【技术交流】GMP认证和GMP认证在欧洲

一次又一次，我们收到关于GMP认证和GMP认证的问题。思考，对于一个GMP认证的过程是类似的ISO认证是一种常见的故障，即误解。因此，所谓“ GMP证书”是不太正确的;但什么是正确的程序？在欧洲，药品和原料药的生产厂家须通过主管机关就符合良好生产规范（GMP）的原则进行监控。每个欧盟成员国出售其自己的监察。生产的位置是至关重要的，因此，为了决定哪些督察负责。例如位于法兰克福（德国）的设施，因此在达姆施塔特当地GMP检查员监视。在伦敦（英国）的设施将由英国机构（ MHRA）进行监控等等。

的GMP检查的基本知识

只有政府机关有权在医药环境中执行GMP验收。认可机构所开展如ISO审计既未被允许发起官方GMP检查，也不证明符合GMP 。由于事实上，没有GMP认证/ GMP证书可以由机构颁发，只有确认。正式名称是： “证书GMP认证制造商的” 。通俗地说，一个人说“ GMP证书” 。欧盟GMP认证是进入EudraGMDP数据库。

这种确认的性能是基于欧盟GMP指令2001/83/EC 。该指令被调换到各成员国的法律。各成员国的主管当局进行巡查的基础上的欧盟指令九十四分之二千○三规定的要求。这些要求的具体解释可以在欧盟GMP指南及其附件中找到。

位于欧盟境外生产基地

如果生产地点位于欧盟境外，以验证在哪个国家的药品将被导入（第一个进入欧盟市场的界定主管机关，例如，如果该产品首次在法兰克福机场，主管进入德国领土是很重要的当局在达姆施塔特将胜任） 。进口医药产品，于欧盟境外公司需要进口许可（包括在欧洲常驻代表） 。在此之前医药产品（并且为了获得进口许可证）的第一进口，于欧盟境外的网站必须由欧盟主管机关检查。来自欧盟当局一个GMP检查时才会欧盟以外生产现场要么有一个有效的营销授权的医药产品（由欧盟主管机关或由EMA颁布）或执行，如果它是由欧盟上市许可持有者引用制造。

此外，检查必须以符合GMP要求检查持续遵守定期进行（根据欧盟指引每2年） 。 GMP监测也适用于API的设施。然而， GMP检查的性能是没有什么不同的医药产品的先决条件。欧盟主管机关自行决定何时检查，必须进行一个API 。

世卫组织的GMP证书

在药用产品制造商的要求，主管欧盟当局可以发出世界卫生组织GMP认证的公司，拥有生产许可证 - 因此按照GMP监测。医药产品的制造商通常需要这些证书的出口，作为非欧盟国家的海关通常要求这些证书。因此，世卫组织证书通常也称为导出证书。

其他GMP证书

因为所有上面提到的原因，存在对于如企业没有GMP证书开发设备与制造工程一样的药品生产或其他服务， IT系统等。药物制造商有责任为服务提供商和供应商的选择。在一个供应商资格的框架内，药品制造商（生产和质量控制的负责人分别为头部）必须证明该公司确实开始，然后监视选定的供应商定期。供应商的资格必须依赖于一个基于风险的方法。

对于供应商，其产品具有较低的潜在风险患者安全，自我评价的形式就足够了。相反，它构成了潜在的高风险病人的安全（例如，所有的API ）的产品必须由制药商进行审核。

员工和经理的GMP认证

欧盟GMP指南要求的人才培养足够的和持续的水平。因此，每一个制药公司必须建立完善的培训制度，计划和记录每一个GMP培训课程。作为欧洲最大的高级培训和信息服务提供商，概念海德堡公司开发的GMP具体的培训课程和认证计划。每年，超过270的GMP研讨会/培训班，讲习班和会议提供。在合作与欧洲合规学院GMP认证计划已经制定

培训课程不仅对相关的药品和原料药行业的员工和管理人员也为服务提供商在制药行业（如IT供应商，合同实验室，保洁公司等） 。涉及设备，工程公司等施工企业也应考虑有关的GMP认证措施的培训。 GMP在内部研讨会也提供较大群体的培训。 GMP的电子学习课程提出了一个有趣的选择。

GMP模拟检查和GMP审计

关于GMP的模拟视察一会谈时 - 由一个权威的官方GMP检查之前 - 一个公司决定让一位经验丰富的GMP审核员核实其GMP认证。我们的目标是找到任何弱点，并加以消除。 GMP审计 - 又 - 是这是开展由公司本身或由外部专业服务商的措施。此外，GMP审核通常携带（原材料，包装，服务供应商，工程等）列于供应商的供应商资格之内或合同制造商。 PCA的咨询世界各地提供这样的服务。

特殊情况在德国： GMP监督Bundeslaender （联邦）

德国37计数监控机构，其中包括27 GMP检查员这是负责监控生产商和进口商。有6个监察的兽用疫苗生产企业和10个额外的药物研究机构。按照周立功（可从2011年只有数据）的统计， 1,470次巡查在那年在德国进行的。约2,000名企业拥有所谓的生产和/或进口许可的医药产品供人类使用，因此这意味着他们生产符合GMP要求。在这种情况下，根据§ 13 AMG或生产许可 - 为进口 - 根据AMG § 72A （ 1 ） 2是必需的证书。监测是类似于药用产品。

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GMP certification and GMP certificate in Europe – an overview

Again and again, we receive questions about GMP certification and GMP certificates. Thinking that the procedure for a GMP certification is similar to that of an ISO certification is a common failure, i.e. misunderstanding. The term "GMP certificate" is therefore not quite correct; but what is the correct procedure? In Europe, manufacturers of medicinal products and APIs are subject to monitoring by competent authorities with regard to compliance with the principles of Good Manufacturing Practices (GMP). Each EU Member State disposes of its own inspectorates. The location of the production is therefore crucial in order to decide which inspectorate is responsible. For example a facility located in Frankfurt (Germany) is therefore monitored by the local GMP inspectorate in Darmstadt. A facility in London (UK) will be monitored by the British authority (MHRA) and so on.

The basics of GMP inspections

Only a governmental authority is entitled to perform a GMP inspection in the pharmaceutical environment. Accredited bodies which carry out e.g. ISO audits are neither allowed to initiate official GMP inspections nor to certify GMP conformity. As a matter of fact, no GMP certification/GMP certificate can be issued by the authority, only a confirmation. The official name is: "Certificate of GMP Compliance of a manufacturer". Colloquially, one says "GMP certificate". The EU GMP Certificates are entered into the EudraGMDP Database.

The performance of such a confirmation is based on the EU GMP Directive 2001/83/EC. This directive was transposed into the laws of each member state. The competent authority of each Member State carries out its inspections based on the requirements laid down in EU Directive 2003/94. The concrete interpretation of these requirements can be found in the EU GMP Guide and its Annexes.

Manufacturing sites located outside the EU

If the manufacturing site is located outside the EU it is important to verify in which country the medicinal product will be imported (the first entry to EU market defines the competent authority e.g. if the product first enters the German territory at the Frankfurt Airport, the competent authority in Darmstadt will be competent). To import a medicinal product, a company located outside the EU needs an import authorization (which includes a permanent representative in Europe). Prior to the first importation of medicinal products (and in order to receive the import license), the site located outside the EU has to be inspected by the competent EU authority. A GMP inspection from an EU Authority will only be performed when the manufacturing site outside the EU either has a valid marketing authorisation for a medicinal product (issued by a competent EU Authority or by EMA) or if it is referenced by a EU marketing authorization holder for manufacturing.

Moreover, inspections have to be performed regularly (every 2 years according to the EU guidelines) in order to check the ongoing compliance with the GMP requirements. GMP monitoring is also intended for APIs facilities. However, the performance of a GMP inspection is not a prerequisite unlike medicinal products. The competent EU authority decides itself when an inspection has to be carried out for an API.

The WHO GMP certificate

At the request of the medicinal products manufacturer, a competent EU authority can issue a WHO GMP certificate for a company that owns a manufacturing authorisation – and therefore is monitored according to GMP. Manufacturers of medicinal products often need these certificates for the export, as the customs of non-EU countries usually require these certificates. Therefore, WHO certificates are often also called export certificates.

Other GMP certificates

Because of all the reasons named above, there exists no GMP certificate for companies that e.g. develop equipment for the pharmaceutical production or other services relating to manufacturing like engineering, IT systems etc. The pharmaceutical manufacturer is responsible for the selection of the service providers and suppliers. Within the framework of a supplier qualification, the pharmaceutical manufacturer (respectively the head of production and the head of quality control) have to demonstrate that the company did monitor the selected suppliers initially and then on a regular basis. The qualification of suppliers must rely on a risk-based approach.

For suppliers whose products have a low potential risk to patient safety, self-evaluation forms may be sufficient. On the contrary, products which pose a potential high risk to patient safety (e.g. all APIs) have to be audited by the pharmaceutical manufacturer.

GMP qualification of employees and managers

The EU GMP Guide requires a sufficient and continuous level of training for the personnel. Therefore, every pharmaceutical company must establish a comprehensive training system which plans and documents each GMP training course. As Europe’s largest advanced training and information service provider, Concept Heidelberg has developed GMP specific training courses and certification programmes. Annually, more than 270 GMP seminars/ courses, workshops and conferences are offered. In co-operation with the European Compliance Academy a GMP Certification Programme has been developed

The training courses are not only relevant for employees and executives in the pharmaceutical and API industry but also for service providers in the pharmaceutical industry (like IT providers, contract laboratories, cleaning companies etc.). Firms involved in the construction of equipment, engineering companies, etc. should also consider GMP training regarding qualification measures. GMP In-house seminars are also offered for the training of larger groups. GMP eLearning courses present an interesting alternative.

GMP Mock inspections and GMP audits

One talks about GMP Mock inspections when - before an official GMP inspection by an authority - a company decides to let an experienced GMP auditor verify its GMP compliance. The objective is to find any weak points and to eliminate them. GMP audits - in turn - are measures which are carried out by the company itself or by external specialized service providers. In addition, GMP audits are often carried out at suppliers (of raw materials, packaging, service providers, engineering etc.) or contract manufacturers within the supplier qualification. The PCA consulting offers such a service worldwide.

Special situation in Germany: GMP supervision by Bundeslaender (Federal States)

Germany counts 37 monitoring authorities, including 27 GMP inspectorates which are in charge of monitoring manufacturers and importers. There are 6 inspectorates for manufacturers of veterinary vaccines and 10 additional drug investigation authorities. According to statistics of the ZLG (only data from 2011 are available), 1,470 inspections were conducted in that year in Germany. Around 2,000 businesses possess a so-called manufacturing and/ or import authorisation for medicinal products for human use which therefore means that they manufacture in compliance with the GMP requirements. In such cases, a manufacturing authorisation according to § 13 AMG or - for the import - a certificate according to AMG §72a (1)2 is required. Monitoring is analogous to that for medicinal products.

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