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International standardization of radiation sterilization of health care products
)
Radiat. Phys. Chem. Vol. 42, Nos 4—6, pp. 867—871, 1993 Printed in Great Britain
0146-5724/93 $6.00 + 0.00 Pergamon Press Ltd
INTERNATIONAL STANDARDIZATION OF RADIATION STERILIZATION OF HEALTh CARE PRODUCFS James L. Whitby Department of Microbiology & Immunology, University of Western Ontario London, Ontario, Canada IN11~ODUCflON Working Group 2 of the International Standards Organizations/Technical Committee 198 (ISO/TC198/WG2) has prepared a Draft International Standard (DIS 11137.2), which has been reviewed, revised and recirculated for final comments, which will be reviewed and resolved at the next ISO meeting in London, UK, in November 1992. The revised Draft International Standard is contained in the first 16 pages of the document. The remaining 68 pages of the document consists of informative annexes on Device and Materials Qualification (Annex A, 7 pages), Dose-setting Methods of Radiation Sterilization (Annex B, 43 pages) and Dosimetry and Equipment Control (Annex C, 18 pages). The initial Draft International Standard, which was voted on during the period October 3, 1992 to March 19, 1992, and received a favourable vote, contained two further informative annexes. Annex B, Microbiological Methods for Irradiation Sterilization of Health Care Products, which was since removed, and Annex E, Further Readings: Papers on X-Ray Processing (Brehmsstrahlung), removed since x-ray processing has been added to the revised Standard. THE REVISED DRAFT STANDARD (D1S11137.2 Introduction There is a general Introduction which discusses the probabilistic nature of sterility.
~Q2~ The scope of the Standard has been expanded and now includes sterilization by x-rays in addition to electron beam and gamma irradiation. Where different requirements are necessary for the differing radiation sterilization processes, these differences are highlighted. Exclusions Facility design, operator training and radiation safety are not covered in the document. Additionally, neither the assessment of the suitability of product for its intended use nor the use of biological indicators are covered in the document. After sections for normative references, definitions, documentation and personnel, there come the two main sections of the document. Sterilization Process Validation (7 pages) The section on Sterilization Process Validation starts with a paragraph of general statements and then includes Figure 1, reproduced here, which includes all the subsequent paragraphs of the section. Throughout this section, there are important differences in the requirements for gamma, electron beam and x-ray facilities that are covered in the separate paragraphs as necessary. The paragraph that it seems most necessary to comment on is 6.2.2, Sterilization Dose Determination. For the selection of dose, there are requirements of a general knowledge of the number and resistance to radiation of the natural microbial population on
867
868
JAMES L. WI-IITBY
6.2 Product qualiflcainm 6.2.1 Product and packaging materiala evaluation
1
8.2.2 Sterilizaticm dma determination
6.3 lnMaflation quali5.cs~on 62.1 Eqidpment documentation
6.3.2 Eq~pmmnt tasting
6.3.3 Equipment eelilzation
___________
1
62.4 Irradiatcr dose map~zng
LI 8.4 Process qualification 6.4.1 Determination of product loading pattern
6.4.2 Product doss mapping __________
LI 6.5 Certification Documentation accumuiationj Review and approval
]
LI 6.6 Maintenance of validation 6.6.1 Calibration program
6.6.2 Irradiator requali&stioo
6.6.3 Sterilization dose auditing
P~gure1. A typical validation program
the product, and that the dose chosen shall be capable of achieving the pre-selected Sterility Assurance Level (SAL). One of two approaches are then to be taken. The first is to use one of the two methods, detailed in Annex B. These methods depend on testing the decline of the viable microbial population on the device as samples are exposed to increasing doses of radiation. The second is to use a sterilization dose of 25 kGy following substantiation of its appropriateness. There is need for access to competent and appropriate microbiological services and, until the ISO Standard for Microbiological Testing (Annex B of the first draft) is ready, users are referred to a document entitled “Microbiological Methods for Gamma Irradiation Sterilization of Medical Products” (Technical Information Report, AAMI TIR8, Arlington, VA, Association for the Advancement of Medical Instrumentation, 1991). Importantly, there is a need for access to a radiation facility capable of delivering accurate and precise doses ranging from 1 kGy upward. There are conditions imposed which, if not met, prevent the transfer of the sterilization dose determined in one facility to another, whether the facilities use the same or different radiation technologies. Most of the other requirements for calibrating, testing and documenting of equipment and for dose mapping, for process qualification, certification and maintenance of validation accord with what one would expect in such a document. Routine Process Control (4 pages) This section requires the establishment of a process specification with paragraphs on product handling, shipment and storage, and process control to ensure specifications are met. Process interruption is covered briefly and dosimetry is covered with respect to monitoring locations, frequency of monitoring and analysis of dosimetric readings. Process documentation consists of line by line statements as to what shall be recorded and reviewed by authorized officials and maintained.
8th International Meeting on Radiation Processing
Management and Control This section is very brief. Users are referred to ISO9001 and/or IS09002, whichever is applicable. THE INFORMATIVE ANNEXES Annex A - Product and Packaging Materials Qualification: Product and Packaging Materials Qualification contains general remarks on how the effects of radiation on materials can be tested and recommendations for accelerated aging studies in order to obtain more rapid information on the likely shelf-life of irradiated materials. There are then some useful Tables with general information on radiation stability of materials and tests that may be used for evaluating the effects of radiation on them. Annex B - Dose-Setting Methods for Radiation Sterilization: This section details two methods for determining the radiation sterilization dose for products and instructions for regular auditing of the appropriateness of the chosen sterilizing dose. The achievement of sterility by the irradiation process is the critical function required from the irradiation of products. It is relatively easy to interrupt the radiation sterilization process so that it is possible to follow the death of the microbial population on devices exposed to different doses of radiation. Both of the methods included in Annex B depend on irradiation of samples at doses where positive and negative samples may be expected in sterility tests. The observations obtained are used to establish a dose where either the whole device or a known proportion of that device has achieved a sterility assurance level of 10-2. From that point, in Method 1, a Table is used to obtain the appropriate sterilization dose. In Method 2, prescribed calculations are made to calculate the appropriate sterilization dose. Table I shows, in summary form, the sequential D 10 values used to obtain different 2sterility assurance sterility level is dictated assurance by levels the bioburden in the Table number for Method and in 1. Table The1,dose the D for i0~ 10 value in the 10-2 column would have to be multiplied by lo~(bioburden #) + 2 to yield the radiation dose appropriate to verif~’the achievement of a 10~sterility assurance level. If more than two positives are obtained at that dose, the Method cannot be used and Method 2 or another Method must be used. At the moment, we give no guidance on other Methods. From Table 1, it can be worked out that a sterilization dose of 24.9 kGy (2.2x5+3.3+3.4+3.6+3.6) kGy would be required for a bioburden of 1,000 organisms. Method 2 is more elaborate and requires more samples. The 10-2 sterility assurance level is established by taking 280 samples from each of three separate batches of product and irradiating 180 samples from each sample batch in batches of 20 in an incremental series of doses from 2.0-18.0 kGy. The doses must be delivered within specified limits and from the results obtained a series of calculations are made to find the dose at which 100 samples of a specified batch are to be irradiated. The number of positive sterility tests obtained when the 100 samples are irradiated is used to make further calculations which will yield an appropriate sterilizing dose. Method 2 should always yield a sterilizing dose. That dose may be lower than that obtained using Method 1 but with bioburdens more resistant than that postulated for Method 1, the dose will be higher. The principle used is to determine the slope of the complex interaction of lines that represents the overall D10 value for the microbial population on the device when that population on the device has already been reduced to an average of >3/device until it falls to 0.01/device. Table 2 shows the differences that might be expected between Methods 1 and 2 for a io.6 sterility assurance level, based on the examples worked in Annex B and assuming that the initial verification dose was the same. In practice in North America, Method I has proven more popular than Method 2 because it is simpler to perform and makes less use of resources. Audit for either Method is carried out by irradiating 100 samples at the dose calculated to be required to achieve a 10-2 sterility assurance level. Instructions are given for actions necessary when the audit results are unsatisfactory.
869
870
JAMES
L.
WI-IITBY
Annex C - Dosimetry and Eciuipment Control The bulk of this Annex deals with the many different methods of dosimetry available, and comments on the appropriateness and selection of dosimeter for different functions, such as reference standards, transfer standards and routine dosimetry. The Annex ends with a brief section on Equipment Control.
DISCUSSION The Draft International Standard is, overall, a helpful document and should be found useful by manufacturers and regulators. However, the methods of dose determination so far recommended are most suitable for products which are made in large batches. There are many devices marketed and more being developed where the potential for use is limited but which are of high medical value. Some of these may well contain components that make them unsuitable for radiation sterilization, but the ability of radiation to penetrate to occluded areas that may be very hard to reach with other sterilization methods will make it a preferred process where the device is sufficiently stable in the sterilization process. There is clearly a need, therefore, to develop methods for validating the radiation sterilization process for devices prepared in small numbers and it is to be hoped that these will be developed and approved before too long. Table 1. D
1~Values for Method 1
Microbial Bioburden
M
D * ax. 10 Value allowed to achieve 102 SAL
D10* Value for Resident Population
-.io~SAL
-40~SAL
-.10~SAL
~.io6 ~AL
0.1
1.3
1.7
2.4
2.7
3.0
1.0
1.5
2.3
2.8
3.0
3.2
10.0
1.8
2.8
3.0
3.3
3.4
100.0
2.0
3.1
3.2
3.4
3.6
1,000
2.2
3.3
3.4
3.6
3.6
10,000
2.4
3.5
3.5
3.8
3.7
100,000
2.5
3.6
3.7
3.8
3.8
All D10 values are expressed in kGy.
Table 2. Comparison of Methods 1 and 2 Based on Worked Examples in ISO/DIS 11137.2 Bioburden
(Method 1)
Verification Dose (kGy)
Sterilization Dose(kGy)
Method 1
Method 2
Method 1
Method 2
227
9.0
9.0
22.5
21.8
520
6.3
6.3
13.3
12.7
11
5.4
5.4
17.8
14.8
8th International Meeting on Radiation Processing
REFERENCES Association for the Advancement of Medical Instrumentation Technical Information Report (1991) “Microbiological Methods for Gamma Irradiation Sterilization’, Arlington, VA, USA. International Standards Organization, Standard 9001 (1987) “Quality Systems - Model for Quality Assurance in Design/Development Production, Installation and Servicing’, Geneva, Switzerland. International Standards Organization, Standard 9002 (1987) ‘Quality Systems - Model for Quality Assurance in Production and Installation’, Geneva, Switzerland. International Standards Organization Technical Committee 198 (1992) Revised Draft International Standard on ‘Sterilization of Health Care Products, Requirements for Validation and Routine Control - Radiation Sterilization’, Arlington, VA, USA.
871
Radiat. Phys. Chem. Vol. 42, Nos 4—6, pp. 867—871, 1993 Printed in Great Britain
0146-5724/93 $6.00 + 0.00 Pergamon Press Ltd
INTERNATIONAL STANDARDIZATION OF RADIATION STERILIZATION OF HEALTh CARE PRODUCFS James L. Whitby Department of Microbiology & Immunology, University of Western Ontario London, Ontario, Canada IN11~ODUCflON Working Group 2 of the International Standards Organizations/Technical Committee 198 (ISO/TC198/WG2) has prepared a Draft International Standard (DIS 11137.2), which has been reviewed, revised and recirculated for final comments, which will be reviewed and resolved at the next ISO meeting in London, UK, in November 1992. The revised Draft International Standard is contained in the first 16 pages of the document. The remaining 68 pages of the document consists of informative annexes on Device and Materials Qualification (Annex A, 7 pages), Dose-setting Methods of Radiation Sterilization (Annex B, 43 pages) and Dosimetry and Equipment Control (Annex C, 18 pages). The initial Draft International Standard, which was voted on during the period October 3, 1992 to March 19, 1992, and received a favourable vote, contained two further informative annexes. Annex B, Microbiological Methods for Irradiation Sterilization of Health Care Products, which was since removed, and Annex E, Further Readings: Papers on X-Ray Processing (Brehmsstrahlung), removed since x-ray processing has been added to the revised Standard. THE REVISED DRAFT STANDARD (D1S11137.2 Introduction There is a general Introduction which discusses the probabilistic nature of sterility.
~Q2~ The scope of the Standard has been expanded and now includes sterilization by x-rays in addition to electron beam and gamma irradiation. Where different requirements are necessary for the differing radiation sterilization processes, these differences are highlighted. Exclusions Facility design, operator training and radiation safety are not covered in the document. Additionally, neither the assessment of the suitability of product for its intended use nor the use of biological indicators are covered in the document. After sections for normative references, definitions, documentation and personnel, there come the two main sections of the document. Sterilization Process Validation (7 pages) The section on Sterilization Process Validation starts with a paragraph of general statements and then includes Figure 1, reproduced here, which includes all the subsequent paragraphs of the section. Throughout this section, there are important differences in the requirements for gamma, electron beam and x-ray facilities that are covered in the separate paragraphs as necessary. The paragraph that it seems most necessary to comment on is 6.2.2, Sterilization Dose Determination. For the selection of dose, there are requirements of a general knowledge of the number and resistance to radiation of the natural microbial population on
867
868
JAMES L. WI-IITBY
6.2 Product qualiflcainm 6.2.1 Product and packaging materiala evaluation
1
8.2.2 Sterilizaticm dma determination
6.3 lnMaflation quali5.cs~on 62.1 Eqidpment documentation
6.3.2 Eq~pmmnt tasting
6.3.3 Equipment eelilzation
___________
1
62.4 Irradiatcr dose map~zng
LI 8.4 Process qualification 6.4.1 Determination of product loading pattern
6.4.2 Product doss mapping __________
LI 6.5 Certification Documentation accumuiationj Review and approval
]
LI 6.6 Maintenance of validation 6.6.1 Calibration program
6.6.2 Irradiator requali&stioo
6.6.3 Sterilization dose auditing
P~gure1. A typical validation program
the product, and that the dose chosen shall be capable of achieving the pre-selected Sterility Assurance Level (SAL). One of two approaches are then to be taken. The first is to use one of the two methods, detailed in Annex B. These methods depend on testing the decline of the viable microbial population on the device as samples are exposed to increasing doses of radiation. The second is to use a sterilization dose of 25 kGy following substantiation of its appropriateness. There is need for access to competent and appropriate microbiological services and, until the ISO Standard for Microbiological Testing (Annex B of the first draft) is ready, users are referred to a document entitled “Microbiological Methods for Gamma Irradiation Sterilization of Medical Products” (Technical Information Report, AAMI TIR8, Arlington, VA, Association for the Advancement of Medical Instrumentation, 1991). Importantly, there is a need for access to a radiation facility capable of delivering accurate and precise doses ranging from 1 kGy upward. There are conditions imposed which, if not met, prevent the transfer of the sterilization dose determined in one facility to another, whether the facilities use the same or different radiation technologies. Most of the other requirements for calibrating, testing and documenting of equipment and for dose mapping, for process qualification, certification and maintenance of validation accord with what one would expect in such a document. Routine Process Control (4 pages) This section requires the establishment of a process specification with paragraphs on product handling, shipment and storage, and process control to ensure specifications are met. Process interruption is covered briefly and dosimetry is covered with respect to monitoring locations, frequency of monitoring and analysis of dosimetric readings. Process documentation consists of line by line statements as to what shall be recorded and reviewed by authorized officials and maintained.
8th International Meeting on Radiation Processing
Management and Control This section is very brief. Users are referred to ISO9001 and/or IS09002, whichever is applicable. THE INFORMATIVE ANNEXES Annex A - Product and Packaging Materials Qualification: Product and Packaging Materials Qualification contains general remarks on how the effects of radiation on materials can be tested and recommendations for accelerated aging studies in order to obtain more rapid information on the likely shelf-life of irradiated materials. There are then some useful Tables with general information on radiation stability of materials and tests that may be used for evaluating the effects of radiation on them. Annex B - Dose-Setting Methods for Radiation Sterilization: This section details two methods for determining the radiation sterilization dose for products and instructions for regular auditing of the appropriateness of the chosen sterilizing dose. The achievement of sterility by the irradiation process is the critical function required from the irradiation of products. It is relatively easy to interrupt the radiation sterilization process so that it is possible to follow the death of the microbial population on devices exposed to different doses of radiation. Both of the methods included in Annex B depend on irradiation of samples at doses where positive and negative samples may be expected in sterility tests. The observations obtained are used to establish a dose where either the whole device or a known proportion of that device has achieved a sterility assurance level of 10-2. From that point, in Method 1, a Table is used to obtain the appropriate sterilization dose. In Method 2, prescribed calculations are made to calculate the appropriate sterilization dose. Table I shows, in summary form, the sequential D 10 values used to obtain different 2sterility assurance sterility level is dictated assurance by levels the bioburden in the Table number for Method and in 1. Table The1,dose the D for i0~ 10 value in the 10-2 column would have to be multiplied by lo~(bioburden #) + 2 to yield the radiation dose appropriate to verif~’the achievement of a 10~sterility assurance level. If more than two positives are obtained at that dose, the Method cannot be used and Method 2 or another Method must be used. At the moment, we give no guidance on other Methods. From Table 1, it can be worked out that a sterilization dose of 24.9 kGy (2.2x5+3.3+3.4+3.6+3.6) kGy would be required for a bioburden of 1,000 organisms. Method 2 is more elaborate and requires more samples. The 10-2 sterility assurance level is established by taking 280 samples from each of three separate batches of product and irradiating 180 samples from each sample batch in batches of 20 in an incremental series of doses from 2.0-18.0 kGy. The doses must be delivered within specified limits and from the results obtained a series of calculations are made to find the dose at which 100 samples of a specified batch are to be irradiated. The number of positive sterility tests obtained when the 100 samples are irradiated is used to make further calculations which will yield an appropriate sterilizing dose. Method 2 should always yield a sterilizing dose. That dose may be lower than that obtained using Method 1 but with bioburdens more resistant than that postulated for Method 1, the dose will be higher. The principle used is to determine the slope of the complex interaction of lines that represents the overall D10 value for the microbial population on the device when that population on the device has already been reduced to an average of >3/device until it falls to 0.01/device. Table 2 shows the differences that might be expected between Methods 1 and 2 for a io.6 sterility assurance level, based on the examples worked in Annex B and assuming that the initial verification dose was the same. In practice in North America, Method I has proven more popular than Method 2 because it is simpler to perform and makes less use of resources. Audit for either Method is carried out by irradiating 100 samples at the dose calculated to be required to achieve a 10-2 sterility assurance level. Instructions are given for actions necessary when the audit results are unsatisfactory.
869
870
JAMES
L.
WI-IITBY
Annex C - Dosimetry and Eciuipment Control The bulk of this Annex deals with the many different methods of dosimetry available, and comments on the appropriateness and selection of dosimeter for different functions, such as reference standards, transfer standards and routine dosimetry. The Annex ends with a brief section on Equipment Control.
DISCUSSION The Draft International Standard is, overall, a helpful document and should be found useful by manufacturers and regulators. However, the methods of dose determination so far recommended are most suitable for products which are made in large batches. There are many devices marketed and more being developed where the potential for use is limited but which are of high medical value. Some of these may well contain components that make them unsuitable for radiation sterilization, but the ability of radiation to penetrate to occluded areas that may be very hard to reach with other sterilization methods will make it a preferred process where the device is sufficiently stable in the sterilization process. There is clearly a need, therefore, to develop methods for validating the radiation sterilization process for devices prepared in small numbers and it is to be hoped that these will be developed and approved before too long. Table 1. D
1~Values for Method 1
Microbial Bioburden
M
D * ax. 10 Value allowed to achieve 102 SAL
D10* Value for Resident Population
-.io~SAL
-40~SAL
-.10~SAL
~.io6 ~AL
0.1
1.3
1.7
2.4
2.7
3.0
1.0
1.5
2.3
2.8
3.0
3.2
10.0
1.8
2.8
3.0
3.3
3.4
100.0
2.0
3.1
3.2
3.4
3.6
1,000
2.2
3.3
3.4
3.6
3.6
10,000
2.4
3.5
3.5
3.8
3.7
100,000
2.5
3.6
3.7
3.8
3.8
All D10 values are expressed in kGy.
Table 2. Comparison of Methods 1 and 2 Based on Worked Examples in ISO/DIS 11137.2 Bioburden
(Method 1)
Verification Dose (kGy)
Sterilization Dose(kGy)
Method 1
Method 2
Method 1
Method 2
227
9.0
9.0
22.5
21.8
520
6.3
6.3
13.3
12.7
11
5.4
5.4
17.8
14.8
8th International Meeting on Radiation Processing
REFERENCES Association for the Advancement of Medical Instrumentation Technical Information Report (1991) “Microbiological Methods for Gamma Irradiation Sterilization’, Arlington, VA, USA. International Standards Organization, Standard 9001 (1987) “Quality Systems - Model for Quality Assurance in Design/Development Production, Installation and Servicing’, Geneva, Switzerland. International Standards Organization, Standard 9002 (1987) ‘Quality Systems - Model for Quality Assurance in Production and Installation’, Geneva, Switzerland. International Standards Organization Technical Committee 198 (1992) Revised Draft International Standard on ‘Sterilization of Health Care Products, Requirements for Validation and Routine Control - Radiation Sterilization’, Arlington, VA, USA.
871