Determination of dermatan sulfate and chondroitin sulfate as related substances in heparin by capillary electrophoresis

Capillary electrophoresis (CE) was applied to the quantitation of dermatan sulfate (DS) and chondroitin sulfate (CS) as related substances in sodium heparin. The method is based on the selective digestion of either CS and DS contained in the main drug heparin, by using chondroitinase ABC (specific for both DS and CS) and chondroitinase AC (specific for only CS). The unsaturated disaccharides released after exhaustive digestion, can be separated by CE using a 110 mM phosphate buffer, pH 3.5 as the background electrolyte in a fused silica capillary (64.5 cm × 50 μm i.d.) at 40 °C and −30 kV. Since the level of each disaccharide released upon enzymatic digestion corresponds to its content in the native glycosaminoglycan, the amount of CS and DS was determined by proportion with the released disaccharides. In particular, ΔUA → GalNAc-4S Na₂ and ΔUA → GalNAc-6S Na₂ were selected for quantitation of CS and DS because of their significant response and short migration time (less than 7 min).The method was validated for linearity, accuracy, precision and it showed to be able in detecting selectively, DS and CS at impurity level (LOD 0.01%, w/w). The proposed CE approach was finally applied to real samples. The results obtained were found in excellent correlation with those achieved by the analysis of the same samples using the official USP method based on high performance anion exchange chromatography (HPAEC) with pulsed amperometric detector.     

Council of Europe Black Sea Area Project: International Cooperation for the Development of Activities Related to Donation and Transplantation of Organs in the Region

Background

In 2011, the European Directorate for the Quality of Medicines & Healthcare of the Council of Europe launched a 3-year collaborative project to address the organ shortage and improve access to transplant health services in Council of Europe member states in the Black Sea area (Armenia, Azerbaijan, Bulgaria, Georgia, Moldova, Romania, Turkey, Ukraine, and the Russian Federation) through the development of safe and ethical donation and transplantation programs.

对我国CEP认证现场检查现状的思考

介绍了EDQM的CEP认证现场检查,结合近年来检查结果的数据统计,分析我国企业CEP认证现状.我国原料药生产企业CEP证书被暂停或撤销的主要原因是:企业申报文件与现场不符、不能达到GMP要求以及我国GMP管理与欧盟存在差距等.建议我国企业加深理解CEP认证现行规定、聘请专家培训、关注EDQM现场检查缺陷,做好CEP认证.     

Official batch control of influenza vaccines: Is it still useful?

IntroductionThe governmental quality control of human vaccines is a long established tradition in many European countries. In Germany, vaccines have been controlled by a governmental agency since 1935. In the beginning, vaccine production and control was a purely national activity. However, that changed fundamentally in 1994 when the so-called Official Control Authority Batch Release Network (OCABR) was implemented shortly after the establishment of the European Union. Today, Official Medicinal Control Laboratories (OMCLs) are part of the European OCABR Network. In many European countries, OMCLs experimentally test every batch of human vaccines before they enter the market. We wanted to gain insights into the benefits of batch release by the Network and address the question whether batch release is still useful. This question was investigated in the context of influenza vaccines.MethodsNotifications on influenza vaccines circulated from 2006 to 2016 within the OCABR network were compiled and organized into 32 cases. The impact of these findings was evaluated, and the communication pathways between companies and respective European control laboratories were examined.ResultsApproximately 5850 batches were tested by the OMCL network between 2006 and 2016. Among these, notifications belonging to 32 cases were observed. The predominant proportion of the circulated notifications related to manufacturing issues. In most cases, the manufacturer itself had withdrawn the batches before they entered the market. However, in three cases, batches of insufficient quality were detected by the respective European Control Laboratory leading to withdrawal of 13 batches.Conclusion13 batches which did not meet the specifications of influenza vaccine were detected by the OMCL network between 2006 and 2016 which would not have been identified by the manufacturer. This demonstrates the impact of governmental batch release. Together with the intrinsic values of the OCABR system and keeping in mind that vaccines are given to healthy often young individuals, governmental batch release of influenza vaccines is still justified.     

Future development of global regulations of Chinese herbal products

Ethnopharmacological relevance

GP-TCM is the first EU-funded Coordination Action consortium dedicated to traditional Chinese medicine (TCM) research. One of the key deliverables of the Work Package 7 in GP-TCM was to investigate information of the existing requirements for registration of TCM products listed by global regulatory bodies. The paper aims to collate data and draw comparison of these regulations. Case studies are also presented to illustrate the problems involved in registering TCM products in different regions worldwide.

Materials and methods

A collaborative network task force was established during the early stage of the GP-TCM project and operated through exchanges, teleconferences and focused discussions at annual meetings. The task force involved coordinators, academics who are actively involved with R&;D of Chinese herbal medicines, experts on monographic standards of Chinese materia medica, representatives from regulatory agencies, experts from industries in marketing Chinese medicines/herbal medicines and natural products. The co-ordinators took turns to chair teleconferences, led discussions on specific issues at AGM discussion sessions, at joint workshops with other work-packages such as WP1 (quality issues), WP3 (toxicology issues) and WP6 (clinical trial issues). Collectively the authors were responsible for collating discussion outcomes and updating written information.

Results

A global overview of regulations on herbal registration has been compiled during the three years of the consortium. The regulatory requirements for registration of herbal products in the EU and China were compared, and this is extended to other regions/countries: Africa, Australia, Brazil, Canada, Japan, Russia, South Korea, Taiwan, and the United States. A wide variation of the regulations for the categories of herbal products exists: food (functional food, novel foods, dietary food for special medical purpose, foods for particular nutritional use, food supplement); cosmetic, traditional herbal medicine products; herbal medicines for human use and veterinary use.

Conclusion

The regulatory issues for registration of herbal products are complicated among the countries and regions worldwide. The information summarised in the text is for reference only. Some regulations which are presented in this review are still in legislation process and may change in due course. Before taking any regulatory action, readers are advised to consult current official legislation and guidance and/or to seek appropriate professional advice. The lessons learnt from global regulation of TCM will provide valuable insights for regulation of other traditional medicine such as Ayurveda and Unani medicine, as well as other forms of indigenous medicine. The WHO is well placed to co-ordinate a consultation process with the aim of putting forward suggestions for harmonisation to key regulatory agencies.     

欧洲官方药品质量控制实验室联盟的功能和职责

目的：介绍欧洲官方药品质量控制实验室联盟的功能和职责,为我国药检系统的建设和发展提供信息和借鉴,进一步为我国药品监管提供技术支持和保障。方法：通过调研和查阅欧洲药品健康管理局（EDQM）系列发布的关于欧洲官方药品质量控制实验室联盟的章程、制度和技术指导原则,以及与欧洲药品质量控制实验室同行面对面的交流,全面详细了解欧洲官方药品质量控制实验室联盟的功能和职责。结果与结论：欧洲官方药品质量控制实验室联盟在保证欧洲药品质量、提升欧洲药典质量标准方面具有完备的功能和职责,建立起紧密的协作关系,为欧洲的药品监管提供了重要的制度保证。对我国药检系统的深入建设具有很强的借鉴意义。     

EDQM机构与职能的简介

简要介绍EDQM这一欧洲权威的药品质量管理部门内设机构及其职能,对于了解欧洲药品监管模式有着重要意义.     

Standardization of allergen products: 1. Detailed characterization of GMP-produced recombinant Bet v 1.0101 as biological reference preparation

Background:  Standardization of allergen extracts requires the availability of well-characterized recombinant allergens, which can be used as reference standards provided by the European regulatory authorities. The objective of this study was the detailed physicochemical and immunological characterization of rBet v 1.0101, which shall be used in a ring trial within the framework of the Biological Standardization Programme BSP090 of the European Directorate for Quality of Medicines and Healthcare.
Methods:  Recombinant Bet v 1.0101 Y0487 was produced under good manufacturing practice conditions and analysed by an array of physicochemical and immunological methods for identity, quantity, homogeneity, folding and denaturation, aggregation state and stability in solution, as well as biological activity.
Results:  Batch Y0487 was shown to contain monomeric and well-folded protein being identical with rBet v 1.0101, as determined by mass spectrometry. SDS-PAGE, isoelectric focusing, deamidation analysis and size-exclusion chromatography with light scattering revealed sample homogeneity of >99.9%. Upon storage at +4°C batch Y0487 retained the monomeric state up to 3 months. Protein quantification determined by amino acid analysis was found coinciding with half-maximal inhibition of serum IgE in ELISA. Biological activity of batch Y0487 was shown to be comparable to natural Bet v 1 by IgG and IgE immunoblotting, as well as basophil and T-cell activation.
Conclusion:  Recombinant Bet v 1.0101 Y0487 was characterized extensively by physicochemical and immunological methods. It was shown highly stable, monomeric and immunologically equivalent to its natural counterpart. Thus, it represents an appropriate candidate reference standard for Bet v 1.     

欧洲药典适用性认证介绍

目的介绍欧洲药典适用性认证程序,为国内药品监管机构和原料药生产企业提供信息,促进我国原料药生产企业的国际化。方法通过查阅调研欧盟相关药品法规和与EDQM同行面对面的交流,详细了解欧洲药典适用性认证的组织机构和具体程序。结果与结论欧洲药典适用性认证程序在对原料药的质量控制有重要作用,加强了药典的监管力度,进一步保证了原料药的质量、安全性和有效性。     

中国被吊销COS证书引发的思考

近年来中国药企COS证书相继被吊销，国内药企为了知名度和出口市场而走捷径或者弄虚作假来申请国际认证，这对企业和最终消费者都是不负责任的表现。药品质量安全的危害和隐患日益凸显。品质至上，做良心药才是制药企业的正道。