Measurement Techniques, Vol. 48, No. 1, 2005
DOSIMETRIC STANDARDS AND METROLOGICAL SUPPORT TO RADIATION STERILIZATION DOSIMETRY
R. A. Abdulov, V. V. Generalova, M. N. Gurskii, A. A. Gromov, A. P. Zhanzhora, G. M. Minyailik, and A. E. Sysak
UDC 621.039.58
Absorbed-dose measurement and metrological support to it are considered for all stages of radiation sterilization. One can provide safety and quality only by using standards harmonized with international and national ones such as GOST R ISO 11137-2000, GOST R 52249-2004, and GOST R 50325-92. Key words: medical devices, radiation processing, radiation sterilization, absorbed dose, dosemeter.
Disposable medical devices are widely used in health facilities and generally. Industrial sterilization of them is based in the main on thermal, gas, and radiation treatment. Radiation sterilization (RS) for medical devices is the most effective and safest as well as economical clean and reliable method. There are hundreds of medical devices used with radiation sterilization: injection syringes, systems for transfusing and taking blood, various forms of catheters and needles, surgical packing materials, surgical linen, transfer materials, and so on. Every year, Russia sterilizes more than 1 billion syringes with needles for single use, more than 30 million devices for taking and transfusing blood, and other medical devices. Irradiation facilities (IF) for sterilizing these products are based on radionuclide sources and electron accelerators. In Russia there are about 20 industrial and semiindustrial plants of this kind. Starting in the 1970s, the USSR State Standards Committee devoted much attention to metrological support to radiation sterilization as one of the important links in producing disposable sterile devices. During that period, VNIIFTRI set up standards for measuring the intensity of gamma and electron radiations, and devised and regularly produced standardized and working means of measuring absorbed dose covering a wide range of technologies (liquid, solid-state, and film chemical detectors). These facilities are used in certifying IF and in periodic and acceptance dosimetry of products after irradiation. Color indicators for absorbed dose are used to distinguish irradiated and unirradiated medical devices on sterilization and production. The RS process is supported by fundamental standardization documents [1–7]. The performance in radiation sterilization cannot be fully tested by nondestructive product controls (sterility testing). The purpose of sterilization is to deactivate microbiological contamination in the unsterile product. Deactivation in RS is subject to an exponential law in terms of the active factor (absorbed dose). Consequently, there is always a finite probability of microorganisms surviving no matter what the dose. The survival probability is dependent on the number and type (strain) of the microorganisms in the product, their radiation resistance, and (sometimes) the conditions in the medium in which they are present. This means that sterility in each particular item in a sterilized product cannot be completely guaranteed. To describe the RS performance, one introduces a calculated parameter called the guaranteed sterility (GS), which defines the probability that there are viable microorganisms in an individual item. The limiting values of the GS are stated in the normative documentation. With a sterility level less than 10–2, it is necessary to monitor a large number of items, which Translated from Izmeritel’naya Tekhnika, No. 1, pp. 62–67, January, 2005. Original article submitted November 1, 2004. 84
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is undesirable. For example, to obtain a sterility level of 10–6, it is necessary to test not less than 1 million items. Therefore, monitoring items for stability after irradiation is not recommended in international practice. The Federal Agency for Technical Regulation and Metrology in the Russian Federation has devoted its main attention to harmonizing the existing and newly devised documents with the requirements of the series ISO 9000 international standards. Much work in this direction has been done by the Standing Committee TC 383 “Sterilizing medical devices,” which is staffed by highly qualified experts from VNIIFTRI and various departments. The metrological support to RS is dependent on the particular tasks to be realized at each stage [8]. Preparing medical devices for RS (certifying products): this is used in conducting tests to establish the sterilizing and maximum permissible doses and uses precision standardized means of measurement with an error in determining the absorbed dose not more than 7%. The extended uncertainty in measurement should not exceed 10% with a coverage factor K = 2 and absorbed doses beginning with 1 kGy. The absorbed dose must be monitored with individual dosemeters for each product unit. The maximum permissible dose is established for each form of product and packing material (with typical tests, items or material specimens are irradiated in the range 10–100 kGy). The sterilizing and maximum permissible doses are established by accredited microbiological laboratories; the absorbed dose in the item (specimen) is determined by specialists in the radiation monitoring laboratory as accredited in the SARK system [9]. Preparation for RS: standardized means of measurement are used in determining the distribution of the absorbed dose in the medical device as appropriately placed in a standard holder for irradiation and with a certified IF for absorbed dose in the product, i.e., one sets up IF parameters for which the RS will provide the issue of high-grade and safe medical products. The RS is certified with precision means of measurement whose error is 5–7%, or else one uses the comparator method, which enables one to transfer the unit of absorbed dose directly from the primary standard to the irradiated object. If the results from the certification are positive, the organization issues a certificate certifying the IF as regards absorbed dose in accordance with [4, 5], while if the results are negative, it reports that the IF is unsuitable, i.e., the RS technology does not meet the requirements of the standard documentation for the product. Performing RS: in this case, one uses the sterilization of a medical product allowed for routine production, with the current and periodic acceptance dosimetric monitoring performed by means of standardized means of measurement with an error of not more than 12% in continuous recording of the monitored IF parameters [2]. Complete obedience to the rules in all stages of preparing for and performing RS is needed to ensure the requirements imposed on radiation-sterilized items (sterility, apyrogenic behavior, lack of toxicity, and the preservation or uncritical change in the physicochemical and mechanical properties); strict obedience is needed to the sterilization conditions laid down in certifying the IF on absorbed dose for a particular product; also the organization and performance of periodic and acceptance dosimetry of RS; and the use of certified or verified means of measurement and testing. In [6], one finds general specifications for metrological support to absorbed-dose measurement for ionizing radiation in tests and on RS of medical devices. The following are the basic standardization documents in RS: instructions on radiation sterilization for a particular item, technical conditions for the item, certificate on the attestation of the IF on absorbed dose for each form of product, technological regulations for RS for each form of product, methods of making measurements in current and periodic dosimetry for particular IF. To meet tight specifications for safety and quality, methods have been developed and standardized for certifying irradiation facilities in accordance with international standards. Every year, up to 20 irradiation facilities with various forms of product (up to 80 types) are subject to metrological test and certification. The certification of an IF is performed by precision chemical detectors with an error of 5–7%. As the irradiation nonuniformity in an IF containing an electron accelerator may attain 300%, the makers of medical devices have to have a clear-cut organization of their radiation sterilization. The following sequence is used in organizing and conducting radiation sterilization as one of the links providing quality and safety in medical devices (sterility, lack of toxicity, apyrogenic, and on physicochemical properties). A. The manufacturing specifics for medical items (geographic position, product volume, features and properties of the materials, and so on) are all used in choosing the type of irradiation facility containing radionuclide sources or electron accelerators. One selects the scheme for packing the items and the sizes of the transport vehicle from an analysis of published papers, experience of other producers, or suitable calculations. 85
Fig. 1. Absorbed dose distribution in a box containing “Disposable injection syringes 5B Luer with needles 0.8 × 38 mm” at various depths Z. Number of syringes 800, mass 7 kg.
Fig. 2. Absorbed dose distribution in a box containing “Sterile medical gauze bandage 5 m × 10 cm” at various depths Z. Number of bandages 400, mass 9 kg.
B. Standardized means of measurement are used to determine the absorbed-dose distribution of a product irradiated on the IF during the cycle. Usually one employs extended film dosemeters, which are located uniformly between layers of packed components in the transport vehicle. This gives the minimal and maximal absorbed doses Dmin and Dmax, which are characteristic of the particular IF, packing scheme, and transport vehicle. The sterilization conditions are set up in accordance with Dmin and Dster, which are derived from microbiological studies by a competent organization accredited for that type of work. The value found for Dmax in that mode of operation is compared with the value stated in the documentation (instructions on sterilization, technical specifications, and standards). If the normalized value is not exceeded, one issues the certificate on the IF for absorbed dose in a given form of product in the standard system with its packing and irradiation. These operations are performed by an accredited organization of the Federal Agency on Technical Regulation and Metrology of the Russian Federation. If not, one needs additional toxicological and health-chemistry tests on the product for Dmax or else to alter the packing scheme, the number of items in the packing, the transport vehicle, the type of IF, and so on in order that this value is reduced to that given in the documentation on the product. All measurements on absorbed dose distribution in the product in that case should be repeated. C. After the sterilization mode has been established and confirmed, a certificate is issued on the IF in relation to absorbed dose in this form of product in accordance with [8–10]. 86
Fig. 3. Absorbed dose distribution in a block of disposable injection syringes 2A Luer with the Sterus-1 IF after irradiation with emergency IF shutdown.
Fig. 4. Absorbed-dose distribution at the surface of an object for various values of the time delay in continuing the irradiation after a shutdown (emergency); Dav average value of the absorbed dose; Tts time shift.
D. The standard data on the biomedical and chemical tests (D10, limiting initial sterilization, Dster, and Dmax) are entered in the certificate, including data on the mode of operation in the IF, which indicates metrological certification or checking of the IF, and this is basic to compiling technological rules for the sterilization. Those rules and the instructions on radiation sterilization are registered with the Ministry of Health Care and Social Development of the Russian Federation. The radiation sterilization rules given the following: general characteristics of the production; characteristics of the final product; specifications for the equipment and means of measurement; standards for the working conditions; descriptions of radiation sterilization and of current and acceptance dosimetry, faults in the IF operation and the elimination of them; staff specifications and safety measures; list of compulsory constantly acting documents (standards, methods of making measurements, and so on), and references to documents that must be periodically updated in accordance with the requirements of the standardization documentation (certificate for the IF, conclusions on toxicological tests during the production, records on the microbiological state of the production, and so on). Tightened requirements apply to disposable medical devices because of the introduction into Russia of various international documents, which are drawn up by the Technical Committee on Standardization TC 383 “Sterilizing medical prod87
ucts” and which have been confirmed by the Federal Agency for Technical Regulation and Metrology of the Russian Federation. In the area of radiation sterilization of medical devices, this applies particularly to GOST R ISO 11137-2000 [2]. These metrological tests and the documentation based on them should provide quality and safety in medical devices sterilized by radiation during production. Nevertheless, certain difficulties arise in the metrological certification of IF that hinder issuing the certificate. While sterilizing doses are determined in accordance with the existing documentation, which contains methods of making measurements such as GOST R ISO 11137-2000, and the values can be verified, on the other hand the establishment of maximum permissible doses for medical devices is at present done in the absence of any methods. The maximum permissible dose characterizes the safety of the product and the functional behavior of the irradiated items. Unsound values for the maximum permissible dose in the product documentation lead in many cases to the need to issue a statement on the unsuitability of the irradiation facility for sterilizing many forms of device. All test centers lack methods of determining maximum permissible doses for medical items, which is reflected in the technical specifications for them, in which in general there are no references to methods of monitoring in the section “Radiation sterilization” of GOST 2.114-95 [11]. Many technical specifications also do not give requirements on the range of permissible absorbed doses in a product produced by radiation sterilization, and merely give a single value for the sterilizing dose, and not always that. Particular attention is needed in the expert evaluation of the metrological state of medical device production to the periodic and acceptance monitoring of the IF. Dosimetric monitoring may not be replaced by monitoring the sterility of isolated items of the product and certification tests on it. The makers of the certified product have complete responsibility for providing correctness and adequacy in all the operations in radiation sterilization, including all the dosimetric measurements and product test methods. Disposable medical devices are mass produced, and any failures or faults in the technological chain may lead to unpredictable consequences. Therefore, there is a certain hazard in the presence of gross faults in the radiation sterilization of medical devices at various organizations. These faults apply not only to metrological support to IF parameter measurement in relation to the RS but also to the content of the technical documentation that should form the basis of the process. We merely note certain of them in general form. 1. In the determination of the sterilizing and maximum permissible doses (basic standardized parameters of the sterilized objects), the requirements of the standards [1, 2] are not met as regards the errors in determining the absorbed dose during test. Organizations under the Ministry of Health and Social Development of the Russian Federation are responsible for determining sterilizing and maximum permissible doses in medical devices, but they issue documents casting doubt on the reliability of the values given there. 2. In the technical specifications for many forms of medical device, sterilization dose ranges are quoted of 15–25 or 25–30 kGy. That type of range is not realized in any IF with radionuclide sources or electron accelerators, as is confirmed by Figs. 1 and 2. With the forms of packing and arranging the products, the range for syringes is 15–40 kGy (the most homogeneous product), while for blood-handling systems it is 15–60 kGy (heterogeneous product), but nevertheless, this fact is ignored at some businesses and poor-quality products are issued. Table 1 gives IF certification results for various products in various years. 3. At certain IF, medical devices are sterilized without instructions on RS for certificates on the metrological certification of the plant as regards absorbed dose in particular forms of product and with particular rules. 4. Current and periodic dosimetric monitoring is not supported by methods of performing measurements for a particular IF, which cast doubt on the quality and safety of the sterilized product. Such methods exist only in accredited laboratories for radiation monitoring at MRTI RAN and IFKh RAN. 5. Acceptance dosimetry on IF is of primary importance for reliable sterilization of medical devices, since RS is a specialized technological process whose performance cannot be verified by retrospective monitoring and testing the product [2]. As a rule, at all RS organizations one leaves aside the question of what to do with items whose irradiation has been interrupted by an emergency stop in the work of the IF. The technological rules for IS imply that such products should be discarded. However, for economic reasons, this is not possible, and each organization performing RS attempts to correct such rejects on its own basis. The items are either irradiated again or their irradiation is continued from the situation at which the shutdown occurred. Virtually nobody performs an experimental confirmation that such a method is correct. Then in the first 88
TABLE 1. Results of Absorbed-Dose Certification of IF at Various Organizations in the Country in Various Years Organization providing radiation sterilization services
Product manufacturer
Product
Confidence range for absorbed doses in product, kGy
MRTI RAN
STERIN Company
Disposable injection syringes (DIS) 5B Luer with needle
15–33 (1998) 15–36 (2000) 15–38 (2001)
KRPZ Company
Ditto
15–35 (1999)
ShOP-1 Novovoronezh plant
»
15–32 (1999)
Polimed 111 Company
»
15–29 (1999)
15–35 (2000)
15–38 (2000) 15–32 (2001) Éskulap Company
Gauze bandage 7 m × 14 cm
15–50 (2000)
Medpolimer Firm Company
PR23-05 blood replacement infusion device
15–50 (2000)
IFKh RAN
KRPZ Company
DIS 5B Luer with needle
15–33 (2000)
Polimed 111 Company
Ditto
15–34 (2000)
Era Company
ShOP-1 Novovoronezh plant
»
15–36 (1997–2000)
PRIM Ltd
PRIM Ltd
DIS 2AB Luer with needle
15–38 (1997–2000)
Biophysics Institute
Polimed 111 Company
DIS 5B Luer with needle
12–30 (1997)
15–32 (2001) 15–41 (2001) 15–33 (1998) 15–32 (2000)
case, the already irradiated part of the product will be irradiated again, i.e., overirradiated. In the second case, the inertia in switching on and halting a conveyor or IF drive may mean that some part of the items may remain unirradiated. Figure 3 illustrates this situation. Figure 3 shows that one cannot continue the irradiation immediately from the position in which the IF shut down. To minimize the unirradiated product, one must first shift the transport system a little back. To determine the best shift, one can for example measure the length of the unirradiated or overirradiated part on the surface of a box containing a homogeneous product, with irradiation with various shifts. As one knows the speed of the conveyor bearing the product, one can define the time shift (Fig. 4). This shows that one can correct for the scrap due to emergency shutdown in the irradiation if it is carefully designed, experimentally tested, and introduced as a separate section in the technological rules for the RS. Conclusions. The certification of a proposed product as regards sterility cannot be performed only from tests on the finished product. The RS itself must be certified. Safety in the product (sterility, lack of toxicity, and apyrogenic behavior) may be provided by irradiation in the absorbed-dose range laid down in the standardization document for the irradiation facility, whose mode of operation is confirmed by a certificate for the metrological certification of IF by absorbed dose in the product. Then periodic and acceptance dosimetry on the IF cannot be replaced by checks on the sterility of individual specimens of the product. The certification of disposable medical devices in sterile form is performed in accordance with [10]. The manufacture of the certified product has complete responsibility for providing correctness and accuracy in all the operations of sterilization and in tests for correspondence with the technical specifications for the product. At the same time, the staff performing the irradiation are responsible for processing the items in the dose range laid down by the certificate for the RS process. The period of validity for the certificate for the product and inspection checks on it are determined from the data 89
characterizing the stability of the process, the reliability of the RS working conditions, and the provision of the necessary means of measurement for the periodic and acceptance dosimetric checks on the IF.
REFERENCES 1. 2. 3. 4. 5. 6.
7. 8. 9. 10. 11.
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GOST R 50325-92, Medical Devices: Dosimetric Methods in Performing Radiation Sterilization [in Russian]. GOST R ISO 11137-2000, Sterilizing Medical Products: Requirements for Validation and Current Monitoring. Radiation Sterilization [in Russian]. MI 2548-99, The State System of Measurements: Irradiation Facilities Containing Radionuclide Sources of Radiation for Sterilizing Medical Devices: Certification Methods [in Russian]. MI 2549-99, The State System of Measurements: Irradiation Facilities Containing Electron Accelerators for Sterilizing Medical Devices: Certification Methods [in Russian]. MI 2649-2001, The State System of Measurements: Absorbed Doses of Photon and Electron Radiation in the Establishment of Sterilizing and Maximum Permissible Doses for Devices: Measurement Methods [in Russian]. MI 2682-2001, The State System of Measurements: Metrological Support to Measurements of Absorbed Dose of Ionizing Radiation in Tests and in the Radiation Sterilization of Medical Devices: General Specifications [in Russian]. MI 2774-2002, The State System of Measurements: Methods of Using a GOST R 50325-92 “Medical Devices: Dosimetric Methods in Radiation Sterilization” [in Russian]. R. A. Abdulov et al., Khimiya Vysokhikh Energii, 36, No. 1, 26 (2002). PR 50.2.030-2001, The State System of Measurements: System for Accrediting Laboratories for Radiation Monitoring SARK): Basic Concepts [in Russian]. R 50.3.004-99, The GOST R Certification System: Analysis of the Production State in Certifying Products [in Russian]. GOST 2.114-95, ESKD: Technical Specifications [in Russian].
