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Tools for better health careRadiation sterilization of medical supplies is set for rapid growth

by Ramendra Mukherjee

In the history of medical care, the development anduse*of the "concept of asepsis" can be credited as amajor breakthrough in achieving successes of clinicalpractice. Despite superior surgical skills, a clinical oper-ation could "fail" even if one item used in surgicalintervention remained "unclean" — that is, if it wereassociated with some contamination of microbes.

Investigations on the "etiology", or causative fac-tors, of infective diseases have long established that onemajor route is through "cross-transfer" of pathogensfrom an infected patient to another patient and/or anotherwise healthy person. This type of cross-infection —

Dr Mukherjee is Head of the Radiation Biology Section in the

Agency's Division of Life Sciences. Views expressed in the article are

his own and do not necessarily reflect those of the IAEA.

also known as "nosocomial disease" — accounts for alarge proportion of all cases of ill health, morbidity, andmortality suffered by mankind. In view of deficient stan-dards of health care and hygiene, the prevalence andrisks of such health hazards could be even greater indeveloping countries.

The gravity of the situation has been illustrateddramatically. One report, by the World Health Organi-zation (WHO), cites a catastrophic outbreak of infectiveebola fever at Yambuki in Zaire killing more than 280people within a few days. It was discovered that in thehospital concerned, only five syringes and hypodermicneedles were used each day to treat all ward patients andan additional 400 out-patients. A pan of water wasusually used to rinse the needles, which were only occa-sionally boiled for better decontamination. The report

Radiation-sterilized medical supplies have made inroads into the health care systems of many developing countries, largely throughpromotional programmes over the past 10 years sponsored by the IAEA, the United Nations Development Programme, and regional inter-

governmental and national organizations. The pro-grammes encompass large-scale irradiation facilities

in some 30 countries, researchsupport and co-ordinated projects,technical advisory assistance, train-ing courses and fellowships.

Egypt• •

Israel Jordan

•Iran• •

IAEA BULLETIN, SUMMER 1986 37

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further noted that the epidemic vanished as dramaticallyas it appeared as soon as this unhygienic practice of med-ical injections ceased.*

Such reports suggest that continuing risks couldthreaten the health and welfare of people in countriesthrough an unlimited spectrum of serious diseases,including even AIDS (autoimmune deficiency syn-drome), debilitating hepatitis, and many others via con-taminated hypodermics and other unsatisfactory medicaldevices used in the health care system.

They also underscore the fact that the health care sys-tem could end up in "failure" and be "self-defeating"if the crucial area of providing "sterile" medical sup-plies — those free from any association of microbialcontaminants — remains neglected. The process of ren-dering a medical item sterile through "complete" des-truction and/or removal of such contaminants to enhanceclinical safety is known as sterilization.

Methods and practices

The principle behind the sterilization process is basedupon the suitable application of a physical, chemical,and/or mechanical agent or agents to destroy, kill, orremove contaminants, without "adversely damaging"the medical item concerned — that is, without renderingit unfit for the desired safe clinical use. Among methodsthat have been conventionally used are: wet and dryheat; chemicals with defined biocide activity, such astoxic ethylene oxide gas (ETO); formaldehyde; andfiltration.

Since the 1950s, the applicability of ionizing radia-tion for medical product sterilization has been recog-nized, as part of comprehensive industrialmanufacturing processes. In these industrial applica-tions, radiation processing techniques have held animportant edge over conventional counterparts —namely, heat and ETO. Advantages particularly relate tothe ability to penetrate materials, even after final pack-aging, and none or negligible rises in temperature duringtreatment, which permits processing of heat-sensitiveplastic polymer materials. Other significant attributescompared to alternatives are energy economy and con-servation, as well as preservation of environmental qual-ity through a pollution-free operation of the technologyand, presumably, a superior sterility assurance of thefinished product.

One further advantage of radiation — possibly of spe-cial significance in the context of technology transfer todeveloping States — is the high ease and reliability in thecontrol of the technology. Unlike both heat and ETOsterilization processes, which require an "integratedcontrol" of temperature, humidity, vacuum, pressure,time, concentration, wrapping, and other factors, thesuccessful operation of the radiation sterilization process

requires only control of "exposure time" estimated todeliver the correct radiation dose by a pre-calibratedirradiator. This feature, therefore, proves to be espe-cially advantageous in terms of "low technology" sincethe process exacts relatively lower demands for high-level skilled operation and maintenance.

Status and trends

Before the 1950s, health care systems in developedand developing countries alike relied almost exclusivelyupon "re-usable" medical supplies. The principal tech-nique of sterilization for those heat-resistent itemsinvolved moist heat (i.e. autoclaving) or dry heat (i.e.processing in ovens). Industrial innovation in techno-logically advanced countries of Europe and NorthAmerica during the mid-1950s and primarily the 1960swas spurred by a new class of polymer materials.Besides being economical, they exhibited enough attrac-tive physical and chemical properties to serve as possibleconstituents of a growing range of "single-use" medicalproducts and their protective sealed packages.

However, most of these polymers could not toleratehigh temperatures of traditional thermal sterilizationprocesses, and there was a growing need for a processthat could work at near room temperatures: in otherwords, "cold sterilization".

The availability of large cobalt-60 radioisotopesources, which emit high-energy, deep-penetratinggamma radiation, provided an alternative solution forsterilizing these new class of medical supplies. Anothertype of radiation, based upon electrical machine-generated electron beams also was useful. (As part oftechnology-transfer activities to developing MemberStates, technical criteria and guidelines for the choice ofdifferent plastic formulations suited to radiation process-ing should be provided.) Additionally, ETO was in useas a "cold sterilization" process, and it still caters fora major share of the demand, despite a progressivedecline for reasons associated with health and environ-mental hazards.

* See Bulletin of World Health Organization, No. 56 (1978). Otherincidents Have been reported on the outcome of a WHO survey onnosocomial infection in Central Africa.

100

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80

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30

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1950

Trends in sterilization techniques

Source: Adapted Irom K.H. Moratmlern

in Procttdingt. Johnson & Johnson Conference,

Vienne. 125-28 April I9 IJ I

Heat (all forms)

Ethylene oxide i S ^ V V k

/ ^ Radiation ^ ^ " ^ " ^ ~ ^ _

19M 1970 1980 1985 1990

38 IAEA BULLETIN, SUMMER 1986

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Currently, ETO seems to have gone past the "hump"and is on a sharp decline, particularly in North Americaand Europe. (See accompanying chart.) In contrast,radiation technology is steadily rising. It appears thatETO's decline would continue to be balanced to a largeextent by growth of radiation sterilization, if problemsof cobalt-60 supply do not become a limiting factor.Obviously, there are big unknowns involved in the field,and the relative proportions suggested in the chartshould be construed as tentative.

Rapid move to radiation

During the past 15 years, radiation processing as awhole is estimated to have grown steadily at about a 10to 15% rate per year. One reliable indicator may be dataon the number and total installed capacity of radiationsources.

Currently, more than 130 industrial gamma irradia-tors using cobalt-60 are installed in 42 countries,representing a processing capacity of approximately200 million cubic feet of medical devices annually. InNorth America alone there are 53 irradiators with acombined design capacity of 100 million curies capableof processing 70 to 90 million cubic feet of medicalproducts annually. (In the United States, contract sterili-zation of disposable medical supplies alone accountedfor $26 million in revenues in 1985, according to theAtomic Industrial Forum.) This represents a rapidincrease in the use of gamma sterilization from anestimated modest 10% of all medical device sterilizationin 1977, when the major share of sterilization wasattributable to ETO, to as much as 40% in 1985. By1990, gamma sterilization is expected to account forabout 80% of all disposable medical product sterilizationin North America.

Worldwide geographic distribution, with particularregard to regions relatively new to this technology,reveals a number of interesting facts. During the pastdecade (1975-85) there has been a significant rise indeveloping regions of Asia, Africa, and Latin Americain installed gamma capacity engaged in sterilizationprocesses. Collectively, this accounts for as much as20% of the current world total.

Despite the recent spurt in North America, the situa-tion in Europe, when it comes to gamma sterilization, isstill somewhat ahead in net quantitative terms. The situa-tion, however, is reversed for electron beam sources.The major share of electron beam use is in NorthAmerica.

Japan has continued to place an emphasis on applica-tions of accelerators for medical supply sterilization onthe premise that electrons cause less physical/mechani-cal degradation and the delivery of a high-dose rateseems to prevent oxidative deterioration of products,which could also be significant for pharmaceutical sub-stances, among others. All these observations suggest acontinued bright future role for radiation applications insterilization of medical supplies.

Sterilized needles and syringes are essential to safe medical care.(Credit: E.I. du Pont de Nemours & Co.)

Technology transfer

The irradiator type, size, and design, plus the opera-tional policy of the irradiation facility and requirementsfor various categories of trained technical and main-tenance personnel infrastructures, are generally dictatedby several factors: (1) types of medical supplies used inpublic health services and by the medical profession; (2)the current and projected average annual demand fordifferent medical products; (3) status of local manufac-turing capability and the attitude of local manufacturersof medical products towards adoption of the radiationsterilization technique; (4) legal and public health clear-ance aspects of radiation-sterilized products; and (5) thecost of the final sterile products. Although the detailedsituation may vary from one country to the other, thefollowing "source" parameter considerations may holda general relevance:• In industrial and pilot-scale operations for radiationsterilization of medical products, gamma rays fromcobalt-60 have been most frequently utilized worldwide(four times or more of installed capacity as compared toaccelerators), and exclusively so in the Agency'sdeveloping Member States. For conditions in manydeveloping countries, experts associated with relevantIAEA technical co-operation projects have generallyrecommended cobalt-60 gamma sources in either dry orwet storage systems.• Experiences in many countries indicate that depen-dence on the large-scale availability of skilled engineersand technicians is less for radioisotope sources than forelectron accelerators in the course of routine operation,maintenance, and servicing. Furthermore, one mustconsider the fact that irradiation facilities in developing


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States most likely have to be designed for "servicesterilization" to a number of different manufacturers ofmedical supplies. This seems to imply that the sourcemust be geared to deal with a number of differentproduct specifications. Under such circumstances, thesource geometry should allow a greater flexibility inaccommodating different volumes, shapes, and sizes ofthe carton/box containers of pre-packed medical itemsand the conveyor should include a provision for varia-tion of its speed. The source efficiency in the deliveryof the prescribed minimum sterilizing dose should beevaluated during the commissioning protocol and moni-tored at routine operations through appropriate use ofdefined physical chemical dosimeters.• Often, developing countries seem to prefer a "mul-tipurpose" irradiator plant to be able to deal with medi-cal devices, food, and other relevant items. In thecontext of introducing a broad-scope radiation process-ing technology under national policy planning, a concur-rent emphasis needs to be assigned to all relevantbranches of industrial advancement. Such an irradiatorshould preferably accompany a flexible conveyor fea-ture, including "output" to lead finished sterile items toan isolated storage area to help avoid accidental mixturewith pre-sterilized items and consequent risks of healthhazards. Such multipurpose irradiator plants already arein use or being planned in more than a dozen countries,including Bangladesh, Belgium, Brazil, Egypt, Hun-gary, India, Indonesia, and Israel.• Generally in developing countries, steps recom-mended for radiation health safety related to sourceoperation, as well as environmental protection, need tobe adopted, taking local conditions into account. Forinstance, automated interlocking devices, and the provi-sion to shut down the source in the event of malfunction,should be installed. Irradiated "sterile" product boxesshould clearly display appropriate labels with a distinc-tive colour change indicator for easy identification andprocess control.

In the case of toxic gases, their use, such as ETO inindustrial sterilization, currently is being subjected tomore and more rigorous quality control, particularly intechnologically advanced States with established criteriafor environmental health protection. This regulatorycontrol was imposed following discovery in the 1970s ofpotent mutagenic and carcinogenic effects of ETOresidues on processed medical supplies and also in work-ing environments. In countries with restrictions on ETOapplication, there are defined levels of permissible ETOresidues on medical supplies. Such low levels (e.g., aslow as 1 ppm in the USA, Japan, and USSR) are difficultto attain with existing technology without provision ofsome expensive control devices. Consequently,manufacturers are progressively shifting over to theradiation sterilization technology.

This subject was reviewed in a recent executive advi-sory meeting of a United Nations DevelopmentProgramme (UNDP) and IAEA co-operative project forAsia and the Pacific on radiation technology. Expressing

concern, experts concluded that most developing Mem-ber States of IAEA do not have a "defined regulatoryposition" on ETO residue levels in their environmentaland occupational health protection guidelines. This fac-tor seems to have been instrumental in the choice ofETO technology in some recent instances by a numberof developing Member States.

Volume of products sterilized

Over the last three decades, the variety of radiationsterilized medical supplies has increased so enormouslythat it is almost impossible to present anything that couldclaim to be a complete list. To name a few, the assort-ment includes bulk hypodermic syringes and needles;transfusion and infusion sets; absorbent and non-absorbent cotton; surgical gloves; medical devices andinstruments; cotton gauze and dressings; surgicalblades; surgical dressings; lancets; pharmaceutical con-tainers; specified medicaments; cat-gut and silk sutures;maternity kits; vasectomy kits; intra-uterine devices;scafold and other temporary implants as surgical aids;permanent inorganic implants; food for pathogen-freediets for immune-compromised intensive-care patients;biological and prophylactic preparations, and a widerange of non-viable biological tissue grafts.

The broad applicability of radiation in a "cold sterili-zation process" has in turn stimulated innovation of awide range of new manufacturing industries for medicaldisposables and their packaging. Additionally, biologi-cal tissue grafts, in growing demand for sterile clinicaluse in reconstructive surgery and in congenital anddisease-associated deformities, rapidly are moving tobecome a suitable candidate for sterilization by ionizingradiation.*

Detailed data on production costs of sterile medicalitems are not easily available from all Member States.However, from provisional figures in a report at therecent UNDP/IAEA executive advisory meeting, thetotal annual cost of radiation-sterilized medical materialsat India's cobalt-60 facility, ISOMED, was estimated tobe about US $10 million, based upon 1984 production.In the context of India's total market for health care sup-plies, this volume is estimated to account for only 10%.Future growth is expected, as there are some specializedsectors of hospitals and industry where such sterileproducts are in growing demand. Comparable situationsare anticipated in Egypt, Hungary, the Republic ofKorea, and Yugoslavia, where Agency-supportedprogrammes have helped implement radiation process-ing for local production of sterile medical supplies.

Worldwide, according to an IAEA estimate, the totalvalue of irradiated medical products is more thanUS $2 billion, with steadily increasing trends in bothquantity and quality.

* See "Atoms for health: A need in Asia", by R. Mukherjee, IAEABulletin, Vol.26, No.3 (September 1984).


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Good manufacturing practices

Production of medical devices and supplies intendedfor sterile clinical use starts in the manufacturing fac-tory, using raw materials and components, and ends inthe sterilization procedure. Obviously, without adequatecontrol of the production cycle and facilities, the laststerilization step alone cannot guarantee the desiredsterility.

Operators of a successful plant must acquire site-specific knowledge regarding what potential contribu-tion raw materials, equipment, the facility environment,and people may make to the "microbial load" of pre-sterilized products. While all these are important, peo-ple, or more specifically workers, could probably be thegreatest contributors to product contamination.

In developing States, socio-economic conditions maytend to dictate a larger proportion of "manual" over"automated" operations — a factor that may hold a spe-cial significance for those regions when it comes tosafety controls of sterile medical items. This is sup-ported in numerous studies where specific plastic items,operated by automatic assembly lines, are among theleast contaminated ones, when compared to itemsassembled manually. Plant hygiene for both people andthe facility are thus essential ingredients for safeproducts in modern manufacturing operations, aad_therecommended protocol should constitute a "goodmanufacturing practice", or GMP, which serves one ofthe most important regulatory roles in quality control ofproducts.

Hygienic standards

Over the past 50 years, the evolution of the conceptof sterility control reveals at least three distinct periodsof development, which may be defined as (1) the periodof "innocence"; (2) the period of "doubt"; and (3) theperiod of "enlightenment".

Early regulatory microbiologists, in the period of"innocence", held the assumption that sterility is"absolute" and "sterility testing" of final productsshould give the "ultimate proof of sterility". With theprogressive development of the faculty of statistics andof the probability theory, statisticians, however, dis-turbed microbiologists by establishing the concept that"sterility is a probability function" and not an absolute.In this view, sterility testing of products became almost"meaningless" because of the implied meagre probabil-ity of discovering instances of low levels of contamina-tion (and hence the status of assurance becoming"doubtful"). Subsequent recognition, however, that athorough technical knowledge of the sterilizationprocess per se, and its control capability, should lay thebasis and provide the greatest assurance of sterilityinitiated some major changes in operational criteria andphilosophy. This is still evolving in light of new data andexperiences from the technology, thereby placing us ina period of "enlightenment" heralded since the late1950s.

Irradiation facilities for medical and other products are operating inmore than 40 countries. (Credit: Isomedix)

Today, the simplicity and reliability of sterilizationprocess control to promote a higher probability ofproduct sterility is easily achievable with radiation. Itrequires only control of exposure time, while the alter-native ETO treatment requires control of many factors.

The probability for safety assurance is generallynumerically expressed as less than 10'6 and it has beengiven two interpretations:• Less than one chance in one million that a con-taminant will survive on a medical product• Not more than one living microorganism in one mil-lion items.

The attempt is to express a theoretical concept inpractical understandable terms. Nevertheless, whatremains missing in health safety terms is the ' 'estimationof the probability of an overt infection" being caused by"one such surviving organism" in a million processedmedical items or by "one non-sterile item" among thegroup of a million items. This probability, althoughmore difficult to define, is expected to be far less com-pared to the probability that a sterilization process wouldyield a non-sterile item.

Regulatory control aspects

Like all other sterilization processes, radiation sterili-zation, as well as the sterilized medical products for clin-ical use, must fulfil "validation criteria" as stipulatedand implemented by the respective national food anddrug administration, national pharmacopoeia commis-sion, and other relevant health regulatory authorities.The purpose is imposition of the strictest quality controlfor radiation-processed items to ensure fulfilment ofobjectives for consumer safety. Often, radiation-processed items may have to be used beyond nationalboundaries. They must then comply as well with regula-tory requirements of the consuming country. This isfacilitated by criteria of international standardization,


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which are distributed to co-ordinate and help implementsuitable regulatory guidelines.

Countries pioneering in these efforts, such as Austra-lia, the United Kingdom, and the United States have for-mulated guidelines to good manufacturing practices(GMPs) for sterile medical devices and surgicalproducts, as well as for pharmaceutical products. Sincethe inception of radiation sterilization for medical sup-plies, the sterilizing dose of 25 kilogray generally hasbeen followed in most countries.

Some distinctive specifications are now in practice,however. In North America, there happens to be nospecified fixed minimum sterilizing radiation dose, andguidelines formulated by the Association for theAdvancement of Medical Instrumentation (AAMI) areprogressively implemented. These refer to dose-settingapproaches based upon the estimated radiation resistancecharacteristics of naturally occurring microbial biobur-den on medical products. Different sterility safety levelsare thus achievable for different categories of medicalitems according to their clinical end uses. Consequently,many devices could in practice be radiation-sterilized atdoses lower than 25 kilogray, while still others may

justify an even higher dose. In contrast, European healthregulatory authorities continue to follow and recom-mend a minimum sterilizing radiation dose of25 kilogray.

This situation is expected to lead to some problems ofinternational clearance of sterilized medical items and inattainment of implied health welfare objectives. Furtherjoint analysis and review of problems and required tech-nical steps should be facilitated through internationalstandardization approaches.

In 1967, an IAEA expert group recommended thebasis for an international code of practice for radiationsterilization of medical products. In co-operation withthe WHO and national health regulatory authorities inMember States, the Agency remains responsive toperiodic updating and revision of those recommenda-tions in light of operational experiences in the field. Onesuch review is planned during an IAEA advisory groupmeeting scheduled in Sri Lanka late in 1986. It is antici-pated that these discussions will involve relevant exper-tise from health regulatory authorities, medicalprofessionals, biomedical researchers, and manufac-turers of sterile medical supplies.


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