Clustering of Tadalafil API Samples According to their Manufacturer in the Context of API Falsification Detection.

This paper reports the results of the active pharmaceutical ingredient (API) fingerprint study, organised by the General European Official Medicines Control Laboratory Network (GEON), on tadalafil. A classical market surveillance study, evaluating compliance to the European Pharmacopoeia, was combined with a fingerprint study, the latter to obtain characteristic data for the different manufacturers, allowing the network laboratories to conduct authenticity tests for future samples, as well as to detect substandard and falsified samples. In total, 46 tadalafil API samples from 13 different manufacturers were collected. For all samples fingerprint data was collected through analysis of impurities and residual solvents, mass spectrometric screening, X-ray powder diffraction and proton nuclear magnetic resonance (1H-NMR). Chemometric analysis revealed that all manufacturers could be characterised based on the impurity, residual solvent and 1H-NMR data. Future suspicious samples in the network will therefore be analysed with these techniques in order to attribute the sample to one of the manufacturers. If the sample cannot be attributed, a more profound investigation will be necessary to reveal the origin of the sample. In cases where the suspect sample is claimed to be from one of the manufacturers included in this study, analysis can be limited to the test distinguishing that manufacturer.

European fingerprint study on omeprazole drug substances using a multi analytical approach and chemometrics as a tool for the discrimination of manufacturing sources.

Like drug products, Active Pharmaceutical Ingredients (APIs) are subject to substandard and falsification issues, which represent a threat to patient health. In order to monitor the quality of drug substances and prevent the use of non-compliant APIs, Official Medicine Control Laboratories work together in a European network developing coordinated strategies and programmes. The API working group proposed a market surveillance study on omeprazole and omeprazole magnesium with the objectives of controlling the pharmaceutical quality of samples, checking compliance with the monographs of the European Pharmacopoeia, and collecting analytical fingerprints that could be further used to differentiate manufacturing sources for future authenticity investigations. The study described in this article reports the analysis carried out by 7 European laboratories on 28 samples from 11 manufacturers with 5 analytical techniques (related substances with HPLC, residual solvents with GC-MS, near infrared spectroscopy, proton nuclear magnetic resonance spectroscopy and X-ray powder diffractometry). The large amount of resulting analytical data were centralized and treated with two chemometric methods: Principal Component Analysis and Hierarchical Clustering Analysis. Data were analyzed separately and in combination (data fusion), allowing us to conclude that NMR and XRPD were suitable to differentiate samples originating from 9 out of 11 manufacturers. Analytical fingerprints associated with chemometrics were demonstrated to be a valuable methodology to discriminate manufacturers of omeprazole and omeprazole magnesium APIs and detect future substandard and falsified APIs.

GEONs API fingerprint project: Selection of analytical techniques for clustering of sildenafil citrate API samples.

Through its Active Pharmaceutical Ingredient Working Group (API-WG) the General European Official Medicines Control Laboratory (OMCL) Network (GEON), co-ordinated by the European Directorate for the Quality of Medicines & HealthCare (EDQM), regularly organises market surveillance studies for specific APIs for conformity to their monograph in the European Pharmacopoeia. During the past years some studies were combined with a fingerprint study of the APIs. The idea is to obtain a fingerprint for each manufacturer of the API under investigation, allowing the OMCL network to identify future samples as well as to detect substandard and falsified APIs. This paper reports the results of the latest fingerprint study, organised on sildenafil citrate API samples. Seventy-nine samples from 14 different manufacturers were collected throughout the Network. Fingerprint data was collected through Mid-Infrared spectroscopy, Raman spectroscopy, liquid chromatography for related substances, gas chromatography for residual solvents, X-ray diffraction and Nuclear Magnetic Resonance (NMR) spectroscopy. Chemometrics applied to the collected data showed that all manufacturers could be discriminated based on the data of only three of these tests, i.e. gas chromatography for residual solvents, X-ray diffraction and proton NMR. Suspicious API samples for sildenafil citrate will therefore be analysed in the future with the selected techniques in order to link the sample to a manufacturer or demonstrate the absence of such link. If the sample cannot be attributed to one of the manufacturers, further analysis and research on provenance and identity will be required. Of course, if the suspected sample claims to originate from one of the manufacturers included in the study, analysis can be limited to the test distinguishing this manufacturer.

Pharmacogenetics and antipsychotic treatment response.

Antipsychotic drugs are widely used in the treatment of schizophrenia and psychotic disorder. The lack of antipsychotic response and treatment-induced side-effects, such as neuroleptic syndrome, polydipsia, metabolic syndrome, weight gain, extrapyramidal symptoms, tardive dyskinesia or prolactin increase, are the two main reasons for non-compliance and increased morbidity in schizophrenic patients. During the past decades intensive research has been done in order to determine the influence of genetic variations on antipsychotics dosage, treatment efficacy and safety. The present work reviews the molecular basis of treatment response of schizophrenia. It highlights the most important findings about the impact of functional polymorphisms in genes coding the CYP450 metabolizing enzymes, ABCB1 transporter gene, dopaminergic and serotonergic drug targets (DRD2, DRD3, DRD4, 5-HT1, 5HT-2A, 5HT-2C, 5HT6) as well as genes responsible for metabolism of neurotransmitters and G signalling pathways (5-HTTLPR, BDNF, COMT, RGS4) and points their role as potential biomarkers in everyday clinical practice. Pharmacogenetic testing has predictive power in the selection of antipsychotic drugs and doses tailored according to the patient's genetic profile. In this perception pharmacogenetics could help in the improvement of treatment response by using different medicinal approaches that would avoid potential adverse effects, reduce stabilization time and will advance the prognosis of schizophrenic patients.

Cross-reactive epitopes present in campylobacter jejuni serotypes isolated from enteritis patients.

Campylobacter jejuni (C. jejuni) infection frequently triggers autoimmune-mediated neuropathies, especially the Guillain-Barre syndrome (GBS). The molecular mimicry between the core oligosaccharides of bacterial lipopolysaccharides (LPSs) and the human gangliosides presumably results in the production of anti-neural cross-reactive antibodies which are likely to be a contributory factor in the induction and pathogenesis of GBS. The aim of our study was to determine the presence of cross-reactive epitopes in C. jejuni LPSs isolated from enteritis patients and to determine their antigen reactivity. For that purpose we collected stool specimens from 21 patients with enteritis and without neurological symptoms. Seven different serotypes of C. jejuni (0:27; 0:6/0:7; 0:38; 0:3; 0:1/0:44; 0:19; 0:37) were detected using the Penner system. Unexpectedly, one serotype from this group was detected as 0:19, a serotype rarely isolated from enteritis patient and in close association with GBS. Binding studies using cholera toxin-B subunit and peanut agglutinin, showed the presence of ganglioside-like epitopes in C. jejuni strains 0:37, 0:19 and 0:27. Reactivity with sera from patient with GBS, with confirmed previous exposure to C. jejuni and with high a titre of anti-ganglioside antibodies, showed that the same three LPSs from C. jejuni serotypes 0:37, 0:19 and 0:27 bear cross-reactive epitopes in their LPSs structures. Our results confirm the results from previous studies that LPSs from certain C. jejuni serotypes bear cross-reactive ganglioside-like epitopes which might be involved in the induction of GBS after C. jejuni infection.