자동합성장치에 따른 $^{18}F$-FDG의 방사선분해 평가

김시활,김동일,지용기,최성욱,최춘기,석재동,Kim, Si-Hwal,Kim, Dong-Il,Chi, Yong-Gi,Choi, Sung-Wook,Choi, Choon-Ki,Seok, Jae-Dong 대한핵의학기술학회 2012 핵의학 기술 Vol.16 No.1

상용화된 자동합성장치는 사용되는 유기용매의 종류가 다르고 합성수율에 차이를 보인다. 따라서 본 연구에서는 자동합성장치에 따른 $^{18}F$-FDG의 방사선분해에 관한 방사화학적순도 변화를 비교하였다. Cyclotron (PETtrace, GE Healthcare)을 사용하여 $^{18}F$를 생산하고, 자동합성장치(FASTlab, Tracerlab MX, GE Healthcare)를 이용하여 FDG로 합성하였다. 방사화화적순도는 Radio-TLC Scanner (AR 2000, Bioscan), GC(Gas Chromatography, Agilent 7890A)를 사용하여 $^{18}F$-FDG에 함유되어 있는 에탄올의 양을 측정하였다. 고정상은 실리카겔로 도포된 유리판($1{\times}10cm$), 이동상은 아세토니트릴과 물 19:1 혼합액을 사용하고, 각각의 합성장치에서 고농도와 저농도의 $^{18}F$-FDG를 생산 후 2시간 간격으로 방사화학적순도를 측정하였다. 저농도 (약 2.59 GBq/mL 이하)에서 순도변화는 Tracerlab MX에서는 99.26%, 98.69%, 98.25%, 98.09%, FASTlab에서는 99.09%, 97.83, 96.89%, 96.62%를 얻었다. 고농도(약 3.7 GBq/mL 이상)에서 순도변화는 Tracerlab MX에서는 평균 99.54%, 96.08%, 93.77%, 92.54%, FASTlab의 경우 99.53%, 95.65%, 92.39%, 89.82%를 얻었다. 그리고 FASTlab에서 생산한 $^{18}F$-FDG의 GC에서는 에탄올이 검출되지 않았으며, Tracerlab MX에서는 100~300 ppm의 에탄올이 검출되었다. 이러한 결과를 비추어 봤을 때 방사선 보호제인 에탄올의 유무보다 방사능농도가 방사선분해에 더 큰 영향을 미치기 때문에 고농도의 $^{18}F$-FDG 생산 후 무균 생리식염수로 희석하여 농도를 낮춘 후 사용해야 한다. Purpose : Among quality control items, the radiochemical impurity must be below 10% of total radioactivity. In this regard, as the recently commercialized automatic synthesis module produces a large amount of 18F-FDG, radiolysis of radiopharmaceuticals is very likely to occur. Thus, this study compared the changes in radiochemical purity regarding radiolysis of $^{18}F$-FDG according to automatic synthesis module. Materials and methods : Cyclotron (PETtrace, GE Healthcare) was used to produce $^{18}F$ and automatic synthesis module (FASTlab, Tracerlab MX, GE Healthcare) was used to achieve synthesis into FDG. For radiochemical purity, Radio-TLC Scanner (AR 2000, Bioscan), GC (Gas Chromatograph, Agilent 7890A) was used to measure the content of ethanol included in $^{18}F$-FDG. Glass board applied with silica gel ($1{\times}10cm$) was used for stationary phase while a mixed liquid formed of acetonitrile and water (ratio 19:1) was used for mobile phase. High-concentration and low-concentration $^{18}F$-FDG were produced in each synthesis module and the radiochemical purity was measured every 2 hours. Results : The purity in low-concentration (below 2.59 GBq/mL) was measured as 99.26%, 98.69%, 98.25%, 98.09% in Tracerlab MX and as 99.09%, 97.83%, 96.89%, 96.62% in FASTlab according to 0, 2, 4, 6 hours changes, respectively. The purity in high-concentration (above 3.7 GBq/mL) was measured as 99.54%, 96.08%, 93.77%, 92.54% in Tracerlab MX and as 99.53%, 95.65%, 92.39%, 89.82% in FASTlab according to 0, 2, 4, 6 hours changes, respectively. Also, ethanol was not detected in GC of $^{18}F$-FDG produced in FASTlab, while 100~300 ppm ethanol was detected in Tracerlab MX. Conclusion : Whereas the change of radiochemical purity was only 3% in low-concentration $^{18}F$-FDG, the change was rapidly increased to 10% in high-concentration. Also, higher radiolysis were observed in $^{18}F$-FDG produced in FASTlab than Tracerlab MX. This is because ethanol is included in the synthesis stage of Tracerlab MX but not in the synthesis stage of FASTlab. Thus, radiolysis is influenced by radioactivity concentration than the inclusion of ethanol, which is the radioprotector. Therefore, after producing high-concentration $^{18}F$-FDG, the content must be diluted through saline to lower concentration.

내독소 검사에서 자동합성장치에 따른 간섭요인 극복에 대한 연구

김동일,김시활,지용기,석재동,Kim, Dong Il,Kim, Si Hwal,Chi, Yong Gi,Seok, Jae Dong 대한핵의학기술학회 2012 핵의학 기술 Vol.16 No.2

방사성의약품 제조 후 품질관리의 중요성이 점점 커지고 있다. 품질관리 항목에는 물리적 성상, PH, 핵종의 순도 측정, 화학적 순도 측정, 방사화학적 순도 측정, 내독소 검사, 크립토픽스 잔류량 측정 등이 있다. 내독소 검사는 발열 및 쇼크등을 일으킬 수 있는 그람음성간균의 리포다당질이 포함된 검체가 인체에 주입되는 것을 방지하기 위한 검사법이다. FASTlab module을 이용하여 합성된 $^{18}F$-FDG의 내독소 검사 시행 시 간섭요인이 발생하여 제대로 된 검사가 시행되지 못하여 희석하는 방법을 이용하였다. LAL free water를 이용하여 비색법은 25 ${\mu}l$, 겔화법은 200 ${\mu}l$를 최소단위로 하여 희석배수가 10배수를 초과하지 않는 범위내에서 희석배수를 10배수, 20배수, 30배수, 40배수로 하여 희석하였다. 희석된 시약을 겔화법은 STT와 PCT에 각각 200 ${\mu}l$를 주입하고 Incubator에 $37^{\circ}C$로 1시간동안 배양하여 겔형성 정도를 확인하고, 비색법은 25 ${\mu}l$를 최소단위로 하여 위와 같이 희석한다. 희석된 시약은 ENDOSAFE-PTS의 Dilution factor를 입력하고 배수 당 하나의 카트리지를 4곳의 주입구에 25 ${\mu}l$씩 주입하고 결과 데이터를 확인한다. 결과는 겔화법은 FASTlab의 경우 40배수에서만 겔이 형성되었고, TRACERlab Mx의 경우 거의 모든 배수에서 겔이 형성되었지만 간헐적으로 형성되지 않는 경우도 있었다. 비색법은 FASTlab의 경우 40배수에서만 Spike Rxn time CV, Sample Rxn time CV, Spike recovery 모두 정상범위 안에 포함되었다. TRACERlab Mx의 경우 10배수에서 Spike Rxn time CV, Sample Rxn time CV, Spike recovery 모두 정상범위 안에 포함되었다. FASTlab에서 생산된 방사성의약품은 중화제인 $H_3PO_4$가 PCT내에 겔 형성에 관여하는 $Mg^{2+}$이온과 결합하여 겔 형성을 하지 못하는 것으로 추측된다. 이에 희석을 할 경우 $H_3PO_4$ 양이 줄어 간섭효과를 제거할 수 있었다. 엔도톡신 검사에서 간섭인자들은 무수히 존재한다. 이 간섭인자들은 합성장치나 시약에 따라 달라질 수 있으므로 이와 같은 간섭인자들을 극복하기 위한 노력으로 품질검사의 정확성과 신뢰를 제공하도록 해야 할 것이다. Purpose : Samsung medical ceter shall find a cause of the interference factor and suggest a solution for it. Materials and Methods : A sample of $^{18}F$-FDG, radioactive pharmaceuticals produced by TRACERlab MX and FASTlab synthesizer. Gel-clot method uses Positive control tube and single test tube. Kinetic chromogenic method uses ENDOSAFE-PTS produced by Charles River. Results : According to Gel clot method of Endotoxin Tests at FASTlab, both turbidity and viscosity increased at 40-fold dilution and Gel clot was detected. In case of TRACERlab MX, Gel clot was detected in most of samples but intermittently not in a few of them. When using ENDOSAFE-PTS, sample CV (Coefficient of Variation) of FASTlab is 0% at all dilution rates whereas spike CV is 0% at 1-fold dilution, 0~35% at 10-fold, 3.6~12.9% at 20-fold, 5.2~7.1% at 30-fold, 1.1~17.4% at 40-fold, spike recovery; 0% at one-fold, 25 ~ 58% at 10-fold, 50 ~ 86% at 20-fold, 70~92% at 30-fold, and 75~120% at 40-fold. Sample CV of TRACERlab MX, is 0% at all dilution rates whereas spike CV is 1.4~4.8% at one-fold dilution, 0.6~19.9% at 10-fold, spike recovery; 35~72% at one-fold dilution and 77~107% at 10-fold. Conclusion : Gel clot does not seem to occur probably to H3PO4 which engages in bonding with Mg2+ion contributing gelation inside PCT. Dilution which is identical to reducing the amount of H3PO4, could remove interfering effects accordingly. Spike recovery was obtained within 70~150% - recommended values of supplier - at 40-fold dilution even in kinetic chromogenic method.

N-13 암모니아 주사액 제조 시 멸균필터의 흡착율 차이에 관한 비교 평가

오창범,김시활,차민정,신진,지용기,최성욱,Oh, Chang Bum,Kim, Si Hwal,Cha, Min Jung,Shin, Jin,Ji, Yong Gi,Choi, Sung Ook 대한핵의학기술학회 2019 핵의학 기술 Vol.23 No.1

기존에 Millex GS 멸균 필터를 사용하여 방사성 의약품 N-13 암모니아 주사액 제조 시 많은 양의 방사성 의약품이 멸균 필터에 흡착되어 있었다. 이에 Satorious의 Minisart 멸균 필터를 사용하여 흡착률의 차이를 확인하고 합성 수율을 증가시키고자 하였다. 실험 대상은 Millex GS 필터와 Satorious Minisart 필터를 대상으로 하였으며 제조된 N-13 암모니아를 각각의 멸균 필터에 통과시킨 후 선량계를 이용하여 흡착률을 구하였다(n=10). 그리고 품질 관리 시험을 시행하여 본원 기준에 적합한지 확인하였다. 실험 결과 Millex GS와 Sartorious Minisart 필터에 각각 $71.0{\pm}17.6%$와 $19.1{\pm}3.2%$ 흡착되었다. 필터를 제거한 product vial에는 Millex GS와 Sartorious 각각 $29.0{\pm}17.6%$와 $80.9{\pm}3.2%$ 여과되었다. 여과된 암모니아 주사액의 양은 GS 필터보다 Minisart 필터를 사용할 때 약 2.8배 더 많이 획득할 수 있었다. 각 멸균 필터를 통과한 N-13 암모니아 주사액의 방사화학적 이물, 화학적 이물, 이 핵종, pH, 엔도톡신, 무균 시험 등 품질 관리 시험 결과 본원 기준에 적합하였다. Millex GS 필터의 얇은 막은 mixed cellulous easter(MCE)로써 acetic acid, sulfic acid, anhydride에 추가로 Nitrocellulose가 약 80%의 비중을 차지하고 있는 필터이다. 때문에 Nitrocellulose가 포함되지 않은 CA계열인 Sartorious Minisart 필터보다 여과할 수 있는 성능은 Millex GS가 우수하나, 품질시험의 평가상 Satorious Minisart 필터를 사용하여도 문제가 없을 것이다. 따라서 N-13 암모니아 주사액 제조 시, Satorious Minisart 필터를 사용함으로써 필터 흡착으로 인한 손실을 최소화하고, 비용도 절감 할 수 있으며, 보다 안정적으로 N-13 암모니아 주사액을 제조 할 수 있을 것으로 생각한다. Purpose In the preparation process for N-13 Ammonia injections, there were radioactive medicines adsorbed on filters remarkably. Hereby, we have compared the adsorption rate and quality test on Millex GS filter and Satorious Minisart filter, both representatively hydrophilic sterilizing filters, also evaluated which filter is more accommodative for N-13 Ammonia injection. Materials and Methods The filters used for sterilization of N-13 Ammonia injections were Millex GS filter($0.22{\mu}m$) mand Satorious Minisart filter ($0.2{\mu}m$), which are generally used to strain aqueous solutions. After the N-13 Ammonia passes through each sterilization filter, the adsorption rate of the filter (n=10) is determined by measuring not only the radioactivity through the filter also the amount of radioactivity remaining in it using a Dose Calibrator. The N-13 Ammonia injections after each filter is tested by the quality control test to conform to the Samsung Medical Center standard. Results The ratio of radioactivity passed through Millex GS indicated $29.0{\pm}17.6%$. Satorious Minisart filters output was $80.9{\pm}3.2%$, respectively. Each ratio of radioactivity adsorbed on the sterile filter was $71.0{\pm}17.6%$ for Millex GS and $19.1{\pm}3.2%$ for the Satorious Minisart filters, respectively. Furthermore, on the ratio of filtered radioactivity, Using Satorious Minisart filter showed about 2.8 times higher than using Millex GS filter. The quality testing of N-13 Ammonia injections through each filter met the Samsung Medical Center standard. Conclusion The Millex GS filter is composed of cellulose acetate and cellulose nitrate, whereas the Satorious Minisart filter if composed only of cellulose acetate. Therefore, the presence of cellulose nitrate in the membrane seems to have made differences. Therefore, the use of Satorious Minisart filter in the preparation of N-13 Ammonia injection solution minimized the loss of radioactive medicines due to filter adsorption, thereby improving the synthesis yield.

방사성의약품 합성에서 발생하는 방사성기체의 효율적 차단

지용기,김동일,김시활,원문희,최성욱,최춘기,석재동,Chi, Yong Gi,Kim, Dong Il,Kim, Si Hwal,Won, Moon Hee,Choe, Seong-Uk,Choi, Choon Ki,Seok, Jae Dong 대한핵의학기술학회 2012 핵의학 기술 Vol.16 No.2

방사성의약품 제조 시 휘발성 기체의 경우에 완전 차폐가 되지 않고, Hot cell 외부로 그리고 배기덕트를 통해 작업자에게 외부피폭은 물론 호흡을 통해 내부피폭을 가져오게 한다. 처음에는 Hot cell 자체의 배출구를 막아서 방사성기체를 차단하려하였으나 장치에 맞는 기체 밀폐형 댐퍼의 제작이 어렵고, 크기가 맞지 않아서 설치 후에 여전히 문제점이 개선되지 않았다. 그러나 Tedlar gas sampling bag의 사용으로 합성 장치의 가스 배출구를 연결하여 방사성 기체를 저장하고 10반감기가 지난 후에 배출함으로써 작업자의 피폭을 확연히 줄이게 되었으며 $^{18}F$ 방사성 기체는 Hot cell 배출구에 활성탄 필터를 연결하고 최종 배출구에 2차 활성탄 필터를 사용함으로써 배출되는 방사능 농도를 90% 이상 줄여주었다. 단 반감기의 핵종인 경우는 위와 같은 경우를 이용하여 다음날 작업을 할 수 있지만 반감기가 긴 핵종들 같은 경우는 다음날 처리 할 수 없는 문제점들이 발생한다. Decay tank의 추가적인 문제점들을 보완하거나 기체상의 여러 방사성 입자들을 포집 할 수 있는 물질들이 만들어져야 할 것이다. 현재 우리나라는 최종 배출 공기 중 방사능 농도만을 규제하고 있으나 유럽 같은 경우 일일 배출 양과 연간 배출도 규제를 하고 있다. 방사성의약품 합성 시 발생하는 많은 방사성 물질들을 보다 효과적으로 친환경적으로 처리할 수 있는 여러 연구들이 이루어져야 할 것이다. Purpose : Methode an effective block was investigated to deal with volatile radioactive gas, short lived radioactive waste generated as a result of the routinely produced radiopharmaceuticals FDG (2-deoxy-2-[$^{18}F$]fluoro-D-glucose) and compound with $^{11}C$. Materials and Methods : All components of the radiation stack monitoring and data management system for continuous radioactive gas detection in the air extract system purchase from fixed noble gas monitor of Berthold company. TEDLAR gas sampling bags purchase from the Dongbanghitech company. TEDLAR gas sampling bags (volume: 10 L) connected via paraflex or PTFE tubing and Teflon 3 way stopcock. When installing TEDLAR gas sampling bags in Hot cell on the inside and not radioactive gas concentrations were compared. According to whether the Hot cell inside a activated carbon filter installed, compare the difference in concentration of the radioactive gas $^{18}F$. Comparison of radiation emission concentration difference of module a FASTlab and TRACElab. Results : Activated carbon filter are installed in the Hot cell, a measure of the concentration of radioactive gas was 8 $Bq/m^3$. Without activated carbone filter in the hot cell was 300 $Bq/m^3$. Tedlar bag prior to installation of the radioactive gases a measure of the concentration was 3,500 $Bq/m^3$, $^{11}C$ synthesis of the measured concentration was 27,000 $Bq/m^3$. After installed a Tedlar bag and a measure concentration of the radioactive gases was 300 $Bq/m^3$ and $^{11}C$ synthesis was 1,000$Bq/m^3$. Conclusion : $^{11}C$ radioactive gas that was ejected out of the Hot cell, with the use of a Tedlar gas sampling bag stored inside. A compound of 11C is not absorbed onto activated carbon filter. But can block the release out by storing in a Tedlar gas sampling bag. We was able to reduce the radiation exposure of the worker by efficient radiation protection.

기체크로마토그래프법을 이용한 [F-18]FDG의 잔류용매 분석

김동일,이일중,김시활,지용기,석재동,Kim, Dong-Il,Lee, Il-Jung,Kim, Shi-Hwal,Chi, Yong-Gi,Seok, Jae-Dong 대한핵의학기술학회 2011 핵의학 기술 Vol.15 No.2

[F-18]FDG 제조 후 품질관리를 수행하는데 있어서 품질관리 항목 중 잔류용매 시험은 최종 [F-18]FDG 바이알에 잔류하는 유기용매를 측정하기 위한 것이다. 본 연구는 자동합성장치에 따른 최종 [F-18]FDG 바이알에 잔류하는 유기용매의 종류를 파악하고, 잔류량을 측정하고자 하였다. 불꽃이온화 검출기(Flame Ionization Detector)가 장착된 기체크로마토그래프(Agilent Technologies 7890A)를 이용하여 제조 후 일주일 이내의 밀봉 바이알에 보관한 [F-18]FDG를 기체크로마토그래프에 $1.0{\mu}L$ 씩 주입한 후 각 피크영역을 구하였다. FASTlab은 평균이 에탄올 72 ppm, 아세토니트릴 54 ppm, 초산 1030 ppm으로 나타났으며, TRACERlab MX는 평균이 에탄올 439 ppm 및 아세토니트릴 79 ppm이 검출되어 모두 의약품 잔류용매기준의 허용량 이내에 있었다. [F-18]FDG 주사액에 있는 잔류용매는 모두 허용량 이내로 환자검사에 사용하는데 적합하였다. 또한 최종 [F-18]FDG 바이알에 있을 수 있는 초산의 최대 이론량은 1167 ppm으로 따로 검량을 하지 않아도 되는 것으로 나타났다. 이 결과에서는 자동합성장치에 따라 방사성의약품의 잔류용매의 종류 및 양이 다를 수 있음을 보였다. Purpose: The general test method of the Korean Pharmacopeia specifies the test method on the clauses of quality control after manufacturing. According to KFDA Guidance for Medicines, standards of residual solvents regulates the maximum permissible dose of acetonitrile as 400 ppm, ethanol as 5,000 ppm, and acetic acid as 5,000 ppm. This study aims at identifying the type of resiual solvents in the final [F-18]FDG vial of an automatic synthesizer and measure its residual quantity. Materials and Methods: The center carried out residual solvents test of [F-18]FDG injection using Agilent Technologies 7890A with a Flame Ionization Detector. The column of Agilent Technologies 7890A used in measuring of residual solvents was CP WAX column ($30m{\times}0.53mm{\times}1.0{\mu}m$) and analysis condition was split mode 1:1 at the initial temperature $70^{\circ}C$ which was increased $20^{\circ}C/minute$ after two minutes and maintained at the final $140^{\circ}C$ for two minutes. The analysis method was as following: Firstly, ethanol-acetonitrile-acetic acid mixture was classified into four types of concentration (250-25-250 ppm, 1,000-100-1,000 ppm, 3,000-300-3,000 ppm, and 6,000-600-6,000 ppm), and $1.0{\mu}L$ of each type of concentration was injected into gas chromatography followed by an analysis of its peak domain. Then, a calibration-curve by the external standard method was drawn based on the analysis result. Results: While ethanol and acetonitrile were detected in TRACERlab MX, FASTlab had additional acetic acid. The residual quantity of the ethanol-acetonitrile-acetic acid mixture evaluated using the calibration-curve was average 72 ppm ethanol, 54 ppm acetonitrile, and 1030 ppm acetic acid for FASTlab, whereas average 439 ppm ethanol and 79 ppm acetonitrile for TRACERlab MX. This indicated that both of them were within the maximum permissible dose. Conclusion: Solvent residues in the [F-18]FDG injection were all within maximum permissible doses and proper to be used to examine a patient. The result indicated that types and quantities of solvent resides of radioactive pharmaceuticals vary depending on the automatic synthesizer.

⁶⁸Ga 표지 PET/CT 검사의 최적화된 매개변수에 대한 연구

곽인석,이혁,김시활,문승철,In Suk Kwak,Hyuk Lee,Si Hwal Kim,Seung Cheol Moon 대한핵의학기술학회 2023 핵의학 기술 Vol.27 No.2

Purpose: Gallium-68 (⁶⁸Ga) is increasingly used in nuclear medicine imaging for various conditions such as lymphoma and neuroendocrine tumors by labeling tracers like Prostate Specific Membrane Antigen (PSMA) and DOTA-TOC. However, compared to Fluorine-18 (¹⁸F) used in conventional nuclear medicine imaging, ⁶⁸Ga has lower spatial resolution and relatively higher Signal to Background Ratio (SBR). Therefore, this study aimed to investigate the optimized parameters and reconstruction methods for PET/CT imaging using the ⁶⁸Ga radiotracer through model-based image evaluation. Materials and Methods: Based on clinical images of ⁶⁸Ga-PSMA PET/CT, a NEMA/IEC 2008 PET phantom model was prepared with a Hot vs Background (H/B) ratio of 10:1. Images were acquired for 9 minutes in list mode using DMIDR (GE, Milwaukee WI, USA). Subsequently, reconstructions were performed for 1 to 8 minutes using OS-EM (Ordered Subset Expectation Maximization) + TOF (Time of Flight) + Sharp IR (VPFX-S), and BSREM (Block Sequential Regularized Expectation Maximization) + TOF + Sharp IR (QCFX-S-400), followed by comparative evaluation. Based on the previous experimental results, images were reconstructed for BSREM + TOF + Sharp IR / 2 minutes (QCFX-S-2min) with varying β-strength values from 100 to 700. The image quality was evaluated using AMIDE (freeware, Ver.1.0.1) and Advanced Workstation (GE, USA). Results: Images reconstructed with QCFX-S-400 showed relatively higher values for SNR (Signal to Noise Ratio), CNR (Contrast to Noise Ratio), count, RC (Recovery Coefficient), and SUV (Standardized Uptake Value) compared to VPFX-S. SNR, CNR, and SUV exhibited the highest values at 2 minutes/bed acquisition time. RC showed the highest values for a 10 mm sphere at 2 minutes/bed acquisition time. For small spheres of 10 mm and 13 mm, an inverse relationship between β-strength increase and count was observed. SNR and CNR peaked at β-strength 400 and then decreased, while SUV and RC exhibited a normal distribution based on sphere size for β-strength values of 400 and above. Conclusion: Based on the experiments, PET/CT imaging using the ⁶⁸Ga radiotracer yielded the most favorable quantitative and qualitative results with a 2 minutes/bed acquisition time and BSREM reconstruction, particularly when applying β-strength 400. The application of BSREM can enhance accurate quantification and image quality in ⁶⁸Ga PET/CT imaging, and an optimization process tailored to each institution's imaging objectives appears necessary.