Alternative technologies for 99mtc generators

THIRD FNCA COORDINATORS MEETING March – , 2002 , Tokyo , Japan THIRD FNCA COORDINATORS MEETING - 2002 - ALTERNATIVE TECHNOLOGIES FOR 99Tcm GENERATORS Le Van So Nuclear Research Institute, Dalat , Vietnam INTRODUCTION Technetium-99m is the most widely used radioisotope in Nuclear Medicine More than 80% of all diagnostic nuclear medicine procedures is based on using 99 Tcm Annually around 15 million patients in Europe and the United States of America were investigated using 99Tcm 99Tcm (6.0 h) is almost exclusively produced from the decay of its 66 h parent 99Mo The present world demand for 99 Mo was estimated at approximately 6000 Ci per week (6 days pre-calibrated) Further growth in demand has been predicted The present sources of 99Mo are research reactors by using the (n,γ) nuclear reaction with natural Mo (98Mo, ~24%), resulting in inexpensive but low specific activity 99Mo or by neutroninduced fission of 235U, which results in expensive but high specific activity of 99 Mo The technology requirements for processing of 99Mo from (n,γ) “activation method” is rather simple, and is within the reach of most developing countries operating research reactors In the “fission method”, the technological and infrastructure requirements are more complex and possibly can be sustained only by countries with advanced nuclear technology At present nearly the entire demand for 99Mo is supplied by a few large producers employing reactors based production by means of thermal neutroninduced fission of enriched uranium The processing technology has been proven and licensed and the 99Mo and 99Tcm have been approved by pharmaceutical regulatory authorities Due to the existing investment in production infrastructure and in the approval of 99Mo and derived products, there will have to be a substantial economic incentive for a large producers of Mo-99 or Tc-99m generators to change to a new process Alternative technologies for 99Tcm generators can be noted below Among these the technologies for 99Tcm generators using Zirconium- or Titanium Molybdate gel, so called “gel technology” and polymer Zirconium- or Titanium compound (PZC , PTC ) based technology are considered as new ones Any new process having a potential influence on the product quality, compared to existing process will have to be demonstrated and licensed fully The product should be qualified by the various regulatory authorities, which is a long and expensive process adding to the market inertia referred to previously GENERAL ASPECTS ON THE 99MO AND 99TCm GENERATOR PRODUCTION Technology and product 99 99 Mo Technology Fission 99Mo 235 • (Portable, simple generator ; Simple technology) 99 (n,γ) reaction 99Mo 98 • – Chromatographic 99Tcm generator using Alumina column U (n,f) 99Mo + Fission products Expensive, high specific activity Mo) • Complex technology • Tcm generator production – Sublimation 99Tcm generators • High temperature sublimation from MoO3 (not portable, complicated design and centralized generators) • Low temperature sublimation from Titanium -(99Mo)Molybdate (Portable , complicated design , gel generator) Mo(n,γ) Mo 99 inexpensive, low specific activity Mo Simple technology 99 99 – 99Tcm solvent extraction generator (not-portable, complicated design , centralized generator) – Chromatographic 99Tcm generator using Titanium - and/or Zirconium – Molybdate gel (Gel type 99Tcm generator) (Portable, simple generator Sophisticated technology.) – Chromatographic 99Tcm generator using PZC and/or PTC column (Portable , simple generator Sophisticated technology ) Radioactive waste generated from 99Mo production The manufacture of a Ci generator produces the following quantities of radioactive waste (n,γγ) 99Mo Fission 99Mo Chromatographic generator (Gel or PZC, TZC column) Chromatographic generator (Alumina column) 99 Mo (10-2 Ci) 235 Other nuclides (10-4Ci) U Fission Products T Ci PROVISION OF THE CHROMATOGRAPHIC 99Tcm GENERATOR PRODUCTION WITH (n,γγ) 99Mo PRODUCED EX-NATURAL MOLYBDENUM For production of chromatographic 99Tcm generator acceptable for clinical diagnosis with (n,γ) 99Mo the following parameters must be considered as indispensable requirements: - Available thermal neutron flux is high enough - High Mo-Content of generator column packing must be available - The column is of good elution performance (high 99Tcm separation yield) By using the following equation, we have: K= 2.055 * 10 −14 A Mo-99 * m *Φ * (1 − e −0.0104t ) K = Mo-content of column-packing material containing molybdenum activated with time t and of m gram weight G = Weight of activated molybdenum element, in gram AMo-99 = Radioactivity of 99Mo, in Curie t = Activation time, in hour Θ = 23.75%; a = 95.94; T = 66.7 hours (haft life of 99Mo) σAct = 0.51 barn (thermal neutron activation cross section of 98Mo) Based on the above equation, fig.1 showed the relationship of Molybdenum content (K) and radioactivity and / or radioactive concentration of 99Tcm elutable from the generators prepared from (n,γ) 99Mo produced ex-natural Molybdenum in reactors of thermal neutron flux of Φ = 2*1013 , Φ = 5*1013 and Φ = 1014 n.cm-2.sec-1 Fig.1 Estimation of 99Tcm Radioactivity of a generator using a column-packing material of Molybdenum content (K) a line: for Φ = 2.1013 n.cm-2.sec-1; b line: for Φ = 5.1013 n.cm-2.sec-1 c line: for Φ = 1014 n.cm-2.sec-1 As shown, if we have a reactor of neutron flux of Φ = 5*1013 n.cm-2.sec-1 the column packing material of Molybdenum content K ≥ 172 mgMo/g can be used to produce a 99Tcm generator of 500 mCi 99Tcm or a 99Tcm -pertechnetate solution of concentration of 50 mCi 99Tcm/ml This 99Tcm solution can be effectively applied in nuclear medicine investigations The Mo-content value of K> 172 mgMo/g can be found in the following cases: - Compound of polymolybdate in gel form such as Titanium-Molybdate, Zirconium-Molybdate, Tin-Molybdate, etc - Zirconium- or Titanium-Oxide of high porosity - Polymer compound of Zirconium or Titanium (PZC ,PTC) PRACTICAL REQUIREMENTS FOR THE PZC COLUMN-BASED 99 Tcm GENERATOR PRODUCTION Requirements for column packing materials High molybdenum content High 99Tcm separation yield Short elution profile Low molybdenum (non-radioactive and radioactive 99Mo) breakthrough High mechanical, chemical, thermal & irradiation stability Requirements for hot cell technology and generator design Sterility for assembling and operating processes Simplicity in assembling with good radiation protection and manipulating process Air-tightness of highest reliability in operation and transportation Labourer protection Easy-to-use for users Basic studies for the development of technology for production of PZC column-based 99Tcm generators Study on the chemistry of molybdate ions in aqueous solutions Provision of reaction mechanism for adsorption and estimation of surface properties of particles Study on the properties of PZC-Mo relating to the polymeric characteristics of molybdate Study on the behaviours of PZC-Mo under irradiation and sterilization process Study on the Mo- adsorption conditions (Solution composition , concentration , pH, temperature, reaction time…) effecting the breakthrough of Molybdenum Study on the additive components to enhance the radiation stability of PZC-Mo column Studies on the elution performance of PZC-Mo, the effect of bed size on the elution profile Studies on the “safety column” , Alumina or others Investigation on quality of elutate and expected performance 10.Study on durability of generator elution Studies on the implementation of production Standardization process for PZC synthesis − Design apparatus for PZC preparation with a set of pre-specified parameters − Specification and characterization of the PZC product Target preparation for the production of neutron activated 99Mo: Purification of Molybdenum-Trioxide for neutron activation Study on hot-cell technology for generator production a) Standardization process for Mo-adsorption on PZC Design of apparatus for Mo-adsorption on PZC with a set of prespecified reaction conditions (pH, Mo concentration, temperature, reaction time, additives….) b) PZC column preparation: Column loading , conditioning , autoclaving for sterilization and 99 Mo radioactivity calibration c) Design of generator d) Generator assembling process (in-cell and out-of-cell) Testing the elution performance and radioactivity calibration (elution profile and efficiency of 99Tcm) In-process quality control of 99Tcm eluate (99Mo breakthrough, radionuclide impurities, chemical purity, radiochemical purity) Set-up a Quality Manual (Work instruction, Standard – OperationProcess (SOP)) for production of 99Tcm generator fulfilling the QA and GMP’s requirements Radiopharmaceutical Registration Collection and summary of test results for registration 99Tcm derived from PZC based generators has to be assessed by a battery of tests and has to be compared against the international standards of acceptability that would apply to presently available generators without exception, the performance characteristics of the PZC based generator should be found to be at least as good as those exhibited by the fission 99Mo generator Besides the quality control results mentioned above, the testing results on the sterility, apyrogenity , toxicity, pre-clinical biological testing and clinical trial must be collected Other considerations Given the close similarity in the technical performances of the two generator types (fission 99Mo generator and PZC – column based generator), it is profitable to examine other considerations to find the incentives for change of technology − Economic considerations The cost of producing (n,γ) 99Mo is less than that for fission 99Mo The costdifferential can be quite substantial: eg: $US 0.83 per Ci as compared to $US 57 per Ci Effective cost are also complicated by such considerations as the post delivery calibration time for the 99Mo activity and the type of elution regime However it would be reasonable to presume that the PZC-based generator technology will offer some savings − Waste and environmental issues The processing of uranium targets for the production of fission 98Mo generators gives rise to quantities of medium-level liquid and solid wastes containing uranium, plutonium and several long-lived fission products which require substantial treatment before final disposal can be contemplated The processing of neutron activated MoO3 does not require as sophisticated a waste management strategy TECHNOLOGY AND PRODUCT QUALIFICATION For Zirconium-Molybdate and Titanium-Molydate Gel Preparation Technological parameters and requirements Technology options From Australia, Thailand, Indonesia, Argentina, India, Hungary From Vietnam + Reaction time (for a reagent volume of one litre) around hours around hour + Reaction facility - not complicated - not complicated + Process automation capability - poor - good + Hot cell technology compatibility - poor - good + Precipitate filterability - difficult to suck the precipitate (12 hours for litre of precipitate) - easy to suck the precipitate (1o minutes required for litre of precipitate) + Temperature for gel drying - around 60oC - around 80oC + Time for gel drying - long (more than 12 hours) - short (about hour) + Gel particle fractionation - need grinding and sieving - grinding and sieving unneeded Quality parameters and property of gel - Technology options From Vietnam From Australia, Thailand, Indonesia, Argentina, India, Hungary - + Hydroscopic property - very hydroscopic - not hydroscopic + Reactor irradiation stability - not good - good + Thermal stability - not good - good enough + Gel particle swelling dispersion - the gel particle swollen and dispersed in aqueous solution - + Mechanical stability - not good - the gel particle and not swollen or/ and dispersed in aqueous solution good + Moisture or crystal water content of the dried gel - higher than 10% - around 6% + Particle size homogencity - not homogeneneous (need grinding and sieving) - + Eluant flow-rate (to pass through the gel column with sintered glass disk of G-3 at bottom + The gel column conditioning - very low (the flow slowed gradually) - homogeneneous (particle size suitable for column packing grinding and sieving unneeded) high and constantly retained - - conditioning not required + Molybdenum breakthrough level - without any coupled safety column - with aluminum or zirconia safety column coupled to gel column - need conditioning with large volume of saline to get higher separation yield of 99 Tcm pertechnetate at medium level around 50 mgMo/ml - over medium level around 80 mgMo/ml - not detected - not detected + (99Tcm) pertechnetate elution yield - more than 60% in case of ZrMo gel - more than 80% in both cases of gel 10 View publication stats ... incentive for a large producers of Mo-99 or Tc-99m generators to change to a new process Alternative technologies for 99Tcm generators can be noted below Among these the technologies for 99Tcm generators. . .ALTERNATIVE TECHNOLOGIES FOR 99Tcm GENERATORS Le Van So Nuclear Research Institute, Dalat , Vietnam INTRODUCTION... transportation Labourer protection Easy-to-use for users Basic studies for the development of technology for production of PZC column-based 99Tcm generators Study on the chemistry of molybdate