LOS APORTES DE NORBERT ELIAS 214
4. Las configuraciones sociales y la duración: el “largo plazo”
The “Committee For Medicinal Products For Human Use (CHMP)” from the European Medicines Agency (EMA) issued the “Guideline On Xenogeneic Cell-Based Medicinal Products ” in 2009 (EMA, January 1, 2010). The guideline should be read together with the introduction and general principles (4) and part 4 of the Annex I to Directive 2001/83/EC, the Regulation (EC) No 1394/2007 on Advanced Therapy Medicinal Products and the Directive 2001/18/EC, when cells are obtained from genetically modified animals. First, the authors define xenogeneic cell-based therapy as the use of viable animal somatic cell preparations, which are suitably adapted for either implantation/infusion into a human recipient or extracorporeal treatment by bringing animal cells into contact with human body fluids, tissue or organs, where the principal objective is reconstitution of cell, tissue or organ functions (EMA, January 1, 2010). This guideline is an annex to the guideline EMEA/CHMP/41086/2006 and deals specifically with scientific requirements unique for xenogeneic cell-based medicinal products . The main issues of the “Guideline On Xenogeneic Cell-Based Medicinal Products” are the source and the testing of the animals, manufacture and quality control and non-clinical and clinical development of xenogeneic cell-based medicinal products. Furthermore, it deals with public health aspects to ensure proper surveillance for infections, especially zoonoses. Sources for xenogeneic material can be non-transgenic, transgenic and genetically-modified animals.
Regarding quality and manufacturing aspects, there are three critical points given in the guideline: the source animals, the procurement and the processing of the organs, tissues and cells (EMA, January 1, 2010). The manufacturing facility should be good manufacturing practice (GMP) approved and separated from the animal facility. The health status of the animals should be monitored and documented, with special attention to organ and tissue specific pathogens. Further should the origin of the animals be fully described, e.g. typically for consumption or for laboratory use and they should be at least be specific pathogen free (SPF) and held under SPF conditions. The cells, tissues and organs for manufacturing xenogeneic cell-based medicinal products should only be produced from animals bred in captivity, in a barrier facility, and only bred for this special purpose. Under no circumstances should cells, tissues and organs from wild animals or from abattoirs be used. Additionally, the tissue of founder animals should not be used.
Cells, tissues or organs may be obtained from genetically modified animals, or may be obtained by ex vivo genetic modification. In any case, genetically modified animals must be fully characterized and have to comply with applicable European legislation. Animal cells from genetically modified animals used as active substance should comply with “Note for Guidance on the Quality, Preclinical and Clinical aspects of Gene Transfer Medicinal Products (CPMP/BWP/3088/99) (EMA, January 1, 2010). The guidance on risk assessment of gene therapy medicinal products in the guideline EMEA/CHMP/GTWP/125491/2006 can be useful for xenogeneic cell-based medicinal products as well.
SOPs for the following procedures should be installed to avoid incidents that negatively affect the health of the herd or colony and thus could negatively impact on the barrier facility or the SPF status of the herd (EMA, January 1, 2010) : detailing the housing of the animals and the containment conditions. Water, bedding, source and handling of feed, including feeding. Entry and exit of the animals, animal transportation, identifying individual animals and recording their movements to, through and out of the facility. Disposition of animal tissues and dead animals and removal from production and disposal of the animals and their by-products. Performance and monitoring of health screening and isolation and quarantine.
The “Guideline On Xenogeneic Cell-Based Medicinal Products” advises to use protocols for monitoring the herd and to introduce a herd health surveillance system with a complete documentation of all veterinary care that the animals received. The specific screening routines
should include physical examination and laboratory tests, where all infectious agents known to potentially infect the source species have to be considered. It recommends that there is no use of any antibiotics or vaccines in the source animals. But, if treatment of animals with any medicines is necessary for animal welfare reasons, the impact on the product should be evaluated and discussed with the competent authority. Any use of vaccines must be justified (EMA, January 1, 2010).
As mentioned above the testing programs for source animals should be tailored for the purpose of the product and updated periodically to reflect advances in the knowledge of infectious disease.
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dequate and validated diagnostic assays and methods have to be available before initiating clinical trials. Some pathogens to be considered are given in the “Guideline On Xenogeneic Cell-Based Medicinal Products”, e.g. endogenous retroviruses (ERV e.g. porcine ERV), infectious agents of humans relating to receptors expressed by transgenic animals (CD46 (membrane cofactor protein, MCP-1) as the cell-surface receptor for measles virus), antibiotic-resistant bacteria, geographically important infectious agents such asTrypanosoma cruzi or African Swine Fever.
Adequate archiving is another crucial point to be discussed, because long-term archiving of tissue samples, cell preparations and paper records will be necessary (EMA, January 1, 2010). Records should be kept for 30 years, which makes an established and validated archiving plan inevitable, to ensure traceability and the possibility for look-back. All records concerning the herd, e.g. feeding and health records, source animal health documentation, should be archived for a period at least equal to that of the archived tissue samples.
Giving a very good overview of the regulatory landscape, especially of cell therapy products in Europe, for example pancreatic islets and hepatocytes, the Review “Regulatory aspects of clinical xenotransplantation” from Henk-Jan Schuurman (reviewed in SCHUURMAN, 2015) has to be mentioned at this place.
2.3.4 Association for Assessment and Accreditation of Laboratory Animal Care