2011 JSDT Standard on the Management of Endotoxin Retentive Filter for Dialysis and Related Therapies (2013)

The contamination of the fluids for dialysis therapy is an important factor that deteriorates the biocompatibility of HD and related therapies. In particular, microbiological contamination is considered to be an important factor that causes dialysis amyloidosis and malnutrition due to the strong physiological activity of endotoxin (ET) 1. High-performance dialyzers are more frequently used in Japan than in other countries; hence, dialysis facilities in Japan are particularly affected by the bacterial contamination of dialysis fluid when it occurs. Moreover, most of the dialysis facilities in Japan use central dialysis fluid delivery systems (CDDSs), which are considered to be less effective in suppressing microbiological contamination than systems used in other countries, which adopt single-patient dialysis machines. Although ET retentive filters (ETRFs) are indispensable for increasing the microbiological quality of dialysis fluid, they may be a source of contamination if not appropriately handled 2. Therefore, the installation of an ETRF, which is the final safety step in the purification of dialysis fluid, does not always guarantee the purity of the final fluid. Rather, it is important to manage the quality of dialysis fluid that passes through the ETRF. In 2008, the Japanese Society for Dialysis Therapy (JSDT) established the Microbiological Quality Standard for Dialysis Fluid, which merely states that users of ETRFs should handle them according to the manufacturer's instructions 3. To date, however, no consistent standard for handling ETRFs has been given by the Japan Medical Devices Manufacturers Association. ETRFs from different manufacturers have been deployed in various dialysis facilities using procedures at the discretion of each facility. Considering this situation, the JSDT has recommended that the management of ETRFs should be standardized and has formulated the JSDT original standard for managing ETRFs with the aim of supplying safe and stable dialysis fluid. The Working Group on the Development of the ETRF Management Standard consisted of members of the JSDT Subcommittee of Scientific Academy for the Function and Efficiency of Blood Purification Therapy as well as representatives of the Japan Medical Devices Manufacturers Association and the Japan Association for Clinical Engineers. To the best of our knowledge, there are few reports with high-level evidence regarding ETRF management. Moreover, CDDSs are predominantly used in Japan and rarely used in the US and Europe, so that makes it extremely difficult to refer to overseas evidence and standards on ETRF management. Therefore, we summarized the opinion of experts based on the results of joint research with related societies, including the Japan Association for Clinical Engineers and the Japanese Society for Hemodiafiltration, as well as the standards presented by the Japan Medical Devices Manufacturers Association and the dialysis-related International Organization for Standardization (ISO) standards. We then formulated the ETRF Management Standard through a Consensus Conference at the 55th Annual Meeting of the JSDT. 1.1. Objective The objective of this ETRF Management Standard is to ensure a regular supply of ultrapure dialysis fluid specified in the "Standard on Microbiological Management of Fluids for Hemodialysis and Related Therapies by the Japanese Society for Dialysis Therapy 2008" 3-5. This ETRF Management Standard will enable ETRF manufacturers to produce ETRFs with the required bacterial and ET retentive performance before shipping and will provide dialysis facilities with safe and effective methods for using and managing ETRFs. 1.2. Inclusions and exclusions This ETRF Management Standard is applicable to ETRFs installed immediately before the dialyzer in the dialysis bedside console of CDDSs or single-patient dialysis machines. Therefore, large-capacity ETRFs installed along a production line of dialysis fluids for multiple patients are excluded. Moreover, ETRFs used as parts of dialysis machines that have been approved as medical devices are also not covered by this ETRF Management Standard because they should have been validated by the manufacturer. Terms and definitions are summarized in Table 1. This chapter explains the Standard on microbiological management of fluids for HD and related therapies by the Japanese Society for Dialysis Therapy 2008 3-5 in order to help readers understand the ETRF Management Standard. 4.1. Microbiological quality management of dialysis fluids based on validation The microbiological quality of dialysis fluids shall be managed using a validated system for producing dialysis fluids. Dialysis facilities also serve as the manufacturers of dialysis fluid and shall be responsible for ensuring the quality of dialysis fluid. Therefore, dialysis facilities must assign persons in charge of product quality. Each step in the purification process of dialysis fluid must be managed through a validated system to maintain quality. 4.2. Microbiological quality standard for dialysis fluids Bacteria: <100 colony forming units (CFU)/mL Bacteria: <100 CFU/mL Bacteria: <0.1 CFU/mL Sterile and nonpyrogenic Bacteria: <10−6 CFU/mL ET: <0.001 EU/mL (lower than the detection limit). The action level (i.e. the contamination level at which steps should be taken to interrupt the trend toward higher, unacceptable levels) shall be set depending on the conditions of each facility. Typically, 50% of the maximum allowable level is recommended by the JSDT. However, the action level cannot be set for a bacterial count lower than 10−6 CFU/mL and an ET level lower than 0.001 EU/mL (lower than the detection limit). The standard values for the online-prepared substitution fluids are theoretical values obtained by validation. Therefore, the dialysis fluid immediately before the final ETRF must be the ultrapure dialysis fluid (UPD). An ETRF with logarithmic reduction values (LRVs) of 3 for ET and 7 for bacteria shall be installed in the final step of preparing substitution fluid to ensure that the fluid will have a bacterial count lower than 10−6 CFU/mL. 4.3. Indications for dialysis systems based on quality of dialysis fluids 4.4. Standard for quality management of dialysis fluids Culture media: Basically, agar plate media, such as R2A or TGEA media, or media that have been confirmed to have an equivalent sensitivity Cultivation conditions (R2A and TGEA): 17–23°C for 7 days 4.4.3. Sampling dates Sampling should be carried out before the start of dialysis performed after the maximal treatment interval (commonly Monday for patients treated on a Monday–Wednesday–Friday schedule). ET: Every 2 weeks until the system stabilizes After the system has been validated by the person in charge of preparing dialysis fluid, online-prepared substitution fluid from each dialysis machine should be monitored monthly. Bacteria: Dialysis fluid immediately before the final ETRF should maintain their microbiological quality at values for ultrapure dialysis fluid. The dialysis fluid immediately before the final ETRF and the online prepared substitution fluids in dialysis machines should be monitored every 2 weeks until the system stabilizes. After the system has been validated by the person in charge of preparing dialysis fluid, the above fluids in at least two dialysis machines should be monitored monthly in turn so that each machine is tested at least once a year. 5.1. Endotoxin retentive filters generally refer to the filters used to remove ET and microorganisms from dialysis fluid for their purification. This ETRF Management Standard addresses the management of an ETRF installed immediately before the dialyzer in a bedside dialysis console. 5.2. An ETRF should maintain LRVs of at least 2 for ET and at least 4 for bacteria to obtain ultrapure dialysis fluid, assuming that the dialysis fluid before the ETRF maintains its microbiological quality at values for standard dialysis fluid specified in the JSDT Standard. In this ETRF Management Standard, ETRFs refer to the filters used to purify dialysis fluids and to prevent the passage of bacteria and ET. The JSDT Standard is consistent with the ISO Standard although there are differences in the definition of ETRFs (see Supplementary note A in Chapter 8). Note that ETRFs are defined in 5.1 of the ETRF Management Standard as follows: "ETRFs generally refer to the filters used to remove ET and microorganisms from dialysis fluids for their purification." In this ETRF Management Standard, it is assumed that facilities have already attained the allowable levels for dialysis water and standard dialysis fluid (i.e. bacterial count < 100 CFU/mL and ET level < 0.050 EU/mL), as determined by the JSDT and given in 4.2. Therefore, the ETRF installed in the final line should produce dialysis fluids with allowable levels for ultrapure dialysis fluid (i.e. bacterial count < 0.1 CFU/mL and ET level < 0.001 EU/mL [lower than the detection limit]). Considering the safety factor, the required performance of ETRF is specified in 5.2 ("An ETRF should maintain LRVs of at least 2 for ET and at least 4 for bacteria to obtain ultrapure dialysis fluid, assuming that the dialysis fluid before the ETRF maintains its microbiological quality at values for standard dialysis fluid specified in the JSDT Standard."). ETRFs have been developed to separate ET and bacteria from dialysis fluids and remove these contaminants based on the principles of filtration and adsorption or adherence. Therefore, the evaluation of ETRF performance should be based on conventional separation principles of ultrafiltration and microfiltration. In addition to separation capability, the durability of ETRFs should also be taken into consideration. 6. Voluntary Standard Established by Japan Medical Devices Manufacturers Association 6.1. The performance of ETRFs should be tested in terms of their capability to remove bacteria and ET. 6.2. Brevundimonas diminuta should be used in the bacterial test. Culture conditions should be the same as those specified in JIS K 3823. The Japanese Pharmacopoeia Reference Standard ET or certified ET should be used in the ET test. 6.3. Bacterial and ET test samples should be prepared so that they have a bacterial count of at least 106 CFU/mL and an ET level of at least 10 EU/mL, respectively. 6.4. The retentive performance of an ETRF should be expressed as LRV, which is given as an integer (e.g. "LRV of at least 00"). The methods for determining bacterial and ET retentive performance of ultrafiltration modules are specified in JIS (bacteria, JIS K 3823 7; ET, JIS K 3824 8). Following these standards, the methods for determining the bacterial and ET retentive performance of ETRFs are summarized in the Voluntary Standards by the Japan Medical Devices Manufacturers Association and were published on its website in July 2010 (see Supplementary note B in Chapter 8). Brevundimonas diminuta (ATCC 19146 or NBRC 14213) should be used in the bacterial test. Culture conditions for the bacterial test solutions prepared before the test and the solution sampled in the test should be the same as those specified in JIS K 3823. ET used in the test should be the Japanese Pharmacopoeia Reference Standard ET or commercially available ET certificated using the Reference Standard ET. For both the bacterial and ET tests, test solutions should be prepared by diluting the original concentrated solutions to the predetermined concentration. The performance of an ETRF is expressed as LRV. For bacteria, LRV is given by the common logarithm of the ratio of the bacterial count in a 1000-mL test solution to that in a 1000-mL filtrate. For ET, LRV is given by the common logarithm of the ratio of the ET level in a test solution to that in a filtrate. LRV should be expressed as an integer for both bacteria and ET. LRV is highly dependent on the bacterial count or ET level in the test solution, as is clear from the equation for calculating LRV. Therefore, it is meaningless to compare the performance of ETRFs on the basis of the calculated LRV. However, LRV can be used as an index that indicates whether the ETRF has a certain level of performance. Specifically, the bacterial count and ET level in a test solution are specified so that the LRVs are at least 8 for bacteria and at least 3 for ET, considering slight variations in the procedure used to prepare test solutions. 7.1. Installation of ETRFs 7.1.1. Manufacturers' instructions for the ETRF installation shall be observed. 7.1.2. To obtain ultrapure dialysis fluid sample, the dialysis fluid at the inlet of the ETRF should be maintained within the allowable level for standard dialysis fluid specified in the JSDT Standard. Currently, commercially available ETRFs have LRVs of at least 3 for ET and at least 7 for bacteria 9. Therefore, when an ETRF is installed and the LRVs for standard dialysis fluid specified in the 2008 JSDT Standard 5 (i.e. bacterial count < 100 CFU/mL and ET level < 0.050 EU/mL) are maintained at the inlet of the ETRF, it is possible to achieve the allowable levels for ultrapure dialysis fluid (i.e. bacterial count < 0.1 CFU/mL and ET level < 0.001 EU/mL). Basically, these values are recommended at the inlet line of the dialyzer after filtration for all HD therapies in accordance with the abovementioned Standard. 7.2. Cleaning and disinfection of ETRFs 7.2.1. Dialysis machines shall be cleaned and disinfected following the methods recommended by the manufacturer. 7.2.2. The inside and outside of hollow fibers shall be cleaned and disinfected during the cleaning and disinfection of ETRFs. 7.2.3. When cleaning and disinfection methods other than those recommended by the manufacturer are used, the durability of ETRFs shall be tested at each facility to confirm their safety. The performance of ETRFs is affected by factors related to cleaning and disinfection, such as the type of cleaning and disinfection agents, concentration, and the duration of disinfection. Hence, users must adopt the cleaning and disinfection methods recommended by the manufacturer. The manufacturer measures the LRVs of ETRFs that have been cleaned and disinfected by the recommended methods in durability tests. The recommended duration of use is based on an appropriate safety margin, thus guaranteeing the ETRF safety. Because ETRFs are generally used for dead-end filtration, the bacterial count and ET level in the filtered fluid may become high when bacteria and ET accumulate on the membrane surface. Therefore, ETRFs should be disinfected and flushed to deactivate and remove bacteria and ET. Both sides of hollow fibers in ETRF should be flushed with a sufficient amount of water at a high flow rate during cleaning and disinfection. When cleaning and disinfection methods other than those recommended by the manufacturer are adopted, the Dialysis Equipment Safety Management Committee shall be responsible for the safety of ETRFs. To ensure ETRF safety, test results on the persistence of cleaning and disinfection agents and the physical and chemical resistance of ETRFs to the agents should be taken into consideration, including the LRVs obtained in a durability test. It is recommended that cleaning and disinfection methods should be assessed by the Dialysis Equipment Safety Management Committee in consultation with the manufacturers of cleaning and disinfection agents and ETRFs. 7.3. Duration of ETRF use 7.3.1. The duration of ETRF use recommended by the manufacturer shall be observed when the dialysis fluid flowing into the ETRF cannot be maintained within the allowable levels for standard dialysis fluids as specified in the JSDT Microbiological Quality Standard for Dialysis Fluids. 7.3.2. The duration of ETRF use should be determined by the Dialysis Equipment Safety Management Committee when the standard dialysis fluid falls within allowable levels. Endotoxin retentive filter manufacturers carry out durability tests on ETRFs and recommend the duration of their use by considering an appropriate safety margin that guarantees the safety of ETRFs. However, leakage due to enlarged pores on the membrane cannot be detected in a leakage test, which is the sole monitoring method for ETRFs. Therefore, the duration of use recommended by the manufacturer must be observed when dialysis fluid at the inlet of the ETRF cannot be maintained within the allowable levels for standard dialysis fluids (ET level < 0.05 EU/mL, bacterial count < 100 CFU/mL). When facilities that maintain at least the allowable levels for standard dialysis fluids at the inlet of ETRF use ETRFs longer than recommended by the manufacturer, the Dialysis Equipment Safety Management Committee shall be responsible for the safety of the ETRFs. To ensure ETRF safety, it is recommended that facilities not only maintain the required LRVs by performing a durability test under their own conditions of ETRF use but also examine the duration of use in consultation with the manufacturer with consideration for the physical and chemical durability of materials used for the membranes and module cases. 7.4. Monitoring and durability test of ETRFs 7.4.1. When ETRFs are used under conditions other than those recommended by the manufacturer, their durability shall be tested at each facility to confirm their safety. 7.4.2. The durability test of ETRFs at each facility shall be performed using randomly samples at the of ETRFs. The durability test of ETRFs at each facility shall be performed by following the method in 6.1. When ET in water at each facility is used for test the solutions should be prepared to have an ET level of at least 10 ETRFs used to obtain ultrapure dialysis fluid shall the in 5.2. When facilities use disinfection agents and methods other than those recommended by the manufacturer, the durability of ETRFs must be tested at each facility. Hence, a method that can be at is Although the standard ET used in the test of ETRF performance from the bacteria in dialysis fluids at facilities are Therefore, a durability test using ET from water at each facility may be this is and can be performed Note that the and level of ET in this method may be different from those in the test method in Chapter 6. of ETRF management When ETRFs are used, the cleaning and disinfection shall be including the concentration, duration and of each cleaning and disinfection used, as well as other should be for at least 3 dialysis fluid delivery systems for the of dialysis systems in This ETRF Management Standard the ETRFs installed immediately before the dialyzer in bedside dialysis of CDDSs and single-patient dialysis machines. Hence, it is to related to the cleaning and disinfection such as the concentration, duration and of each cleaning and disinfection used, as well as on the management of ETRFs (i.e. ETRF installation date, and and related must be for at least 3 after their or after the of the ETRFs in accordance with the 2008 JSDT Microbiological Quality Standard for Dialysis Fluids. However, according to the of the Japanese Medical are to a for related to such as test and other than in charge of managing the safety of dialysis fluids should and manage the and them to the Dialysis Equipment Safety Management for of ETRF Management Standard of ultrapure dialysis fluid and ETRF the by 10 in it has been that bacterial contamination of dialysis fluid is a of not only dialysis but also such as dialysis-related installed ultrafiltration filters to produce ultrapure dialysis fluid, thus in the of dialysis-related dialysis have the of the bacterial contamination of dialysis fluid and the of ETRFs for the effective of 10 to the dialysis fluid that through the ETRFs as but not the quality required for In determined the theoretical level for online-prepared substitution fluids to be 10−6 CFU/mL during the of of online To achieve this they specified the ET level and bacterial count required for the dialysis fluid before the final ETRF to be lower than the detection and which were defined as the allowable levels for ultrapure dialysis fluid. Because conventional ETRFs have LRVs of 3 for ET and 7 for bacteria, the level of bacteria for online-prepared substitution fluids and the quality of the fluids can be maintained when an contamination occurs. the definition of has been established as a dialysis fluid with an ET level lower than the detection and a bacterial count lower than CFU/mL. However, these levels were considered as merely for preparing online substitution fluids. dialysis fluid as an important for dialysis fluids only after the were published in dialysis fluid also in the JSDT Microbiological Quality Standard for Dialysis Fluids 3-5. assumed that the final ETRF used for preparing online substitution fluid be and maintain LRVs for ET and bacteria equivalent to those of a ETRF. ETRFs used to prepare ultrapure dialysis fluid are in all countries, thus an appropriate ETRF management standard to the of ultrapure dialysis fluid. of ETRF Management Standard for CDDSs dialysis fluid delivery systems generally of devices by or multiple manufacturers and have been considered to microbiological this the JSDT the of bacterial contamination of dialysis fluids at the of The results that of the dialysis facilities attained an ET level of less than EU/mL in dialysis fluid, that the quality of dialysis fluid in CDDSs in Japan high on a 2. However, only of the dialysis facilities carried out a test to the ET level at least which recommended in the ISO standard under at that Moreover, only of the dialysis facilities carried out a test to the bacterial and the test carried out less than once a However, these results have In the ETRFs were also ETRFs were used in of dialysis and of the dialysis bedside Japan were with ETRFs. The ET level and bacterial count in dialysis fluid for facilities that installed ETRFs to be lower than those for facilities not using the of ETRFs for dialysis fluid. However, facilities not using ETRFs also an ET level lower than the detection and a bacterial count lower than 0.1 contamination observed in facilities using ETRFs 2. results that the ETRFs be the of dialysis fluid contamination at an appropriate ETRF management of JSDT on ETRFs Bacteria: <100 CFU/mL Bacteria: <100 CFU/mL Bacteria: <0.1 CFU/mL Bacteria: <10−6 CFU/mL ET: <0.001 EU/mL (lower than the detection Endotoxin retentive filters are defined as filters used to purify dialysis water and dialysis fluids. ETRFs are also used to prepare substitution fluid the LRVs of the ETRF must be confirmed by determining the bacterial retentive performance using the method in JIS K 3823 7 and the ET retentive performance using the method in JIS K 3824 of ISO on ETRFs filter used to remove ET and microorganisms from dialysis water or dialysis fluid The performance of an ETRF is expressed as LRV. Voluntary Standard on for ETRF by Japan Medical Devices Manufacturers Association The Japan Medical Devices Manufacturers Association has the methods used to the performance of ETRFs used as of dialysis The Japan Medical Devices Manufacturers Association has formulated the following Voluntary Standard on the methods for determining the bacterial and ET retentive performance with the aim of dialysis fluids. for determining bacterial retentive performance of ETRFs 1. This Standard the methods for determining the bacterial retentive performance of ETRFs using ETRFs are used as of dialysis bedside single-patient dialysis and dialysis systems to remove bacteria from dialysis water or dialysis fluids. 2. Terms and definitions The terms and definitions used in this Standard are as filters (ETRFs) used to remove bacteria and ET from dialysis water or dialysis fluids Bacterial retentive performance test bacterial count in test solution test bacterial count in 3. and media diminuta 19146 or NBRC should be used as the test Japanese Pharmacopoeia water for ET test or water that has been to and then through a membrane with a less than or to the membrane of the ETRF tested media used for bacterial count available media can also be used for The agar media used for the bacterial count should be as agar This should be prepared in accordance with the manufacturer's agar This should be prepared in accordance with the manufacturer's for bacterial retentive performance The system for bacterial retentive performance should be as 4.1. and of system for bacterial logarithmic reduction The system should a a an ETRF, these devices including a a a and used for A line can also be set in the system to the amount of water to the ETRF or the test bacterial solution should be of such as or The system should be and and water should be from the The system should also prevent contamination by bacteria from the outside and the test an of the system 5.1. of test bacterial solutions a concentrated bacterial solution as in JIS K 3823. water in into a predetermined by the concentrated bacterial solution, thus the test bacterial the test bacterial solution to have a bacterial count of 106 CFU/mL or 6. The test procedure is given 6.1. water in into a 6.2. the and set the test conditions as The at the ETRF inlet should be set and can be within the at ETRF inlet at ETRF can be considered to be when the of the for the is to the The flow rate should be set at which is the standard flow rate for dialysis fluid or within of the maximum allowable flow rate for the ETRF. The flow rate can be at the of the ETRF. 6.3. a the filtration of water in the After at least of water has been obtain a of the and the bacterial count in the 6.4. the concentrated bacterial solution to the and the solution in the to obtain a bacterial count of 106 CFU/mL or When at least 10 has after the addition of the concentrated bacterial solution, an 10 of the test bacterial least 10 is required to the test bacterial solution The solution in the should be using a line or by other The should be sampled after the fluid in the line has been by the filter the test bacterial solution in the dead-end and of the to the bacterial count in the The should be sampled using a the with the solution, to the during which the sampled is to the the bacterial count cannot be immediately after the sampled at 5 and start the within the bacterial count in the sampled filtrate. In the of bacterial the membrane filtration method using a filter with a than is The used should then be on a agar or conventional agar at for test bacterial count in test solution test bacterial count in LRV for bacteria on the test particularly the bacterial count in the test When the bacterial count is it is possible to LRV by assuming B 1. to be The following should be Bacterial count Bacterial obtained in the test, test bacterial solution, and specified in 6. Bacterial retentive performance LRV for bacteria for determining ET retentive performance of ETRFs 1. This Standard the methods for determining the ET retentive performance of ETRFs using test solutions that ET from ETRFs are used as of dialysis bedside single-patient dialysis and dialysis systems to remove ET from dialysis water or dialysis fluids. 2. Terms and definitions The terms and definitions used in this Standard are as Endotoxin retentive filters (ETRFs) used to remove bacteria and ET from dialysis water or dialysis fluids ET retentive performance ET level in test solution ET level in ET solution with an ET level of at least EU/mL obtained using Japanese Pharmacopoeia Reference Standard ET or commercially available ET certificated using the Reference Standard ET ET solution A solution with an ET level of at least 10 EU/mL that is obtained by diluting concentrated ET solution with water 3. ET and ET: Japanese Pharmacopoeia Reference Standard ET or commercially available ET certificated using the Reference Standard ET Japanese Pharmacopoeia water for ET test or water that has been to then through a membrane with a less than or to the membrane of the ETRF for ET retentive performance The system for ET retentive performance should be as 4.1. and of system for endotoxin logarithmic reduction The system should a a an ETRF, these devices including a a a and used for A line can also be set in the system to the amount of water to the ETRF or the test ET solution should be of such as or The system should be and and water should be from the The system should also prevent contamination by bacteria from the outside and the test solution 2 an of the system 5.1. of ET solution The ET solution used in the test should be prepared as Japanese Pharmacopoeia Reference Standard ET or commercially available ET certificated using the Reference Standard ET. the test solution to have an ET level of at least 10 an of the test solution to ET level by an method or specified in of the Japan Pharmacopoeia test ET 6. The test procedure is given 6.1. water in into a 6.2. the and set the test conditions as The at the ETRF inlet should be set and can be within the at ETRF inlet at ETRF can be considered to be when the of the for the is to the The flow rate should be set at which is the standard flow rate for dialysis fluid, or within of the maximum allowable flow rate for the ETRF. The flow rate can be at the of the ETRF. 6.3. a the filtration of water in the After at least of water has been obtain a of 10 A for is that can be at for at least or a commercially available and the ET level in the 6.4. After the test, the concentrated ET solution to the water in the thus the test ET When at least 10 has after the addition of the concentrated ET solution least 10 is required to the test ET solution The solution in the should be using a line or by other The should be sampled after the fluid in the line has been by the 10 of the test ET filter the test ET solution in the dead-end and 10 of the filtrate. The samples obtained as in and should be immediately to an method or as specified in of the Japan Pharmacopoeia test ET the cannot be performed immediately after the samples and start the within ET level in test solution ET level in LRV for ET on the test particularly the ET level in the test When is lower than the detection of the it is possible to LRV by assuming to be to the detection to be The following should be ET level ET levels obtained in the test, test ET solution, and specified in 6. ET retentive performance LRV for ET