Guidance for applicants on biologicals

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Question 1 (June 2007) What is the definition of a biological medicinal product?

A biological medicinal product is a product, the active substance of which is a biological substance. A biological substance is a substance that is produced by or extracted from a biological source and for which a combination of physico-chemical-biological testing and the production process and its control is needed for its characterisation and the determination of its quality.
This definition is given both in Part I of Annex I of Directive 2001/83/EC (as amended by Directive 2003/63/EC) and in the introductory statements to Annex I of EC/1084/2003 and EC/1085/2003.
According to this definition the substance should be of biological origin and, due to its complexity, a combination of physico-chemical-biological testing together with testing and control of the production process is needed for its characterisation and determination of quality.

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Question 2 (June 2007) How is this definition applied?

The legislation makes it explicit that as a result, the following shall be considered as biological medicinal products: recombinant proteins, monoclonal antibodies, blood products, immunological medicinal products such as sera and vaccines, allergens, and advanced technology products such as gene and cell therapy products.
In addition, on scientific grounds, a number of other products should be considered biological medicinal products, because they meet the aforementioned legal criteria of biological origin and complexity.
For a (non-exhaustive) list of these other biological medicinal products, click here. Based on scientific reasoning, analogous products not mentioned in this list should also be considered as biological medicinal products.

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Question 3 (June 2007, updated October 2007) Are there special requirements for biological medicinal products?

Yes, the regulatory approach to biological medicinal products differs in several ways.

• For abridged applications of biological medicinal products the legal basis should be Article 10(4) of Directive 2001/83/EC.
• Given the complexity of the characterisation of the product, bibliographic applications according to Article 10a of Directive 2001/83/EC are normally not applicable. In that case, a full application according to Article 8(3) of Directive 2001/83/EC would be the appropriate legal basis. In exceptional cases however, Article 10a might be considered based on the available bibliographic data and should in that case be discussed with the RMS well in advance of submission to give the RMS the opportunity to discuss this in CMDh.
•  Due to this complexity, it is also not possible to use the ASMF-procedure (see Guideline CPMP/QWP/227/02 rev 2).
  With regard to variations, specific conditions apply for biological medicinal products because of their complexity. (EC/1084/2003 and EC/1085/EC).
• Separate guidelines are available for biological medicinal products. These can be accessed at the EMA website (www.emea.europa.eu/htms/human/humanguidelines/biologicals.htm).
• Biological medicinal products can be registered through the mutual recognition or decentralised procedures, provided that they do not fall within the Annex to Regulation (EC) No 726/2004 - Medicinal products to be authorised by the Community, in which case the centralised procedure has to be followed.

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