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This assessment of subcluster detection in analytical chemistry offers a nonparametric approach to address the challenges of identifying specific substances (molecules or mixtures) in large hyperspaces. The paper introduces the concept of subcluster detection, which involves identifying specific substances within a larger cluster of similar samples. The BEST (Bootstrap Error-adjusted Single-sample Technique) metric is introduced as a more accurate and precise method for discriminating between similar samples compared to the MD (Mahalanobis distance) metric. The paper also discusses the challenges of subcluster detection in large hyperspaces, such as the curse of dimensionality and the need for nonparametric methods. The proposed nonparametric approach involves using a kernel density estimator to determine the probability density function of the data and then using a quantile-quantile algorithm to identify subclusters. The paper provides examples of how this approach can be used to analyze small changes in the near-infrared spectra of drug samples and identifies the benefits of this approach, such as improved accuracy and precision.

SOLU-CORTEF^Ⓡ Sterile Powder is a type of anti-inflammatory glucocorticoid that contains hydrocortisone sodium succinate as its active ingredient. It can be administered intravenously or intramuscularly, and comes in several packages including 100 mg plain vials without diluent. The diluent, which is part of the ACT-O-VIAL system, contains only Water for Injection and no preservatives. The pH of each formula is adjusted with sodium hydroxide to ensure it falls within the specified range of 7 to 8 after reconstitution. Intralot variability was detected in lot GA6092. Measuring in the PC subspace using just PCs 4, 5 and 6, vial 12 plots 4.2 BEST SDs from the center of the cluster, and vial 7 is 3.7 SDs from the center. Vial 18 appears 3.1 SDS from the center of the cluster (3/18, 17%). Interlot variability was also found in the spectral library (lots GA6092, GK7048, GM6839, GR8925, FL8062, FN6860, FR1914, and FR5098) containing the spectra of 126 hydrocortisone sodium succinate vials.

Carfilzomib is a prescription injectable drug approved for use by the FDA as an antineoplastic agent, part of a drug class of medications known as proteasome inhibitors, and used to stop and slow the growth and progression of cancer cells within the body. The drug is approved as an agent to treat multiple myeloma. It is provided as a single-use vial that contains 60 mg of carfilzomib as a sterile, white to off-white lyophilized cake or powder. Intra-lot and inter-lot variability in the spectra of carfilzomib vials was detected in the Drug Quality Study (DQS) using Fourier transform near-infrared spectrometry (FTNIR). One of 12 vials of lot 1143966 manufactured for Onyx Pharmaceuticals, Inc. appeared 4.7 multidimensional standard deviations (SDs) from the other 11 vials in a 3-D space formed by the first 3 principal components, which captured 81% of the total spectral variation. Spectra of 168 vials from 18 lots in the spectral library formed two groups in the 3-D space formed by the first 3 principal components. One group contained 155 vials and the other group contained 13 vials. The 2 groups had different locations and scales using a subcluster detection test at p=0.02.

Thyrotropin alfa is a heterodimeric glycoprotein containing human thyroid stimulating hormone (TSH). It is used as an adjunctive diagnostic tool for serum thyroglobulin (Tg) testing with or without radioiodine imaging in the follow-up of patients with well-differentiated thyroid cancer who have previously undergone thyroidectomy. Inter-lot variability in the Fourier transform near-infrared spectra of 30 samples obtained from four separate lots of Thyrogen^® was detected in the Drug Quality Study (DQS). The vials fell into two distinct groups (r_tst = 0.90, r_lim= 0.98, p=0.02). In addition, one vial of the 30 (3%) appeared 4.7 multidimensional SDs from all of the other vials, suggesting that it also represents a different material.

ULTIVA® (remifentanil hydrochloride) is a sterile, nonpyrogenic, preservative-free, white to off-white lyophilized powder for intravenous (IV) administration after reconstitution and dilution. Each vial contains 1, 2, or 5 mg of remifentanil base; 15 mg glycine; and hydrochloric acid to buffer the solutions to a nominal pH of 3 after reconstitution. ULTIVA® is a μ-opioid agonist with rapid onset and peak effect, and short duration of action. Intra-lot and inter-lot variability in the spectra of ULTIVA® was measured in the Drug Quality Study (DQS) using Fourier transform near-infrared spectrometry (FTNIR). In 6 vials sampled, 1 came from lot 220453F while 5 came from lot 30020BF. The 1 vial sampled from lot 220453F appeared 122 multidimensional SDs from the other vials from lot 30020BF, suggesting that it represents a different formulation or material. Consequently, additional spectra from other lots were analyzed. Spectra of 90 vials from 9 lots in the spectral library contained vials that were outside the main group (50.3 SDs using a subcluster detection test), suggesting that the 35 library vials (39% of the total) contain different materials from the other 55 vials.

Intra-lot and inter-lot variability in dacarbazine was detected in the Drug Quality Study (DQS) using Fourier transform near-infrared spectrometry (FTNIR). One vial of six vials sampled from Fresenius Kabi Lot 6125612 appeared 7.8 SDs from the center of the rest of the vials on the DQS FTNIR screening assay. Spectra of 54 vials from six lots in the library clustered in two groups (p=0.02), suggesting they represent different material.

Pemetrexed is a folate analog metabolic inhibitor used in treatment of locally advanced or metastatic nonsquamous non-small cell lung cancer and for mesothelioma. Intra-lot and inter-lot variability in the spectra of ALIMTA® was detected in the Drug Quality Study (DQS) using Fourier transform near-infrared spectrometry (FTNIR). One vial of 12 (8%) sampled from lot S20I013A appeared 3.0 multidimensional SDs from the other vials, suggesting that it represents a different material. Consequently, additional spectra from other lots were analyzed. Spectra of 147 vials from 23 lots in the spectral library contained 14 vials that were outside the main group (26.4 SDs using a subcluster detection test), suggesting that the 14 library vials (9.5% of the total) also contain differing materials.