Gamma Radiation Sterilization:

Effects on Medical Devices

ABSTRACT
This paper will highlight the need for selecting appropriate plastic polymers for medical devices. Today, gamma
radiation processing is one of the most important means for the terminal sterilization of these products. the physical
changes which occur within the various resins after receiving a sterilizing dose are well documented. However, the
other contributing causes of part failures are less well known.

INTRODUCTION
The trend toward the use of gamma radiation as the method of choice for the sterilization of medical devices has
increased the knowledge of the mechanisms of action of radiation on various resins. This trend has sped up the
process of developing new resins and blends which will withstand gamma radiation creating more options for the
medical device manufacturer today than ever before. However, the selection of a plastic resin for a medical device
has largely been a matter of intended use of the product, design constraints and material costs with the method of
sterilization added as an ‘afterthought’.

PRESENT CONCERNS
This paper addresses the concerns of the medical device industry regarding the gamma irradiation process. Concerns
such as how to begin an investigation into the use of gamma radiation process; how to select the right materials;
what tests to perform; how to integrate national and international regulations for the process; GMP requirements; the
need to design for more than one sterilization technology; embrittlement; discoloration; material costs and
availability; interaction with drug components.

Our intent, is to assist you, the medical device manufacturer to obtain the greatest benefit from the use of gamma
radiation sterilization; to direct your efforts along the most productive routes; to provide appropriate information; to
help you avoid ‘re-inventing the wheel’ and; to facilitate the gathering of appropriate data for regulatory approval.
To that end the reader is urged to refer to the review articles listed in the reference section (1,2,3,4).

WHAT IS GAMMA RADIATION PROCESSING?

Gamma radiation processing can be defined as the controlled exposure of a product to ionizing radiation. This
controlled exposure must ensure that the specified dose of radiation is delivered to the product. The specified dose is
that which will reduce the bioburden to the desired level without damaging the product. It encompasses both the
minimum and maximum dose of radiation. The minimum dose (Dmin ) ensures the proper microbiological
reduction, while the maximum process dose (Dmax) ensures that the functional specifications of the product are
met. By controlling the time spent in the irradiation chamber, and the manner in which the product is loaded in the
product transfer device, the radiation dose received by the product is kept within these limits.

Gamma radiation processing involves the deposition of ionizing energy. Radiant energy is deposited within the
molecules of resin causing changes in the molecular structure and the formation of free radicals. As the energy is
dissipated, there is some heating of the product. Further information on the physical characteristics of ionizing
radiation can be found in reference 5.

A successful gamma radiation process encompasses three basic elements (6). They are Product Qualification,
Equipment Qualification and Process Qualification. All three combine to provide a validated process. While the
primary focus of this paper is on Product Qualification, Process Qualification will also be discussed.

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PRODUCT QUALIFICATION
The ‘Quick-Look’
The steps required to qualify a medical device for gamma sterilization are very straight forward. However, before
beginning any in-depth product qualification program it is best to take what is called a ‘Quick Look’. This involves
exposing a few samples of the product to radiation doses of 15, 30 and 50 kGy. The intent is to identify quickly
those products which will be easy to sterilize with gamma and to "zero in" on the most appropriate radiation dose(s)
for further testing. Two questions need to be answered. "Will the product/device withstand any radiation dose?"
"What effects/changes should be sought?" A low dose, 15 kGy, will answer the first question; a high dose of 50 - 75
kGy, will answer the second.. Once this is done then the Sterilization Planning and Materials selection/review can
begin for those products which will fail the initial screening.

Part of what determines how high a dose of radiation will be used is a consideration of whether the product will be
put through more than one sterilization cycle.

The Product Qualification Steps

The very first step is to learn what physical and chemical changes occur in the polymer with increasing radiation
dose (18,19) and how those changes affect the mechanical properties of the device. It is best to choose the simplest
products first. so that a measure of success can be experienced and provide that added push for some of the harder
products which will inevitably follow.

The most important outcome of product qualification is the Maximum Tolerated Dose.
The second step is to determine the magnitude of any changes. A product qualification program will also suggest the
impact any physical or chemical changes will have on the shelf life of the device, any pharmaceutical/device
interactions, e.g., pH shifts, precipitates, or color changes, and the toxicity or cytotoxicity of the device if the device
is to be implanted. It is also important to stress the materials in order to ascertain their failure point. Then, if there is
ever a problem with a slight overdose, data will be available from which to make an informed decision about the fate
of that product.

The latter tests require a knowledge of extractables. Both the pharmaceutical and medical device industry are
looking for resins with low extractables. Lubricants and other additives, or their radiation breakdown products, have
the potential to interact with body fluids and perhaps cause an adverse reaction in the recipient. They may also
interfere with the drug product in those special cases where a drug is included as part of the device.

We would encourage resin manufacturers to include in their literature the effect of both gamma and electron beam
radiation on a particular resin using standardized test bars. While of limited value, based on the many unique
applications to which the resin will be subjected, it still provides a baseline against which results can be judged, or
initial choices of materials made. This would be a good place to list the types of additives, and the materials which
can be extracted by test solutions. The test solutions are usually formulated to represent body fluids.

In assessing the radiation effects (samples vs. controls), simple functional and physical quality checks are best. They
are the "torture" tests, which assess both physical as well as cosmetic/aesthetic changes over time. The following
table is provided as a sample.

"TORTURE" TESTS EXAMPLES

Component Material Test Acceptable Results

ABS Spike Bend Tips 45o No Break

ABS Luer Crush Diameter 10% No Break/Stress Whitening
Acrylic Luer Bend Tip 10o No Break
Polyethylene Protector Stretch 0.005 Oversize No Break
ABS ‘Y’ Connector Pull Pin Against ‘Y’ Stress Whitening
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Polypropylene filter Cap Crush 50% No Break

Polypropylene Minidrip Crush 50% No Break
Polypropylene Clamp Twist 45o No Break
Polypropylene Clamp 24 hr. doubled tubing Must Shut Off
Polypropylene Clamp 48/72 hr. single tubing Must Shut Off

Accelerated Aging
Accelerated aging studies for shelf life determination, can speed up the development process. However, real time
studies should be performed as well. Remember that radiation sterilization deposits energy into a material. If that
material contains any type of crystal structure or resonating structure it has the potential to store that energy for quite
some time. This is the source of long-lived radicals. They will eventually decay but the process could take months to
years and the diffusion of oxygen into the crystalline areas will result in chain scission. Accelerated aging studies, if
used, should be initiated simultaneously with real time studies. They may prove to be an indicator of future trends.
During shelf life studies frequent sampling early in the program will help to establish any trend.

MATERIALS SELECTION
This process is used when resins have been used which are known to cause problems and must be replaced if the
product is to be sterilized by gamma radiation. For radiation stability "the Good" are, in descending order, a Benzene
Ring, Benzene Ring as a side branch to main chain, Benzene Ring as a part of main chain. The "Bad" are, Triple
Bonds, Double Bonds main chain, High Energy (Stable) side branches (electron withdrawing). The following table
lists some of the materials which have been successfully used to manufacture gamma-stable devices and the types of
device in which they have been used. The reader is also referred to references 7 and 8.

Materials Used to Manufacture Selected Medical Devices

Typical Materials Tubes Sutures Syringes IV Sets

PVC x x
PP x x x x
Natural Rubber x x x
Silk x
PAmide x x
PET x
Collagen x
PE x x
PS x
Glass x
SBR x x
PC x
PAcrylics x

In summary there are preferred polymers which are listed below. In addition there are those to avoid if at all
possible. To date most of the problem resins have been successfully substituted with one of the polymers listed
below.

Thirteen Preferred Radiation-Stable Polymers

1. Polystyrene & Copolymers, ABS,SAN,HIPS
2. Polyethylene, LDPE< LLDPE, HDPE
3. Polyesters and PETG
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4. Polycarbonate and Alloys

5. Polysulfone
6. PVC Flexible & Semi-Rigid, Color Corrected
7. Polyurethane (8 Chemical varieties)
8. "High-End" engineering Resins, PEK, PEEK, Polyetherimide
9. Thermosets - Epoxies, Phenolics, Polyimides, Polyurethanes, Polyesters
10. Elastomers - TPE (SEBS, TPO), Natural (Isoprene), EPDM, Silicone, Urethane, Nitrile
11. Polyamides (nylon), especially 12,11, 6/12 & 6/10
12. Polypropylenes & Co-Polymers, Radiation Stabilized
13. Fluoroplastics (other than PTFE & FEP) - PVDF, PCTFE, PETFE

ACTION PLAN FOR MATERIAL SELECTION

A sample action plan for material selection might include the following topics. It begins with avoiding those
materials known to be radiation sensitive, moves on to ensuring that you discuss with your resin supplier your
particular needs. Many resins have been developed for a wide variety of applications. The action plan will also
include looking at the additives used in the resin to ascertain how they will affect both the cosmetic and functional
performance of the product.

REMEMBER!
1. Avoid using Teflon PTFE
2. Avoid using Acetals
3. Evaluate all filters, vents and membranes

DO!
1. Get PVC samples with color correction and HCl stabilization
2. Get 2-3 modified polypropylenes
3. Sample semi-rigid PVC’s

General Guidelines for Material Selection

1. Aromatic polymers are more stable than aliphatics
2. Polymers with low radical yields (G - values) after irradiation are more stable
3. Phenolic antioxidants contained in most polymers are responsible for discoloration. The use of non-phenolic
additives will usually eliminate the problem.
4. Most polypropylenes and polytetrafluoroethane are unstable with irradiation. PVC and PP should be specially
stabilized to improve radiation compatibility.
5. High levels of antioxidants help radiation stability. In general, you may need to increase the level if the product is
to be radiation sterilized.
6. Within a given polymer class, the lower the density the greater the radiation stability.
7. The elastic modulus is not greatly affected with one sterilizing dose of radiation.
8. Fillers and reinforcing materials usually improve the radiation stability of adhesives, coatings and potting
compounds.
9. Polymers used in adhesives, films, fibers, coatings and encapsulates react much the same way to irradiation as the
materials from which they are derived.
10. Take extra care with nucleated polymers - nucleation increases embrittlement.
11. If co-polymerization with ethylene is possible - try it.

Additives
1. Phenols
2. Sulfurs
3. Phosphite
4. HALS

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Counteracting Discoloration
1. Avoid/minimize phenolic-type antioxidant additives in polymer and packaging
2. Use a coloring agent to mask the yellow color. Ultramarine blue is frequently used for this purpose.

Counteracting Embrittlement
Embrittlement can be initiated by UV and near UV visible light, high temperature, high energy radiation. The rate of
embrittlement is function of molding technique; the amount and duration of irradiation. Ultimate Brittleness is
function of molding technique; the amount and duration of irradiation.

Embrittlement can be counteracted by one or more of: lower processing temperature, lower mechanical shear of
melt, rapid cooling, lower crystallinity material, incorporating melt stabilizer, incorporating antioxidants,
excluding/minimizing access to oxygen, incorporating mobilizing agents, co-polymerization with ethylene,
protecting against light optimizing nucleation level.

With this information in hand, analytical techniques can be adjusted, or developed, to assess the impact of the
sterilization process on those products. Control samples should always be included in any shipments of test materials
to an irradiation facility. They separate the effects due to transportation or storage from those due to radiation. A
radiation dose of 5-10 kGy is low for most plastics, especially those used in the medical device industry. However,
they will be typical of those normally required by pharmaceuticals.

MANUFACTURING TIPS
Despite best efforts to select the correct materials and work within the radiation dose limits for the device/resin,
parts sometimes fail. The chart included as Appendix A with this handout will help in analyzing the source of the
part failure and provide the most common solution to prevent that form of failure. To assist in interpreting the chart
it is necessary to review some of the factors which can and do, contribute to part failure. There are several articles by
Messrs. Stubstad and Hemmerich on preventing plastic part failure () and I highly recommend them to you. In
addition, they have been frequent participants in Nordion’s "Team Gamma" seminars.

Controlling the injection molding process is probably the most important part of the manufacturing process. It has
the greatest potential, once the proper resin and mold shape are optimized to adversely affect the device. For
example, standard injection molding techniques can rob a polymer resin of 80 to 90% of its elongation properties.
Figure 1 shows how a resin with 600% elongation (according to the manufacturer), ends up after molding with only
50% elongation! Factors such as melt temperature, mold temperature, cooling water temperature (difference
between day and nighttime temperatures), and cycle times all have a bearing on the physical properties of the
finished device.

PROCESS QUALIFICATION
Process qualification should include, but is not limited to, a consideration of the following subjects: the sterilization
approach, the minimum process dose, the maximum process dose, dose distribution studies, product loading
patterns, biological challenge reduction studies and cycle interruptions. In a few cases temperature considerations
may also be important. Each will be briefly addressed under its own heading.

Sterilization Approach:
This can best be done by following the ISO Standard for Gamma Radiation Processing (ISO 11137) (9). In ISO
11137, two methods are given for determining the sterilization dose. Either Method I or Method II may be used,
however, Method I is the simplest and least expensive method to begin with both in terms of product cost and testing
costs. The use of Method II may result in the lowering of the radiation dose if the bioburden is skewed towards
organisms with less resistance to radiation. A lower radiation dose reduces the damage to the device and lowers the
processing costs as less time is required in the irradiator

Minimum and Maximum Process Dose

The minimum process dose is established by the sterilization criteria established using ISO 11137. In practice, the
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irradiator operator will chose a dose slightly above this to prevent ‘underdosing’ the product. The maximum process
dose is set from the product qualification results. The upper limit is specified by the device manufacturer and is
below the dose which causes part failure. The ratio of the Maximum Process Dose to the Minimum Process dose is
known as the sterilization window (Dmax/Dmin ratio). The closer this ratio is to 1, the better from a product
irradiation point of view. However, in practice this is very difficult to achieve. Most irradiator operators want this
window to be as wide as possible as it simplifies scheduling. For many plastics, this sterilization window is quite
wide. A rule of thumb is a ratio of 1.2-1.5 depending upon the density of the product.

Dose Distribution Studies

Dose distribution studies (sometimes called ‘dose - mapping), are performed to determine the Dmax and Dmin
positions for the a given product in the product transport mechanism. Dose distribution studies should be performed
according to written procedures using appropriately placed dosimeters which have been calibrated against a known
standard (3).

Product Loading Patterns

The manner in which the product is loaded into the product transport mechanism for conveyance through the
irradiator is critical to achieving the desired Dmax/Dmin ratio, the required Dmax and Dmin, and therefore the
required SAL. A detailed 'map' of how the product is to be placed in the transport mechanism forms a part of the
process validation documentation.

Cycle Interruptions
For those products which are capable of sustaining microbial growth it is necessary to specify the maximum
acceptable length of time from the completion of the manufacturing process to the completion of sterilization.
Normally, all of a production lot would be simultaneously exposed to the gamma radiation source over a period of
hours. There will be some exceptions for large lot sizes. It will be necessary to define the maximum permitted length
of time for a cycle interruption, and its point of occurrence in the sterilization cycle. It will be necessary to have the
appropriate procedures in place to direct the operator as to the appropriate person to contact in the event of a cycle
interruption, or a delay in the commencing or completion of the sterilization cycle.

PROCESS MONITORING
The sterilization process must be monitored routinely to ensure that the validation process conditions were met as
specified and that the Dmax/Dmin parameters were attained as per the validated cycle. For either Method I or
Method II sterilization approaches audits are performed quarterly.

SUMMARY
The needs of the medical device and pharmaceutical industry are varied and complex. The importance of the raw
materials used in plastics cannot be overemphasized. Only when all the ingredients are known can the effects of
exposure to gamma radiation be predicted with any accuracy. Knowing the potential reactants, allows the skillful
formulator to add or delete the correct ingredients to offset any potential radiation effects. Similarly, a thorough
knowledge and understanding of the manufacturing process including the molding step will allow better products to
be manufactured regardless of the method of sterilization.

REFERENCES
1. Landfield, H.: "Radiation Effects on Device and Packaging Materials," MD & DI, (May): (1980).
2. Gopal, N.G.S. et.al. : "Radiation Sterilization of Plasticized PVC and Some Pharmaceuticals," Proc. National
Symposium on Isotope Applications in Industry, (Feb.): 294-308 (1979).
3. Charlesby, A: "Some Reflections on Radiation Research and Technology," Radiat. Phys. Chem. 28 (5-6): 473-477
(1986).
4. Sipos, M.; Adamis, Z.: "The Effects of Radiation Sterilization on Different Types of Plastics," Korhaz-Es
Orvostechnika, (Nov.) Vol. 28(6): 164-168 (1990).
5. McLaughin and N.W. Holm: "Physical Characteristics of Ionizing Radiation," in Manual on Radiation
Sterilization of Medial and Biological Materials: Technical Reports Series No. 149, Chapter 1: 5-12, (1973).
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6. Hoxey: "Validation of Sterilization Procedures," Medical Device Technology (June): 25-27(1991).

7. Schonbacher, H.: "How Plastics Perform Under Nuclear Radiation," Modern Plastics, (Dec.): 64-68 (1985).
8. Miller-Mizia, R.: "The Sterilizability of Polycarbonate and Polyphthalate Carbonate," MD & DI November, 35-
37, (1986).
9. ISO 11137, and all similar documents, are available from each country’s national standards office.

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