirements on the Irradiation Source. .................................................................... 10
4.2.2 Transferring the sterilization dose. .............................................................................. 10
4.2.3 Transferring the maximum acceptable dose. .............................................................. 11
5 IMPACT OF IRRADIATION TO POLYMERS ............................................................................................ 12
6 RISK-BASED TESTING APPROACH TO QUALIFICATION OF X-RAY ........................................................ 13
6.1 Identifying Materials & Component Tests that Best Assess the Risk ......................................... 14
6.1.1 Connector-Specific Testing Rationale .......................................................................... 20
6.1.2 Container and Film-Specific Testing Rationale ............................................................ 20
6.1.3 Sensor-Specific Testing Rationale ................................................................................ 21
6.1.4 Tubing-Specific Testing Rationale ................................................................................ 21
6.1.5 Filter-Specific Testing Rationale ................................................................................... 22
6.2 Single-use assemblies ................................................................................................................. 23
7 THE PATH FORWARD .......................................................................................................................... 24
7.1 Key Technical Steps for Collective Industry Approach ................................................................ 24
3
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
7.2 Implementation of X-ray as Alternative to Gamma-Irradiation ................................................. 25
Disclaimer .................................................................................................................................................... 25
About BPSA ................................................................................................................................................. 25
8 REFERENCES ........................................................................................................................................ 26
4
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
1 EXECUTIVE SUMMARY A prospective assessment of the contract gamma-irradiation used for sterilization of bioprocess single-use systems,
highlights increasing capacity constraints that may impact delivery and business continuity for a rapidly growing single
use market by 2022. X-ray sterilization, now considered a mature technology, is positioned as a highly similar alternative
to gamma, and contract irradiators are planning much of the future irradiation sterilization capacity in the form of X-ray.
Qualification of alternate sterilization modalities such as X-ray, in addition to addressing industry capacity constraints,
offers increased flexibility to accommodate disruptions or demand spikes and may result in less unwanted effects on
plastics. Technical similarities and differences between X-ray and gamma are reviewed herein, as well as a risk-based
testing strategy for evaluation of x-ray sterilization of single-use systems. The consensus testing strategy indicates the
types of data that may be generated by single-use suppliers on representative single-use materials and is expected to
confirm that existing gamma-irradiation validation packages can be considered applicable to X-ray.
2 OVERVIEW Continued success and rapid growth of single-use technologies in bioprocessing relies critically on a robust irradiation-
sterilization supply chain well-prepared to address growing market demand and unique business continuity challenges.
There is growing global demand for contract irradiation, increasing business and regulatory challenges associated with
cobalt 60 (60Co), limited construction of new gamma-irradiation sites, and the advent of new accelerator technologies.
Coupled with new X-ray service providers entering the market, historically focused on e-beam, a growing biotech single-
use community will likely need to embrace these highly similar, accelerator-based alternatives to gamma irradiation,
such as X-ray.
In addition to reviewing alternatives to gamma-irradiation that can help ensure future business continuity, ISO-11137
prescribed requirements as other recent industry guidances for qualifying e-beam or X-ray as alternative irradiation
modalities are summarized. Whereas as the requirement to demonstrate a minimum sterilizing dose is achieved
through X-ray is relatively straight forward, arguments that X-ray irradiation at the maximum dose impacts single-use
materials in a way that is equivalent or better than gamma, while well-supported by an abundance of heuristic, science-
based rationale by industry experts, is limited by a paucity of publicly available data.
A holistic approach to assessment and qualification of X-ray sterilization entails a fundamental understanding of the
impact of X-ray on single-use materials and components, as well as an overall assessment of the final packaged
assembly. Working as a collective industry group of end-users and suppliers of single-use systems, the BPSA working
team employed the 2015 BPSA quality matrix tool of standard tests performed on single-use components [1], to identify
which tests would most incisively characterize any potential impact of X-ray irradiation as compared to gamma. In
addition to establishing a cross-industry consensus view on the types of testing that will best assess any potential risk,
the working team has identified specific tests that will be performed on representative components and the data shared
with the single-use community. It is expected this risk and data-based assessment of materials and components used in
the biotech single-use industry will support the strongly-touted arguments that X-ray is equivalent or better than
gamma, thereby enabling much of the qualification data already in place for gamma, to be leveraged as fully applicable
to X-ray. Lastly, the path forward including steps required to fully qualify X-ray irradiation and provide appropriate
customer notification timelines is outlined. A successful industry approach to qualifying alternative modes of irradiation
sterilization may strengthen business continuity in the rapidly growing single-use industry, with the end goal of ensuring
innovative patient therapies can be rapidly developed and delivered [2].
5
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
3 SUPPLY-CHAIN RISKS ASSOCIATED WITH GAMMA IRRADIATION Virtually all supplier-sterilized single-use systems (SUS) on the rapidly growing biotech market today are sterilized
through gamma-irradiation by cobalt-60 (60Co), which is associated with a number of unique supply chain risks. These
risks range from the complex production of the 60Co isotope, regulatory restrictions and approvals for handling and
distributing 60Co, a growing overall market demand for ionizing radiation, and fundamental requirements for accurate
long-term planning. The markets for 60Co supply and contract gamma irradiation have been reported to be highly
consolidated [3] [4]. In order to ensure business continuity and mitigate risks, sterilization experts from pharma, medical
device and contract irradiators have advocated exploring multiple sterilization modalities to support sustainable
business continuity plans [2].
3.1 Growing Demand for Gamma-Irradiation in a Highly Consolidated Market The global sterilization market, which is largely dominated by ethylene oxide (EtO, 50%) and gamma-irradiation (40%),
was reported as $4.7 B in 2016 and expected to reach $6.9B by 2021, at a CAGR of 8.8% [5]. For gamma-irradiation,
there are over 200 large-scale gamma irradiators scattered globally utilizing 400- million curies (Ci) of 60Co. As 60Co is
constantly decaying with a radioactive half-life of 5.2 years, each irradiation site must replenish its 60Co at a rate of 12%
per year [4] [6], or 48 MCi/yr globally. Regionally, 60Co utilization is split by the US (51%), EMEA (20%), Asia (15%), and
LATAM (14%); among contract irradiation sites located in North America (24%), Europe (25%), APAC (40%), and LATM
(7%) [6] [7] [4]. In the current scenario, with a high and increasing demand for gamma-irradiation, the need for
accurate long-term planning, and a limited number of service providers in the market, the long-term security of supply
for Biotech SUS providers depends strongly on substantial, long-term commitments to irradiators to ensure their
products receive priority, both for routine processing as well as in the event of any disruption.
3.2 Production and Resupply Challenges with 60Co Production and distribution of 60Co used in contract gamma irradiation of SUS is complex, highly regulated, and strongly
dependent on accurate 2-3 year out market need forecasts. 60Co is produced in nuclear reactors by exposing naturally
occurring and stable cobalt-59 to a neutron flux, where a neutron is added to the nucleus to produce 60Co. As of 2017, 60Co was currently produced in approximately 40 nuclear reactors located in eight countries, with Canada and Russia the
largest producers [6]. However, the vast majority of 60Co generated for use in contract sterilization was produced in
Ontario, Canada. The production in CANDU nuclear reactors is performed using adjuster rods made primarily out of 59Co
instead of the typical stainless steel. After 1 to 3 years, the rods are harvested during a routine shutdown, and
encapsulated in stainless steel pencils to prevent leakage. Production starting today will need to satisfy demand 2-3
years from now, when the 60Co is harvested. Future demand forecasts estimate 4.4 % growth [6], and suggest demand
will double in 15-18 yrs [4] [6].
Current market shortages in availability of 60Co have largely stemmed from decommissioning or refurbishments of
reactors used to produce the isotope. As a result, Nordion, the primary global supplier of 60Co used in contract gamma
irradiation, has reported taking a number of key steps to ensure continued availability for 60Co that include securing IP
enabling 60Co production a broad range of reactors and new multinational supply agreements with Russia, China and
India [8] [9]. However, it remains unclear how much industry capacity can be economically added [4].
Resupply of a contract gamma irradiator’s source 60Co to address the activity lost to radioactive decay is typically
performed once per year and needs to be planned well in advance to address security, logistic and installation
requirements. A well-planned installation process typically requires several days, with 1 full day dedicated to
installation, during which time no processing can take place. Although the resupply process is generally reliable, known
issues have occurred leading to an inability to access the irradiation areas for weeks or months [6]. Other scenarios
6
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
include reports of irradiators requiring 6 weeks to complete maintenance repairs during resupply, while asking SUS
suppliers to reduce shipments by 50% during this period.
3.3 Off-Switch Not Included (Always On, Always Irradiating) As costly 60Co continuously produces photons, regardless of whether it is being used for commercial sterilization
purposes, or sitting unused, there is a high commercial pressure to ensure the right amount is located in the region and
facility needed, and to maximize 60Co utilization 24 hrs/day, 7 days/week. However, for an irradiator who has
successfully-optimized its 60Co utilization and is operating at or near capacity, any disruptions to its operations will
quickly ripple through the supply chain causing delays or capacity restraints in irradiation of goods. Similarly, demand
spikes in the need for biopharma goods, such as observed during the 2020 COVID pandemic, can also stress the supply
chain impacting factors such as single-use availability, contractual-commitments and industry need.
3.4 Regulatory, Government, and Security Pressures The radioactive nature of 60Co and fears that such isotopes – due to accident, oversight or sabotage – could be acquired
and used in radiological dispersal devices (“dirty bomb”). Its use and transport remains highly scrutinized by authorities
[10] [11], with growing pressure from US [11] and European [12] authorities to research and evaluate alternative
technologies for their radioactive sources. One example of the regulatory challenges and approval timelines associated
with construction of new contract gamma irradiation, is the Gammatec facility (Languedoc-Roussillon, France) which
opened in 2013, 7 years following the license application in 2006 [13]. In the US, a 2015 US Appropriations Bill that
would have phased out the use of radioisotopes was proposed and failed. The US Committee on Homeland and National
Security then established an interagency working group on alternatives to high-activity radioactive sources, with the
remit to establish best practices for transitioning to non-radioisotopic technologies [11]. Consequently, whereas it
remains possible to expand irradiation capacity at existing facilities, there are enormous and increasing regulatory
hurdles for construction of any new gamma irradiation sites.
3.5 Market Plans to Support Future Irradiation Capacity The contract irradiation market has and continues to experience significant consolidation. This consolidation appears to
be impacting strongly how and how quickly the industry is allocating future capacity of X-ray vs gamma. Due to business
sensitivities, the market-drivers and how they impact the urgency for qualification of X-ray sterilization are beyond the
scope of this paper.
3.6 Urgency, Timelines, and Need for Action In today’s interconnected global economy that underpins a $300B biologics drug manufacturing industry critical to
public health, business continuity risks such as hurricanes, tsunamis, and global pandemics no longer sound so far-
fetched. Moreover, the current shortage of 60Co, increasing demand for sterilization, and plans by the leading contract
sterilizer to build future capacity with X-ray suggests the gamma-irradiation market is strained and susceptible to risk.
Although hard numbers in terms of total market irradiation capacity, requirements for the rapidly growing SUS industry,
and impact of other irradiation consumers (e.g. medical device, food irradiation) are difficult to exact and predict, an
analysis by a SUS supplier focused on Western Europe has been shared within the BPSA X-ray working group, including
contract sterilizers, with general agreement that it is representative of the larger, global industry trend already being
observed today (Figure 1). Whereas this analysis suggests irradiation capacity will start to have a more significant
impact on market dynamics in 2022, the specific time frames and degree of impact remain educated best guesses based
on limited predictive data. Regardless, the bulk of future capacity appears planned in alternative modalities. Gamma
irradiation will continue to be a cornerstone of overall irradiation market capacity.
7
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
Figure 1: Analysis of gamma-irradiation market demand for SUT vs expected market capacity (Western Europe). Vertical axis indicates estimated biotech consumption of 60Co irradiation capacity. Red arrow indicates expected time in which demand starts to significantly outpace capacity.
4 ALTERNATIVES TO GAMMA IRRADIATION Current major accepted sterilization practices for the medical device and healthcare industry include EtO (50%), gamma-
irradiation (40%), e-beam (4.5%), and a variety of other modalities (5%) including steam and X-ray [14]. In a recent
response to emissions and closures of EtO sterilization facilities, the FDA issued an innovation challenge to identify new
sterilization methods and technologies [15], from which five applications were accepted focusing on supercritical carbon
dioxide, nitrogen dioxide, vaporized hydrogen peroxide, vaporized hydrogen peroxide-ozone, and accelerator-based
sterilization, such as e-beam and X-ray. Note that although UV radiation has been accepted for disinfection of air,
drinking water and contact lenses, its germicidal effectiveness and use is highly material, organism and application
dependent as it generally does not have sufficient energy to ionize particles in the same way as gamma, X-ray and e-
beam [16] [17].
With regard to ionizing radiation, the definitive standard employed and referenced for sterility validation of single-use
systems, ISO 11137-1:2006 “Sterilization of health care products — Radiation — Part 1” [18], is agnostic with respect to
the modality of irradiation, and treats the requirements for gamma, X-ray or e-beam equally. In this sense, both X-ray
and e-beam offer similar technical and validation strategies to gamma, and avoid complications associated with gas and
8
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
vapor-based sterilization techniques. Both X-ray and e-beam could be used to sterilize single use systems mainly
depending on their configuration and thickness.
E-beam sterilization, initially developed for commercial sterilization of medical devices by J&J in 1956, is a viable, low-
cost alternative to gamma sterilization, and started to gain increasing market share in the 1980’s and 1990’s with
advancements in accelerator power and reliability allowing it to be routinely used for applications such as sutures,
gloves, gowns, face masks, dressings, syringes and surgical staplers [5]. Fundamentally e-beam employs electromagnetic
fields controlled via an accelerator to emit a highly charged stream of electrons that directly impact the product and
DNA of microorganisms. However, unlike the photons emitted via 60Co-generated gamma irradiation, e-beam charged
particles (electrons) possess a charge and very small mass that limits their ability to penetrate product. The poorer
penetration and hence dose uniformity properties of e-beam limit its use to lower density (~0.25g/cm3) products and
box-sizes, as opposed to the larger palettes often used with gamma.
X-ray sterilization technology has rapidly evolved and promises to overcome the hurdles associated with penetration
and dose uniformity, and potentially offer some improvements over gamma. The first commercial dedicated X-ray
facility commenced operations in Hawaii in 2000 for phytosanitary treatment of food products, and a second facility
opened near Philadelphia in 2001, which has been relegated to decontamination of mail [6]. Continued technological
advances in accelerator technology led to the 2010 opening of the Daniken, Switzerland commercial site focused on
sterilization of medical devices and additional X-ray sterilizations sites opening by 2021 near Dallas, Texas;
Northborough, MA; Libertyville, IL, Venlo, Netherlands and Germany. Although this added capacity is currently small
compared to that for existing gamma irradiation, advances in X-ray equipment (IBA, Mevex, and CGN Dasheng), low cost
to entry, and investments by major contract sterilizers position X-ray as the leading technology to supplement market
capacity needs.
4.1 TECHNICAL EVALUATION OF X-RAY AS COMPARED TO GAMMA Both gamma-irradiation and X-ray-irradiation are fundamentally the same in that they both rely on a stream of well-penetrating photons to interact with the product, eliciting Compton-scattering effects whereby scattered electrons generate the killing effects on microorganism DNA [19]. However, the way the initial stream of photons is generated is different [6]. In other words, the key feature demarcating X-rays from gamma-rays is how they originate [20]. Gamma-rays arise from atomic nuclei through isotopic decay while X-rays are produced when high energy electrons decelerate on impact with the nucleus of another molecule [20]. X-ray irradiation equipment are basically electron beam systems where a tantalum (or Tungsten) target is added in front of the e-beam. As the high energy, directed electrons interact with the nucleus of the target, energy is released in the form of a similarly-directed X-ray photon (Bremsstrahlung effect) [5]. The conversion efficiency of the electron to X-ray photon is approximately 12% for a typical 7 MeV electron beam indicating equipment power and cost requirements are substantially higher than e-beam. Although extraordinarily similar, the key differences in X-ray and gamma irradiation in their ability to impact polymers are generally considered in the dimensions below.
4.1.1 Irradiation Beam Characteristics Energy Spectra. Although both gamma and X-ray rely on beams of photons impacting the product material, the energy spectral characteristics of the X-ray and gamma ray are different. Gamma rays from 60Co decay are monoenergetic, having discrete energy peaks at 1.17 and 1.33 MeV. However, scattering within the source and surrounding environment can lead to photons at other energies. In contrast, X-rays generated via Brehmsstrahlung irradiation exhibit a much broader and continuous spectrum of energies, including energies below and above those for gamma [4]. X-rays are
sometimes mistakenly considered to be less energetic than gamma-rays, but their energy bands actually overlap [20]. The
9
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
higher X-ray energies (i.e. > 1.33 MeV) are thought to lead to improved penetration of X-rays (and consequently dose uniformity) as described further below. Directionality. The resulting beam of directed X-ray photons allows the flux to be concentrated in the single direction of
the product, irradiating the product only when in front of the beam and optimizing the photon capture rate [4]. In
contrast, photons generated by 60Co gamma irradiation are isotropic, radiating in all directions. To make best use of the
valuable 60Co source, gamma facilities are designed to position optimal volumes of products around the source, both
vertically and horizontally [6].
Dose Rates. Dose rate, or the amount of irradiation dose absorbed per unit time, is inherently faster with accelerator-
based technologies such as e-beam and X-ray when the product is in front of the beam. Hence a product subjected to X-
ray may receive the target dose approximately 6x faster than when subjected to gamma. Typical reported dose rates of
60 kGy/hr have been reported for X-ray sites (372 kW electron beam power), whereas average dose rates of 10 kGy/h
may be expected for similar gamma-irradiation sites [6]. However, it is worth noting that whereas X-ray exhibits a
constant dose rate when product is exposed to the beam, the dose rate for gamma is an average of both lower and
higher dose rates as the product moves on a conveyer over a period of hours around the gamma facility initially far from
and then closer to the 60Co source.
The higher dose rates, and hence shorter irradiation times, are considered advantageous with regard to material impact
[4], typically associated with key benefits including decreased odor generation, color change, and ozone-induced
oxidation [6].
4.1.2 Product Impact Characteristics Penetration. Both the directionality [21] and broader energy spectra [22] of X-rays are thought to contribute to
improved penetration properties of the product [19] [4] as compared to gamma. The directionality, or more narrow
angular distribution of X-rays (i.e. shooting directly at the target product) enables better penetration of materials as
compared to omnidirectional gamma, because the most intense zone of emitted radiation is perpendicular to the
surface of the target products [21].
Dose Uniformity. The directionality and improved penetration achieved with X-ray also contributes to better
consistency and uniformity of absorbed dose across the product as compared to gamma. From a directionality
perspective, X-ray systems improve uniformity by irradiating product loads consistently as the product moves
continuously through the X-ray beam via multiple passes from both sides and at different elevations [21]. For all areas
of the product to receive the absolute minimum sterilizing dose, some portions of the product will invariably receive
higher doses. The Dose Uniformity Ratio (DUR), defined as the ratio between the maximum dose and minimum dose, is
never less than unity, and characterizes the level of overdosing or wasted energy. Trials comparing X-ray and gamma-
irradiation processes under matched conditions have demonstrated DURs as low as 1.25 can be achieved with X-ray,
which contrasts with a poorer DUR of 1.45 for the same pallet irradiated by a 60Co source [21]. Another example with a
pallet of medical devices requiring a minimum sterilization dose of 25 kGy, indicated a X-ray pallet could be processed
with a maximum dose of no more than 30 kGy, whereas the equivalent gamma process would be expected to receive a
maximum dose of 35 kGy [6]. In the immediate field of complex single-use systems used in biomanufacturing where
gamma irradiation windows easily range from 25 kGy to as much as 50 kGy, the improved DURs associated with X-ray
could lead to either more consistently irradiated SUS at lower levels of irradiation, or slightly larger volumes processed
within the same irradiation pallet.
10
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
Oxidative Effects on Polymers. In medical device conferences and white papers from irradiation equipment and service
providers, gamma is frequently touted as much harsher on plastics compared to X-ray and e-beam [6] [21] [23]. The
rationale for diminished oxidative effects is attributed to the high dose rates and shorter exposure times, which
minimize time exposed to ozone [21] and the time for oxygen replenishment required for radical-oxygen reactions,
frequently associated with irradiation [23].
Temperature Effects on Polymers. It is generally regarded that gamma-irradiation is associated with higher ambient
temperatures during processing as compared to X-ray. Although temperatures within the gamma irradiation chamber
vary seasonally, the high density of product around a 60Co source, whereby the product and room equipment are
constantly absorbing irradiation over many hours contributes to higher ambient room temperatures associated with
gamma, as compared to X-ray or e-beam, where absorption occurs only in front of the beam [24]. Comparative data
report temperatures reaching as high as 50C in summer months associated with gamma versus 32.7C for the same
month with X-ray [24]. Temperature increases associated with adsorption of ionizing radiation may also be considered,
but the shorter duration of exposure and lower ambient temperatures associated with X-ray suggest temperatures are
unlikely to approach meaningful transition temperatures within the materials.
4.2 ISO11137 REQUIREMENTS TO TRANSITION FROM GAMMA TO X-RAY The requirements for sterilization of healthcare products via irradiation, whether by gamma, X-ray or e-beam, are
defined in ISO 11137-1. In order to qualify an alternate irradiation modality, such as switching from gamma to X-ray,
three key points need to be evaluated as described by the Panel on Gamma and Electron Irradiation [25]. These include
requirements on the irradiation source, transfer of the sterilization dose, and transfer of the maximum acceptable dose.
4.2.1 Requirements on the Irradiation Source.
ISO 11137-1 (5.1.2) requires the energy levels of the X-ray or e-beams be specified and that, in cases where the level for
X-ray exceeds 5 MeV (7 MeV is typical) or 10 MeV for e-beam, the potential for inducing radioactivity in the product be
assessed. This is also referred to as activation of the irradiated product.
In assessing product radioactivity, the ISO11137 (A5.1) guidance section references a publication by Gregoire et al,
which provides a comprehensive review of materials associated with medical devices and concludes that any imparted
radioactivity in the such devices is negligible and lower than the most conservative regulations [26]. Materials
evaluated by Gregoire using a 7.5 MeV beam with doses up to 50 kGy included the categories below.
materials that have very small potential for becoming radioactive (non-metallic hydrocarbon-based materials,
e.g. polyethylene and polystyrene);
materials that have a potential to be activated at a measurable but low level (e.g. stainless steel and brass); and
materials that have a potential to be activated to comparatively higher levels (e.g. tantalum) requiring detailed
evaluation.
Materials not covered by existing reviews may require further detailed evaluation due to their potential for activity (e.g.
silver and gold) [26].
4.2.2 Transferring the sterilization dose. ISO 11137 Section 8.4.2 addresses transfer of the sterilization dose (and corresponding verification dose) and requires
data indicating that any differences in the operation conditions of the two irradiation sources have no effect on the
microbial effectiveness. To demonstrate that the microbial effectiveness is not altered, a successful dose verification
11
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
experiment is considered sufficient [25] [27]. Such dose verification studies, described in ISO11137-2, are routinely
performed on representative SUS as part of the bioburden assessment and dose audit process for gamma sterilization,
and would need to be similarly performed on representative systems subjected to X-ray. In other words, X-ray
verification dose experiments can be performed with the same irradiation dose used in gamma verification dose
experiments or dose audits.
Data supporting the position that X-ray irradiation dose and gamma-irradiation dose achieve equivalent killing
effectiveness are largely available in existing literature. To answer the question whether there are differences between
the effectiveness of the irradiation modalities, D-values or decimal reduction dose values need to be compared. The D-
value determines the dose that is necessary to kill 90% (or 1 log) of relevant microorganisms [28]. Several studies have
been performed to compare logarithmic survival data or D-values. Tallentire et al. showed that microbicidal
effectiveness’s for gamma, electron and X-ray radiations are equal [29] for the spores of Bacillus pumilus. For other food
borne microorganisms like Escherichia coli, Salmonella typhimurium, Staphylococcus aureus, Listeria monocytogenes no
significant differences in bactericidal efficiency could be observed [30]. Furthermore, decontamination efficiency of X-
ray and gamma irradiation on spices [31] and dried pepper powder [32] were compared with no major differences being
observed. Overall no differences are expected between X-ray and gamma sterilization dose audit experiment studies,
which demonstrate sterility of the single use products.
4.2.3 Transferring the maximum acceptable dose. ISO 11137-1 Section 8.4.1 indicates the maximum acceptable dose for an existing modality (i.e. gamma) can be
transferred through a documented assessment indicating any differences in irradiation conditions do not affect the
validity of the established maximum dose [25]. Guidance associated with clause 8.4.1 pays specific attention to
temperature and dose rate with the remark that higher dose rates, such as with the move from gamma to X-ray, may
lower unwanted effects upon product.
In the biotech industry, there is typically an abundance of historical test data (e.g. extractables, performance
characterization, etc.) performed on SUS and components subjected to the maximum gamma irradiation dose (e.g. 50
kGy +/- 10%) qualified by the SUS supplier. These data packages support justification that SUS irradiated in the range
from the minimum sterilization dose to the maximum dose are well-suited for biopharmaceutical applications in which
they have been qualified. In order to transfer the existing maximum irradiation dose established with gamma to X-ray,
an assessment is required to demonstrate the X-ray photons do not detrimentally impact the materials as compared to
the equivalent levels of photons generated by gamma irradiation. In this way, existing data support packages generated
with gamma at the maximum dose, can be justified as fully relevant and applicable to X-ray sterilization.
Ongoing cross-industry efforts qualifying X-ray sterilization of medical devices, such as that led by Team NABLO of
Pacific-Northwest-National-Labs, have generally indicated X-ray continues to be less detrimental, yielding equivalent or
better results compared to gamma irradiation [33] [24]. These studies, which aim to support increased acceptance of
alternative irradiation modalities to gamma, typically combine a fundamental evaluation of the impact of X-ray on the
basic materials of construction as well as limited scope performance testing of the device. As more data is shared in the
public domain evaluating the impact of X-ray on materials, the expectation is that X-ray will be seen as a gentler or
equivalent alternative to gamma, which can help ensure business continuity and sustainable growth of single use
systems.
12
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
5 IMPACT OF IRRADIATION TO POLYMERS When radiation from a gamma, electron beam, or X-ray source interact with a polymer material, it either directly (e-
beam) or indirectly (X-ray, gamma) yields an abundance of electron interactions within the product material, that are
responsible for the killing effects on microorganisms as well as any impact to the polymer itself [34]. Thus nearly all
physical and chemical changes in polymers are produced by energetic electrons, and no major differences are expected
with respect to effects caused by the different irradiation forms.
The results of these electron interactions can lead to active species such as radicals, which initiate various chemical
reactions. The fundamental processes that result from these interactions are summarized below, where degradation
related to chain scission, and oxidative or free radical effects are generally a primary concern for bioprocess polymers.
[35]
Crosslinking where polymer chains join forming a network
Chain scission where the molecular weight of the polymer is reduced
Oxidation where the polymer molecules react with oxygen via peroxide
Radical formation (oxidation and chain scission often occur simultaneously)
Long-chain branching where polymer chains are joined, but a three-dimensional network is not yet formed
Grafting where a new monomer is polymerized and grafted onto the base polymer chain
In general, many polymers can, based on their intrinsic chemical structure, be grouped into categories indicating how
they respond to ionizing irradiation [34].
Cross-linkable polymers: PE, PMA, PCL, PDMS; Polymers with more hydrogen atoms on the side
Radiation degraded polymers: PP, PMMA, PLA, PTFE, POM; polymers with a methyl group (e.g., polypropylene),
di-substitutions (e.g., polymethylmethacrylate) and per-halogen substitutions (e.g., PTFE)
Radiation resistant polymers: PS, PC, PET, aromatic polymers with benzene rings either in the main chain or on
the side
The level of resistance a polymer exhibits to degradation by ionizing radiation generally depends on the base structure
of the polymer as well as additives that may be included to enhance stability [36] [37] [35]. AAMI Technical Report 17
generally serves as the definitive guide on polymer compatibility with various sterilization methods, but in regard to
ionizing radiation, it strongly focused on studies obtained via gamma irradiation and does not discriminate between
modalities such as gamma, X-ray or e-beam. Combined with other published studies [37] [38] [39] and reviews [40] [41]
[42] [43] helps to paint a fuller picture of the general ionizing irradiation compatibility of polymers typically employed in
bioprocessing components (Figure 2).
13
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
Figure 2: Irradiation compatibility of polymers frequently used in bioprocess components, compiled from multiple sources. Table is intended to be representative of polymers used with bioprocess components, but not exhaustive. (green circle) highly resistant, (yellow triangle) limited resistance, (red diamond) poor resistance at 50 kGy.
Polymers known to be highly resistant to ionizing irradiation effects will generally be expected to warrant less attention,
than those with limited or poor compatibility. Hence data showing that polymers with limited ionizing radiation
compatibility perform equivalent or better when subjected to X-ray as compared to gamma, will be critical to
establishing a sound, fundamental rationale that X-ray is in most all cases less impactful or less harsh to polymers as
compared to gamma.
Conventional approaches for evaluating polymer compatibility with ionizing radiation tend to focus on polymer stress-
strain or physical measurements following exposure. This fundamental assessment of polymer compatibility will be
strengthened through the use of additional techniques such as FTIR, DSC, and coloration that help provide a more
robust characterization of the physicochemical characteristics of the polymer. The use of the spectrometric technique
FTIR-ATR (Fourier Transform Infrared – Attenuated Total Reflectance) allows specifically to examine the polymers
surface [44]. The changes due to irradiation are estimated from the relative increase or decrease in the band intensities
of functional groups present in the polymeric chain. DSC (Differential Scanning Calorimetry) is used to measure and
analyze the reaction of polymers to heat, including properties such as heat capacity, glass transition temperature,
crystallization temperature, and melting temperature [45].
6 RISK-BASED TESTING APPROACH TO QUALIFICATION OF X-RAY Given that the physics associated with X-ray and gamma interaction with materials is comparable, and supporting data
and arguments suggest that X-ray is equivalent or better regarding their impact of materials, a risk-based testing
approach is advocated that seeks to verify through incisive testing of representative components and systems that
existing qualification data for gamma, can directly be applied to X-ray as worst case. Collectively this assessment of the
impact to materials, components and then single-use assemblies represents a holistic approach to risk assessment of X-
ray sterilization.
HD
PE
LDP
E
PC
PEE
K
PEI
PET
PS
PSU
PU
E
PV
DF
EPD
M
Po
lyam
ide
(N
ylo
n)
PB
T
PES
PP
PV
C
Sili
con
e
TPE
FEP
PTF
E
PEB
A
Fun
ctio
nal
ize
d M
ate
rial
s
Ce
llu
lose
Compatiility with Ionizing Radiation - -
Connectors
Containers (bags, bottles, carboys)
Ports on containers
Sensors
Tubing
Filters
TFF devices
Fittings and molded parts
Pumps, check valves
Needles
O-rings, Gaskets, Seals
Packaging
Sin
gle-
Use
Co
mp
on
ents
14
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
6.1 Identifying Materials & Component Tests that Best Assess the Risk The 2015 BPSA quality matrix [1], which defines typical standardized tests used to characterize the quality and
performance characteristics of single-use components, is used as a jump off point to identify dimensions of risk that
could be addressed through a standardized testing approach. For each of the standardized testing categories, we
assessed as low (blue), medium (yellow), or high (orange) whether each of the specified test types would be expected to
add significant value in identifying and assessing risks from X-ray irradiation as compared to gamma. In addition,
participating suppliers indicated via filled circles specific tests being planned on representative components, to help
verify no additional risks were being introduced by X-ray.
Table 1: In determining which standard component tests help best address any potential risk from x-ray irradiation as compared to gamma, colored circles are used to indicate low, medium, or high value. Filled circles indicate a component manufacturer has volunteered to generate and share representative data.
In evaluating which tests could most meaningfully verify the absence of any significant risk related to X-ray, efforts were
made to keep the original structure of the 2015 BPSA quality matrix [1], with the only additions related to material
physicochemical characterization. For several test dimensions, such as material color, biological reactivity, and
particulates, the recommendations and thinking rationale are highly consistent for all categories of components and
summarized below the primary table section. More detailed recommendations and rationale specific to individual types
of components can be found in sections 6.1.1 to 6.2, as well as the supplemental appendix.
15
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
Table 2: Overview of physical testing per components
A. PHYSICAL TESTS
TEST TYPE TEST REFERENCES Connectors
Valves Retainers
Containers &
Film Sensors Tubing Filters
Pressure Burst Test Manufacturer-defined
method, ISO 7241, ASTM D1599, EN 12266, ISO 1402
-
Integrity (Leak) Test Manufacturer-defined
method, ASTM E515 modified, ASTM D4991, ASTM 1003
Tensile (Pull-Off) Test Manufacturer-defined method - - - -
Tear Resistance ASTM D624, ISO 34, ASTM
D1938-14 - - -
O2 and CO2
Permeability ASTM D3985, ASTM F1927,
ISO 15105-2 - - - -
WVTR ASTM F1249, ISO 15106 - - -
Compression Set Test ASTM D395, ISO 815 - - - -
Durometer (Hardness) ASTM D2240, ISO 868 - - - -
Elongation ASTM D412 - - - -
Tensile Strength ASTM D882, ISO 527 - - -
Material Color Manufacturer-defined method
Glass Transition Temperature by DSC
ASTM D3418, ISO11357-2
Material by FTIR-ATR Manufacturer-defined method
The following physical tests from the BPSA 2015 Quality matrix were assessed as low risk, with no additional testing recommended.
(films) Seal Integrity-Peel, Helium leak, puncture, Integrity leak specifically per ISO 9393-2, and helium-leak integrity. (tubing) specific
gravity. “-“ indicates testing not indicated for component type in 2015 BPSA Quality Matrix
Materials assessment. As the higher dose rates associated with X-ray are thought to result in lower unwanted effects on
the product [46], then it can be argued that the material impact profiles and component functionalities following
gamma irradiation may generally be regarded as a worst-case. To verify that materials are equivalently or less impacted
by X-ray, fundamental physicochemical characterization of representative materials will be performed for all component
types following irradiation (i.e. time zero assessment). FTIR can be employed to assess fundamental information on the
modification of polymers due to irradiation. Any changes due to irradiation can be estimated by the relative increase or
decrease in band intensities of functional groups present in the polymeric chain [47]. Differential scanning calorimetry
(DSC) can also be used to determine any changes in the transition temperatures and heat capacity [48]. It is expected
that such testing will verify that the impact of gamma and X-ray irradiation are equivalent. Packaging materials must
be evaluated as well.
16
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
Material Color & Visual Inspection. With all modalities of ionizing radiation, dose-dependent color changes to the
material (i.e. yellowing) are one of first observations reported. Although largely cosmetic, these observations do reflect
the impact of ionizing radiation on the material and are expected to be assessed for representative materials subjected
to X-ray as compared and gamma. Most observations to date indicate yellowing of X-ray irradiated components is
equivalent or less than gamma.
Table 3: Overview of functional testing per components
B. FUNCTIONAL TESTS
TEST TYPE TEST REFERENCES Connectors
Valves Retainers
Containers &
Film Sensors Tubing Filters
Water Flow Rate and Pressure Drop
ISO 7241-2, ISO 3968, Manufacturer-defined
method -
IEC60534-2-3, DIN EN 1267 - - -
Accelerated Aging (Shelf Life)
Manufacturer-defined method, ASTM F1980
Particulate Matter USP <788>, ANSI/AAMI BF7,
BPSA recommandations, EP2.9.19
Kink Resistance/ Bend Radius
Manufacturer defined method - - - -
Filter Integrity Test Manufacturer defined method - - - -
Bacterial Retention Test (Sterilizing Grade Filters)
ASTM F838 - - - -
Bacterial Challenge/ Soiling Test
Manufacturer-defined method, ANSI/AAMI BF7
- - - -
The following functional tests from the BPSA 2015 Quality matrix were assessed as low risk, with no additional testing recommended.
For all components, Packaging Testing/ Transportation & Shipping Integrity are not recommended; for the films, Break at Cold
Temperature Test, Low Temperature Brittleness, Dart Drop, Gelbo, Haze and Transmittance, Plastic Containers Qualification of
Parenteral / Opthalmics testing are not recommended; for the filters, Solute Rejection testing is not recommended.
Shelf life. Shelf life, which indicates the length of time a component may be stored while remaining fit for use, is not
expected to be impacted by X-ray as compared to gamma irradiation [18]. Although the process of irradiation may
impact shelf life, it is expected that the thermal and mechanical materials analysis described above, will verify that any
detrimental impact of X-ray on polymers is equivalent or better to that expected from gamma. The needs and
magnitude of a full-term shelf life study can be evaluated through a risk assessment based on existing information (e.g.
gamma shelf life data) and time zero materials data comparing X-ray and gamma. If results demonstrate meaningful
differences in materials properties at time zero then further evaluation of shelf life requirements may be warranted.
17
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
Particulates are predominately dependent on the manufacturing environment and conditions, and not expected to be
significantly impacted by irradiation. Furthermore, because gamma irradiation may be regarded as a worse case with
regard to material impact, particulates attributable to X-ray are considered to be low risk [46]. Successful verification
that the material properties are equivalent following X-ray or gamma, will help confirm the absence of any potential risk
of particulate generation related to X-ray. If any of these tests indicate any potential risks for particulate matter, then
representative samples will be tested by participating suppliers in a preliminary study.
Table 4: Overview of biological testing per components
C. BIOLOGICAL TESTS
TEST TYPE TEST REFERENCES Connectors
Valves Retainers
Containers & Film
Sensors Tubing Filters
Biological Reactivity - In Vitro
USP <87>, ISO 10993-5
Biological Reactivity - In Vivo
USP <88>, ISO 10993-1,6,10,11
Bacterial endotoxin and hemolysis testing were assessed as low risk, with no additional testing recommended for all components.
Biological reactivity. As the materials of construction, manufacturing process and environment, and use of ionizing
radiation remain unchanged, there is no expected change to biological reactivity compliances (e.g. USP <87> and <88>),
and existing compliances are expected to remain fully valid. To further substantiate this assessment, limited scope USP
<87>/ISO10993-5 testing may be performed on some representative single-use materials.
Endotoxin levels are primarily associated with raw materials handling strategy and environmental manufacturing’s
conditions, which are identical for X-ray and gamma irradiation. Hence no impact is expected, and testing is not
planned.
18
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
Table 5: Overview of chemical testing per components
D. CHEMICAL TESTS
TEST TYPE TEST REFERENCES Connectors
Valves Retainers
Containers & Film
Sensors Tubing Filters
Chemical Process Compatibility
Manufacturer defined method typically aligned with ASTM
D543-14 and/or risk assessment
Extractables Manufacturer defined method, <665> - Moderate risk, <665>
high risk, BPOG
Physicochemical Container Test
USP <661>a
EP/ Physicochemical EP 3.1.xb - -
Conductivity Test USP <645> - - - -
pH Shift Test USP <791> - - - -
Total Organic Carbon (TOC)
USP <643> - - - -
USP <381> Elastomeric closures for injections testing were assessed as low risk, with no additional testing recommended for
connectors, valves, and tubing. a The current version of USP <661> is taken as reference in the present protocol. b The purpose of the
EP 3.1 test series is to analyze Materials used in the Manufacture of Pharmaceutical Containers. Raw materials are considered. We
extended to the EP 3.1 series not to include silicone testing as it was referenced in the BPSA 2015 matrix.
Chemical Process Compatibility is generally assessed based on the materials of construction and process contact
conditions including process fluid formulation, temperature, and exposure duration. As these parameters remain
identical between X-ray and gamma- irradiation, no additional risks are expected, or testing recommended.
Extractables are typically generated by suppliers following reasonable worst-case application conditions, including
following exposure to heat or ionizing radiation. As the expectation, data, and scientific arguments to date indicate X-ray
irradiation yields a less deleterious impact on the materials, limited scope verification testing on representative
components using the USP <665> moderate-risk component testing protocol may be appropriate.
19
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
Table 6: Overview of regulatory testing
E. REGULATORY TESTS
TEST TYPE TEST REFERENCES Connectors
Valves Retainers
Containers &
Film Sensors Tubing Filters
Animal Origin Free
EMA 410/01
TSE BSE Statement
EMA 410/01, EC 1774
REACH EC/1907/2006
RoHS 2002/95/EC
Food Contact 21 CFR 177 (2600, 2400, 1550,
2510)
Resin and Material compliances. Many compliances including REACH, TSE/BSA and EP physicochemical compliance
(section 3.1) are largely based on the materials of construction and resin formulation, which are not impacted by the
modality or ionizing radiation. These compliances are expected to remain valid, and no additional testing is
recommended.
Table 7: Overview of sterilization and sanitization testing per components
F. STERILIZATION AND SANITIZATION TESTS
TEST TYPE TEST REFERENCES Connectors
Valves Retainers
Containers & Film
Sensors Tubing Filters
Sterilization Process Compatibility
Manufacturer defined method
Irradiation Validation ANSI/AAMI/ISO 11137, AAMI
TR33, CEN ISO/TS 13004
The following functional tests from the BPSA 2015 Quality matrix were assessed as low risk, with no additional testing recommended.
For the filters, sanitization testing is not recommended.
Sterilization Process Compatibility relates to confirmation of manufacturers’ specified performance claims following
sterilization. Functional performance characteristics and suggested testing are described under physical and functional
tests, with further details and rationales provided in sections 6.1.1 to 6.2.
Irradiation Validation per ISO 1113, AAMI TR33, CEN ISO/TS 13004 are key requirements for all components as
described in Section 3.2. It is not necessary to perform the complete dose verification, but is appropriate and sufficient
to perform a dose audit when changing from gamma to X-ray [18] [49]. The key focus of this section (6.1) is on the
impact assessment of the maximum irradiating dose.
20
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
6.1.1 Connector-Specific Testing Rationale Materials of Construction. Common materials of construction include polysulfone, polyetherimide and polycarbonate
for the connector body. Seals and O-rings generally consist of silicone and there can be a stainless-steel spring.
Physical Testing. As pressure burst testing addresses what is considered a high risk, it may be prudent to ensure that the
device burst pressure is comparable regardless of sterilization modality, gamma irradiation vs X-ray irradiation. Pressure
burst tests can be performed per respective manufacturer defined method. Successful pressure burst testing is expected
to mitigate risk of hydrostatic leaks from the connector. Impact to integrity (leak) test and tensile (pull-off) tests are
considered moderate risk and can be performed per respective manufacturer defined method.
6.1.2 Container and Film-Specific Testing Rationale Materials of Construction. Common materials for containers and films include for instance polyolefins and linked
copolymers ((L)LPDE, EVA, EVOH, PA, polyesters) used in construction of the webs, as well HPDE, EVA, PVC used in
construction of the different components directly sealed to the bag chamber.
Physical tests. Key evaluation consists on highlighting chemical changes in the polymers and chain entanglement
though gas permeability measurements (oxygen, carbon dioxide, water vapor). The film strength or physical resistance
will be evaluated with tensile tests. Chamber integrity, seal integrity-peel check, pressure burst test and integrity (leak)
are performed before irradiation in routine process and no impact of irradiation have been observed on seals. Another
key evaluation involves physical change investigation, which could be evaluated by polymer molecular weight
distribution (by size exclusion chromatography for instance) and the surface energy (analyzed through the traditional
contact angle approach for instance).
Functional Tests. No changes are expected following X-ray irradiation as compared to gamma for the cold temperature
break point and the low temperature brittleness, if no change of the glass transition temperature (Tg) or other specific
thermal features occur. This will be reviewed once the thermal properties are obtained as described in the materials
analysis. Gamma is considered as a worse case compared to X-rays with regards to deleterious or unwanted effects on
plastics [18]. No plastics change/degradation is expected under conditions of normal that would prevent re-evaluation
of haze and transmittance properties if warranted.
As post-gamma shelf life data exist, and time zero post-X-ray data are expected to show equivalency to gamma, then no
new risks to shelf life are expected. No increases in particulates is expected after gamma or X-rays irradiation if materials
are not degraded in relation with physical testing results. This will be reviewed once material testing results become
available.
Packaging material attributes, such thermal properties and chemical fingerprints may require evaluation (e.g. DSC, FTIR).
If, as expected, packaging materials show no degradation with regard to material and physical testing following X-ray,
then the packaging integrity and sterility results for gamma can be expected to fully apply to X-ray. If significant
degradation is observed following X-ray as compared to gamma, then reevaluation may be warranted.
Chemical tests. No impact to chemical compatibility between materials and the process is expected. Initial compatibility
assessments typically based on formation, contact duration, temperature and base polymer composition, will remain
unchanged. The extractables degradation profile is expected to be equivalent or better to gamma and will be evaluated
as per the current evaluation plan. No additional physicochemical container tests are indicated as extractables testing is
expected to provide more incisive information.
21
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
6.1.3 Sensor-Specific Testing Rationale Functional Tests: The most important testing required for sensors is functionality testing. Changes to sensor
performance post X-ray sterilization are considered to be high risk, especially for single use components with active
electronics. A risk analysis is recommended to evaluate the extent of testing required for different single use sensors.
Functionality testing will vary depending on sensor type. In general, tests should either compare pre- and post-
irradiation performance, or test against an acceptance criterion based on the sensor’s specifications. If risk analysis
demonstrates low risk, then a rational referencing post gamma irradiation results may be used instead. Other
functionality testing, such as shelf life and particulate matter, are considered low risk for sensors and do not need to be
performed at this time. Post-gamma shelf life data can be used as a replacement as material change is expected to be
less significant with X-ray irradiation because of the lower energy per photon. Likewise, post gamma particulate matter
test results can be used to qualify a sensor as irradiation is not anticipated to produce particulates and any effects of X-
ray are anticipated to be less than gamma.
Physical Tests: Physical testing, specifically leak and burst testing should also be conducted on sensors as there is a
moderate risk. Integrity (leak) testing should be considered for all sensor types. Although the risk for a leak post X-ray
sterilization is considered to be relatively low based on existing post gamma data, testing is advised as a precaution. The
integrity test can be performed at the relevant operating pressure for the sensor. For burst testing, a risk analysis can be
conducted to determine if a sensor is at risk for bursting based on its typical usage. Depending on the risk analysis, post
gamma burst test results may be used as an alternative rational, if available. If a sensor manufacturer uses a similar
design or materials for multiple sensors, then the burst test results of the highest risk sensor may be used as a
justification for all other related sensor types if the risk analysis provides this rational.
Biological and Chemical Tests: A risk analysis is also recommended for biological and chemical testing of sensors. Most
sensors are expected to present low overall risk and not require any additional testing. Materials that comprise single
use sensors are expected to have already met all biological and chemical testing requirements post gamma irradiation,
which is assumed to have a more significant effect than X-ray irradiation. In cases where post gamma data does not
exist, justifications can be made using the test results of other components, which use the same material. Depending on
the risk assessment, a rationale to not conduct testing may also be built around the small surface area to volume ratio of
the sensor. If a sensor only marginally contributes to the overall surface area of a single use assembly, then it likely
presents low risk to the overall biological reactivity, extractables, bacterial endotoxins, chemical compatibility, etc. If this
data is also not available, or the risk analysis deems a sensor to be high risk, then important tests, such as USP<88> or
extractables may be required.
6.1.4 Tubing-Specific Testing Rationale Summary: Several BPSA Quality Test Matrix tests will be applied to various grades of tubing to evaluate the impact of an
alternative sterilization method to gamma irradiation. X-ray sterilization may affect both silicone and thermoplastic
elastomers differently than gamma irradiation, and the effects will be compared. Areas of high interest to evaluate
include the changes in cross link density, material degradation, and physical properties of the material. These changes
may affect product performance tests.
Each test, unless noted, will be performed on unreinforced silicone tubing, unreinforced thermoplastic elastomer tubing,
and braid-reinforced silicone tubing, sized 3/8” ID x 5/8” OD. Where noted, some tests will be performed on silicone
tubing overmolded with liquid silicone rubber. Samples will be split between X-ray sterilization at 50 kGy and gamma
irradiation at 50 kGy, and the results will be compared.
22
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
Physical Test Program: Several physical tests will be explored.
A burst pressure test can be performed on all tubing samples because the method of irradiation could affect the level of
cross linking and/or lead to degradation of the material itself. This could lead to a deterioration in tensile properties,
reduction in tear strength and changes in modulus. Any such changes would be expected to result differences in burst
test performance.
An integrity leak test can be performed for silicone over molded tubing samples because any change in compound
stiffness or elasticity could affect sealing performance. Additionally, any change in the level of cross-linking present in
the elastomeric component of a TPE or the silicone could affect stiffness/elasticity. Changes in elasticity and crosslink
network or the occurrence degradation would result in changes in material relaxation properties, which would have a
direct effect on the ability of the material to for a seal.
Tear strength may be evaluated on representative samples because a reduction in tear strength would be of importance
in terms of damage resistance, therefore tear strength test would be a primary indicator of the effect of sterilization. It is
particularly relevant in respect of silicone elastomers since the tear strength of these materials is generally lower than
that of other elastomers.
Compression set can be evaluated on representative samples because it will measure any differences in relaxation
properties, indicating likely changes in crosslinking, elasticity and stiffness.
Durometer, elongation and tensile strength can be evaluated on representative samples because changes in elasticity
and modulus could be the result of degradation or changes to state of cure.
DSC (Differential Scanning Calorimetry) and TGA (thermogravimetric analysis) will also be performed on samples as
described in the materials assessment. TGA polymer degradation temperatures can indicate degradation. DSC may
indicate changes in state of cure.
The physical appearance and any noted changes of all samples will also be documented.
Functional Test Program: Several functional tests will be explored. Adhesion testing will be performed on over-molded
samples to evaluate if the bond in over-molded junctions between tubing and LSR that would be affected if state of cure
is changed by sterilization method. Fatigue testing will be performed on all tubing samples and may show differences
related to sterilization technique if material modulus/elasticity is altered.
Sterilization and Sanitation Test Program: Several sterilization tests will be explored. Sterilization process compatibility
(confirmation of manufacturer's specified performance claims after sterilization process), irradiation validation
(qualification of the sterilization of healthcare products by irradiation), and moist heat sterilization validation will be
evaluated using representative sample types, per ISO 11137 and other applicable industry standards.
6.1.5 Filter-Specific Testing Rationale Sterilizing-grade, bioburden reduction, clarification and virus-removal filters are commonly used in SUT bioprocesses,
with sterilizing grade filters being used in high-risk, downstream applications near the formulation and filling stage.
Materials of Construction. Common materials for bioburden and sterilizing grade filters include polypropylene, silicone
gasket materials, and PET, used in construction of the filter capsules hardware, as well functionalized PES, PVDF or nylon
membranes used in construction of the retentive membrane.
23
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
Physical tests. As the physical integrity of filter capsules, often used under significant driving pressures, is key to
operator safety, pressure burst tests will be performed in accordance with a manufacturer-defined method aligned to
ASTM. Introduction of hydrostatic leaks (ASTM 1003) or loss to filter capsule integrity is not expected to be a
significant risk related to the mode of irradiation, but will be verified as part of the burst-test process. Junctions between
filters and connected tubing in single-use assemblies will be assessed for integrity, including leak and pull-strength
testing.
Functional Tests. The pressure versus flow performance characteristics of sterilizing-grade filters, as well as their ability
to render a product free of bacteria are identified as key risks requiring verification testing. Pressure vs flow
characteristics will be evaluated using manufacturer-defined methods. Bacterial retention capability will be assessed
post-irradiation by testing filters post-irradiation by a manufacturer-defined filter integrity test as well as a bacterial
challenge test aligned to ASTM F838. Both the filter integrity test and the bacterial challenge test are standard QC
release test performed on non-irradiated filters as part of the filter manufacturing process.
Chemical tests. Extractables testing such as that prescribed by USP <665> provides a robust characterization of
chemical entities that could potentially migrate from the irradiated material into the drug manufacturing process. As X-
ray irradiation is expected to generate equivalent or better (i.e. less degradation) profiles as compared to gamma,
limited scope verification testing in 50% ethanol/water will be performed in accordance with the USP <665> PF
requirement for medium risk components. This specific solvent generally produces a large number of peaks
characteristic of filter materials and is regarded as providing the most incisive profile of the industry consensus USP
<665> and BioPhorum proposed solvents. Although nonspecific chemical tests such as conductivity, pH shift, and TOC
are regarded as low risk and less insightful than compound-specific extractables profiling, they may be included as these
are typically performed as manufacturing QC release tests for non-irradiated filters.
6.2 Single-use assemblies Whereas the sections above focus on tests typically applied at a material or component level, irradiation is typically
applied to an assembled single-use system, which has been packaged to maintain a sterile barrier around the system
and accommodate transportation requirements. Hence a holistic approach to X-ray qualification for single-use systems
may require a general, fundamental assessment of the impact to materials and components coupled with an overall
impact assessment to the final assembly and packaging.
Table 8: Overview of assembly testing
Single Use-Assembly
TEST TYPE TEST REFERENCES Representative final system
System Integrity Manufacturer-defined methods for junctions or system integrity
Packaging Integrity ASTM D4169, ASTM D4725, DIN ISO 2872, ISTA 2A
Transportation Validation
24
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
Single-Use System Integrity. SUS integrity, both in terms of an ability to maintain a sterile barrier as well as in terms of
loss of drug substance, has been a key concern that has been seen strong improvements in recent years. Although
radiation in general, or in this case a move from gamma to X-ray, would not be expected to damage or directly
compromise the sterile barrier, a risk assessment focusing on the strength and integrity of junctions, such as between
flexible tubing and a rigid barbed fitting may be warranted. Industry data demonstrating that the strength and
viscoelastic properties of flexible materials remain equivalent or better to gamma follow X-ray, will likely mitigate much
of this concern. In addition, some suppliers have manufacturing defined methods for validating junctions between
single-use components under stress, and such studies would help further demonstrate the suitability for use following X-
ray.
Packaging. The single-use system packaging, in addition to being compatible with irradiation, must protect sterilized
items against microbial contamination during storage, transport and all steps up until the intended use. For the purpose
of transitioning from gamma to X-ray, the suitability of selected packaging materials has been already validated
following gamma irradiation, and hence the general compatibility of the materials are deemed compatible with ionizing
radiation. General physicochemical features such as thermal and tensile properties of the packaging materials can be
evaluated following X-ray irradiation to confirm the material properties are equivalent or better to gamma. Once
confirmed, integrity of the packaging sterile barrier can be expected to remain in the same or better condition
throughout the existing product shelf life claim. Given concerns and criticality around the sterile packaging barrier,
testing of representative packaging systems to verify sterility as a function of shelf life may help further support this
rationale.
Transportation Validation. Following a careful review of the X-ray irradiation process with the contract irradiators, it is
largely expected that no changes to the packaging will be required, and that existing transportation validation studies
can be fully applied to X-ray-treated single-use systems. If considering e-beam as an alternative, where e-beam is much
more suitable to box or tote-size irradiator loading as compared to pallets, this may warrant a further review of whether
packaging changes may be warranted, as well as a revisit to the transportation validation studies. For further guidance
related to transit testing, please see the BPSA transit testing guidance for single use assemblies [50].
7 THE PATH FORWARD Successful evaluation and qualification of X-ray sterilization for single-use systems may mitigate key business continuity
concerns linked to the market experiencing rapidly growing demand for sterilized SUS, and overall growing overall
market demand for contract sterilization. Whereas the existing gamma-irradiation market is not disappearing and will
continue to support current capacity needs, much of the future capacity planning is being rapidly built solely through X-
ray and e-beam. As a biotech single-use industry looking to qualify possible alternatives to gamma sterilization to
mitigate the impact of availability and lead times critical to the delivery of life changing therapies, a voluntary industry
approach among suppliers, end users, and regulators is expected to yield the greatest benefit.
7.1 Key Technical Steps for Collective Industry Approach As part of an industry-approach, testing that addresses the key risks identified in Section 6 may be performed on
representative single-use components or systems and the results shared as a representative, cross-industry dataset. The
expectation is that resulting data may serve to verify that X-ray yields an equivalent or gentler impact on materials
typically associated with bioprocessing, and that existing datasets establishing compatibility with the maximum gamma
irradiation dose, can be used as worst-case data for an equivalent maximum X-ray irradiation dose. Moreover, the
fundamental material assessments will help support and extend this rationale to a more generalized approach
demonstrating X-ray compatibility of polymer families, such as polypropylene, silicone, PES and so forth.
25
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
The ISO 11137 requirement to assess inducement of radioactivity in X-rayed materials will also be evaluated based on
literature, and any additional testing deemed critical in conjunction with the irradiation service provider.
The ISO11137 requirement to ensure sterility at the minimum or target dose will also be verified through an assessment
of bioburden and sterility testing following irradiation at the verification dose, similar to the routine process performed
on representative gamma-irradiated materials in conjunction with the quarterly dose audit process.
During qualification with an X-ray facility, dose mapping studies may need to be reviewed or repeated to verify the
minimum dose is achieved throughout the pallet and the maximum dose is not exceeded.
7.2 Implementation of X-ray as Alternative to Gamma-Irradiation Per BPSA and Biophorum change notification requirements, a change to the irradiation modality is considered a major
change, requiring a formal notification at least 12 months in advance of the change. The formal notification would be
expected to include relevant validation reports supporting the change qualification as well as detailed guidance
clarifying how the change will be implemented.
Disclaimer
This document is not intended to, nor should it be used to support a cause of action, create a presumption of a breach of legal duty, or form a basis for civil liability. Nothing expressed or implied in this informational document is intended, or shall be construed, to confer upon or give any person or entity any rights or remedies under or by reason of this informational document.
Determination of whether and/or how to use all or any portion of this document is to be made in your sole and absolute discretion. Use of this document is voluntary.
BPSA shall not be responsible or liable for any inaccuracies in the document or the information presented. All warranties express or implied are disclaimed and waived.
Manufacturers, suppliers and end users should consult with their own legal and technical advisors relative to their SUT use and participation. No part of this document constitutes legal advice.
About BPSA
The Bio-Process Systems Alliance (BPSA) was formed in 2005 as an industry-led corporate member trade association dedicated to encouraging and accelerating the adoption of single-use manufacturing technologies used in the production of biopharmaceuticals and vaccines. BPSA facilitates education, sharing of best practices, development of consensus guides and business-to-business networking opportunities among its member company employees.
For more information about BPSA, visit www.bpsalliance.org.
Visit https://bpsalliance.org/technical-guides/ for the full catalog of BPSA guidance documents.
BPSA educational webinars can be found here.
26
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
8 REFERENCES
[1] Bio-Process Systems Alliance (BPSA), "Single-Use Manufacturing Component Quality Test Matrices," 2015.
[Online]. Available: https://bpsalliance.org/technical-guides/.
[2] V. Le and A. Tuggles, "The Case for Qualifying More Than One Sterilization Modality," Industrial Sterilization
Process Optmization and Modality Changes, 2020.
[3] S. Sugden, "Use of gamma radiation for sterilisation and other industrial applications," 2020.
[4] T. Krocs, J. Thangaraj, R. Penning and R. Kephart, "Accelerator-driven Medical Sterilization to Replace Co-60
Sources," . Illinois Accelerator Research Center, Fermilab, 2017.
[5] GIPA & IIA, "A Comparison of Gamma, E-beam, X-ray and Ethylene Oxide Technologies for the Industrial
Sterilization of Medical Devices and Healthcare Products," 2017.
[6] P. Dethier, "INDUSTRIAL GAMMA AND X-RAY: “SAME BUT DIFFERENT”," 2016.
[7] Market & Markets, "Sterilization Services Market Overview. “STERIS (UK) and Sterigenics International (US)
Dominated the Global Sterilization Services Market”".
[8] R. Weins, "Ensuring long-term cobalt supply for industrial sustainability and growth," Nordion, 2014.
[9] R. Weins, "Inside Story: Nordion," Medical Design Briefs, 2020.
[10] Canadian Nuclear Safety Commission (CNSC), "Security of Nuclear Substances: Sealed Sources REGDOC-2.12.3,"
Ottowa, 2013.
[11] J. Chou, M. Skornicki and J. Cohen, Unintended consequences of the potential phase-out of gamma irradiation, vol.
7:346, F1000Research, 2018.
[12] World Institute for Nuclear Security (WINS) and International Irradiation Association (IIA), "Security of Radioactive
Sources Used in Industrial Radiation Processing (v1.0)," 2020.
[13] Autorite De Surete Nucleaire, "Nuclear Research Facilities and Various Nuclear Installations".
[14] STERIS-AST, "Market share data: iia/GIPA (2017)," pp. source of other information: STERIS‐AST.com
(https://www.steris-ast.com/services/technology-comparison/) .
[15] FDA, "FDA Innovation Challenge 1: Identify New Sterilization Methods and Technologies," 2019.
[16] Center for Disease Control (CDC), "Miscellaneous Inactivating Agents. Guideline for Disinfection and Sterilization in
Healthcare Facilities," 2008.
[17] P. A. Lambert, "Radiation Sterilization (15.2)," in Russel, Hugo & Ayliffe's Principles and Practice of Disinfection,
Preservation and Sterilization, 5th ed., A. P. Fraise, J. Maillard and S. A. Sattar, Eds., Blackwell Publishing, 2013.
27
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
[18] ISO 11137-1:2006 , "Sterilization of health care products — Radiation — Part 1: Requirements for development,
validation and routine control of a sterilization process for medical devices".
[19] T. Krocs, "Electron and X-ray Sterilization of Medical Devices. FDA Advisory meeting. GHPUDP," 2019.
[20] G. Sadler, W. Chappas and D. E. Pierce, "Evaluation of e-beam, c- and X-ray treatment on the chemistry and safety
of polymers used with pre-packaged irradiated foods: a review," Food Additives and Contaminants, vol. 18, no. 6,
pp. 475-501, 2001.
[21] IBA, "X-RAY STERILIZATION FOR MEDICAL DEVICE: THE X FACTOR".
[22] IBA, "Review of Radiation Sterilization Technologies for Medical Devices".
[23] B. McEvoy, H. Michel, D. Howell and P. Roxby, "X-ray: An Effective Photon," Industrial Sterilization Process
Optimization and Modality Changes, pp. 23-30, 2020.
[24] J. Logar and T. Krocs, "X-Ray Sterilization Requirements for Single-Use Equipment (BPSA Webinar)," BPSA, 2020.
[25] Panel on Gamma & Electron radiation, "Change of Irradiation Modalities in Radiation Sterilization of Medical
Devices– Normative Requirements and Aspects in EN ISO 11137-1," 2020.
[26] O. Gregoire, M. R. Cleland, J. Mittendorfer, M. V. Donckt and J. Meissner, "Radiological Safety of Medical Devices
Sterilized with X-Rays at 7.5 MeV," Radiation Physics & Chemistry, vol. 67, pp. 149-167, 2003.
[27] STERIS Applied Sterilization Technologies, "TECHNICAL TIP; Transfer of sterilization dose, verification dose and
maximum accetable do," Steris, [Online]. Available: https://www.steris-ast.com/techtip/transfer-of-sterilization-
dose-verification-dose-or-maximum-acceptable-dose-between-radiation-sources-2/se between radiation sources.
[Accessed Dec 2020].
[28] U.S. Food and Drug Administration, "Inspection Guides - Sterilizing Symbols (D, Z, F)," [Online]. Available:
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-
guides/sterilizing-symbols-d-z-f .
[29] A. Tallentire and A. Miller, "Microbicidal effectiveness of X-rays used for sterilization purposes," Radiation Physics
and Chemistry, vol. 107, pp. 128-130, 2015.
[30] B.-S. Song, Y. Lee, B.-G. Moon, S.-M. Go, J.-H. Park, J.-K. Kim, K. Jung, D.-H. Kim and S. Ryu, "Beom-Seok Song,
Yunjong Lee, Byeong-Geum Moon, Seon-Min Go, Jong-Heum Park, Jae-Kyung Kim, Koo Jung, Dong-Ho Kim,
Sangryeol Ryu, Comparison of bactericidal efficiency of 7.5MeV X-rays, gamma-rays, and 10MeV e-beams,"
Radiation Physics and Chemistry, vol. 125, pp. 106-108, 2016.
[31] S. V. Calenberg, G. Vanhaelewyn, O. V. Cleemput, F. Callens, W. Mondelaers and A. Huyghebaert, "Comparison of
the Effect of X-ray and Electron Beam Irradiation on Some Selected Spices, LWT," Food Science and Technology,
vol. 31, pp. 252-258, 1998.
28
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
[32] H. Kyung, S. Ramakrishnan and J. Kwon, "Dose rates of electron beam and gamma ray irradiation affect microbial
decontamination and quality changes in dried red pepper (Capsicum annuum L.) powder," J. Sci. Food Agric., pp.
632-638, 1999.
[33] M. Murphy, L. S. Fifield and T. Faucette, "Transitioning from Co60 to e-beam or X-ray for sterilization – a model for
collaboration," Pacific Northwest National Laboratory., 2019.
[34] A. G. Chmielewski, Future development in radiation processing, in Applications of ionizing radiation in material
processing, vol. 2, 2017, p. 501.
[35] K. Makuuchi and S. Cheng, Radiation Processing of Polymer Materials and its Industrial Applications, Hoboken, NJ:
John Wiley & Sons, Inc, 2012.
[36] AAMI, "AAMI TIR17: 2017 - Compatibility of materials subject to sterilization".
[37] Croonenborghs, Smith and Strain, "X-ray versus gamma irradiation effects on polymers," Radiation Physics and
Chemistry, vol. 76, p. 1676*1678, 2007.
[38] O. Vrain, "Effects of irradiation technologies on some polymers commonly used in SUDs," in ECI, 2015.
[39] Portnoy, Berejka, Galloway and Cleland, "A comparison of the effects of polypropylene using sterilizing doses from
three difference sources of ionizing radiation," in ANTEC, 2007.
[40] Nordion, Gamma compatible Materials Reference Guide.
[41] Sterigenics, Material considerations for irradiation processing.
[42] L. McKeen, The Effects of Sterilization Methods on Plastics and Elastomers (4th Edn).
[43] Handbook of Food Science, Technology, and Engineering, United Kingdom: Taylor & Francis, 2006.
[44] F. Gaston, N. Dupuy, S. R. Marque, M. Barbaroux and S. Dorey, "One year monitoring by FTIR of γ-irradiated
multilayer film PE/EVOH/PE," Radiation Physics and Chemistry, vol. 125, pp. 115-121, 2016.
[45] J. Drzeżdżon, D. Jacewicz, A. Sielicka and L. Chmurzyński, "Characterization of polymers based on differential
scanning calorimetry based techniques," TrAC Trends in Analytical Chemistry, vol. 110, pp. 51-56, 2019.
[46] ISO, ISO 11137-1 - Sterilization of health care products — Radiation — Part 1: Requirements for development,
validation and routine control of a sterilization process for medical devices, 2016.
[47] S. P. M. k. Meenakshi Choudhary, "FTIR Analysis of Infrared Irradiated Polymers," International Journal of
Engineering Research & Technology, vol. 12, 2013.
[48] S. Dorey, F. Gaston, N. Girard-Perier, N. Dupuy, S. R. Marque and L. Delaunay, "Effect of gamma irradiation on the
oxygen barrier properties in ethyl-vinyl acetate/ ethylene-vinyl alcohol/ethyl-vinyl acetate multilayer film. J Appl
Polym Sci. 2020;," Journal of Applied Polymer Science, vol. 137, no. 44, p. 49361, 2020.
29
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
© 2021 Bio-Process Systems Alliance. Copying and Distribution Prohibited.
[49] Steris-AST, "Radiation Technology Transfer For Sterilization Processing," 2020 (Sept. 30).
[50] BPSA, "Transit Testing Guidance for Single-Use Components and Assemblies," 2021.
[51] IBA, "Ahead of the Curve," Medical Device Developments.
[52] Steri-Tek, "State-of-the-art E-beam and X-ray irradiation sterilization," [Online]. Available: https://www.steri-
tek.com/. [Accessed 29 October 2020].
[53] S. Shiv, F. Peter, A. Samia, H. Farah, S. Staphane and L. Monique, "Microbial radiosensitization using combined
treatments of essential oils and irradiation- part B: Comparison between gamma-ray and X-ray at different dose
rates," Microbial Pathogenesis, vol. 143, p. 104118, 2020.
[54] Sterigenics, "Sotera Health’s Sterigenics Announces Acquisition of Iotron Industries," Sterigenics, 3 Aug 2020.
[Online]. Available: https://sterigenics.com/sotera-healths-sterigenics-announces-acquisition-of-iotron-industries/.