Cirkulære om strålesterilisering af medicinske utensilier (engangsmateriel) overvejende bestående af plast. (Til fremstillere og forbrugere af medicinske utensilier.)

BILAG 2

INTERNATIONAL ATOMIC ENERGY AGENCY

Recommended

Code of practice for radiosterilization of medical products

1. INTRODUCTION

In common with other methods of sterilization, the efficiency of radiation sterilization is dependent upon the numbers and types of contaminating organisms presented to the process, an also upon the environmental conditions in which they occur.

The choice of radiation dose will be determined by the microbiological standards achieved and by the degree of control that can be exerted upon the pre-sterilization contamination of the products concerned. In addition to microbiological control procedures, a Code of Practice must also include control procedures for the operation of the radiation facility.

2. MANUFACTURE

2.1. PREMISES, MATERIALS AND PRODUCTION

The place of manufacture of each component, places of assembly and packaging of the product, of sterilization and of storage before distribution, should be open to inspection by the appropriate authority.(* 1) The places of manufacture and packaging should be separated from any unrelated industrial processes which might constitute a source of contamination.

Premises should be ventilated with clean air and should have adequate handwashing and toilet facilities. The construction and furnishing should be conducive to regular and thorough cleaning. Storage areas should be clean, dry and free from vermin.

Manufacturing conditions and transport conditions between places of assembly should be such as to minimize contamination of the final product, before sterilization, with pathogens or large numbers of any micro-organisms.

2.2. PERSONNEL

Staff engaged in manufacture should be instructed about ways in which contamination can result, and of the importance of a high standard of personal and production hygiene. They should be supervised in respect of systemic or local disease which might constitute a source of contamination, and in respect of their personal hygiene. For this purpose medical advice should be available.

2.3. PRODUCTS

2.3.1. The product should be handled as little as possible in the course of processing, and should be as clean as practicable.

2.3.2. Products should be packaged so as to maintain sterility, and packs should be designed to facilitate aseptic removal of the contents.

2.3.3. Instructions for storage and handling shall be furnished.

2.3.4. Labels shall indicate the following

(a) Contents

(b) The name and address of the responsible supplier or manufacturer

(c) That the contents are radiation sterilized

(d) Means of identification of the place and time of manufacture and sterilization.

Where practicable, this information should be on the individual pack, or, if this is not possible, on the smallest multiple pack.

2.3.5. Sterile and unsterile goods must be kept separate and readily identifiable. Storage and handling arrangements should be such as to prevent unsterile articles being issued for use.

3. MICROBIOLOGICAL CONTROL

3.1. EFFICIENCY OF THE FACILITY

The efficiency of the facility shall be tested on commissioning, and whenever the process is altered, by means of microbiological reference standards. These microbiological reference standards should comprise at least one with bacteria in the vegetative form and one with endospores of bacteria.

The microbioligical standard preparations should be obtained through the International Atomic Energy Agency, Vienna, from a laboratory approved by the Agency.

3.1. NOTE 1. Microbiological reference standards

The use of microbiological reference standards is considered necessary because the inactivating effect of ionizing radiation on micro-organisms is not determined by the absorbed dose alone. The efffect of a given dose may, for example, vary as a consequence of changes in the environment of the organisms before, during or after irradiation. Also the physical characteristics of the radiation, especially the dose rate, may influence the microbiological effect of a given dose.

The factors that may lead to variation in the microbiological effect of a given dose do not always appear to have the same influence om vegetative bacteria and bacterial spores. Likewise, differences in species may be of importance. It is proposed to have at least one microbiological standard with vegetative bacteria and one with bacterial spores. These reference standards should have a reproducible number of viable units per test piece and a reproducible radiation resistance.

At least three points on the inactivation curves in the dose range commonly use for sterilization should be determined with each microbiological reference standard preparation. Each point should be determined by counts of survivors in not less than three units of the standard preparation irradiated on at least three separate occasions. The irradiation should be carried out in a mode similar to that used in the industrial process. The results should be compared with an inactivation curve for the microbiological reference standard used. This curve should be forwarded to the irradiation facility together with the microbiological standard preparation. Possible differences between the measured results and the standard inactivation curve should be taken into consideration in the choice of dose. Standard curves and records of the measurements should be kept, and made available to the appropriate authority if required. New measurements should be made whenever the process is altered.

The microbiological reference standards will be determined by the IAEA Committee of Experts. The standard with vegetative bacteria may consist of test pieces of STREPTOCCUS FAECIUM, strain A2-1 (ATTC. 19581). The standard with endospores may consist of test pieces with spores of BACIILLUS PUMILUS E 601.

3.2. CHOICE OF DOSE

The choice of dose will be dependent upon the particular item to be sterilized, the microbiological contamination to be found on the item and the margin of safety required for the end-use of the item.

The margin of safety is to be assessed by perusal of the data available concerning the radiation resistance of micro-organisms. Since the margin of safety for a particular dose is dependent upon the initial number and species, and their resistance in the particular environment, control of the pre-sterilization load is required. This control should be exerted by quantitative and qualitative examination of the pre-sterilization bacterial contamination of articles selected from finished packaged goods before the sterilization is applied. Further, the margin of safety should be checked by exposure to the sterilization treatment of suitable test-pieces and of articles deliberately contaminated to the maximum extent within the production premises. The process must prove effective for these test-peices or articles.

3.2. NOTE 1. Countion of the pre-sterilization bacterial contamination

The initial count is defined as the number of viable micro-organisms that can be isolated from the item itself and from the inside of the packaging.

The determination of the initial count should be made om samples taken randomly from the packaged, non-sterilized items.

The number of initial count determinations should be adjusted to the size of the production batch. In continuous production not divided naturally into batches, counts should be made on a representative number of units from each independent production line. In batch production, samples for determination of initial counts can be taken according to a recognized sampling pattern (e.g. World Health Organization, Techn. Rep. Ser. No. 200 (1960)).

When the initial counts is used for evaluation of the standard of production hygiene and for the choise of dose, the average count as well as the maximum count per unit should be taken into consideration.

The average count at any time in continuous production should be calculated on the basis of the counts from that date and those from the preceding nine working days.

For any item the initial count shall be as low as good manufacturing conditions can produce. When the radiation resistance of micro-organisms isolated from a given product, in conditions approximating to their environment on the product, is regularly examined, the results of such investigations may be included in the considerations of the choice of dose for the product concerned.

The microbiological technique used for initial count determinations should be selected with due regard to the nature of the product. Whenever a technical failure occurs in the determinations the cause should be traced and recorded, and re-sampling should be done as soon as possible.

3.2. NOTE 2. Choice of dose

The minimum dose should be related to the average initial count, as established according to 3.2. Note 1. This will also take into account the desired microbial inactivation factor, which will depent upon the most stringent margin of safety required for the intended use of the product. The minimum inactivation factor may be decided by the appropriate authority, e.g. for some products an inactivation factor of 10exp5 may be suitable, but for equipment such as blood bank devices a figure of 10exp8 may be required. If the type and sensitivity of the most resistant organisms contained in the product is not known, reference should be made to the inactivation factors obtained for the most resistant organism under environmental conditions which maximize their resistance (such as the biological reference standard; this standard is now under discussion and will be published by the IAEA in 1968).

The results of the regular examinations of initial counts should be open to appraisal by the regulation authority. If the average initial count exeeds an agreed limit, and cannot be reduced to the satisfaction of this authority by control af factory hygiene, the dose shall be increased so as to maintain the desired microbial inactivation.

If it is conceivable that, during the period when the limits were exeeded, units of the product have been contaminated with more than ten times the acceptable maximum number of organisms, then the items from that period (at least the item produced on the same day as the most badly contaminated units, plus those from not less than one preceding and three following working days) should be considered non-sterile. When the excess in counts is less than ten times the permissible limit, the items from the period in question may be considered sterile.

3.2. NOTE 3. Sterility testing

Where initial count and desired microbiological inactivation factors have been taken into consideration, conventional sterility testing of material produced in agreement with the present Code of Practice may generally not be necessary. Under certain circumstances sterility testing may be of value, for instance in the case of complicated devices produced in small numbers.

The national health authority may require microbiological control of random samples of finished packaged and sterilized goods.

For these situations in which sterility testing is used, incubation times in the testing media may have to be prolonged as some irradiated micro-organisms have been found to grow slowly or to have a long lag phase.

4. OPERATION OF RADIATION STERILIZATION FACILITIES

4.1. SUITABILITY

The irradiation facility to be used must be approved by the appropriate authority as suitable for the purpose intended.

4.2. SAFETY

The installation must conform to the safety and health reqiurements laid down in the country of operation, and the energy level of the radiation source should be kept at a level where no hazards due to induced radioactivity can reach the consumer.

4.3. DOSIMETRY

Recognized methods of dosimetry must be employed and complete records of results obtained must be kept. Records should be kept of the various parameters controlling the plant operation.

4.3. NOTE 1. Dosimetry at gamma ray irradiation plants

(a) GENERAL

The dose delivered at a particular location in a product package of a given size, conveyed through an irradiation field in a multi-pass mode, depends on the source strength, the conveyor speed, and the densities and atomic numbers of the materials passing through the system for irradiation.

The aim of dosimetry is to make sure that every unit receives at least the required minimum dose and that excessive doses are not given. The fulfillment of this requirement should be ensured on the commissioning of the plant, and whenever the process parameters are altered, and should be controlled during routine operation.

(b) DOSIMETRY ON COMMISSIONING

For a given mode of conveyor operation and a given source geometry, the dose is inversely proportional to the conveyor speed. The conveyor speed is therefore an important parameter in the dose determination, and it should be ensured that the reproducibility of speed setting and the constancy of the system during operation are within the limits required for obtaining correct dosage.

It should be verified that positive indication is given when the source is in its correct operating position during processing, and that the conveyor is operating properly. Action should occur automatically when this is not the case.

In order to derive correct setting for the conveyor speed, the dose distribution in a standard package(* 2) has to be evaluated for the given mode of conveyor operation. Because of the absorption characteristics of a multi-pass geometry, packages in any production run should be of known weight and composition. The dose distribution may be determined by placing not less than ten dosimeters in a hoomogeneous phantom material of simular density and chemical composition as the production packages, or dosimeters may be placed in a standard production package at specific locations representative of areas which might give the best indication og dose variability. This procedure should be repeated in order to test the reproducibility of the integrated process.

Recognized dosimetry systems should be employed, e.g. ferrous sulphate, Fe-Cu sulphate, oxalic acid, and film systems (polyvinyl cloride, coloured or uncoloured polymethyl methacrylate). Systems whose yield is not well known, or systems known to be sentitive to impurities, (e.g. ceric sulphate) dose-rate, irradiation temperature, humidity or other external conditions, should be calibrated under actual working conditions against, for example, ferrous sulphate or by calorimetry.

Once the dose distribution is determined, conveyor settings should be fixed so as to ensure that at least the specified minimum dose is given to all the products. Provided it has been established that the speed can be set and controlled accurately, the dose distribution can be determined at doses different from those intended for use in production, and conveyor speeds may consequently be calculated by scaling.

When the process (including materials and packaging) is altered, those parts of the foregoing procedures which are influenced by the alterations should be repeated.

(c) ROUTINE DOSIMETRY

Once the plant is calibrated and the minimun absorbed dose in the production packages determined as a function of conveyor speed, the routine control may be limited to the following steps

I. Positive indication of the correct operational position of the source, as described in 2.2.

II. Continous-line recording of cenveyor speed, and/or the plant cycle should be monitored by a system mechanically locked to the conveyor drive. The recording paper should be date-marked so that the proper correction factor can be calculated to compensate for the source decay since the time of calibration.

III. Either the packages should be labelled with a radiation indicator, or the entrance area to the source should be physically separated from the exit area to prevent irradiated and non-irradiated packages from being intermixed.

In addition to these measures, it is recommended that the dose be regularly checked by including dosimeters in the production packages.

4.3. NOTE 2. Dosimetry at electron irradiation plants

(a) GENERAL

The type of accelerator plant referred to in this section is one with the following characteristics

I. A scanning system providing a sweep of the electron beam so as to give a homogeneous surface dose distribution over the width of the production package.

II. A conveyor system which moves the production packages in a direction perpendicular to the beam and scanning directions.

III. A sweep velocity high enough to ensure good beam-spot overlap on products passing at the highest cemveyor speed.

With constant beam and scanning, the dose delivered at a particular location in a product package depends on the beam parameters (energy, average current and scan width), the conveyor speed, and the thickness, density and atomic number of the materials placed between the beam exit window and the location in the package.

The aim of dosimetry is to make sure that every item processed receives at least the required minimum dose and that excessive doses are not given. This should be ensured on the commissioning of the plant and whenever the process parameters are altered, and should be controlled during routine operation.

Absolute standardization of the beam parameters is not required to obtain correct dosage, although the electron energy should be approximately known in order to evaluate the induced activity hazard.

The relative levels of the beam parameters, however, are to be monitored continuously whenever the process is to be carried out without dosimeters being attached at minimum dose locations in all packages.

(b) DOSIMETRY ON COMMISSIONING

For a given set of beam parameters, and for a given geometry of the irradiation field, the dose is inversely proportional to the conveyor speed. The conveyor speed is therefore an important parameter in the dose determination, and it should be ensured that the reproducibility of speed setting and the constancy (or corrective regulation, see 3.3.) of the system during operation are within the limits required to obtain correct dosage.

A system should be provided to deal with a failure of the beam operation (e.g. automatic and immediate shut-down of the product conveyor).

The beam parameters can be standardized as follows

Absolute current measurement of the scanned beam can be made by having the electrons absorbed in, for example, an aluminimum absorber thick enough to absorb all the electrons entering it, and by metering the resulting current flowing to ground. Correction must be made for electrons scattered back from the absorber. (Values for different electron energies and absorber materials may be found in NBS Handbook 97 (1964).)

Routine current measurement may be carried out by means of a non-intercept monitor. A simple technique may be used, e.g. the scanner chamber of the accelerator might be provided with secondary emission plates mounted symmetrically around the beam and collecting electrons back-scattered from the accelerator exit window. It should be ascertained that the system preferred gives accurate readings which are not significantly influenced by other factors such as minor changes in beam focusing.

Absolute calibaration of the beam energy may be carried out by various methods, such as I. magnetic spectrometry II. threshold-detector methods III. film-stack dosimetry

One way of obtaining a relative measure of the electron energy is readily available when the accelerator is fitted with a bending magnet located before the scanning system. In this case current required to bend the beam by 90 degrees (or any other angle chosen) is a relative measure of the electron energy. If the process parameters are to be integrated into the dosimetry procedure, it should be ensured that the energy remains constant during processing. A system of secondary emission plates such as referred to above may be used to control this parameter. If the energy varies, the beam, for a constant current in the bending magnet, will deviate from the angle chosen and thereby cause a greater reponse from one of the plates than from the other. This system can be made to trigger an alarm or to control an automatic energy-regulation circuit. Another system is based on the fact that the current necessary to scan the beam over a certain width is a function of the beam energy. This principle can be applied to a monitoring system by installing two bars or wires at each end of the scanner house (under the exit window) and making the scanned beam strike the inner, but not the outer bars. Whatever method is used, it should be ensured that the response is not influenced significantly by minor changes in other physical factors.

The scan width can be controlled by the bar method referred to above or by an automatic feedback system to the driver circuit. Deficient operation should cause automatic shut-down of the process.

In order to obtain correct setting of the conveyor speed for a given set af beam parameters, the dose distrubution in the standard production packages should be evaluated. Because of the absorption characteristics of high-energy electrons, packages in any production run should be of similar weight and composition, and the contents should be homogeneously distributed throughout the package. The dose distrubution may be determined by placing not less than ten dosimeters in a homogeneous phantom material of similar average density and chemical composition as the production packages, or, better, the dosimeters may be placed at representative location in the production package. It will normally be found that the part of the package farthest from the beam receives the smallest dose. This procedure should be repeated in order to test the reproducibility of the integrated process.

Recognized dosimetry systems should be employed. The low penetration of electron radiation as compared with gamma radiation makes it necessary to use film systems (e.g. polyvinyl chloride, coloured or uncoloured polymethyl methacrylate). As these systems are influenced by external conditions such as temperature, humidity, and dose rate, calibration should be carried out under actual working conditions (e.g. by calorimetry).

Once the dose distribution is determined for a given set of beam parameters, conveyor settings should be fixed so that the specified minimum dose is delivered to all product locations.

Whenever the process is altered, those parts of the foregoing procedures which are influenced by the alteration should be repeated.

(c) ROUTINE DOSIMETRY

Once the plant is calibrated and the minimum absorbed dose in the production packages determined as a function of conveyor speed, the routine control may be limited to the following steps: I. The employment of an interlock system between beam current monitor and conveyor as discribed in 3.2. II. Continuous monitoring and continuous-line recording of current, energy, scan width, and conveyor speed, as described in 3.2. The electron current signal, as monitored by secondary emission plates or some other non-intercept monitor, may be used to feed the conveyor driver circuit, thereby ensuring a constant surface dose. III. Either the packages should be labelled with a radiation indicator, or the entrance area to the accelerator room should be physically separated from the exit area in order to prevent irradiated and non-irradiated packages from being intermixed.

In addition to these measures, it is recommended that the dose be regularly checked by attaching dosimeters to the production packages at the place farthest from the beam.

Whenever a mixed production (light and heavy packages together) is processed, or whenever monitoring of the production parameters is not carried out according to the requirements listed above, a dosimeter should be attached to each package.

4.4. PROTECTION IN EVENT OF MECHANICAL FAILURE

Suitable devices must be provided to ensure that a failure of the mechanical systems does not result in an incorrect dose.

5. SUPERVISION

One person should be designated by the management to ensure that the requirements of the Code of Practice for the processes are met. This person should be designated by name by the management and approved by the appropriate authority, should be of senior status and well qualified by training and experience for this responsibility. He should have direct access both to production management and top management of his own organization, and to the representative of the appropriate authority. He should also have the support of a competent microbiologist and physicist, each with adequate laboratory facilities and staff, for microbiological monitoring and for dosimetry, respectively, or he himself might be the microbiologist or physicist.

The formulation of a Code of Practice for the Radiosterilization of Medical Products was first proposed at the International Atomic Energy Agency's Panel Meeting on Radiosterilization of Medical Products, Pharmaceuticals and Bioproducts, which was held in January 1966 in Vienna;(* 3) 14 Member States, WHO and ENEA (OECD) were represented. The Panel Members, bearing in mind the existing legislations in the various Member States, named a working party who were to prepare the first draft recommendations for a Code of Practice. The members of the working party were J.H.Brewer (USA), E.A.Christensen (Denmark), C.G.Crawford (UK), N.W.Holm (Denmark), F.J.Ley (UK), L.O.Kallings (Sweden); A.Tallentire (WHO), E.Wallauschek (ENEA), F.Antoni and W.Lotz (IAEA).

The working party meeting was held in London in April 1966. The first draft from the working party was discussed at the Agency Panel Meeting - Code of Practice on the Radiosterilization of Medical Product - which was held in Vienna in December 1966. The Panel's final recommendations for a Code of Practice, as published here, were forwarded to all Member States and WHO for comment, and were then put before the Budapest Symposium for discussion.

Cirkulære om strålesterilisering af medicinske utensilier (engangsmateriel) overvejende bestående af plast.

(Til fremstillere og forbrugere af medicinske utensilier.)

Medens strålesterilisering af medicinske utensilier i Danmark hidtil har fundet sted på atomenergikommisionens forsøgsanlæg på Risø, er der nu åbnet mulighed for, at dette kan ske andensteds. Dette forhold giver sundhedsstyrelsen anledning til ved nærværende cirkulære at redegøre for de principper, der fremover bør anvendes ved fastsættelsen af procedure og bestrålingsdoser, og som hidtil er anvendt på Risø på grundlag af et løbende samarbejde mellem Atomenergikommisionen, Statens Seruminstitut og Sundhedsstyrelsen.

Som et resultat af det ovennævnte samarbejde blev det for nogle år siden klart, at fastsættelsen af bestrålingsdosis måtte ske på grundlag af det ubestrålede materiales komtamineringsgrad bestemt ved en mikrobiologisk undersøgelse samt under hensyn til bestrålingsanlæggets mikrobiologiske effekt. Det er da også på denne basis, den af den internationale atomenergiorganisation udsendte »Code of Practice for Radiation Sterilization of Medical Products« er opbygget. Heri er det blandt andet fastsat, at bestrålingsdosis skal øges, hvis det gennemsnitlige initiale kimtal under kontrollen af en løbende produktion overstiger en af de relevante sundhedsmyndigheder fastsat grænseværdi, hvis producenten ikke omgående kan finde og fjerne årsagen til den øgede forurening.

Sundhedsstyrelsen skal ved nærværende cirkulære henlede opmærksomheden på, at men anser det for uforsvarligt at anvende strålesteriliserede medicinske utensilier, medmindre varerne er fremstillet i nøje overensstemmelse med de principper, der er gengivet i den som bilag 1 til nærværende cirkulære optagne rekommandation vedrørende strålesteriliserede medicinske utensilier.

I den givne anledning henstiller sundhedsstyrelsen derfor til alle brugere af strålesteriliserede medicinske utensilier, at de ved ethvert indkøb af disse varer på passende måde sikrer sig fabrikantens skriftlige garanti for, at fremstillingen af varerne er sket i nøje overensstemmelse med de i rekommandationen anførte bestemmelser.

Den af den internationale atomenergiorganisation udsendte »Code of Practice for Radiation Sterilization of Medical Products« er ligeledes vedføjet som bilag til nærværende cirkulære.

SUNDHEDSSTYRELSEN, DEN 19. AUGUST 1968.

Esther Ammundsen

/A. Skovgaard

BILAG 1.

SUNDHEDSSTYRELSENS REKOMMANDATION VEDRØRENDE FREMSTILLING AF STRÅLESTERILISEREDE MEDICINSKE UTENSILIER.

Ved fremstilling af strålesteriliserede medicinske utensilier bør den af International Atomic Energy Agency udsendte »Code of Practice for Radiation Sterilization of Medical Products« følges. Det må dog bemærkes, at der endnu ikke er etableret en officiel kontrolordning i Danmark, og den under punkt 2.1 omtalte inspektion af fabrikations-, pakke-, steriliserings- og lagerlokaler vil derfor først kunne gennemføres, når en sådan kontrolordning er etableret. Den under punkt 4.1 omtalte godkendelse af bestrålingsanlægget samt den under punkt 5 omtalte godkendelse af den person, som er ansvarlig for, at fremstillingen finder sted i overensstemmelse med de stillede krav, vil ligeledes først kunne finde sted, når en kontrolordning er etableret.

Den i appendix til punkt 3.2 under punkt 3.2.2 anførte grænseværdi for gennemsnitskimtallet for usteriliseret materiel er af sundhedsstyrelsen fastsat til 50. Ved strålesterilisation af tørt engangsmateriel overvejende bestående af plast bør anvendes en minimumsbestrålingsdosis på 3,5 megarad under forudsætning af, at det anvendte bestrålingsanlægs doser har samme mikrobiologiske effekt som atomenergikommissionens acceleratoranlæg på Risø.

Hvis gennemsnitskimtallet overskrider denne grænseværdi, bør producenten forsøge at finde årsagen hertil, og med hensyn til det steriliserede materiel forholdes som anført i punkt 3.2.2. Hvis kimtallet mere end en gang i løbet af 50 efter hinanden følgende produktionsdage overstiger grænseværdien, bør dosis øges svarende til nedenstående værdier

Ved et gennemsnitskimtal på indtil 500 anvendes en minimumsdosis på 4,5 megarad.

Ved et gennemsnitskimtal på over 500, men under 5000, anvendes en minimumsdosis på 5,0 megarad.

Materiel, der før sterilisationen er forurenet med så stort et antal kim, at gennemsnitstallet er 5000 eller derover, er ikke anvendeligt til strålesterilisation.

(* 1) Authority is taken to be the appropriate national health authority.

(* 2) The standard package is here defined as the standard volume unit fitting into the conveyor carrier.

(* 3) Radiosterilization of Medical Products, Pharmaceuticals and Bioproducts, Report of a Panel, Vienna, 17-19 Jan. 1966, Technical Reports Series No. 72, IAEA, Vienna (1967) 94 pp.