3. Key GxPs in Medicine

1. Manufacturing / Import Authorisation (MIA)

Any company located in the European Economic Area (EEA) that intends to produce or import human medicines, needs an authorisation issued by the respective regulatory authority. A manufacturing / import authorisation (MIA) will only be issued when the company can show it complies with GMP (e.g., follows the EU GMP guidelines) and passes regular inspections. Importers are also responsible to ensure that the third country manufacturer they are importing from complies with GMP.

Of Note: "Import" refers to goods coming from third countries into the EU and not to movement of goods between Member States. Movement within the EU on the other hand, is subject only to the holding of a Wholesale Distribution Authorisation.

2. GMP overview

GMP sets out best practice methods and standards for manufacturers to ensure their products are of consistent high quality, appropriate for their intended use, are safe and comply with the marketing authorisation or clinical trial authorisation, are packaged and labelled correctly, are uncontaminated and contain the ingredients and have the strength they claim to have. This applies to all medicines intended for the EU market and to all manufacturing sites no matter where in the world they are located. Legislation in the EU to control and guarantee that these requirements are observed is detailed and continuously adapted to new scientific, technical and system developments. In fact, GMP can be considered one key element of what the EU guidelines call quality management, which, along with quality control and quality risk management, forms part of an overall pharmaceutical quality system. (see also section 3 Quality system)

It should be noted that GMP standards are not prescriptive or “cookbook” instructions on how to manufacture products. They are a series of performance-based requirements that must be met during manufacturing. There may be many ways, a company can fulfil GMP requirements. It is the company's responsibility to determine the most effective and efficient quality process that meets both, business and regulatory needs.

Practically all legislation and guidelines concerning GMP in numerous countries across the world follow a series of basic principles which are listed in a high-level outline in the following. For more information the relevant detailed legislative documents and guidelines should be consulted.

The guidelines concern all aspects of production, requiring, for example, that:

• Manufacturing facilities are of adequate size and kept in good condition with clean and hygienic manufacturing areas and access restricted to authorised personnel only
• Manufacturing facilities maintain controlled environments in order to prevent cross-contamination that may render the product unsafe for human use.
• Manufacturing processes are clearly defined and controlled. All critical processes are validated to ensure consistency and compliance with specifications.
• Equipment is properly calibrated and maintained in order to consistently produce reliable results
• Any changes to the manufacturing process are evaluated and changes that affect the quality of the product are validated as necessary.
• Instructions and procedures are clear and unambiguous
• Employees have the appropriate qualifications and training
• Processes are reliable and consistent; this needs to be properly documented and archived following Standard Operating Procedures (SOPs), manufacturing instructions, analytical methods, etc.
• The correct materials, containers and labels are used; they need to comply with their specifications and be correctly identified. Their use must be recorded and traceable.
• Quantity and quality of the product are within defined limits and any deviations investigated and documented.
• Records of manufacture (including distribution) that enable the complete history of a batch to be traced are retained in a comprehensible and accessible form.
• A system is in place for recalling any batch from sale or supply.
• Complaints about marketed products are examined, the causes of quality defects are investigated, and appropriate measures are taken with respect to defective products and to prevent recurrence.

Legal basis:
Regulation No. 1252/2014 and Directive 2003/94/EC, applying to active substances and medicines for human use;

Directive 2001/83/EC (Title IV Manufacture and Import)

Directive 2001/20/EC (Article 13 Manufacture and import of investigational medicinal products)

Eudralex Volume 4 of "The rules governing medicinal products in the European Union" contains the EU GMP guidelines which provide interpretation of these principles and guidelines, supplemented by a series of annexes that modify or augment the detailed guidelines for certain types of product, or provide more specific guidance on a particular topic.

Commission Delegated Regulation (EU) 2017/1569 supplementing Regulation (EU) 536/2014 by specifying principles and guidelines for GMP for investigational medicinal products for human use and arrangements for inspections (applicable as from the date of entry into application of Regulation (EU) No 536/2014 on Clinical Trials)

Commission Directive (EU) 2017/1572 supplementing Directive 2001/83/EC as regards the principles and guidelines of GMP for medicinal products for human use (applicable as from the date of entry into application of Regulation (EU) No 536/2014 on Clinical Trials)

Specific GMP Guidelines have been developed for ATMPs
Guidelines on Good Manufacturing Practices (GMP)