Method for preparing validation sample for fluorescent x-ray analyzer, and validation method for fluorescent x-ray analyzer

Abstract

The present invention involves: dividing target elements including Cd, Pb, As, Hg, Co, V, and Ni into a plurality of groups so that As and Pb belong to the same group and are separated from a group Hg belongs to; and adding, for each group, a liquid (12, 121 to 128) containing target elements belonging to the group to powder (11) made of a material not containing any of the target elements and mixing the liquid with the powder so that the target elements belonging to the group each reach a predetermined concentration.

Description

Method for preparing samples for analytical validation of an X-ray fluorescence analyzer and method for analytical validation of an X-ray fluorescence analyzer

[0001] The present invention relates to a method for preparing a sample used in performing analytical validation (validation test) of an X-ray fluorescence analyzer, and a method for analytical validation of an X-ray fluorescence analyzer using the sample.

[0002] If harmful metal elements are mixed as impurities into pharmaceuticals, foods, etc., they may cause health problems for those who consume them. For this reason, standards have been established to regulate the concentrations of specific metal elements. In particular, for pharmaceuticals, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) has established an international standard called the "Guideline for elemental impurities Q3D" (hereinafter referred to as "ICH Q3D") (see Non-Patent Document 1).

[0003] ICH Q3D defines acceptable daily intakes for 24 metal elements, and the acceptable concentrations for each drug product are determined based on these acceptable intakes. The 24 metal elements are classified into four classes (Class 1, Class 2A, Class 2B, and Class 3) based on their toxicity and the likelihood of contamination in pharmaceuticals. Class 1 consists of four elements with particularly high toxicity: Cd (cadmium), Pb (lead), As (arsenic), and Hg (mercury). Class 2A consists of three elements: Co (cobalt), V (vanadium), and Ni (nickel), which are derived from natural products and have a high likelihood of contaminating pharmaceuticals. Class 2B consists of 10 elements, including Pd (palladium), which are unlikely to be present in natural products but may be present in pharmaceuticals from catalysts and other materials used in the manufacturing process. Class 3 consists of seven elements that are less toxic than the 17 elements listed above and do not require assessment for oral formulations but are subject to assessment for injectable and inhaled formulations.

[0004] When evaluating the concentrations of metal elements in pharmaceuticals based on ICH Q3D, at least seven elements belonging to Class 1 and 2A are included in the evaluation. Furthermore, if any of the ten elements belonging to Class 2B are present and there is a possibility that they may be mixed into the pharmaceutical during manufacturing, these elements are also included in the evaluation. For example, when evaluating an oral formulation manufactured using Pd, eight elements, including the seven elements mentioned above and Pd, are evaluated. Pd is an element used as a catalyst in the manufacturing of many pharmaceuticals. Furthermore, in the case of injectables and inhalants, some or all of the seven elements belonging to Class 3 are included in the evaluation as necessary.

[0005] In Non-Patent Document 1, inductively coupled plasma mass spectrometry (ICP-MS) is used as a method for analyzing the concentration of the elements to be evaluated, but ICP-MS has the problem of requiring time-consuming sample pretreatment. In contrast, it has recently been proposed to analyze the concentration of the elements to be evaluated using X-ray fluorescence spectrometry, which allows for easier sample pretreatment (Non-Patent Document 2). With X-ray fluorescence spectrometry, sample pretreatment requires only grinding the pharmaceutical into a uniform powder.

[0006] In X-ray fluorescence analysis, in order to confirm that the equipment and analytical conditions used for analyzing the concentration of the target element are appropriate, it is necessary to periodically perform analytical validation by performing X-ray fluorescence analysis on analytical validation samples containing the target element at known concentrations to confirm that the correct concentration has been obtained.Since the actual analyte is measured in powder form, the analytical validation sample is prepared by adding a predetermined amount of a standard solution containing a predetermined concentration of the target element to a powder (for example, cellulose powder, which is a pharmaceutical additive) and mixing it.

[0007] Takayuki Ichinose and 1 other person, "Pharmaceutical Elemental Impurity Guidelines (ICH Q3D) and ICP-MS: Current Status from the Analyst's Perspective," Kanto Chemical Co., Ltd., THE CHEMICAL TIMES, Vol. 255, pp. 7-13, January 2020 issue, "Pharmaceutical Elemental Impurity Management," [online], Shimadzu Corporation, [Retrieved October 30, 2023], Internet <https: / / www.an.shimadzu.co.jp / products / elemental-analysis / edx-fs / pharmaceutical-elemental-impurities-analysis-system / index.html>

[0008] If analytical validation samples are prepared element by element, the analytical validation procedure must be repeated for each element to be evaluated, which is time-consuming. On the other hand, by adding predetermined amounts of standard solutions of multiple elements to the same powder, analytical validation samples containing these elements can be prepared, reducing the number of analytical validation procedures to less than the number of elements. However, while analytical validation performed using the same X-ray fluorescence analyzer using analytical validation samples prepared element by element yields the correct concentration, using analytical validation samples containing multiple elements yields concentration values ​​lower than the actual value, and the concentration values ​​vary for each sample prepared, making analytical validation inaccurate.

[0009] The problem to be solved by the present invention is to provide a method for preparing a sample for analytical validation of an X-ray fluorescence analyzer, and a method for analytical validation of an X-ray fluorescence analyzer, which enable accurate analytical validation to be performed while reducing the amount of work required.

[0010] In order to solve the above problems, the present invention provides a method for preparing samples for analytical validation of an X-ray fluorescence analyzer, which involves dividing target elements including Cd, Pb, As, Hg, Co, V, and Ni into a plurality of groups, with As and Pb in the same group and As, Pb, and Hg in separate groups, and then, for each of the plurality of groups, adding and mixing a liquid containing the target elements belonging to that group to a powder made of a material that does not contain any of the target elements, so that the target elements belonging to that group each reach a predetermined concentration.

[0011] The analytical validation method for an X-ray fluorescence analyzer according to the present invention measures the concentration of the target element by performing X-ray fluorescence analysis on each of a plurality of analytical validation samples prepared by the above-described preparation method using the X-ray fluorescence analyzer that is the subject of analytical validation, and determines whether the difference between the obtained concentration and the predetermined concentration is within a predetermined range.

[0012] The analytical validation sample prepared by the method for preparing an analytical validation sample for an X-ray fluorescence analyzer according to the present invention must contain, as target elements, seven elements consisting of all elements belonging to Class 1 (Cd, Pb, As, and Hg) and all elements belonging to Class 2A (Co, V, and Ni). In addition to these seven elements, other elements such as Pd may also be contained as target elements in the analytical validation sample according to the present invention. Of course, the analytical validation sample may contain only the above seven elements (excluding the constituent elements of the powder).

[0013] The inventors prepared various samples with different combinations of target elements in the same group and performed analytical validation using these samples on an X-ray fluorescence analyzer previously confirmed to be functional. They found that when As and / or Pb and Hg were grouped together, the concentrations of one to three of these elements, As, Pb, and Hg, were lower than the actual values, and the values ​​varied from sample to sample. While the cause of this is unclear, it is presumed that when a solution containing Hg is added to a powder along with a solution containing As and / or Pb, some of these elements do not adhere to the powder for some reason. Therefore, in this invention, As, Pb, and Hg are separated into separate groups, and analytical validation samples are prepared for each group. This prevents the As, Pb, and Hg concentrations obtained during analytical validation from being lower than the specified concentrations, ensuring accurate analytical validation.

[0014] On the other hand, elements with similar characteristic X-ray wavelengths must be included in the same group. This is because, when the sample to be evaluated contains multiple elements, the profiles obtained by X-ray fluorescence analysis are overlapped, and data processing known as overlap correction is performed to identify the concentration of each element. Therefore, analytical validation is performed under the same conditions as when analyzing the sample to be evaluated, with the profiles overlapped. Among the elements of interest in this invention, the Kα line energy of As (10.532 keV) and the Lα line energy of Pb (10.552 keV) are similar. Therefore, in this invention, by including As and Pb in the same group, analytical validation samples that enable accurate analytical validation can be obtained.

[0015] Furthermore, the method for preparing analytical validation samples of the present invention prepares samples containing multiple elements for at least one group including As and Pb, which reduces the effort required for analytical validation compared to preparing individual samples for all target elements.

[0016] 1 is a schematic diagram showing one embodiment of a method for preparing a sample for analytical validation of an X-ray fluorescence analyzer according to the present invention, and shows a state (e) of the sample for analytical validation of an X-ray fluorescence analyzer obtained through the steps of (a) preparing a powder, (b) preparing a liquid containing each target element for each target element, (c) adding the liquid containing the target element to the powder, (d) drying the powder to evaporate the liquid containing the target element, and (e) stirring the powder. A diagram for explaining the operation of analytical validation of an X-ray fluorescence analyzer performed using the sample for analytical validation prepared by the preparation method of this embodiment.

[0017] An embodiment of a method for preparing a sample for analytical validation of an X-ray fluorescence analyzer and a method for analytical validation of an X-ray fluorescence analyzer according to the present invention will be described with reference to FIGS. 1 and 2. FIG.

[0018] In this embodiment, we will explain both the case where seven target elements are Cd, Pb, As, Hg, Co, V, and Ni, which belong to Class 1 and Class 2A, and the case where eight target elements are added, including Pd, among the seven elements belonging to Class 2B. Pd is an element used as a catalyst in the manufacturing process of many pharmaceuticals. The following explanation will be given using the case where Pd is included as a target element as an example. If only the seven elements are targeted, the process described below can be performed without the treatment for Pd. In this embodiment, these eight (or seven) target elements are divided into a first group consisting of Cd, Pb, As, Co, and Ni, and a second group consisting of Hg, V, and Pd (Hg and V in the case of "seven elements"). A first analytical validation sample 101 containing the target elements of the first group and a second analytical validation sample 102 containing the target elements of the second group are prepared.

[0019] The grouping of target elements and the number of groups are not limited to this example. Also, as long as the above seven elements are included, other elements belonging to Class 2B or Class 3 may be included in the target elements. However, As and Hg must be divided into different groups, and As and Pb must be included in the same group.

[0020] Figure 1 shows the steps of the method for preparing analytical validation samples according to this embodiment. First, a powder 11 is prepared, which is made of a material that does not contain any of the eight target elements. Materials suitable for the powder 11 include cellulose, lactose hydrate, and other additives used in pharmaceutical tablets and powders. Alternatively, powders from the same production lot as pharmaceutical tablets or powders that have been confirmed to be free of the eight elements (in the case of tablets, they may be crushed) may be used. The powder 11 is divided into two portions (first powder 111 and second powder 112), and each is smoothed so that its top surface is flat (Figure 1(a)).

[0021] Additionally, eight liquids (target element-containing liquids) 12 containing one of each of the eight elements are prepared (FIG. 1(b)). The target element-containing liquids 12 are a Cd-containing liquid 121 containing Cd, a Pb-containing liquid 122 containing Pb, an As-containing liquid 123 containing As, an Hg-containing liquid 124 containing Hg, a Co-containing liquid 125 containing Co, a V-containing liquid 126 containing V, a Ni-containing liquid 127 containing Ni, and a Pd-containing liquid 128 containing Pd.

[0022] As the target element-containing liquid 12, for example, a liquid used as a standard sample in an atomic absorption spectrometer, an inductively coupled plasma optical emission spectrometer, or an inductively coupled plasma mass spectrometer can be suitably used.

[0023] Furthermore, for example, because Hg, V, and Pd form stable complexes in hydrochloric acid, salts of Hg, V, and Pd may be added to hydrochloric acid to prepare Hg-containing liquid 124, V-containing liquid 126, and Pd-containing liquid 128. Since Hg, V, and Pd share the common characteristic of forming stable complexes in hydrochloric acid, even if they are mixed in the same analytical validation sample, this does not cause a decrease in the concentrations of these elements obtained during analytical validation.

[0024] Next, predetermined amounts of Cd-containing liquid 121, Pb-containing liquid 122, As-containing liquid 123, Co-containing liquid 125, and Ni-containing liquid 127 are added to the upper surface of first powder 111, and predetermined amounts of Hg-containing liquid 124, V-containing liquid 126, and Pd-containing liquid 128 are added to the upper surface of second powder 112 ( FIG. 1( c) ). The amounts of each of target element-containing liquids 121-128 are determined so that, when all of the target elements remain in the final first analytical validation sample 101 and second analytical validation sample 102, the target elements will have predetermined concentrations in the first analytical validation sample 101 and second analytical validation sample 102. These predetermined concentrations are determined so that characteristic X-rays of sufficient intensity can be obtained by X-ray fluorescence analysis of the first analytical validation sample 101 and the second analytical validation sample 102.

[0025] When adding the target element-containing liquid 12 to the first powder 111 or the second powder 112, if target element-containing liquids containing different target elements are mixed together, the concentrations of some of the target elements will be detected as lower than they actually are (although the cause is unclear). Therefore, it is preferable to add each target element-containing liquid 12 to a different position in the first powder 111 or the second powder 112 (see FIG. 1(c)).

[0026] After the target element-containing liquid 12 is added to the first powder 111 and the second powder 112, the first powder 111 and the second powder 112 are dried without stirring to evaporate the solvent in the target element-containing liquid 12 (FIG. 1(d)). The first powder 111 and / or the second powder 112 may be heated. However, if the target element complex contained in the target element-containing liquid 12 is volatile, the temperature is lower than the temperature at which the complex volatilizes. The temperature is, for example, in the range of 30 to 70°C, and the heating time is, for example, in the range of 8 to 72 hours.

[0027] Next, the first powder 111 is stirred so that the target elements of the first group, Cd, Pb, As, Co, and Ni, added to the first powder 111, are distributed as uniformly as possible. The powder can be stirred using a mortar, a commercially available grinder, or the like. The second powder 112 is also stirred so that the target elements of the second group, Hg, V, and Pd, are distributed as uniformly as possible. Through the above operations, an analysis validation sample 10 of this embodiment is obtained, which includes a first analysis validation sample 101 in which the target elements of the first group have been added to the first powder 111, and a second analysis validation sample 102 in which the target elements of the second group are contained in the second powder 111 ( FIG. 1( e)).

[0028] Next, we will explain the results of an experiment using an actually prepared analytical validation sample 10. In this experiment, we used an X-ray fluorescence analyzer that had been previously verified to be capable of measuring the contents (concentrations) of the above eight target elements within a normal error range by performing analytical validation using a known method.

[0029] First, in Example 1, an analytical validation sample 10 was prepared, consisting of a first analytical validation sample 101 containing Cd, Pb, As, Co, and Ni, and a second analytical validation sample 102 containing Hg and V (but not Pd). In Comparative Example 1, a single analytical validation sample was prepared by adding seven target element-containing liquids 12 (121-127), each containing one of the seven target elements, to the same powder 11. Powder 11 was made from an organic pharmaceutical active ingredient that had been confirmed to contain none of the seven target elements. In both Example 1 and Comparative Example 1, the concentrations and amounts of the target element-containing liquids were adjusted so that the target concentrations of the target elements in each sample were 3.0 ppm for Cd, 3.0 ppm for Pb, 9.0 ppm for As, 20 ppm for Hg, 30 ppm for Co, 60 ppm for V, and 100 ppm for Ni. Here, "ppm" stands for "μg / g," that is, the mass (unit: μg) of the target element contained in a liquid containing the target element with a unit mass (unit: g).

[0030] For the first analytical validation sample 101 and the second analytical validation sample 102 of Example 1, as well as the analytical validation sample of Comparative Example 1, fluorescent X-ray measurements were performed using an X-ray fluorescence analyzer that had been confirmed to be normal, and the concentration of the target element in each sample was quantified. The fluorescent X-ray measurements were performed three times for each sample, and the concentration was calculated as the average of the values ​​obtained from the three measurements. The results are shown in Table 1. The "recovery rate" in Table 1 is the percentage obtained by dividing the quantitative concentration value measured by the fluorescent X-ray analysis by the target concentration value at the time of addition of the target element-containing liquid.

[0031] The analytical validation sample of Comparative Example 1 had a low As recovery rate of 77.7%. The Hg recovery rate and Pb recovery rate were also somewhat low, at 91.5% and 93.3%, respectively. In contrast, in Example 1, the quantitative concentration values ​​and recovery rates of As, Hg, and Pb were all higher than those of Comparative Example 1. This is thought to be because, while As, Hg, and Pb were contained in the same analytical validation sample in Comparative Example 1, "Hg (and V)" and "As and Pb" were contained in different analytical validation samples in Example 1 (the former in the first analytical validation sample 101 and the latter in the second analytical validation sample 102).

[0032] Next, in Example 2 and Comparative Example 2, analytical validation samples were prepared using powder 11 obtained by crushing pharmaceutical tablets instead of the drug substance powder. In both Example 2 and Comparative Example 2, the concentrations and amounts of the liquids containing each target element were adjusted so that the target concentrations of the target elements in each sample were 3.0 ppm for Cd, 3.0 ppm for Pb, 9.0 ppm for As, 18 ppm for Hg, 30 ppm for Co, 60 ppm for V, and 120 ppm for Ni. In Example 2, a first analytical validation sample 101 containing Cd, Pb, As, Co, and Ni, and a second analytical validation sample 102 containing Hg and V (but no Pd), were prepared in the same manner as in Example 1. In Comparative Example 2, an analytical validation sample containing all seven target elements was prepared in the same manner as in Comparative Example 1. Other experimental conditions were the same as in Example 1 and Comparative Example 1. The results are shown in Table 2.

[0033] The analytical validation sample of Comparative Example 2 had low recoveries of Hg and Pb, at 72.2% and 80.0%, respectively. Furthermore, the recovery rate of Ni, which was not significantly reduced (98.1%) in Comparative Example 1, was a low 80.5% in Comparative Example 2. In contrast, the quantitative concentration values ​​and recovery rates of Hg, Pb, and Ni in Example 2 were higher than those in Comparative Example 2. This is thought to be because "As, Pb, and Ni" and "Hg and V" were contained in the same analytical validation sample in Comparative Example 2, whereas in Example 2 they were contained in different analytical validation samples (the former in the first analytical validation sample 101 and the latter in the second analytical validation sample 102).

[0034] Furthermore, it was found that adding the seven elements together can also cause variations in Co concentration. In the following Comparative Example 3, the quantitative value of Co concentration decreased, and the recovery rate was 95%, significantly lower than 100%. In contrast, when the first analytical validation sample 101 containing Cd, Pb, As, Co, and Ni and the second analytical validation sample 102 containing only Hg and V were prepared and the quantitative values ​​of concentration and recovery rates were determined, the quantitative value of Co concentration also increased, and the recovery rate of Co was achieved to nearly 100%.

[0035] In both Examples 1 and 2, when V was added to the second analytical validation sample 102 together with Hg, a recovery rate close to 100% was obtained. Experiments conducted by the inventors of the present application have shown that Hg and V can exist in a stable complex state in the same solvent (hydrochloric acid), and therefore, even when added to the same sample, it is believed that the concentration is unlikely to decrease. A similar trend is observed between Hg and Pd, and therefore, when Pd is added to the target element, it is believed that Hg and Pd can be added to the same sample.

[0036] As shown in Table 4, Comparative Example 4, even though the target elements were added to a powder made of a material containing none of the target elements to achieve the same concentration as Comparative Example 3, the measured concentration was sometimes lower than that of Comparative Example 3. The sample in Comparative Example 4 showed a recovery rate of 69.5% for Hg, which is even lower than that of Comparative Examples 1 to 3. When the Hg recovery rate (and quantitative concentration value) is particularly low, it is recommended to use one of the multiple analytical validation samples containing only Hg. In Example 4 shown in Table 4, a first analytical validation sample containing six target elements other than Hg and a second analytical validation sample containing only Hg were prepared. As a result, the Hg recovery rate improved to 100.0%. Furthermore, the recoveries of not only Hg but also the other six target elements were higher than in Comparative Example 4, reaching or approaching 100%. In the above-described Examples 1 to 3, Hg and V were included in the same analytical validation sample. However, the results of Example 4 show that adding Hg alone to an analytical validation sample separate from the other six target elements not only improves the recovery rate of Hg itself, but also improves the recovery rates of the other six target elements. The target elements other than Hg may belong to the same group (i.e., added to the same sample) as in Example 4, or they may be divided into multiple different groups. To reduce the number of analytical validation operations (measurements using an X-ray fluorescence analyzer) and thereby reduce the effort required, it is preferable that the target elements other than Hg belong to the same group.

[0037] Next, a method for performing analytical validation of an X-ray fluorescence analyzer using an analytical validation sample prepared by the preparation method of this embodiment will be described. The analytical validation method of this embodiment applies mutatis mutandis to the method described in "3. Requirements for Validation of Analytical Methods, 3.1 Procedure for Limit Tests" in "General Tests, 2. Physical Tests, 2.6.6 Elemental Impurities" of the Japanese Pharmacopoeia, 18th Edition. Note that, in the method described in the Japanese Pharmacopoeia, 18th Edition, the apparatus subject to analytical validation is not limited to an X-ray fluorescence analyzer. In this embodiment, the following method is used to determine whether the three compatibility criteria of (i) detection sensitivity, (ii) specificity, and (iii) accuracy are met.

[0038] In the analytical validation method of this embodiment, two types of analytical validation samples are prepared according to the preparation method of this embodiment, each with a different concentration of the target element. In one analytical validation sample (hereinafter referred to as "Sample A"; note that Sample A itself is composed of multiple samples corresponding to the multiple groups), the concentration of each target element is adjusted to satisfy the formula below, which is calculated by dividing the permissible daily exposure (PDE) of each target element in the original drug being analyzed by the maximum daily dose of the drug, and multiplying this by a coefficient of 0.3. In the other analytical validation sample (hereinafter referred to as "Sample B"; also composed of multiple samples corresponding to the multiple groups), the concentration of each target element is adjusted to 0.8 times the concentration of each target element determined in Sample A.

[0039] 2, the first analytical validation sample 1011 belonging to sample A contains the target elements Cd, Pb, As, Co, and Ni at concentrations calculated by the above formula, while the second analytical validation sample 1021 also belonging to sample A contains the target elements Hg and V (which may contain Pd) at concentrations calculated by the above formula. Meanwhile, the first analytical validation sample 1012 belonging to sample B contains the target elements Cd, Pb, As, Co, and Ni at 80% of the concentrations calculated by the above formula, while the second analytical validation sample 1022 also belonging to sample B contains the target elements Hg and V (which may contain Pd) at 80% of the concentrations calculated by the above formula.

[0040] For each sample belonging to each group of sample A and each sample belonging to each group of sample B, characteristic X-rays are measured three times using the X-ray fluorescence analyzer subject to analytical validation, and the concentration of each target element is calculated using a known method based on the average of the three measurement results. If the calculated concentration of all target elements is within ±15% of the original concentration of the sample belonging to each group of sample A and the sample belonging to each group of sample B, and the concentration calculated for sample B is smaller than the concentration calculated for sample A, then it is determined that (i) the detection sensitivity compliance criterion is met (otherwise, it is not met).

[0041] Furthermore, if the peaks of each target element (except for As and Pb, which are essential target elements and can be corrected for overlap) can be clearly distinguished from the obtained X-ray fluorescence profile, the difference in peak intensity between the unspiked sample and the sample spiked with the standard sample is clear, and the accuracy requirement is met (recovery rate is within the range of 85-115%), then (ii) the specificity suitability criterion is judged to be met (otherwise, it is not met).

[0042] Furthermore, for sample A, measurements are performed six times, and if the relative standard deviation (RSD) of the quantitative concentration values ​​for each target element measured is 20% or less, it is determined that (iii) the accuracy compliance criterion is met (otherwise it is not met).

[0043] The above describes embodiments of the method for preparing a sample for analytical validation of an X-ray fluorescence analyzer and the method for analytical validation of an X-ray fluorescence analyzer according to the present invention. However, the present invention is not limited to the above embodiments and various modifications are possible.

[0044] For example, in the above embodiment, the target elements are seven elements, namely Cd, Pb, As, Hg, Co, V, and Ni, or eight elements, namely, these elements plus Pd. However, as long as the target elements include the above seven elements, the target elements may also include one or more of the 24 elements (16 elements excluding the above eight elements) specified in ICH Q3D.

[0045] In the above embodiment, the target elements are divided into two groups and samples are prepared for each group, but they may be divided into three or more groups and samples prepared for each group. However, since an increase in the number of samples requires more time and effort for measurement during analytical validation, it is preferable to set the number of groups to two in order to reduce this time and effort.

[0046] Aspects It will be apparent to those skilled in the art that the exemplary embodiments described above are examples of the following aspects.

[0047] (Item 1) A method for preparing analytical validation samples for an X-ray fluorescence analyzer according to one embodiment of the present invention involves dividing target elements including Cd, Pb, As, Hg, Co, V, and Ni into a plurality of groups, with As and Pb in the same group and As, Pb, and Hg in separate groups, and for each of the plurality of groups, adding and mixing a liquid containing a target element belonging to that group to a powder made of a material that does not contain any of the target elements, so that the target elements belonging to that group each reach a predetermined concentration.

[0048] The analytical validation sample prepared by the method according to paragraph 1 must contain seven target elements, consisting of all elements belonging to Class 1 (Cd, Pb, As, and Hg) and all elements belonging to Class 2A (Co, V, and Ni). In addition to these seven elements, other elements such as Pd may also be contained as target elements in the analytical validation sample according to the present invention. Of course, the sample may contain only the seven elements listed above (excluding the constituent elements of the powder).

[0049] The inventors prepared various samples with different combinations of target elements in the same group and performed analytical validation using these samples on an X-ray fluorescence analyzer previously confirmed to be functional. They found that when As and / or Pb and Hg were grouped together, the concentrations of one to three of these elements, As, Pb, and Hg, were lower than the actual values, and the values ​​varied from sample to sample. While the cause of this is unclear, it is presumed that when a solution containing Hg is added to a powder along with a solution containing As and / or Pb, some of these elements do not adhere to the powder for some reason. Therefore, in the preparation method described in paragraph 1, As, Pb, and Hg are separated into separate groups, and analytical validation samples are prepared for each group. This prevents the As, Pb, and Hg concentrations obtained during analytical validation from being lower than the predetermined concentrations, ensuring accurate analytical validation.

[0050] On the other hand, among elements requiring analytical validation, elements with similar characteristic X-ray energies must be included in the same group. This is because, when the sample to be evaluated contains multiple elements, the profiles obtained by X-ray fluorescence analysis overlap, and the concentrations of each element are determined after performing data processing known as overlap correction. Therefore, analytical validation is performed under the same conditions as when analyzing the sample to be evaluated, with overlapping profiles. Among the elements targeted by the method according to paragraph 1, the Kα line energy of As (10.532 keV) and the Lα line energy of Pb (10.552 keV) are similar. Among the elements targeted by the preparation method according to paragraph 1, the Kα line energy of As (10.532 keV) and the Lα line energy of Pb (10.552 keV) are similar. Therefore, by including As and Pb in the same group, analytical validation samples that can be used for accurate analytical validation can be obtained.

[0051] Furthermore, in the method for preparing analytical validation samples according to paragraph 1, samples containing multiple elements for at least one group including As and Pb are prepared, and therefore the effort required for analytical validation can be reduced compared to preparing individual samples for all target elements.

[0052] The minimum number of groups is two, and the maximum is one less than the number of target elements (because As and Pb belong to the same group). For example, if the target elements are only seven types, Cd, Pb, As, Hg, Co, V, and Ni, the maximum number of groups is six. However, as the number of groups increases, the number of analytical validation samples to be measured during analytical validation increases, which requires more work. If this point is important, the number of groups may be set to two.

[0053] (Item 2) The method for preparing a sample for analytical validation of an X-ray fluorescence analyzer according to item 2 is the method according to item 1, in which Hg and Ni and / or Hg and Co belong to different groups.

[0054] According to the preparation method of the second aspect, it is possible to prevent the Ni and / or Co concentration from being lower than the actual value, thereby enabling accurate analytical validation.

[0055] (Clause 3) The method for preparing samples for analytical validation of an X-ray fluorescence analyzer according to paragraph 3 is the method according to paragraph 1 or 2, in which Hg and V belong to the same group.

[0056] Since Hg and V can exist in a stable complex state in the same solvent (hydrochloric acid), their concentrations are unlikely to decrease even when added to the same sample. Therefore, Hg and V may belong to the same group, as in the preparation method according to item 3.

[0057] (Item 4) The method for preparing a sample for analytical validation of an X-ray fluorescence analyzer according to Item 4 is the method according to any one of Items 1 to 3, further including Pd as the target element.

[0058] Pd is a Class 2B element that is used as a catalyst in the manufacturing process of many pharmaceuticals. In the preparation method according to paragraph 4, by including Pd in ​​the target elements to be contained in the analytical validation sample, a validation sample can be obtained that can be used to appropriately validate the analytical properties of the X-ray fluorescence analyzer used to evaluate the impurities of pharmaceuticals that evaluate Pd.

[0059] (Item 5) The method for preparing samples for analytical validation of an X-ray fluorescence analyzer according to Item 5 is the same as the method according to Item 4, in which Hg and Pd belong to the same group.

[0060] Since Hg and Pd can exist in the form of a stable complex in the same solvent (hydrochloric acid) (as in the case of Hg and V), Hg and Pd may belong to the same group as in the preparation method according to item 5. In addition to Hg and Pd, V may also belong to the same group.

[0061] (Item 6) The method for preparing samples for analytical validation of an X-ray fluorescence analyzer according to Item 6 is the method according to any one of Items 1 to 3, wherein the plurality of groups are composed of two groups: a first group consisting of Cd, Pb, As, Co, and Ni, and a second group consisting of Hg and V.

[0062] (Item 7) The method for preparing a sample for analytical validation of an X-ray fluorescence analyzer according to Item 7 is the preparation method according to Item 6, further comprising Pd as the target element, the Pd belonging to the second group.

[0063] According to the preparation methods of items 6 and 7, Hg and V, which may belong to the same group as Hg (and further, Pd if Pd is included as a target element), are placed in the same group (second group), and other target elements are placed in another group (first group). This prevents the concentration of each target element from being lower than the actual value, and makes it possible to obtain an analytical validation sample that enables correct analytical validation.

[0064] (Item 8) The method for preparing a sample for analytical validation of an X-ray fluorescence analyzer according to Item 8 is the method according to any one of Items 1 to 3, wherein one of the plurality of groups contains only Hg among the target elements.

[0065] According to the preparation method of paragraph 8, by selecting one of the multiple groups as a group containing only Hg, which tends to exhibit a particularly significant decrease in concentration, it is possible to prevent the Hg concentration from being lower than the actual value, thereby obtaining an analytical validation sample that allows for accurate analytical validation. Note that all target elements other than Hg, including non-essential target elements such as Pd, may belong to the same group, or these target elements other than Hg may be further divided into multiple groups. To reduce the number of analytical validation operations (measurements using an X-ray fluorescence analyzer) and thereby reduce the effort required, it is preferable that all target elements other than Hg belong to the same group.

[0066] (Item 9) Item 9 relates to a method for preparing a sample for analytical validation of an X-ray fluorescence analyzer, which is the method according to any one of items 1 to 8, in which, for each of the plurality of groups having a plurality of target elements, multiple types of liquids each containing one target element belonging to that group are added to different positions on the powder, and the powder is stirred after the multiple types of liquids have dried.

[0067] According to the production method of the ninth aspect, the target elements (the same number as the liquids) do not mix with each other until the liquids (note that the "plurality" here is different from the "plurality" that refers to the number of groups), each containing one type of target element, have dried, thereby more reliably preventing a decrease in the concentration of the target element.

[0068] (Item 10) An analytical validation method for an X-ray fluorescence analyzer according to one aspect of the present invention measures the concentration of a target element by performing X-ray fluorescence analysis on each of a plurality of analytical validation samples prepared by the preparation method according to any one of items 1 to 9 using the X-ray fluorescence analyzer that is the subject of analytical validation, and determines whether the difference between the obtained concentration and the predetermined concentration is within a predetermined range.

[0069] According to the analytical validation method of item 10, by using a plurality of analytical validation samples prepared by the preparation method of any one of items 1 to 9, the concentrations of As, Pb, and Hg obtained during analytical validation can be prevented from being lower than the predetermined concentrations, and accurate analytical validation can be performed.

[0070] 10...Sample for analysis validation 101, 1011, 1012...First analysis validation sample 102, 1021, 1022...Second analysis validation sample 11...Powder 111...First powder 112...Second powder 12...Liquid containing target element 121...Cd-containing liquid 122...Pb-containing liquid 123...As-containing liquid 124...Hg-containing liquid 125...Co-containing liquid 126...V-containing liquid 127...Ni-containing liquid 128...Pd-containing liquid

Claims

1. A method for preparing samples for analytical validation of an X-ray fluorescence analyzer, comprising: dividing target elements including Cd, Pb, As, Hg, Co, V and Ni into a plurality of groups such that As and Pb are in the same group and As, Pb and Hg are in different groups; and for each of the plurality of groups, adding and mixing a liquid containing a target element belonging to that group to a powder made of a material that does not contain any of the target elements, so that the target elements belonging to that group each reach a specified concentration.

2. A method for preparing a sample for analytical validation of the X-ray fluorescence analyzer described in claim 1, wherein Hg and Ni and / or Hg and Co belong to different groups.

3. A method for preparing a sample for analytical validation of an X-ray fluorescence analyzer as described in claim 1, wherein Hg and V belong to the same group.

4. A method for preparing a sample for analytical validation of an X-ray fluorescence analyzer as described in claim 1, further comprising the step of including Pd as the target element.

5. A method for preparing a sample for analytical validation of an X-ray fluorescence analyzer as described in claim 4, wherein Hg and Pd belong to the same group.

6. A method for preparing samples for analytical validation of an X-ray fluorescence analyzer as described in claim 1, wherein the plurality of groups consists of two groups: a first group consisting of Cd, Pb, As, Co, and Ni, and a second group consisting of Hg and V.

7. A method for preparing a sample for analytical validation of an X-ray fluorescence analyzer as described in claim 6, further comprising the step of including Pd as the target element, the Pd belonging to the second group.

8. A method for preparing a sample for analytical validation of an X-ray fluorescence analyzer as described in claim 1, wherein one of the plurality of groups contains only Hg among the target elements.

9. A method for preparing a sample for analytical validation of an X-ray fluorescence analyzer as described in claim 1, comprising adding, for each of the plurality of groups having a plurality of target elements among the plurality of groups, a plurality of types of liquids each containing one of the target elements belonging to the group to different positions on the powder, and stirring the powder after the plurality of types of liquids have dried.

10. A method for validating an analytical X-ray fluorescence analyzer, comprising: performing X-ray fluorescence analysis on each of a plurality of analytical validation samples prepared by the method for preparing samples for analytical validation of an X-ray fluorescence analyzer according to any one of claims 1 to 9, using the X-ray fluorescence analyzer that is the subject of analytical validation, to measure the concentration of the target element; and determining whether the difference between the obtained concentration and the specified concentration is within a specified range.

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