Pharmeuropa bio & scientific notes最新文献

Gas chromatography (GC) is a powerful tool in the separation science of chiral analytes. The development of a new chiral test mixture for cyclodextrin (CD) coated GC columns allows comparing, choosing and identifying most suitable columns for a given separation challenge. This test mixture contains 12 enantiomer pairs of a broad range of functional groups and it is the first mixture suitable for all types of modified cyclodextrin capillary columns. Column changes can be observed and system performance can be monitored by means of this test mixture, which is therefore a base for reliable results. Furthermore, this publication is thought to be a start-up aid for chiral GC.

A human plasma reference preparation in International Units (IU) must be used in each potency assay of the human coagulation factors V, VIII and XI in human plasma pooled and treated for virus inactivation, according to the European Pharmacopoeia (Ph. Eur.) monograph 1646 and general chapters 2.7.4 and 2.7.22 respectively, and in the potency assay of human coagulation factor XIII in fibrin sealant kits, according to Ph. Eur. monograph 0903. International reference standards for all of these factors are now established, however, regional reference standards were not available for the required routine use. It was therefore proposed by European OMCLs and manufacturers to establish a European reference preparation, and it was the goal of this study to accomplish that. Two candidate biological reference preparations (BRPs), separate lyophilisation lots of the same normal human plasma bulk material, were calibrated against the International Standards (ISs) for human coagulation factors V, VIII, XI and XIII. Twelve European laboratories including OMCLs and manufacturers participated. The candidate material was tested against the ISs in 4 separate assays for each factor using the methods described in the relevant Ph. Eur. monographs and general chapters. No discernable difference was noted between the activities of the 2 candidates. They were shown to be suitable for their intended use and it was recommended to assign to both batches a potency of 0.73 IU/mL for factor V, 0.74 IU/mL for factor VIII, 0.59 IU/mL for factor XI and 0.79 IU/mL for factor XIII. Candidate batch B is proposed to be used first as lot 1, followed upon its depletion by candidate batch A (lot 2). The BRP batches will be monitored regularly for potency throughout their lifetime. EDQM BRP batches 1 and 2 of coagulation factors V, VIII, XI and XIII plasma were formally adopted by the Ph. Eur. Commission at their session in June 2011.

Biological indicators (BIs) are test systems containing viable microorganisms (usually spores of bacteria) providing a defined challenge to a specified sterilisation process. General chapter 5.1.2 of the European Pharmacopoeia [1] (Ph. Eur.) sets specifications for BIs and gives some guidance for their use. As shown in this text, the approach followed by Ph. Eur. as well as by ISO standards is outdated and could create nowadays some confusion among the users of the pharmacopoeia. It is the objective of this paper to provide the theoretical background of BIs as tools for the design and qualification of reliable moist heat sterilisation processes. The principles laid down in this article will form the basis of a future draft on a revised chapter on BIs in Pharmeuropa.

An international collaborative study has been organised by the European Directorate for the Quality of Medicines & HealthCare (EDQM) to establish the World Health Organization (WHO) 2nd International Standard (IS) for Vancomycin. Twelve laboratories from 10 different countries participated. The potency of the candidate material, a freeze-dried preparation, was estimated by microbiological assays with sensitive micro-organisms. As the stocks of the 1st IS for Vancomycin had been completely depleted, in order to ensure continuity between consecutive batches of the WHO IS, the European Pharmacopoeia Chemical Reference Standard (CRS) for Vancomycin batch 2 was used as a standard. It had been calibrated in a large international collaborative study against the WHO 1st IS for Vancomycin. Based on the results of the study, the 2nd IS for Vancomycin was adopted at the meeting of the WHO Expert Committee on Biological Standardisation (ECBS) in 2010 with an assigned antimicrobiological activity of 109,700 IU per vial. The 2nd IS for Vancomycin is available from the EDQM.

This article presents some experience obtained by applying capillary gas chromatography coupled with thermal conductivity detection (GC/TCD) to the determination of water in substances for pharmaceutical use. This technique represents a useful, orthogonal tool complementary to water determination methods based on volumetric or coulometric titration. It can also represent an alternative technique when such titrations are not applicable. This article presents the preliminary results obtained in a number of case studies where a GC/TCD procedure was applied in comparison with pharmacopoeial methods to substances with different water contents.

A physico-chemical method has been developed as an alternative to the current bioassay in normocythaemic mice for estimating the biological activity of erythropoietin batches. Capillary zone electrophoresis was used for quantification of the isoforms and their substructures were further elucidated by N-glycan mapping techniques. The analytical study was carried out on a total of 40 batches of epoetin beta which were selected to cover an adequate range of precisely established potency values. The relationship between the biological and chemical parameters was evaluated statistically in order to identify suitable covariates for the prediction of the biological activity. Out of several alternatives, a prediction model which is based on the percentages of isoforms per batch and the degree of sialidation was selected and tested. This model is comparable in terms of accuracy to the established in vivo bioassay, but is far superior in terms of precision. Further advantages of the method are improved animal welfare and savings in time and effort. The question whether the prediction model already meets the requirements for replacing the bioassay according to the ICH guideline Q6B is discussed.

In trying to estimate the separation efficiency of Capillary Electrophoresis (CE) methods, the resolution (RS), the number of theoretical plates (N) and the peak-to-valley ratio (p/v) are often used assessment criteria. This study demonstrates that these criteria are not as suitable to describe the separation efficiency in case of Capillary Zone Electrophoresis (CZE) methods as they are for Liquid Chromatography (LC) methods. The investigations were performed by means of a validated CZE method for the evaluation of tetracyclines and their related substances. Four impurities of tetracycline hydrochloride are described in the European Pharmacopoeia. Three were found in the sample used for our investigations, i.e. epi-tetracycline formed by keto-enol-tautomerism, anhydrotetracyclin and epi-anhydrotetracyline. It could be shown that higher values of these assessment criteria like RS do not necessarily represent better separation. Thus, a discussion on the usefulness of separation selectivity and efficiency as assessment criteria for capillary electrophoresis as well as on the introduction of additional parameters is needed.

A joint collaborative study was organised by the European Directorate for the Quality of Medicines & HealthCare (EDQM) and the World Health Organization (WHO)/National Institute for Biological Standards and Control (NIBSC) to establish replacement batches for the European Pharmacopoeia (Ph. Eur.) Tetanus Vaccine (adsorbed) Biological Reference Preparation (BRP) batch 2 and for the WHO 3rd International Standard (IS) for Tetanus toxoid (adsorbed). Two freeze-dried stabilised tetanus vaccine (adsorbed) candidate preparations (Preparation A, 08/218 and Preparation B, 08/102) were calibrated against the current 3rd IS/BRP batch 2 (Preparation C) using challenge methods in guinea pigs and mice as described in the Ph. Eur. general chapter 2.7.8. Assay of tetanus vaccine (adsorbed). They were also assayed by serology methods. The WHO 2nd IS for Tetanus toxoid adsorbed (TEXA-2) was additionally included in the sample panel as Preparation D. Thirty-four laboratories (regulatory organisations and manufacturers) from 22 countries participated in the collaborative study. The majority of participants performed 2 independent challenge tests. Nine laboratories performed challenge assays in guinea pigs and 30 laboratories performed challenge assays in mice. Eight laboratories performed serology in guinea pigs and 1 laboratory performed serology in mice. For Preparation A, the geometric mean (GM) potency estimate (with 95 % confidence interval (CI)) in guinea pigs for all laboratories that provided valid results (n = 6) was 488.5 (354.2-673.6) IU/ampoule. For valid mouse assays (n = 25) the GM potency (with 95 % CI) was 259.8 (223.5-302.0) IU/ampoule. The inter-laboratory geometric coefficient of variation (GCV) was 36 % for guinea pig assays and 45 % for mouse assays. This compared favourably with the calibration of the 3rd IS/BRP batch 2 where the inter-laboratory GCV was 36 % and 42 % in guinea pigs and mice, respectively. For Preparation B, the GM potency estimate (with 95 % CI) in guinea pigs for all laboratories that provided valid results (n = 6) was 107.9 (64.1-181.7) IU/ampoule. For valid mouse assays (n = 24) the GM potency (with 95 % CI) was 147.9 (126.3-173.1) IU/ampoule. The inter-laboratory GCV was 64.3 % for guinea pig assays and 45.2 % for mouse assays. From the collaborative study, Preparation A appeared more suitable to be the replacement Ph. Eur. BRP as it is similar to the Tetanus vaccine (adsorbed) BRP batch 2, except for nature of the stabiliser. Preparation A was confirmed to have higher potency, readily detectable tetanus toxoid, and confirmed satisfactory stability and performance in challenge assays. Preparation A was adopted in January 2011 by the Ph. Eur. Commission as the Tetanus vaccine (adsorbed) BRP batch 3, with assigned potencies of 490 IU/ampoule in the guinea pig challenge assay and of 260 IU/ampoule in the mouse challenge assay. The same Preparation A was adopted in October 2010 as the WHO 4th IS for Tetanus toxoid (adso

To guarantee the safety of medicinal products as regards infectious agents, numerous national guidelines and recommendations have in recent years been included in the pharmacopoeia general monographs and have influenced the content of the substance monographs. Although the stipulations of the European Pharmacopoeia set out objectives, there is still a certain scope in how the requirements are implemented. This is reflected in the very different responses in Europe to the problems of safety from infection. Different traditions in the use of homoeopathic and anthroposophic therapy and varying levels of expertise among the regulatory authorities within the European Union have resulted in varying standard of assessment. The aim of this publication is to present a standard form of assessment for medicinal products in these therapeutic systems. Demonstrated hereunder is an approach that can be adopted to ensure that the high safety standard required is met for homoeopathic and anthroposophic medicinal products.

A collaborative study was run by the Biological Standardisation Programme (BSP) under the aegis of the European Directorate for the Quality of Medicines & HealthCare (EDQM, Council of Europe) and the European Union (EU) Commission, to address the issue of the poor standardisation of serological assays used for the evaluation of seasonal influenza vaccines in Europe. The Phase 1 of the study focused on the compliance to Committee for Human Medicinal Products (CHMP) criteria by 6 manufacturers and 5 public laboratories. It confirmed the poor inter-laboratory correlation of haemagglutination inhibition (HI) test results. Phase 2 consisted in a reproducibility study examining the impact of extended method standardisation and the use of reference sera on inter-laboratory variation. Six manufacturers and 5 public laboratories contributed HI results, while the 5 public laboratories also performed single radial haemolysis (SRH) tests on the same sample panels. Results showed that method standardisation failed to significantly improve the inter-laboratory variation. Correction for pre-vaccination titres (Beyer correction) was found to have limited effect to improve the bias constituted by the Protection Rate (PR) criterion. The reasons underlying the difficulty in standardisation of HI and SRH tests are discussed and improved approaches for the compliance testing to CHMP criteria are suggested.