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ICP-MS Method Validation Study of Iridium, , , and in Polyethylene Glycol 3350 Utilizing USP <233>

A method validation study for Iridium, Palladium, In this method validation study, a commercial sample of Polyeth- Platinum, Rhodium and Ruthenium was performed ylene Glycol 3350 with a prescribed daily dosage of 17 /day on a sample of polyethylene glycol 3350 in accor- was evaluated in accordance to USP <233>. Polyethylene glycol dance with USP <233>. The analysis utilized an 3350 powder, when considered as a finished dosage form, is an ex- ICP-MS and evaluated Iridium, Palladium, Platinum, ception to this. For instance, since 17 grams is used daily (one capful Rhodium and Ruthenium based on 6 validation of powder), it would be necessary to use a larger sample mass for the characteristics: precision, accuracy, linearity, spec- finished product as opposed to evaluating a 10g daily dosage intake ificity, ruggedness, and range. Results of these amount for a raw material. Based on the data presented , it is thought studies met or exceeded all acceptance criteria. that this difference would not be significant. These studies are ad- equate for the finished powder product, as well as the raw material, INTRODUCTION given the exceptional linearity demonstrated with the ICP-MS instru- ment. With the data shown in this study, the range is covered up to The United States Pharmacopeia (USP) general chapters <232> and 170% for the finished dosage mass of 17 grams per day. <233>, as well as the nutritional supplement chapter <2232> have become official in the USP as of March 2013. These general chapters The USP is advocating a policy of “informed risk” in regards to testing will be replacing the current wet chemical procedure, <231> Heavy the catalyst such as those analyzed in this study. That is, if Metals. Manufacturer compliance will be mandated as of December the element is not expected to be present based on the manufactur- 1, 2015. ing process and associated materials, then testing is unnecessary. The concomitant risk would be if the element turns up unexpectedly Chapter <232> is principally concerned with the limits of elemental at levels exceeding the threshold, then the manufacturer will be held impurities present in finished dosage forms for drug and nutritional responsible. It is thought that a careful analysis of raw materials and products. Alternatively, it does give manufacturers the option of us- a thorough assessment of the manufacturing process would make ing a summation of the individual impurity contributions from excipi- the probability of such an occurrence vanishingly small. Such an ents and drug substances present in the finished product, as long as analysis and assessment would further benefit the manufacturer in the drug product manufacturing process is shown not to contribute holding unnecessary testing expenses to a minimum. Further clari- elemental impurities to the drug product. Minimally, a manufacturer fication on how the Food and Drug Administration (FDA) will interpret must show compliance for Arsenic, Cadmium, and for the new monographs has been presented in the their products. guidelines drafted by the FDA in their Elemental Impurities Q3D document. Also, see our previously In the case of excipients and drug substances, the limits, as given released feature paper, “Understanding USP in Table 1, are more of a guidance than a hard limit. Common sense General Chapter <232>- Elements and Limits should be exercised and a risk-based strategy for suppliers and man- of Elemental Impurities in Pharmaceutical ufacturers is advocated by the USP. The limits suggested for the cat- Products, Substances and Excipients,” alyst elements Ir, Pt, Pd, Os, Rh, and Ru in excipients and substances which highlights the current thinking of is 10 μg/g for finished oral dosage forms or 10g or less intake per day. the FDA.

TABLE 1: DEFAULT CONCENTRATION LIMITS FOR DRUG SUBSTANCES AND EXCIPIENTS AS DEFINED IN USP <232> Ir Pd Pt Os Rh Ru (μg/g) (μg/g) (μg/g) (μg/g) (μg/g) (μg/g) 10 10 10 10 10 10

Page 1 of 5 PEG 3350 Method Validation Utilizing USP <233>

This study was carried out using the <232> limits for the follow- STANDARDS AND BLANK: ing catalyst metals: Iridium, Palladium, Platinum, Rhodium, and Multi-element stock standards were prepared and used for prepara- Ruthenium. Testing was performed on a Thermo Scientific X Series tion of diluted standards and for spiked preparations. II ICP-MS system, running in CCT-KED mode, employing an internal standard technique. Results of these studies met or exceeded all ac- The blank and multi-element standards of concentrations corre- ceptance criteria. The validation characteristics and corresponding sponding to 0.5J, 1.0J, and 2.0J were prepared in the same matrix conforming limits for this study are presented in Table 2. as the sample, omitting only the polyethylene glycol 3350.

TABLE 2: VALIDATION CHARACTERISTICS FROM USP <233> INTERNAL STANDARD: Validation The internal standard was prepared at a 10 ppb level using 6Li, Sc, Y, Lower Limit Upper Limit Characteristics Tb, and Bi in a matched solvent matrix. An online internal-standard 20% Coefficient of addition system was used to automatically add internal standard to Precision (n=6) Not Applicable Variation the instrument during analysis. Linearity R > 0.995 Not Applicable Accuracy 85% Recovery 115% Recovery INSTRUMENTATION: Limit of Detection Not Applicable Not Applicable A Thermo Scientific X-Series II ICP-MS system equipped with a CETAC ASX-520 autosampler and a H/He collision cell running in 25% Coefficient of Ruggedness (n=12)* Not Applicable Variation CCT/KED mode was employed for all of the following analyses. Assess from Perfor- Assess from Perfor- Specificity mance Reports and mance Reports and RESULTS Blanks Blanks *-not performed in this study PRECISION: The results of the precision study are presented in Table 3. Note EXPERIMENTAL that the precision data utilized 80% spiked levels of the Target Concentrations for each appropriate reference material. The results PRECISION AND RUGGEDNESS STUDIES: below are reported to the correct precision for the analysis. The sample masses were spiked with the reference materials at a level that equated to the 0.8J as described in the Alternate Procedure TABLE 3: PRECISION STUDY OF IR, PD, PT, RH AND RU TRACE METALS Validation section of <233> prior to dilution. To reiterate the meaning RECOVERED FROM PEG 3350 AT A LEVEL OF 0.8J of J, as defined in the USP, J is “the concentration of the elements of Ir Pd Pt Rh Ru Replicate interest at the Target Limit, appropriately diluted to the working range (μg/g) (μg/g) (μg/g) (μg/g) (μg/g) of the instrument.” Ruggedness was not performed in this study. 1 7.9 7.8 7.9 7.9 7.9 2 7.9 7.9 7.9 8.0 8.0 ACCURACY/LINEARITY STUDY: 3 8.0 7.9 8.0 8.0 8.0 Prior to digestion, the sample masses were spiked at levels that cor- 4 8.0 8.0 7.9 8.0 8.0 respond to 0.4J, 0.8J, 1.2J, 1.6J and 2.0J after subsequent dilution. 5 8.2 8.2 8.1 8.2 8.2 An unspiked sample was also prepared as a digestion blank. 6 8.1 8.1 8.1 8.2 8.2 SAMPLE PREPARATION TECHNIQUE: Average: 8.0 8.0 8.0 8.0 8.0 Known masses of PEG 3350 were transferred to volumetric flasks, % RSD 1.2 1.5 1.0 1.4 1.4 along with standard spikes. The preparations were dissolved and quantitatively diluted with solvent. LINEARITY: The results of the linearity studies are presented in Figures 1 through 5.

Page 2 of 5 PEG 3350 Method Validation Utilizing USP <233>

FIGURE 1: IRIDIUM LINEARITY FIGURE 4: RHODIUM LINEARITY

Correlation Coefficient (R)> 0.999 Correlation Coefficient (R)> 0.999

FIGURE 2: PALLADIUM LINEARITY FIGURE 5: RHODIUM LINEARITY

Correlation Coefficient (R)> 0.999 Correlation Coefficient (R)> 0.999

FIGURE 3: PLATINUM LINEARITY ACCURACY: The results of the accuracy study are presented in Table 4.

TABLE 4: ACCURACY STUDY FOR IR, PD, PT, RH AND RU. Ir Pd Pt Rh Ru Level Recovery Recovery Recovery Recovery Recovery (Percent) (Percent) (Percent) (Percent) (Percent 0.4J 101.3 98.8 99.7 99.9 99.4 0.8J 100.9 99.0 99.8 100.1 100.3 1.2J 100.2 100.4 99.9 100.6 100.3 1.6J 99.8 99.0 99.6 100.6 100.4 2.0J 101.1 101.1 100.5 101.8 101.8

Correlation Coefficient (R)> 0.999 Average: 100.6 99.7 99.9 100.6 100.4 % RSD 0.7 1.0 0.3 0.7 0.9

LIMIT OF DETECTION AND QUANTITATION: LOD and LOQ values are cal- culated using the background equivalent concentration (BEC) from the calibration curve and the coefficient of variation (%RSD) of the 15 repli- cate determinations on the system blank. This is one of two theoretically equivalent methods advocated by Thomsen, et al., in Spectroscopy 18 (12) pp. 112-114.

Page 3 of 5 PEG 3350 Method Validation Utilizing USP <233>

TABLE 5: LIMIT OF DETECTION TABLE 7: CERIUM-CERIUM RATIO DATA Element LOD(ug/g) LOQ (ug/g) Run 156CeO/140Ce Ratio Iridium 3.87x10-3 1.94x10-2 1 0.014 Palladium 2.43x10-3 1.21x10-2 2 0.014 Platinum 6.01x10-4 3.01x10-3 3 0.014 Rhodium 2.12x10-4 1.06x10-3 4 0.013 Ruthenium 8.91x10-5 4.45x10-4 5 0.014 Average 0.014 RUGGEDNESS: This study was NOT performed at this time due to time %RSD 2.04 constraints. The precision study would be repeated on a different day, to give a total of 12 preparations for comparison. DISCUSSION was also attempted in this study. Due to the peculiarities of SPECIFICITY: With ICP-MS, specificity depends on the mass discrimi- handling osmium (permeability in plastics), the data was excluded nation of the mass filter (quadrupole) and the presence or absence of after preliminary evaluation. If osmium is to be run, it will be neces- isobaric interferences. The mass filter is checked daily via performance sary to run it separately, with all preparations made in glass. Inves- reports to make certain adequate instrumental resolution is observed. tigation is ongoing into what set of conditions would be appropriate Table 6 presents a summary of the Mass Calibration verification data for testing osmium. Given the propensity for tetra-oxide formation demonstrating that the instrument accurately identifies masses to with- under even mild oxidative conditions, the permeability of osmium in in 1 amu, and that the breadth of the mass peaks affords adequate res- plastic, and the volatility of the tetra-oxide, a separate study will have olution. to be performed

TABLE 6: MASS CALIBRATION VERIFICATION DATA CONCLUSION Width Max Peak Peak A method for the determination of Iridium, Palladium, Platinum, Rho- Limits Error Width Error dium and Ruthenium in polyethylene glycol 3350 raw material has 7Li 0.65-0.85 +/- 0.10 0.71 -0.05 been verified. The method is precise, linear, accurate, specific, and 115 In 0.65-0.85 +/- 0.10 0.77 -0.00 has adequate range. 238U 0.65-0.85 +/- 0.10 0.76 0.00 The information used to formulate this study is in accordance with the current USP, but revisions are currently being considered (to be The absence of isobaric interferences are accomplished by se- published in Pharmacopeial Forum 40 (2). There will also be chang- lecting that don’t have the same mass (e.g.. 204Pb and es to the type and number of studies needed for testing. USP will 204Hg), and elimination of polyatomic interferences by use of be calling the requisite support studies for a product, substance or kinetic energy discrimination(KED) and a collision cell (CCT). The excipients, a “Validation” versus “Verification. Changes in the studies kinetic energy discrimination creates a minimal kinetic energy will include a larger ruggedness set (3 sets of 6 measurements, ver- barrier that ions having lower momentum cannot overcome. The sus 2 sets) and less thorough Limit of Detection, Range, and Linearity collision cell creates a chemical environment where polyatomic studies than what currently is required. ions are broken up by physical or chemical means. To check for polyatomic interferences, a performance report run in CCT-KED mode is acquired and the 156CeO+/140Ce+ ratio is checked to assure that the instrument is eliminating polyatomic interferences. Table 7 presents the 156CeO+/140Ce+ ratio data for both days required to perform the validation study.

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REFERENCES

UNITED STATES PHARMACOPEIA 35 / NATIONAL FORMULARY 30, 2nd Supplement, General Chapters <232> and <233>, (2012)

X-SERIES ICP-MS OPERATORS COURSE, Thermo Fisher Scientific, (2012)

X-SERIES 2 ICP-MS GETTING STARTED GUIDE, Revision D – 121 9590, Thermo Fisher Scientific, (August, 2009)

“LIMITS OF DETECTION IN SPECTROSCOPY,” Thomsen, V., et al., SPEC- TROSCOPY 18 (12), pp. 112-114, December

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