The manufacture of medicinal products in the European Union (EU) is subject to manufacturing authorisation. Any company wishing to manufacture a medicinal product must hold a manufacturing authorisation issued by the national competent authority of the Member State where they carry out these activities.
To obtain a manufacturing authorisation, all medicinal products for human use intended for the European Union market must be produced in accordance with EU quality standards: Good Manufacturing Practice (GMP) principles and guidelines, and the European Pharmacopeia. The manufacturers are also obliged to have a qualified person responsible for ensuring that the requirements adopted for the manufacturing authorisation and the applicable legislation are respected.
Ensuring the quality of medicines is a criterion to obtain marketing authorisation and corresponds to Module 3 of the Marketing Authorisation Application dossier, "Chemical, pharmaceutical, and biological documentation" (Chemistry, Manufacturing and Controls -CMC) that aims to determine the specifications capable of guaranteeing the reproducibility of the medicine’s composition.
This stage is particularly challenging for Advanced Therapy Medicinal Products (ATMPs) regarding their level of complexity and their specific characteristics of ATMPs, especially the use of substances of human origin such as blood, tissues and cells, and the reproducibility when using live biological samples. That is why, Guidelines on GMP specific to ATMPs has been published by the European Commission, in accordance with Article 5 of Regulation (EC) No 1394/2007.
Manufacturer / Manufacturing authorisation applicant and Manufacturing authorisation holder: The people, company manufacturing ATMPs having to comply with EU quality standards (Good Manufacturing Practice and European pharmacopeia) in order to obtain a manufacturing authorisation that is valid in the European Union.
Marketing Authorisation Applicant and Marketing Authorisation holder (or sponsor in the case of investigational Advanced Therapy Medicinal Products): The people, company applying for or benefiting from a marketing authorisation submitted through the "Centralised procedure", and who are in relation to and cooperate with the manufacturer to ensure that the manufacturing sites, manufacturing processes and quality control comply with GMP and the European Pharmacopeia.
National competent authorities: National competent authorities assess the application for a manufacturing authorisation and provide support and scientific advices and guidelines to ensure the respect of the EU GMP. Manufacturers located within European Union /European Economic Area are under national supervision of Member State inspection agencies, which have to control by regular and repeated on-site inspections that marketing authorisation and EU GMP requirements are complied with. National competent authorities also control laboratory samples to verify the products compliance with the declared composition. They are also informed by the manufacturer of any changes or variations within the manufacturing activity.
In the case of ATMPs (as for other biological medicinal products), the national competent authority is responsible for the official release of the batches by the control authorities.
European Medicines Agency (EMA): EMA is an agency of the European Union whose goal is to protect and promote human and animal health. The agency is responsible for the scientific assessment of medicinal products to be marketed within the European Union and the European Economic Area. The EMA has a key role for GMP inspections of manufacturing sites for ATMPs. EMA also contributes to coordinate and harmonise GMP activities at the European level to ensure a common interpretation, and maintains a compilation of GMP inspection-related procedures and forms agreed by all Member States.
The Good Manufacturing and Distribution Practice Inspectors Working Group (GMP/GDP IWG): chaired by the European Medicines Agency and composed with senior GMP inspectors from the European Economic Area. The GMP/GDP Inspectors Working Group meets four times a year, interacts with Member State inspection agencies and provides guidance and recommendations on harmonization and coordination of GMP and GDP matters.
The European Directorate for the Quality of Medicines and Health Care (EDQM): is a directorate of the Council of Europe which cooperates with the European Medicines Agency on matters related to the quality of medicinal products and protection of public health. The EDQM is involved in the mutual recognition of controls and inspections carried out at Member State level and provides guidance and quality standards for a safe use of medicinal products.
Manufacturing authorisation: A manufacturing authorisation is an authorisation that shall be hold by any company wishing to manufacture a medicinal product in the European Union, and that is issued by the national competent authority of the Member State where they carry out these activities.
The manufacture of medicinal products in the European Economic Area (EEA) is governed by European directives and is subject to the holding of relevant authorisations in accordance with Article 40 of Directive 2001/83/EC for medicinal products for human use.
Good Manufacturing Practice (GMP): GMP is a code of quality standards concerning the manufacture, processing, packing, release and holding of a medicinal product placed within the European Economic Area. GMP describes the minimum standard that a medicines manufacturer must meet in their production and quality control processes, including those involving medicinal products intended for export only and medicines and active substances imported into the EU.
Under European Union law, GMP is defined as “the part of the quality assurance which ensures that medicinal products are consistently produced, imported and controlled in accordance with the quality standards appropriate to their intended use” (Article 2(3) of Commission Directive (EU) 2017/1572). GMP applies to raw materials for pharmaceutical use and active substances to guarantee high standards of quality and safety.
The manufacture of Advanced Therapy Medicinal Products (ATMPs) must comply with the General Manufacturing Practice for ATMP’s issued to minimise the variability of biological medicines, because they come from living materials, and to reduce the possibility of contamination. The manufacturer of the ATMP’s has to maintain specifications capable of guaranteeing the reproducibility of the medicine’s composition in accordance with quality standards relevant to its use and the specific requirements of the ATMP marketing authorisation.
Once the marketing authorisation is granted and during its five-years duration, the compliance with the quality standards of the whole manufacturing operations and process will be evaluated by regular and repeated inspections carried out on site and analysing of medicinal products samples.
Opportunities and incentives
National competent authorities providing advices, guidance, and financial and scientific support are the entry point for the manufacturing authorisation applicants.
To obtain a manufacturing authorisation, all medicinal products for human use intended for the European Union must be produced in accordance with EU Good Manufacturing Practice (GMP) principles. The European Commission has issued detailed guidelines on GMP applicable to medicinal products and Advanced therapy Medicinal Products (ATMPs). Compliance with these principles and guidelines is mandatory within the European Economic Area to hold a manufacturing authorisation.
The European Medicines Agency is a key actor for ATMPs. It publishes common interpretation of EU GMP and also issues scientific advices and guidelines, notably for the micro, small and medium-sized enterprises (SMEs).
The European Medicines Agency maintains a compilation of GMP inspection-related procedures and forms agreed by all Member States, and chairs and provides the secretariat for the GMP/GDP Inspectors Working Group of senior inspectors appointed by the national competent authorities from the entire European Economic Area.
To go further: more information on the European Medicines Agency role on GMP here.
Applicants for manufacturing authorisation can also access the EudraGMDP database. EudraGMDP is the name for the Union database (referred to in Article 111(6) of Directive 2001/83/EC). The database is mostly publicly accessible and contains manufacturing and import authorisations, registration of active substance manufacturers, GMP certificates and non-compliance statements issued after inspections. The content of the database is provided by national competent authorities, and the database is maintained and operated by EMA.
Interactions with regulators
Interactions between manufacturing authorisation applicant and national competent authority:
A manufacturing authorisation is an authorisation that shall be hold by any company wishing to manufacture an Advanced Therapy Medicinal Product in the European Union. This authorisation is issued by the national competent authority of the Member State where they carry out these activities. Therefore, the national authority will register, review and assess the application for manufacturing authorisation of medicinal products intended for the use within the European Union. Application form, timeline, financial, technical and scientific publications, and guidelines are issued by the authority to support and guide the applicants.
Interactions between manufacturing authorisation holder and national competent authority:
The manufacturing authorisation holder will be regularly evaluated by the national regulatory authority which is responsible for conducting regular inspections of manufacturing sites to ensure any process carried out in the course of manufacturing the medicinal products, including quality control, meets the mandatory EU GMP.
Interactions between marketing authorisation applicant/holder and manufacturing authorisation holder: The manufacturer has to comply with the specifications and instructions provided by the marketing authorisation holder and in accordance with EU GMP to ensure the quality, safety and efficacy of the medicinal products.
Interactions between the European Medicines Agency, the GMP/GDP Inspectors Working Group and the manufacturing/marketing authorisation holder: The manufacturing holder will access guidelines reflecting a harmonised approach of the European Union Member States and the Agency, and scientific guidance published by the European Medicines Agency in charge of coordinating and harmonising Good Manufacturing Practice at the European level. The GMP inspections conducted by the competent national authorities are compiled by the European Medicines Agency who chairs the GMP/GDP Inspectors Working Group appointed by all the European Economic Area competent regulatory authorities.
Text prepared by Luc-Sylvain Gilbert, EuroGCT ELSI Legal Information Officer, and Aurélie Mahalatchimy, WP4 Convenor.