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

[F1 2. SOMATIC CELL THERAPY MEDICINAL PRODUCTS (HUMAN AND XENOGENEIC) U.K.

For the purposes of this Annex, somatic cell therapy medicinal products shall mean the use in humans of autologous (emanating from the patient himself), allogeneic (coming from another human being) or xenogeneic (coming from animals) somatic living cells, the biological characteristics of which have been substantially altered as a result of their manipulation to obtain a therapeutic, diagnostic or preventive effect through metabolic, pharmacological and immunological means. This manipulation includes the expansion or activation of autologous cell populations ex vivo (e.g., adoptive immuno-therapy), the use of allogeneic and xenogeneic cells associated with medical devices used ex vivo or in vivo (e.g., micro-capsules, intrinsic matrix scaffolds, bio-degradable or not).

Specific requirements for cell therapy medicinal products regarding Module 3 U.K.

Somatic cell therapy medicinal products include:

• Cells manipulated to modify their immunological, metabolic or other functional properties in qualitative or quantitative aspects;

• Cells sorted, selected and manipulated and subsequently undergoing a manufacturing process in order to obtain the finished medicinal product;

• Cells manipulated and combined with non-cellular components (e.g. biological or inert matrixes or medical devices) and exerting the principle intended action in the finished product;

• Autologous cell derivatives expressed in vitro under specific culture conditions;

• Cells genetically modified or otherwise manipulated to express previously unexpressed homologous or non-homologous functional properties.

The whole manufacturing process from the collection of the cells from the patient (autologous situation) up to the re-injection to the patient shall be considered as one single intervention.

As for other medicinal products, the three elements of the manufacturing process are identified:

• starting materials: materials from which the active substance is manufactured, i.e., organs, tissues, body fluids or cells;

• active substance: manipulated cells, cell lysates, proliferating cells and cells used in conjunction with inert matrixes and medical devices;

• finished medicinal products: active substance formulated in its final immediate container for the intended medical use.

a)

General information on active substance(s)

The active substances of cell therapy medicinal products consist of cells which as a consequence of in vitro processing display prophylactic, diagnostic or therapeutic properties different from the original physiological and biological one.

This section shall describe the type of cells and culture concerned. Tissues, organs or biological fluids from which cells are derived as well as the autologous, allogeneic, or xenogeneic nature of the donation and its geographical origin shall be documented. Collection of the cells, sampling and storage prior further processing shall be detailed. For allogeneic cells, special attention shall be paid to the very first step of the process, which covers selection of donors. The type of manipulation carried out and the physiological function of the cells that are used as active substance shall be provided.

b)

Information related to the starting materials of active substance(s)

1. Human somatic cells U.K.

Human somatic cell therapy medicinal products are made of a defined number (pool) of viable cells, which are derived from a manufacturing process starting either at the level of organs or tissues retrieved from a human being, or, at the level of a well defined cell bank system where the pool of cells relies on continuous cell lines. For the purposes of this chapter, active substance shall mean the seed pool of human cells and finished medicinal product shall mean seed pool of human cells formulated for the intended medical use.

Starting materials and each step of the manufacturing process shall be fully documented including viral safety aspects.

(1) Organs, tissues, body fluids and cells of human origin U.K.

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

Description of sampling including site, type, operating process, pooling, transportation, storage and traceability as well as controls carried out on sampling shall be documented.

(2) Cell banking systems U.K.

Relevant requirements depicted in part I shall apply for the preparation and quality control of cell banking systems. This may essentially be the case for allogeneic or xenogeneic cells.

(3) Ancillary materials or ancillary medical devices U.K.

Information shall be provided on the use of any raw materials (e.g., cytokines, growth factors, culture media) or of possible ancillary products and medical devices e.g., cell sorting devices, biocompatible polymers, matrix, fibres, beads in terms of bio-compatibility, functionality as well as the risk of infectious agents.

2. Animal somatic cells (xenogeneic) U.K.

Detailed information related to the following items shall be provided:

• Sourcing of the animals

• Animal husbandry and care

• Genetically modified animals (methods of creation, characterisation of transgenic cells, nature of the inserted or excised (knock out) gene)

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

• Testing for infectious agents including vertically transmitted micro-organisms (also endogenous retro viruses)

• Facilities

• Cell banking systems

• Control of starting and raw materials.

a) Information on the manufacturing process of the active substance(s) and the finished product U.K.

The different steps of the manufacturing process such as organ/tissue dissociation, selection of the cell population of interest, in vitro cell culture, cell transformation either by physico-chemical agents or gene transfer shall be documented.

b) Characterisation of active substance(s) U.K.

All of the relevant information on the characterisation of the cell population of interest in terms of identity (species of origin, banding cytogenetics, morphological analysis), purity (adventitious microbial agents and cellular contaminants), potency (defined biological activity), and suitability (karyology and tumorigenicity tests) for the intended medicinal use shall be provided.

c) Pharmaceutical development of finished medicinal product U.K.

Apart from the specific method of administration used (intravenous infusion, site-injection, transplantation surgery), information shall also be provided on the use of possible ancillary medical devices (bio-compatible polymers, matrix, fibres, beads) in terms of bio-compatibility and durability.

d) Traceability U.K.

A detailed flow chart shall be provided insuring the traceability of the products from the donor to the finished medicinal product.]

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).