Under European Union (EU) law, the manufacture or import of medicinal products in the European Union is subject to manufacturing or import 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 or import authorisation, all medicinal products for human use intended for the European Union market must be produced in accordance with EU Good Manufacturing Practice (GMP) principles and guidelines. 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. GMP is mandatory for all medicinal products that have been granted a marketing authorisation as well as for the manufacture of investigational medicinal products.
GMP is also applicable to Advanced Therapy Medicinal Products (ATMPs). However, regarding the level of complexity and the specific characteristics of ATMPs (use of substances of human origin such as blood, tissues and cells), the European Commission has published in accordance with Article 5 of Regulation (EC) No 1394/2007 on ATMPs, Guidelines on GMP specific to ATMPs. These guidelines provide the GMP requirements that should be applied in the manufacturing of ATMPs that have been granted a marketing authorisation and/or used in clinical trial setting.
Stakeholders
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: 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 (often national medicines 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 its manufacturing activity.
In the case of ATMPs (as for other biological medicinal products), National competent authorities are responsible for the official release of the batches by the control authorities.
European Medicines Agency (EMA): The European Medicines Agency (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.
Definitions
GMP: Under EU 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.
Pharmaceutical quality system: The manufacturer has to establish, implement and maintain a pharmaceutical quality system, “the total sum of the organised arrangements made with the objective of ensuring that medicinal products are of the quality required for their intended use”. (Article 2(2) of Commission Directive (EU) 2017/1572)
EudraGMDP database: EudraGMDP is the name for the Union database referred to in Article 111(6) of Directive 2001/83/EC. The database, mostly publicly accessible, contains manufacturing and import authorisations, registration of active substance manufacturers, GMP certificates and non-compliance statements issued after inspections, and GMP-inspection planning in third countries to facilitate the exchange of information between Member States inspectors and a common use of inspectional resources. The content of the database is provided by Member States regulatory authorities and maintained and operated by EMA.
Challenges
Any company involved in manufacturing and/or importation activities relating to advanced therapy medicinal products or advanced therapy investigational medicinal products within the European Union market, is required to comply with EU GMP rules and principles issued by the Commission to ensure a high quality level and a safe use of medicinal products.
Manufacturing or marketing authorisation holder must demonstrate the compliance of its manufacturing process (starting materials, excipients, premises, equipment, procedures, personnel) with GMP, and with information provided in the relevant marketing or clinical trials authorisations. Manufacturers, including active substances manufacturers, are under national supervision of Member State regulatory authority which has to inspect and control the manufacturing of the medicinal products. The regular and repeated on-site inspections evaluate the quality standards of the manufacturing, and if all the manufacturing operations are performed in line with the GMP and the relevant marketing authorisation. Controls on laboratory sample are also conducted to verify the compliance of products with the declared composition.
After every inspection a GMP certificate (positive outcome) or non-compliance statement (negative outcome) is issued by the inspecting authority and consolidated at European level in the EudraGMDP database, which is accessible by regulators in other countries.
When inspections or controls identify deficiencies, deviations or serious GMP non-compliance, health protection measures are taken often in accordance with the precautionary principle. European legislation provides that manufacturer and import authorizations may be suspended or not granted as a result of non-compliance with GMP. Urgent measures including prohibition of manufacture, importation or supply, and/or withdrawal of all, or of specific batches from the market, can also be taken.
At the national level, the discovery of non-conformities or shortcomings by an inspection may be followed by an injunction to regularise the situation within a specified period.
Opportunities and incentives
Any company involved in manufacturing and/or importation activities relating to Advanced Therapy Medicinal Products (including investigational ones) within the European Union market, is required to comply with EU GMP rules and principles issued by the European Commission to ensure a high level of quality and a safe use of medicinal products.
The European Commission has issued mandatory detailed guidelines on GMP applicable to medicinal products and on GMP specific to Advanced therapy Medicinal Products (ATMPs) to ensure a high level of quality and a safe use of medicinal products.
In support for GMP compliance, manufacturers and marketing authorisation holders may refer to the documents provided by their national regulatory authority, and to European Union guidance on GMP questions and answers issued by the European Medicines Agency (EMA). They can also maintain and improve their GMP practices with regulatory inspections reports from the compilation of GMP inspection-related procedures and forms agreed by all Member States issued and maintained by EMA.
Manufacturers and marketing authorisation holders can also access the EudraGMDP database operated by the European Medicines Agency to search for GMP compliance information as such GMP compliance certificates and non-compliance statements issued after inspections.
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 European Union Good Manufacturing Practice.
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.
To go further: more information on the EMA role on GMP here.
Acknowledgements
Published: 03/04/2023
Authors:
Luc-Sylvain Gilbert, EuroGCT ELSI Legal Information Officer