Survey to Identify Substandard and Falsified Tablets in Several Asian Countries with Pharmacopeial Quality Control Tests and Principal Component Analysis of Handheld Raman Spectroscopy

In May 2017, definition of substandard and falsified medical products (SFs) was announced by the World Health Organization.1 Substandard medical products (also called “out of specification”) are authorized by national regulatory authorities but fail to meet either national or international quality standards or specifications, or in some cases, both. On the other hand, falsified medical products deliberately or fraudulently misrepresent their identity, composition, or source.1–5 Many surveys of falsified medical products and analytical procedures for investigation of the authenticity of medical products have been reported by various public institutes.2–12 In 2015, the Pharmaceutical Security Research Institute reported that Asia experienced the highest incidence of drug crime cases among seven regions in the world. In that year, a total of 3,002 cases of drug crime cases were recorded, among which around 1,000 involved the Asia-Pacific region.13 Many cases where defective products have been transported across national borders have been reported.14 Relatively little work has been carried out on analytical methods for investigating the actual status of substandard medical products, including their distribution, and their physical and chemical properties.14,15 One reason for this maybe concern about the possibility of excessively hindering the development of medicines and access to medicines in developing countries.16 Also, regular quality control and surveillance of medicines after marketing tend to be more difficult in developing countries for various reasons, including high cost, the need for sophisticated equipment and skilled technicians, and lack of pharmacological knowledge to recognize the need for implementation of countermeasures.6,15,17–19 Furthermore, medicines may be transported across national borders without proper quality checks through various distribution channels.14,20 These are serious issues to be taken measure of, because SFs can cause treatment failure, development of antimicrobial resistance, and serious adverse drug reactions, thereby damaging public confidence in medicines.2,21,22 The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q6A provides guidance to establish a harmonized set of global specifications consisting of analytical procedures and acceptance criteria for new drug substances (DS) and drug products (DP) for human use (1999).23 Specifications of DS and DP are proposed and justified by the manufacturer, and approved by regulatory authorities in each country. The specifications and acceptance criteria are focused on those chemical, physical, and biological properties considered to be important for ensuring the safety and efficacy of DS and DP. Thus, they can be adopted to identify substandard products. Possible issues include 1) out-of-specification content of active pharmaceutical ingredient (API),24,25 2) significant dissolution delay,24 3) contamination with toxic substances,26,27 and 4) lack of sterility.28,29 These points can be checked by means of assay, content uniformity testing, measurements of dissolution properties and impurities, and microbial tests. In this study, candesartan cilexetil tablets were collected in China, Indonesia, Japan, and Myanmar and subjected to quality control tests (assays, content uniformity, and dissolution tests) according to the Japanese pharmacopeia.30 The acceptance criteria for these tests in the Japanese pharmacopeia were adopted as thresholds for identification of SFs. Many issues of quality and bioavailability are considered to be due to technical deficiencies in the manufacturing process design and differences in the nature of the excipients.31–33 Although many studies have shown that excipients influence quality, the excipients are not generally stipulated in quality tests. Our previous study found that the types of the excipients used in candesartan cilexetil tablets differ depending on the manufacturer, and Raman spectra of the tablets showed the different pattern reflecting the chemical nature of the excipients.34 Here, we focused on the methodology for detecting substandard and falsified medicines by principal component analysis (PCA)12,22,35–43 of raw data obtained by handheld Raman spectroscopy. We aimed to clarify the chemical features of substandard medicines by comparing them with authentic medicines, and by extracting the principal components of the Raman spectrum to visualize the relationships among the tablets. We chose the handheld Raman device as a simple spectroscope suitable for in situ observation in developing countries, and we used PCA as a mean to extract critical information despite the limited resolution and sensitivity of the device. We also compared signal preprocessing methods of Raman spectra for PCA and selected the multiplicative scattering correlation (MSC) method as being particularly suitable to extract the desired signals from the strong fluorescence background.43 This approach proved highly effective to evaluate the degree of similarity among samples.