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NIST radiopharmaceutical measurement assurance program
Appl. Radiat. lsot. Vol. 49, No. 4, pp. 329-334, 1998
Pergamon PII: S0969-8043(97)00049-3
© 1998ElsevierScienceLtd. All rights reserved Printed in Great Britain 0969-8043/98 $19.00+ 0.00
NIST Radiopharmaceutical Standard Reference Materials and the NEI/NIST Radiopharmaceutical Measurement Assurance Program D A N I E L B. G O L A S Nuclear Energy Institute, Washington, DC, U.S.A. In cooperation with the Nuclear Energy Institute (NEI), the National Institute of Standards and Technology (NIST) supervises and administers two measurement assurance programs for radioactivity measurement traceability. One, in existence since the mid 1970s, provides traceability to suppliers of radiochemicals and radiopharmaceuticals, dose calibrators, and nuclear pharmacy services. The second program, begun in 1987, provides traceability to the nuclear power industry for utilities, source suppliers, and service laboratories. The radiopharmaceutical program is described and the results of measurements of samples of known, but undisclosed, activity, prepared at NIST and measured by the participants, are presented. NIST Radiopharmaceutical Standard Reference Materials (SRMs) are also produced as part of this program, and these are described. © 1998 Elsevier Science Ltd. All rights reserved
The National Institute of Standards and Technology (NIST), formerly the National Bureau of Standards, was created by a Congressional Act in 1901 to be the source and custodian of standards for physical measurement in the United States. As part of its congressional mandate, the goals of NIST are to: develop reference and definitive methods of analysis, certify and issue standards, and assure their effective use in the measurement community, thereby helping to achieve accurate measurements in the United States and throughout the world. To help achieve these goals, the NIST Standard Reference Material Program distributes more than 1300 different Standard Reference Materials (SRMs), developed and certified in the NIST laboratories in Gaithersburg, MD and Boulder, CO (NIST, 1995). The Radioactivity Group of the Ionizing Radiation Division in the NIST Physics Laboratory produces about 60 out of 1300 of these SRMs, intended for the calibration of radioactivity measuring instruments and the monitoring of chemical and geochemical processes. Of these 60 or so that are produced by the Radioactivity Group, a subset of these are the (usually) short-lived radioactivity SRMs intended for nuclear medicine quality control, and these are known as the '4400' series SRMs because they all appear in the SRM catalog beginning with number ~44~,
Figure 1 shows the entire list of 4400 SRMs that have been calibrated and produced since these standards were first issued in the mid 1970s. The last column in this table shows that many of these are not produced any more. A few, such as 36C1or 9°Sr, were only issued once, mainly for users to check the response of dose calibrators to 13-particle emitting radionuclides. Others, such as 2°3Hg, t97Hg, 59Fe, and 758e, are no longer in demand because they have been replaced by other radionuclides that are easier to use or deliver a smaller radiation dose to a patient. Still others such as 1231are not produced even though they are still in use, and very popular, because the high cost of the radiochemical used to produce the SRM would make it too expensive. 895rwould also fit in this last category. Even though it was recently calibrated, it does not seem likely that it will be reissued any time soon unless there are many requests for it, due to the high cost of the material. The letters at the end of the SRM numbers indicate how many times they have been issued as SRMs since they were developed. The radiopharmaceutical SRMs are produced through a Cooperative Research and Development Agreement (CRADA) with the Nuclear Energy Institute (NEI). NIST has nearly 400 CRADAs in which individual companies work directly with NIST researchers to achieve joint goals. NIST collaborates on two such programs with NEI: one is a
329
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Daniel B. Golas
Radionuclide Chromium-51 Iodine-131 Tin-113-indium-113m Strontium-85 Thallium-201 Gold-198 Phosphorus-32 Iodine-125 Cobalt-57 Selenium-75 Technetium-99m Iron-59 Molybdenum-99 Mercury-197 Iodine-123 Xenon-133 GaUium-67 Indium-111 Mercury-203 Ytterbium-169 Lead-203 Gold-195 Chlorine-36 Strontium-90 Sulfur-35 Samarium-i 53 Strontium-89 Yttrium-90
SRM Number
Life
4400N 4401V 4402C 4403B 4404S 4405B 4406N 4407T 4408F 4409D 4410V 4411B 4412U 4413A 4414C 4415T 4416Q 4417P 4418A 44 19C 4420B 442IA 4422A 4423A 4424A 4425B 4426A 4427A
27.702 days 8.02070 days 115.09. days 64.84 days 3.040 days 2.69517 days 14.262 days 59.408 d a y s 271.79 days 119.79 days 6.01 hours 44.503 days 65.94 hours 64.14 hours 13.27 hours 5.243 days 3.2612 days 2.8047 days 46.612 d a y s 32.026 days 51.873 h o u r s 186.098 d a y s 3.01 x 105 years 28.78 years 87.51 days 46.27 hours 50.53 days 64.10 hours
Last Issued July 1992 January 1996 October 1980 April 1977 June 1996 August 1978 October 1995 December 1995 July 1995 August 1981 September 1996 January 1979 February 1996 May 1976 June 1980 March 1996 May 1996 August 1996 November 1976 October 1986 November1984 December1979 April 1980 November 1985 October 1988 July 1996 April 1995 October 1994
Fig. 1. List of 4400 SRMs calibrated and produced.
Measurement Assurance Program (MAP) for the radiopharmaceutical industry; and one is a MAP for the nuclear power industry. It is through the first program that the radiopharmaceutical SRMs are produced. The remainder of this paper will briefly describe the radiopharmaceutical measurement assurance program, concentrating on four areas: (1) the participants in the program; (2) the standards and other services they receive; (3) how the programs are supported financially; and finally (4) a summary of the results of the participants' measurements compared to the NIST values. Previous publications (Gray et al., 1990; Golas and Calhoun, 1983; Hoppes, 1990; Golas, 1993) can provide more detail on certain aspects of each program. The Nuclear Energy Institute is the commercial nuclear power industry's Washington, DC-based policy organization. Its main function is to support the nuclear power industry. NEI represents a broad spectrum of nearly 400 companies in the U.S. and overseas, and is involved with these measurement assurance programs only as a service to its member companies. The companies that were interested in starting these measurement assurance programs already belonged to NEI, and the organization
provided a common infrastructure already in place to hire people to work at NIST to provide the services that the companies desired. The radiopharmaceutical measurements assurance program began in the mid 1970s. The companies that started these programs did so because the programs that already existed did not fully meet their needs. At that time there was a lack of calibrations for many of the short-lived radionuclides used in nuclear medicine. The Standard Reference Materials or SRMs that were available were often in the wrong physical form needed by companies, i.e. solid point source instead of solution, and most had activity levels too low to be useful to them. Also, much of the decay information was not well known for many of these radionuclides, and this presented a problem for many companies because of complaints from their customers when a certain amount of activity from one company did not agree with the same amount from another company due to different measurement techniques and decay data used. Also, NBS at the time could not hire anyone to work on these problems. Through NEI, or the Atomic Industrial Forum as it was known in the 1970s, the radiopharmaceutical program was formed and a
NEI/NIST radiopharmaceutical standards research associate was hired to work at NBS to make the SRMs that these companies wanted. There are several advantages that these MAPs have that others do not. First, they provide the participants with a direct link from their measurements to the national standards. Second, the participants can receive the kind of radionuclides that they want and at the activity levels that they want. In the case of the nuclear power MAP, they also get the radionuclides in the mixtures that they want, with the interferences that they want, and in the form that they want. Third, the participants find the programs cost effective because the cost of the program is offset by savings on customer complaints due to improved measurement accuracy, as in the radiopharmaceutical program, or the need to perform fewer audits on source suppliers, as in the power plant program. Finally, the participants have a ready access to an independent third party if a measurement dispute occurs between participants or between a participant and a customer or regulator. The current participants in the radiopharmaceutical program are shown in Fig. 2. Together, the participants represent the entire spectrum of the radiopharmaceutical industry, from bulk radiochemical suppliers, to radiopharmaceutical manufacturers, to a radiopharmacy that provides unit doses of radiopharmaceuticals in the form of filled syringes and capsules to hospitals for individual diagnostic tests and treatments. The Food and Drug Administration also participates through an inter-agency agreement with NIST. Figure 3 shows the production schedule for 1997. Ten different Standard Reference Materials are produced yearly, one per month, except for May and November. During these two months, PARTICIPANTS IN THE NEI/NIST RADIOACTIVITY MEASUREMENTS ASSURANCE PROGRAM FOR THE RADIOPHARMACEUTICAL INDUSTRY BristoI-Meyera Squibb Company New Brunswick, NJ DuPont Merck Pharmaceuticals Company North BIIledca, MA Mallinckrodt Medical, Incorporated Maryland Heights, MO MeW+Physics, Incorporated Arlington Heights, IL
Nordion Intematlonal, Incorporated Kanata, Ontado, Canada Packard Instmmente, Incorporated Downers Grove, IL Syncor International Corporation Chatsworth, CA (Food and Drug Administration) Winchester, MA
Fig. 2. Current participants in the radiopharmaceuticals program.
331
1 9 9 7 DISTRIBUTION SCHEDULE FOR THE NEI/NIST RADIOPHARMACEUTICAL PROGRAM January
1:~1
750 MBq (20 mCI)
26 MBq (700 pCi)
February
~Mo
March
I:~Xe
7.5 QBq (200 mCI)
750 MBq (20 rnCI)
Apdi
e7Oa
375 MBq (10 mC||
20 MBq (600 pCi)
May
OPEN
n/a
n/a
June
:°ITI
225 MBq (6 mCI)
35 MBq (900 pCi)
July
'"Sm
375 MBq (10 mCi)
20 MBq (500 pCi)
August
"1In
375 MBq (10 mCI)
20 MBq (500 pCi)
September gs~l'c October
32p
November OPEN December
~2Sl
3~
(80 mCI)
76 MBq (2 mCi)
7.5 GBq (200 mCi)
n/a
2.2 GBq (60 mCi)
13 MBq (350 pCi)
n/a
n/a
750 MBq (20 mCi)
6 MBq (150 pCI)
Fig. 3. Production schedule for 1997. known as 'open months', participants can elect to submit samples to NIST for verification. This allows participants to get traceability on radionuclides that are important to them but are not on the schedule during the year, or to perform a test on something where they may have had a problem with a measurement, or to resolve a complaint from a customer. Except for 99mTc,each monthly distribution consists of a high-level and a low-level SRM. The high levels are in the MBq to GBq (multi-miUicurie) range of activity, while the low levels are usually in the MBq range (one to several hundred microcuries). All the standards are in the form of 5 ml of solution in standard NIST glass ampoules, except for ~33Xe which is provided in a 5 ml Pyrex ~ ampoule. The SRMs are supplied to the participants with the NIST-measured activity undisclosed, or as 'blinds'. The participants make their measurements on the sources and report their results on a questionnaire supplied with the source. After the questionnaire is received at NIST, a report is issued which compares the participant's measurement with the NIST value, providing traceability for the measurement (Fig. 4). The low-level standards are also available for sale to the general public, and the sale of these helps to support the operation of the program. The SRMs provided to the public are not available as 'blinds'. The participants that got together to create and support the program believed that allowing anyone to receive the SRMs as blinds would take away one of the main incentives to belong to the program, instead of buying the SRMs directly from NIST, and this would result in the program collapsing from lack of support with the result that the SRMs might not be available at all since NIST would have no one available to prepare the radiopharmaceutical SRMs. Figure 5 is a diagram of how the radiopharmaceutical program operates. First, the participants meet at an annual steering committee meeting to
332
Daniel B. Golas
decide on the ten standards that are to be prepared the following year. The participants decide on which high- and low-level SRMs they want to receive, and they pay NEI for these along with a participation fee to belong to the program, currently $6000. The participation fee covers the cost of the two 'open months', which are provided to the participants at no additional charge. Participants must also pay to belong to NEI. NEI charges a membership fee which is different for each company, based on a formula that takes into account the company's income related
to the nuclear industry. This charge is separate from these measurement assurance programs and is charged whether or not they belong to one of these programs. NEI uses the money collected from the participants to pay NIST for the Standard Reference Materials provided to the participants and for the supplies and raw materials (approximately $10,000 per year) needed to prepare the standards. Payment for the SRMs provided to the participants is done quarterly. The research associates are employees of NEI and are paid as any other NEI employee. NEI
U.S. DEPARTMENT OF COMMERCE
National Institute of Standards & Technology
Gaithersburg, MD 20899
REPORT OF TRACEABILITY SAMARIUM-I$3 Participant
Source identification Source description Solution density Mass
Your Company Gaithersburg,Maryland 4425H-B-1 Solution in 5-mL ampoule 1.017 ± 0.002 g.mL -t at 23.0 *C 5.12334 grams PARTICIPANT'S DATA
NIST DATA Radioactivity concentration
3.233 x 107 Bq.g -1 6.76 mCi
Activity Reference time Relative expanded uncertainty H~flife
1400 EST July 16, 1996
1400 EST July 16, 1996
1.51 percent
4.5 percent
46.27 ± 0.01 hou~ +1.51 percent
Difference from NIST Measuring instrument
NIST pressurized"47"-/ionization chamber calibratedby 4~r~ liquid-
Pressurizedgamma ray ionization chamber
scintillationcounting using NIST/CIEMAT efficiencyextrapolation technique Photon-emitting impurities (Activity ratios at reference time)
IS4Eu/mSm: (3.0 + 0.3) x 10-4 tSSEu/mSm: (5.2 + 0.5) x 10-5 15eEu/t'Sm." (8.2 .4- 0.8) x 10-4
Not examined
For the Director, Sample dispatched: July 17, 1996 Questionnaire received: August 15, 1996 (Results telephoned to NIST on July 27, 1996)
J.M. Robin Hutchinson, Group Leader Radioactivity Group Physics Laboratory
(over) Fig. 4. Traceability of measurements.
NEI/NIST radiopharmaceutical standards
[Participants]
1 ,2 /
$
Research Associates J
[General Public) Fig. 5. Operation of radiopharmaceutical program. employs two research associates, one for each of the measurement assurance programs, and a technician who was hired for the nuclear power program. However, all the work for both programs is done cooperatively, so the salary costs are averaged between both programs. As previously mentioned, the low-level SRMs are advertised for sale to the general public to help support the program. The current price for these is $545.00 each. The current price for the high levels that are only available to the
333
participants is $595.00. The higher cost is to pay for extra shielding during shipment and for the larger quantity of radiochemical needed to produce the higher level SRM. From the sale of each one of these, $177.50 is kept by NIST and the rest is returned to NEI, also quarterly. Of the $177.50 kept by NIST, $50.00 of this is for supporting the Standard Reference Material clerk who handles the orders and other paperwork. The other arrows on the diagram indicate that the research associates help NIST personnel with some of their needs in the production of other SRMs, and NIST personnel assist the research associates with the preparation of the radiopharmaceutical SRMs, as well as the sources for the power plant program. All parties are in agreement that the contributions of each balance out. Figure 6 is a histogram of the results received from the radiopharmaceutical participants since the beginning of the program. The histogram represents 1622 results submitted from June 1975 through June 1996. Approximately 85% of the results are within _+5% of NIST, and about 96% are within + 10% of NIST. Of the 1.2% that are greater than _+20% of NIST, most of these are results from the earlier years. It is likely that measurements have improved over the years, but it is also possible that companies that made poor measurements just stopped submitting results. Because the people that receive these SRMs know that they are making their measurements in order to become traceable to NIST, one could assume, probably correctly, that these results are the best that anyone is likely to do, on average. It can only be guessed how well others not in the program routinely do. It is reassuring to see that the values are centered around the NIST value, proving that no matter what the different participants use to calibrate their
300 250
2oo1 150
z IO0 < -20%
=
|
> +20%
0 -20
-15
-10
-5
0
+5
+10
+15
+20
P e r c e n t Difference from NIST
Fig. 6. Radiopharmaceutical program results: June 1975 through June 1996.
334
Daniel B. Golas
measuring equipment, on the whole they agree with NIST, As well as providing calibrated sources and SRMs to the participants in these programs, another task is to assist any participant with any problems they may have encountered in measuring these sources. This is done directly, if someone calls with a problem, but participants can also get useful information from the summaries that are issued after everyone has submitted their results. The summary for the radiopharmaceutical program is fairly simple. For each radionuclide distributed, a list is generated which shows all deviations from the NIST value for each participant, and the type of detector used to make the measurement. An average difference of the results from the NIST value is also generated so individual participants can compare their difference from everyone elses. The results are reported with the companies unidentified, so that no one can tell what result belongs to which participant. The summary provides only a few details for this program, because it would be easy to identify a company after a while if too much of the measurement technique was described. In conclusion, this has been a summary of the radiopharmaceutical Standard Reference Materials produced by the National Institute of Standards and Technology, and the NEI/NIST measurement assurance program for the radiopharmaceutical industry:
who the participants are; how the program is structured; how the program is financed; and how well the participants are making their measurements. The two MAPs fill a need in each industry, and the participants find the programs useful, necessary, and cost effective. If they do not meet their needs, they have an opportunity each year at the annual steering committee meeting to change their programs to adapt to any changes that are taking place, to meet new demands or regulations.
References Golas, D. B. and Calhoun, J. M. (1983) U.S. National Bureau of Standards/Atomic Industrial Forum Radioactivity Measurements Assurance Program. Int. J. Nuel. Med. Biol. 10(2/3), 163-168. Golas, D. B. (1993) USCEA/NIST Measurement Assurance Programs for the radiopharmaceutical and nuclear power industries. Proceedings of the Workshop on Measurement Quality Assurance for Ionizing Radiation, March 16-18, 1993, pp. 191-206. Gray, D. H., Golas, D. B. and Calhoun, J. M. (1990) Review of the USCEA/NIST Measurement Assurance Program for the nuclear power industry. Radioactiv. Radiochem. 2(1), 30--41. Hoppes, D. D. (1990) Demonstrated measurement traceability for nuclear power radiochemistry departments. Radioactiv. Radiochem. Winter, 9-12. NIST Standard Reference Materials Catalog (1995-1996), NIST Special Publication 260, p. iii.
Pergamon PII: S0969-8043(97)00049-3
© 1998ElsevierScienceLtd. All rights reserved Printed in Great Britain 0969-8043/98 $19.00+ 0.00
NIST Radiopharmaceutical Standard Reference Materials and the NEI/NIST Radiopharmaceutical Measurement Assurance Program D A N I E L B. G O L A S Nuclear Energy Institute, Washington, DC, U.S.A. In cooperation with the Nuclear Energy Institute (NEI), the National Institute of Standards and Technology (NIST) supervises and administers two measurement assurance programs for radioactivity measurement traceability. One, in existence since the mid 1970s, provides traceability to suppliers of radiochemicals and radiopharmaceuticals, dose calibrators, and nuclear pharmacy services. The second program, begun in 1987, provides traceability to the nuclear power industry for utilities, source suppliers, and service laboratories. The radiopharmaceutical program is described and the results of measurements of samples of known, but undisclosed, activity, prepared at NIST and measured by the participants, are presented. NIST Radiopharmaceutical Standard Reference Materials (SRMs) are also produced as part of this program, and these are described. © 1998 Elsevier Science Ltd. All rights reserved
The National Institute of Standards and Technology (NIST), formerly the National Bureau of Standards, was created by a Congressional Act in 1901 to be the source and custodian of standards for physical measurement in the United States. As part of its congressional mandate, the goals of NIST are to: develop reference and definitive methods of analysis, certify and issue standards, and assure their effective use in the measurement community, thereby helping to achieve accurate measurements in the United States and throughout the world. To help achieve these goals, the NIST Standard Reference Material Program distributes more than 1300 different Standard Reference Materials (SRMs), developed and certified in the NIST laboratories in Gaithersburg, MD and Boulder, CO (NIST, 1995). The Radioactivity Group of the Ionizing Radiation Division in the NIST Physics Laboratory produces about 60 out of 1300 of these SRMs, intended for the calibration of radioactivity measuring instruments and the monitoring of chemical and geochemical processes. Of these 60 or so that are produced by the Radioactivity Group, a subset of these are the (usually) short-lived radioactivity SRMs intended for nuclear medicine quality control, and these are known as the '4400' series SRMs because they all appear in the SRM catalog beginning with number ~44~,
Figure 1 shows the entire list of 4400 SRMs that have been calibrated and produced since these standards were first issued in the mid 1970s. The last column in this table shows that many of these are not produced any more. A few, such as 36C1or 9°Sr, were only issued once, mainly for users to check the response of dose calibrators to 13-particle emitting radionuclides. Others, such as 2°3Hg, t97Hg, 59Fe, and 758e, are no longer in demand because they have been replaced by other radionuclides that are easier to use or deliver a smaller radiation dose to a patient. Still others such as 1231are not produced even though they are still in use, and very popular, because the high cost of the radiochemical used to produce the SRM would make it too expensive. 895rwould also fit in this last category. Even though it was recently calibrated, it does not seem likely that it will be reissued any time soon unless there are many requests for it, due to the high cost of the material. The letters at the end of the SRM numbers indicate how many times they have been issued as SRMs since they were developed. The radiopharmaceutical SRMs are produced through a Cooperative Research and Development Agreement (CRADA) with the Nuclear Energy Institute (NEI). NIST has nearly 400 CRADAs in which individual companies work directly with NIST researchers to achieve joint goals. NIST collaborates on two such programs with NEI: one is a
329
330
Daniel B. Golas
Radionuclide Chromium-51 Iodine-131 Tin-113-indium-113m Strontium-85 Thallium-201 Gold-198 Phosphorus-32 Iodine-125 Cobalt-57 Selenium-75 Technetium-99m Iron-59 Molybdenum-99 Mercury-197 Iodine-123 Xenon-133 GaUium-67 Indium-111 Mercury-203 Ytterbium-169 Lead-203 Gold-195 Chlorine-36 Strontium-90 Sulfur-35 Samarium-i 53 Strontium-89 Yttrium-90
SRM Number
Life
4400N 4401V 4402C 4403B 4404S 4405B 4406N 4407T 4408F 4409D 4410V 4411B 4412U 4413A 4414C 4415T 4416Q 4417P 4418A 44 19C 4420B 442IA 4422A 4423A 4424A 4425B 4426A 4427A
27.702 days 8.02070 days 115.09. days 64.84 days 3.040 days 2.69517 days 14.262 days 59.408 d a y s 271.79 days 119.79 days 6.01 hours 44.503 days 65.94 hours 64.14 hours 13.27 hours 5.243 days 3.2612 days 2.8047 days 46.612 d a y s 32.026 days 51.873 h o u r s 186.098 d a y s 3.01 x 105 years 28.78 years 87.51 days 46.27 hours 50.53 days 64.10 hours
Last Issued July 1992 January 1996 October 1980 April 1977 June 1996 August 1978 October 1995 December 1995 July 1995 August 1981 September 1996 January 1979 February 1996 May 1976 June 1980 March 1996 May 1996 August 1996 November 1976 October 1986 November1984 December1979 April 1980 November 1985 October 1988 July 1996 April 1995 October 1994
Fig. 1. List of 4400 SRMs calibrated and produced.
Measurement Assurance Program (MAP) for the radiopharmaceutical industry; and one is a MAP for the nuclear power industry. It is through the first program that the radiopharmaceutical SRMs are produced. The remainder of this paper will briefly describe the radiopharmaceutical measurement assurance program, concentrating on four areas: (1) the participants in the program; (2) the standards and other services they receive; (3) how the programs are supported financially; and finally (4) a summary of the results of the participants' measurements compared to the NIST values. Previous publications (Gray et al., 1990; Golas and Calhoun, 1983; Hoppes, 1990; Golas, 1993) can provide more detail on certain aspects of each program. The Nuclear Energy Institute is the commercial nuclear power industry's Washington, DC-based policy organization. Its main function is to support the nuclear power industry. NEI represents a broad spectrum of nearly 400 companies in the U.S. and overseas, and is involved with these measurement assurance programs only as a service to its member companies. The companies that were interested in starting these measurement assurance programs already belonged to NEI, and the organization
provided a common infrastructure already in place to hire people to work at NIST to provide the services that the companies desired. The radiopharmaceutical measurements assurance program began in the mid 1970s. The companies that started these programs did so because the programs that already existed did not fully meet their needs. At that time there was a lack of calibrations for many of the short-lived radionuclides used in nuclear medicine. The Standard Reference Materials or SRMs that were available were often in the wrong physical form needed by companies, i.e. solid point source instead of solution, and most had activity levels too low to be useful to them. Also, much of the decay information was not well known for many of these radionuclides, and this presented a problem for many companies because of complaints from their customers when a certain amount of activity from one company did not agree with the same amount from another company due to different measurement techniques and decay data used. Also, NBS at the time could not hire anyone to work on these problems. Through NEI, or the Atomic Industrial Forum as it was known in the 1970s, the radiopharmaceutical program was formed and a
NEI/NIST radiopharmaceutical standards research associate was hired to work at NBS to make the SRMs that these companies wanted. There are several advantages that these MAPs have that others do not. First, they provide the participants with a direct link from their measurements to the national standards. Second, the participants can receive the kind of radionuclides that they want and at the activity levels that they want. In the case of the nuclear power MAP, they also get the radionuclides in the mixtures that they want, with the interferences that they want, and in the form that they want. Third, the participants find the programs cost effective because the cost of the program is offset by savings on customer complaints due to improved measurement accuracy, as in the radiopharmaceutical program, or the need to perform fewer audits on source suppliers, as in the power plant program. Finally, the participants have a ready access to an independent third party if a measurement dispute occurs between participants or between a participant and a customer or regulator. The current participants in the radiopharmaceutical program are shown in Fig. 2. Together, the participants represent the entire spectrum of the radiopharmaceutical industry, from bulk radiochemical suppliers, to radiopharmaceutical manufacturers, to a radiopharmacy that provides unit doses of radiopharmaceuticals in the form of filled syringes and capsules to hospitals for individual diagnostic tests and treatments. The Food and Drug Administration also participates through an inter-agency agreement with NIST. Figure 3 shows the production schedule for 1997. Ten different Standard Reference Materials are produced yearly, one per month, except for May and November. During these two months, PARTICIPANTS IN THE NEI/NIST RADIOACTIVITY MEASUREMENTS ASSURANCE PROGRAM FOR THE RADIOPHARMACEUTICAL INDUSTRY BristoI-Meyera Squibb Company New Brunswick, NJ DuPont Merck Pharmaceuticals Company North BIIledca, MA Mallinckrodt Medical, Incorporated Maryland Heights, MO MeW+Physics, Incorporated Arlington Heights, IL
Nordion Intematlonal, Incorporated Kanata, Ontado, Canada Packard Instmmente, Incorporated Downers Grove, IL Syncor International Corporation Chatsworth, CA (Food and Drug Administration) Winchester, MA
Fig. 2. Current participants in the radiopharmaceuticals program.
331
1 9 9 7 DISTRIBUTION SCHEDULE FOR THE NEI/NIST RADIOPHARMACEUTICAL PROGRAM January
1:~1
750 MBq (20 mCI)
26 MBq (700 pCi)
February
~Mo
March
I:~Xe
7.5 QBq (200 mCI)
750 MBq (20 rnCI)
Apdi
e7Oa
375 MBq (10 mC||
20 MBq (600 pCi)
May
OPEN
n/a
n/a
June
:°ITI
225 MBq (6 mCI)
35 MBq (900 pCi)
July
'"Sm
375 MBq (10 mCi)
20 MBq (500 pCi)
August
"1In
375 MBq (10 mCI)
20 MBq (500 pCi)
September gs~l'c October
32p
November OPEN December
~2Sl
3~
(80 mCI)
76 MBq (2 mCi)
7.5 GBq (200 mCi)
n/a
2.2 GBq (60 mCi)
13 MBq (350 pCi)
n/a
n/a
750 MBq (20 mCi)
6 MBq (150 pCI)
Fig. 3. Production schedule for 1997. known as 'open months', participants can elect to submit samples to NIST for verification. This allows participants to get traceability on radionuclides that are important to them but are not on the schedule during the year, or to perform a test on something where they may have had a problem with a measurement, or to resolve a complaint from a customer. Except for 99mTc,each monthly distribution consists of a high-level and a low-level SRM. The high levels are in the MBq to GBq (multi-miUicurie) range of activity, while the low levels are usually in the MBq range (one to several hundred microcuries). All the standards are in the form of 5 ml of solution in standard NIST glass ampoules, except for ~33Xe which is provided in a 5 ml Pyrex ~ ampoule. The SRMs are supplied to the participants with the NIST-measured activity undisclosed, or as 'blinds'. The participants make their measurements on the sources and report their results on a questionnaire supplied with the source. After the questionnaire is received at NIST, a report is issued which compares the participant's measurement with the NIST value, providing traceability for the measurement (Fig. 4). The low-level standards are also available for sale to the general public, and the sale of these helps to support the operation of the program. The SRMs provided to the public are not available as 'blinds'. The participants that got together to create and support the program believed that allowing anyone to receive the SRMs as blinds would take away one of the main incentives to belong to the program, instead of buying the SRMs directly from NIST, and this would result in the program collapsing from lack of support with the result that the SRMs might not be available at all since NIST would have no one available to prepare the radiopharmaceutical SRMs. Figure 5 is a diagram of how the radiopharmaceutical program operates. First, the participants meet at an annual steering committee meeting to
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Daniel B. Golas
decide on the ten standards that are to be prepared the following year. The participants decide on which high- and low-level SRMs they want to receive, and they pay NEI for these along with a participation fee to belong to the program, currently $6000. The participation fee covers the cost of the two 'open months', which are provided to the participants at no additional charge. Participants must also pay to belong to NEI. NEI charges a membership fee which is different for each company, based on a formula that takes into account the company's income related
to the nuclear industry. This charge is separate from these measurement assurance programs and is charged whether or not they belong to one of these programs. NEI uses the money collected from the participants to pay NIST for the Standard Reference Materials provided to the participants and for the supplies and raw materials (approximately $10,000 per year) needed to prepare the standards. Payment for the SRMs provided to the participants is done quarterly. The research associates are employees of NEI and are paid as any other NEI employee. NEI
U.S. DEPARTMENT OF COMMERCE
National Institute of Standards & Technology
Gaithersburg, MD 20899
REPORT OF TRACEABILITY SAMARIUM-I$3 Participant
Source identification Source description Solution density Mass
Your Company Gaithersburg,Maryland 4425H-B-1 Solution in 5-mL ampoule 1.017 ± 0.002 g.mL -t at 23.0 *C 5.12334 grams PARTICIPANT'S DATA
NIST DATA Radioactivity concentration
3.233 x 107 Bq.g -1 6.76 mCi
Activity Reference time Relative expanded uncertainty H~flife
1400 EST July 16, 1996
1400 EST July 16, 1996
1.51 percent
4.5 percent
46.27 ± 0.01 hou~ +1.51 percent
Difference from NIST Measuring instrument
NIST pressurized"47"-/ionization chamber calibratedby 4~r~ liquid-
Pressurizedgamma ray ionization chamber
scintillationcounting using NIST/CIEMAT efficiencyextrapolation technique Photon-emitting impurities (Activity ratios at reference time)
IS4Eu/mSm: (3.0 + 0.3) x 10-4 tSSEu/mSm: (5.2 + 0.5) x 10-5 15eEu/t'Sm." (8.2 .4- 0.8) x 10-4
Not examined
For the Director, Sample dispatched: July 17, 1996 Questionnaire received: August 15, 1996 (Results telephoned to NIST on July 27, 1996)
J.M. Robin Hutchinson, Group Leader Radioactivity Group Physics Laboratory
(over) Fig. 4. Traceability of measurements.
NEI/NIST radiopharmaceutical standards
[Participants]
1 ,2 /
$
Research Associates J
[General Public) Fig. 5. Operation of radiopharmaceutical program. employs two research associates, one for each of the measurement assurance programs, and a technician who was hired for the nuclear power program. However, all the work for both programs is done cooperatively, so the salary costs are averaged between both programs. As previously mentioned, the low-level SRMs are advertised for sale to the general public to help support the program. The current price for these is $545.00 each. The current price for the high levels that are only available to the
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participants is $595.00. The higher cost is to pay for extra shielding during shipment and for the larger quantity of radiochemical needed to produce the higher level SRM. From the sale of each one of these, $177.50 is kept by NIST and the rest is returned to NEI, also quarterly. Of the $177.50 kept by NIST, $50.00 of this is for supporting the Standard Reference Material clerk who handles the orders and other paperwork. The other arrows on the diagram indicate that the research associates help NIST personnel with some of their needs in the production of other SRMs, and NIST personnel assist the research associates with the preparation of the radiopharmaceutical SRMs, as well as the sources for the power plant program. All parties are in agreement that the contributions of each balance out. Figure 6 is a histogram of the results received from the radiopharmaceutical participants since the beginning of the program. The histogram represents 1622 results submitted from June 1975 through June 1996. Approximately 85% of the results are within _+5% of NIST, and about 96% are within + 10% of NIST. Of the 1.2% that are greater than _+20% of NIST, most of these are results from the earlier years. It is likely that measurements have improved over the years, but it is also possible that companies that made poor measurements just stopped submitting results. Because the people that receive these SRMs know that they are making their measurements in order to become traceable to NIST, one could assume, probably correctly, that these results are the best that anyone is likely to do, on average. It can only be guessed how well others not in the program routinely do. It is reassuring to see that the values are centered around the NIST value, proving that no matter what the different participants use to calibrate their
300 250
2oo1 150
z IO0 < -20%
=
|
> +20%
0 -20
-15
-10
-5
0
+5
+10
+15
+20
P e r c e n t Difference from NIST
Fig. 6. Radiopharmaceutical program results: June 1975 through June 1996.
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measuring equipment, on the whole they agree with NIST, As well as providing calibrated sources and SRMs to the participants in these programs, another task is to assist any participant with any problems they may have encountered in measuring these sources. This is done directly, if someone calls with a problem, but participants can also get useful information from the summaries that are issued after everyone has submitted their results. The summary for the radiopharmaceutical program is fairly simple. For each radionuclide distributed, a list is generated which shows all deviations from the NIST value for each participant, and the type of detector used to make the measurement. An average difference of the results from the NIST value is also generated so individual participants can compare their difference from everyone elses. The results are reported with the companies unidentified, so that no one can tell what result belongs to which participant. The summary provides only a few details for this program, because it would be easy to identify a company after a while if too much of the measurement technique was described. In conclusion, this has been a summary of the radiopharmaceutical Standard Reference Materials produced by the National Institute of Standards and Technology, and the NEI/NIST measurement assurance program for the radiopharmaceutical industry:
who the participants are; how the program is structured; how the program is financed; and how well the participants are making their measurements. The two MAPs fill a need in each industry, and the participants find the programs useful, necessary, and cost effective. If they do not meet their needs, they have an opportunity each year at the annual steering committee meeting to change their programs to adapt to any changes that are taking place, to meet new demands or regulations.
References Golas, D. B. and Calhoun, J. M. (1983) U.S. National Bureau of Standards/Atomic Industrial Forum Radioactivity Measurements Assurance Program. Int. J. Nuel. Med. Biol. 10(2/3), 163-168. Golas, D. B. (1993) USCEA/NIST Measurement Assurance Programs for the radiopharmaceutical and nuclear power industries. Proceedings of the Workshop on Measurement Quality Assurance for Ionizing Radiation, March 16-18, 1993, pp. 191-206. Gray, D. H., Golas, D. B. and Calhoun, J. M. (1990) Review of the USCEA/NIST Measurement Assurance Program for the nuclear power industry. Radioactiv. Radiochem. 2(1), 30--41. Hoppes, D. D. (1990) Demonstrated measurement traceability for nuclear power radiochemistry departments. Radioactiv. Radiochem. Winter, 9-12. NIST Standard Reference Materials Catalog (1995-1996), NIST Special Publication 260, p. iii.