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Manufacturing Authorisation

Introduction

The manufacture of medicinal products in the European Union (EU) is subject to manufacturing authorisation. Any legal entity, generally a 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 EU 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 (especially for manufacturing processes) and their specific characteristics, 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 have been published in 2017 by the European Commission, in accordance with Article 5 of Regulation (EC) No 1394/2007. 

Stakeholders

Manufacturer or Manufacturing authorisation applicant/ holder: The legal entity 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 EU.

Marketing Authorisation Applicant/ holder: The legal entity applying for or benefiting from a marketing authorisation submitted through the "Centralised procedure", and who is 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.

Sponsor: The legal entity applying for or benefiting from a clinical trial authorisation, and who is 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: assess the application for a manufacturing authorisation and provide support, scientific advices and guidelines to ensure the respect of the EU GMP. Manufacturers located within EU / European Economic Area (EEA) 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.

The list of National Competent Authorities issuing GMP and Good Distribution Practice (GDP) authorisations/certificates is available on the EudraGMDP database here.

European Medicines Agency (EMA): an agency of the UE 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 EU/EEA. The EMA has a key role for GMP inspections of manufacturing sites for ATMPs as it 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 EMA and composed with senior GMP inspectors from the EEA. The GMP/GDP IWG meets four times a year, interacts with Member State inspection agencies and provides guidance and recommendations on harmonisation and coordination of GMP and GDP matters. More information on the EMA website can be found here.

The European Directorate for the Quality of Medicines and Health Care (EDQM): is a directorate of the Council of Europe which cooperates with the EMA 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.

Definitions

Manufacturing authorisation: is an authorisation that shall be hold by any legal entity wishing to manufacture a medicinal product in the EU. It is issued by the national competent authority of the Member State where the manufacturer carries out these activities. 

(Article 40 of Directive 2001/83/EC for medicinal products for human use)

Good Manufacturing Practice (GMP): a code of quality standards concerning the manufacture, processing, packing, release and holding of a medicinal product placed within the EEA. 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 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.

Challenges

The use of substances of human origin composed of live cells with a short shelf life from the starting point of procurement of the cellular starting material up to the final product’s administration raises complex manufacturing challenges for ATMPs: 

  • High production & development costs:
    • need for specialised premises, equipment, skilled personnel, rigorous monitoring and quality control system, linked with a relatively long-term return on investment;
    • autologous cell therapies: need to scale-out and potential need for manufacturing at point-of-care;
    • for smaller companies and academic institutions: lack of qualified personnel, infrastructure and capital for moving to late phase studies.
  • Extreme logistical complexity due to specific characteristics of ATMPs: collection of patients’ cells, transportation to manufacturing facility, and supply of the finished ATMP to the patient's healthcare;
  • Maintaining sterility throughout the entire manufacturing process;
  • Need for continuous monitoring and controls;
  • Degree of variability of the finished product due to the use of biological materials and/or complex manipulation steps, especially in autologous setting;
  • Demonstration of comparability between production processes and batches; 
  • Difficulty to validate the consistency of the ATMP production process: autologous nature of the products and small sample sizes limiting the number of analytical tests; 
  • Complex manufacturing process & regulatory approval timelines leading to potential delays in patients’ access to ATMPs.

Although these challenges are considered within the EU guidelines on GMP specific to ATMPs, it shall be highlighted that quality insurance and GMP compliance is an ongoing process that does not end with the manufacturing or marketing authorisation’s granting.

Indeed, 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 analyses of medicinal products samples.

Finally, the manufacturing of ATMPs also raised unsolved issues yet regarding multiple sites manufacturing, especially in scaling-out production of autologous ATMPs in case of decentralised manufacturing sites. Under current EU law requirements, each production site must hold a manufacturing authorisation and comply with the GMP specific to ATMPs.

Decentralised sites can be portable on unit demands allowing a rapid adaptation on demand, or point of care manufacturing such as hospital, manufacturing nodes, patients’ bedside or patients’ home. Their advantage, for ATMPs with limited shelf-life or limited options for storage and shipping, is to be close to patient, and when manufacturing requires customization, close to clinical setting.

To ensure the quality of the manufacturing process for each manufacturing site involved, mitigating costly transition to GMP and time-consuming confirmatory clinical qualification studies, the 2023 Proposal for a Directive reforming the Union code relating to medicinal products for human use contains provision on decentralised production sites potentially near to the patient. In particular, Article 142 states that by derogation “the manufacturing authorisation shall not be required for […] the decentralised sites carrying out manufacturing or testing steps under the responsibility of the qualified person of a central site referred to in Article 151(3)”. However, it is still too early to say whether this proposed amendment will be adopted.

Opportunities and incentives

National competent authorities providing regulatory and scientific advices and guidance are the entry point for the manufacturing authorisation applicants.

Moreover, at the EU level, the European Commission has issued detailed guidelines on GMP applicable to medicinal products, and ATMPs specifically. 

The EMA 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 EMA also 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 IWG of senior inspectors appointed by the national competent authorities from the entire EEA.

To go further: more information on the EMA role on GMP can be found here.

Applicants for manufacturing authorisation can also access the EudraGMDP database. EudraGMDP is the name for the EU 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 (as well Good Distribution Practices- GDP certificates; see "Distribution of ATMPs" entry, currently under development), and non-compliance statements issued after inspections. It is maintained and operated by the EMA, and its content is provided by national competent authorities.

Interactions with regulators

Interactions between manufacturing authorisation applicant and national competent authority

The national competent authority will register, review and assess the application for manufacturing authorisation of medicinal products intended for the use within the EU. Application form, timeline, financial, technical and scientific publications, scientific advice 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 competent 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 with EMA

EMA offers scientific advice and protocol assistance to manufacturers, publishes common interpretation of EU GMP, and issues guidance helping manufacturers to navigate the complex regulatory landscape and optimise their ATMPs development and manufacturing processes. 

For more information, please see Support for innovative medicines’ development at the EMA level and Support specific to ATMPs’ development at EMA level.

Interactions between the EMA, the GMP/GDP IWG and the manufacturing/marketing authorisation holder

The manufacturing holder can access guidelines reflecting a harmonised approach of the EU Member States and the EMA, and scientific guidance published by the EMA in charge of coordinating and harmonising GMP at the European level, including through the chairing of the GMP/GDP IWG. The EU procedures on exchange of information and inspections conducted by the competent national authorities are compiled by the EMA are available here.

Other interactions

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.

Practical steps

Manufacturing Authorisation application

Any legal entity wishing to manufacture a medicinal product in the EU has to apply to the national competent authority of the Member State where they carry out these activities. The  national competent authority will register, review and assess the application for manufacturing authorisation of medicinal products intended for the use within the EU. To receive an authorisation to manufacture ATMPs, the applicant must demonstrate compliance with the principles of EU quality standards, GMP principles and guidelines, and the European Pharmacopeia.

Due to the level of complexity and 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, guidelines on GMP specific to ATMPs have been published by the European Commission (see below).

The national competent authority will also conduct repeated on-site inspections to ensure that EU guidelines on GMP specific to ATMPs are complied with. They also participate to regular meetings of the GMP/GDP IWG.

Regulatory provisions

  1. Compliance with EU GMP for ATMPs

In compliance with Article 5 of Regulation (EC) No 1394/2007, the European Commission has published on September 2017 a set of Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products to provide assistance and support for ATMPs manufacturers. The guidelines, drafted with the Committee for Advanced Therapies, the GMP/GDP IWG, national competent authorities and external stakeholders, adapted the GMP requirements for medicinal products to the specific characteristics of ATMPs and their complex manufacturing to issue mandatory guidelines for ATMPs applicable to all type of settings. The guidelines are ‘mandatory’ as they specify how to fulfil the legal obligation provided by Article 5 of Regulation (EC) No 1394/2007, strictly speaking they are ‘quasi-binding’.

The guidelines foster a risk-based approach to manufacture and test ATMPs, as well as to design the organisational, technical, and structural measures to provide flexibility, while ensuring a high "pharmaceutical quality system" that safeguards ATMP’s quality. 

The requirements and measures to be put in place by manufacturers to safeguard a high level of patient protection, cover the following sections:

  • Risk-based approach
  • Personnel
  • Premises
  • Equipment
  • Documentation
  • Starting and raw materials
  • Seed lot and cell bank system
  • Production
  • Qualification (premises and equipment) and validation (cleaning, process, test methods and transport conditions)
  • Qualified person and batch release
  • Quality control
  • Outsourced activities
  • Quality defects and product recalls
  • Environmental control measures for ATMPs containing or consisting of GMOs
  • Reconstitution of product after batch release
  • Automated production of ATMPs
  1.  European Pharmacopeia 

The ATMPs manufacturer applicant has also to comply with the quality standards for medicinal products contained in the European Pharmacopeia elaborated by the EDQM. The European Pharmacopeia is made up of common quality standards noted both in monographs and general methods texts to provide a regulatory and scientific basis for quality control during the development, production and marketing processes of medicinal products and their components.

More information on the background and mission of the European Pharmacopeia can be found here.

  1. The general principles of ICH Q5E

Only the general principles of ICH Q5E on ‘Comparability of biotechnological/biological products subject to changes in their manufacturing process’ can be applied to ATMPs.

European Union Legislation

Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, OJ L 311, 28.11.2001, p. 67-128, CELEX number: 32001L0083. 

Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (Text with EEA relevance), OJ L 324, 10.12.2007, p. 121-137, CELEX number: 32007R1394

Commission Directive (EU) 2017/1572 of 15 September 2017 supplementing Directive 2001/83/EC of the European Parliament and of the Council as regards the principles and guidelines of good manufacturing practice for medicinal products for human use (Text with EEA relevance), C/2017/6127, OJ L 238, 16.9.2017, p. 44-50, CELEX number: 32017L1572

Commission Delegated Regulation (EU) 2017/1569 of 23 May 2017 supplementing Regulation (EU) No 536/2014 of the European Parliament and of the Council by specifying principles of and the guidelines for good manufacturing practice for investigational medicinal products for human use and arrangements for inspections,  (Text with EEA relevance), OJ L238, 16.9.2017, p. 12-21, CELEX number: 32017R1569

  • Original text (available in the 24 official languages of the EU)

Proposal for a Directive of the European Parliament and of the Council on the Union code relating to medicinal products for human use, and repealing Directive 2001/83/EC and Directive 2009/35/EC, (Text with EEA relevance), COM/2023/192 final, CELEX number: 52023PC0192

European Union Guidance

EMA Guidance documents

GMP/GDP Inspectors Working Group

Relevant Literature

See also the literature relevant to the Good Manufacturing Practice for ATMPs entry.

Acknowledgements

Published: 10/01/2023

Updated: 13/06/2024

Authors:

Luc-Sylvain Gilbert, EuroGCT ELSI Legal Information Officer

and Aurélie Mahalatchimy, EuroGCT WP4 Convenor, UMR 7318 DICE CERIC, Aix-Marseille University, CNRS, Aix-en-Provence- France

Reviewed by: 

Under internal review by EuroGCT Manufacturing Working Group.

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