Directive 2001/83/EC of the European Parliament and of the CouncilDangos y teitl llawn

[F1 1. GENE THERAPY MEDICINAL PRODUCTS (HUMAN AND XENOGENEIC) U.K.

For the purposes of this Annex, gene therapy medicinal product shall mean a product obtained through a set of manufacturing processes aimed at the transfer, to be performed either in vivo or ex vivo, of a prophylactic, diagnostic or therapeutic gene (i.e. a piece of nucleic acid), to human/animal cells and its subsequent expression in vivo. The gene transfer involves an expression system contained in a delivery system known as a vector, which can be of viral, as well as non-viral origin. The vector can also be included in a human or animal cell.

1.1. Diversity of gene therapy medicinal products U.K.

a) Gene therapy medicinal products based on allogeneic or xenogeneic cells U.K.

The vector is ready-prepared and stored before its transfer into the host cells.

The cells have been obtained previously and may be processed as a cell bank (bank collection or bank established from procurement of primary cells) with a limited viability.

The cells genetically modified by the vector represent an active substance.

Additional steps may be carried out in order to obtain the finished product. By essence, such a medicinal product is intended to be administered to a certain number of patients.

b) Gene therapy medicinal products using autologous human cells U.K.

The active substance is a batch of ready-prepared vector stored before its transfer into the autologous cells.

Additional steps may be carried out in order to obtain the finished medicinal product.

Those products are prepared from cells obtained from an individual patient. The cells are then genetically modified using a ready-prepared vector containing the appropriate gene that has been prepared in advance and that constitutes the active substance. The preparation is re-injected into the patient and is by definition intended to a single patient. The whole manufacturing process from the collection of the cells from the patient up to the re-injection to the patient shall be considered as one intervention.

c) Administration of ready-prepared vectors with inserted (prophylactic, diagnostic or therapeutic) genetic material U.K.

The active substance is a batch of ready-prepared vector.

Additional steps may be carried out in order to obtain the finished medicinal product. This type of medicinal product is intended to be administered to several patients.

Transfer of genetic material may be carried out by direct injection of the ready-prepared vector to the recipients.

1.2. Specific requirements regarding Module 3 U.K.

Gene therapy medicinal products include:

• naked nucleic acid

• complex nucleic acid or non viral vectors

• viral vectors

• genetically modified cells

As for other medicinal products, one can identify the three main elements of the manufacturing process, i.e.:

• starting materials: materials from which the active substance is manufactured such as, gene of interest, expression plasmids, cell banks and virus stocks or non viral vector;

• active substance: recombinant vector, virus, naked or complex plasmids, virus producing cells, in vitro genetically modified cells;

• finished medicinal product: active substance formulated in its final immediate container for the intended medical use. Depending on the type of gene therapy medicinal product, the route of administration and conditions of use may necessitate an ex vivo treatment of the cells of the patient (see 1.1.b).

A special attention shall be paid to the following items:

a)

Information shall be provided on the relevant characteristics of the gene therapy medicinal product including its expression in the target cell population. Information concerning the source, construction, characterisation and verification of the encoding gene sequence including its integrity and stability shall be provided. Apart from therapeutic gene, the complete sequence of other genes, regulatory elements and the vector backbone shall be provided.

b)

Information concerning the characterisation of the vector used to transfer and deliver the gene shall be provided. This must include its physico-chemical characterisation and/or biological/immunological characterisation.

For medicinal products that utilise a micro-organism such as bacteria or viruses to facilitate gene transfer (biological gene transfer), data on the pathogenesis of the parental strain and on its tropism for specific tissues and cell types as well as the cell cycle-dependence of the interaction shall be provided.

For medicinal products that utilise non-biological means to facilitate gene transfer, the physico-chemical properties of the constituents individually and in combination shall be provided.

c)

The principles for cell banking or seed lot establishment and characterisation shall apply to gene transfer medicinal products as appropriate.

d)

The source of the cells hosting the recombinant vector shall be provided.

The characteristics of the human source such as age, sex, results of microbiological and viral testing, exclusion criteria and country of origin shall be documented.

For cells of animal origin, detailed information related to the following items shall be provided:

• Sourcing of the animals

• Animal husbandry and care

• Transgenic animals (methods of creation, characterisation of transgenic cells, nature of the inserted gene)

• Measures to prevent and monitor infections in the source/donor animals

• Testing for infectious agents

• Facilities

• Control of starting and raw materials.

Description of cell collection methodology including location, type of tissue, operating process, transportation, storage and traceability as well as controls carried out during the collection process shall be documented.

e)

The evaluation of the viral safety as well as the traceability of the products from the donor to the finished medicinal product, are an essential part of the documentation to be supplied. E.g., the presence of replication competent virus in stocks of non-replication competent viral vectors must be excluded.]

Textual Amendments

F1 Substituted by Commission directive 2003/63/EC of 25 June 2003 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use (Text with EEA relevance).