X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT 2021
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2021
X-RAY STERILIZATION OF SINGLE-USE
BIOPROCESS EQUIPMENT
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
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X-RAY STERILIZATION OF SINGLE-USE BIOPROCESS EQUIPMENT:
PART I – INDUSTRY NEED, REQUIREMENTS AND RISK EVALUATION
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.
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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
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7.2 Implementation of X-ray as Alternative to Gamma-Irradiation ................................................. 25
Disclaimer.................................................................................................................................................... 25
About BPSA ................................................................................................................................................. 25
8 REFERENCES ........................................................................................................................................ 26
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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].
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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,
60
Co 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
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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.
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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
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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
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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.
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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
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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.
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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).
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Functionalized Materials
Polyamide (Nylon)
Cellulose
Silicone
EPDM
HDPE
PVDF
PEBA
LDPE
PEEK
PTFE
PUE
PVC
PSU
PBT
PET
TPE
PES
FEP
PEI
PP
PC
PS
Compatiility with Ionizing Radiation - -
Connectors
Containers (bags, bottles, carboys)
Ports on containers
Single-Use Components
Sensors
Tubing
Filters
TFF devices
Fittings and molded parts
Pumps, check valves
Needles
O-rings, Gaskets, Seals
Packaging
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.
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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.
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Table 2: Overview of physical testing per components
A. PHYSICAL TESTS
Connectors Containers
TEST TYPE TEST REFERENCES Valves & Sensors Tubing Filters
Retainers Film
Manufacturer-defined
Pressure Burst Test method, ISO 7241, ASTM -
D1599, EN 12266, ISO 1402
Manufacturer-defined
Integrity (Leak) Test method, ASTM E515 modified,
ASTM D4991, ASTM 1003
Tensile (Pull-Off) Test Manufacturer-defined method - - - -
ASTM D624, ISO 34, ASTM
Tear Resistance
D1938-14
- - -
O2 and CO2 ASTM D3985, ASTM F1927,
ISO 15105-2
- - - -
Permeability
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
ASTM D3418, ISO11357-2
Temperature by DSC
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.
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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
Connectors Containers
TEST TYPE TEST REFERENCES Valves & Sensors Tubing Filters
Retainers Film
ISO 7241-2, ISO 3968,
Water Flow Rate and Manufacturer-defined -
Pressure Drop method
IEC60534-2-3, DIN EN 1267 - - -
Accelerated Aging Manufacturer-defined
method, ASTM F1980
(Shelf Life)
USP , ANSI/AAMI BF7,
Particulate Matter BPSA recommandations,
EP2.9.19
Kink Resistance/ Bend
Manufacturer defined method - - - -
Radius
Filter Integrity Test Manufacturer defined method - - - -
Bacterial Retention
Test (Sterilizing Grade ASTM F838 - - - -
Filters)
Bacterial Challenge/ Manufacturer-defined
method, ANSI/AAMI BF7
- - - -
Soiling Test
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.
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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
Connectors
Containers &
TEST TYPE TEST REFERENCES Valves
Film
Sensors Tubing Filters
Retainers
Biological Reactivity -
USP , ISO 10993-5
In Vitro
Biological Reactivity -
USP , ISO 10993-1,6,10,11
In Vivo
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 and ),
and existing compliances are expected to remain fully valid. To further substantiate this assessment, limited scope USP
/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.
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Table 5: Overview of chemical testing per components
D. CHEMICAL TESTS
Connectors
Containers &
TEST TYPE TEST REFERENCES Valves
Film
Sensors Tubing Filters
Retainers
Manufacturer defined method
Chemical Process
typically aligned with ASTM
Compatibility D543-14 and/or risk assessment
Manufacturer defined method,
Extractables - Moderate risk,
high risk, BPOG
Physicochemical
USP a
Container Test
EP/ Physicochemical EP 3.1.xb - -
Conductivity Test USP - - - -
pH Shift Test USP - - - -
Total Organic Carbon
USP - - - -
(TOC)
USP 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 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 moderate-risk component testing protocol may be appropriate.
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Table 6: Overview of regulatory testing
E. REGULATORY TESTS
Connectors Containers
TEST TYPE TEST REFERENCES Valves & Sensors Tubing Filters
Retainers Film
Animal Origin
EMA 410/01
Free
TSE BSE
EMA 410/01, EC 1774
Statement
REACH EC/1907/2006
RoHS 2002/95/EC
21 CFR 177 (2600, 2400, 1550,
Food Contact
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
Connectors
Containers &
TEST TYPE TEST REFERENCES Valves
Film
Sensors Tubing Filters
Retainers
Sterilization Process
Manufacturer defined method
Compatibility
ANSI/AAMI/ISO 11137, AAMI
Irradiation Validation
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.
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