Preclinical safety and toxicology testing of cell-based medicinal products

Today’s incurable diseases such as diabetes, congestive heart failure or Parkinson’s disease in the future may be overcome by cell therapy, aimed at restoring the body’s proper function. Introduction of foreign cells into a patient’s body, however, may lead to rejection and other unexpected outcomes. The use of patient-derived cells produced from so-called adult induced pluripotent stem cells could be a way out.

© Fraunhofer ITEM
H&E staining of a humanized mouse liver, showing subtle cellular infiltrates.

The safety and toxicology of such cell-based medicinal products (CBMPs) cannot be assessed relying on the standard repertoire used for classical pharmaceuticals. Such assessment, however, is pivotal for regulatory acceptance and to get approval for initiation of the clinical phase of development. In order to fill this gap and to support the translational development of CBMPs to clinical use, we are aiming to evolve as a competent partner for non-clinical safety and toxicology research on such Advanced Therapy Medicinal Products (ATMPs).

Fraunhofer ITEM is specialized in the development of product-specific testing strategies for preclinical evaluation of biologics and non-biologics and already has a track record in pharmacology research on cell-based therapies. Thus, we are excellently positioned to translate such emerging technologies into clinical application.


Before bringing a new cell-based therapy from basic research to trials in patients, it must first be tested for safety and toxicology. For this class of products, the transition to clinic is a particular challenge, since they represent novel approaches that have never been tried in humans.

With standard protocols applied to classical pharmaceuticals, the safety and toxicology of ATMPs such as cell therapies cannot be assessed. Fraunhofer ITEM with its background in product-specific strategies for preclinical testing and toxicology is uniquely positioned to establish non-standard test systems and subsequently transfer them from the research lab to the institute’s GLP environment.

Requirements for the registration of human CBMPs for the European market

The European Medicines Agency (EMA) regulates the basic requirements for the registration of human CBMPs for the European market. In its “Guideline on human cell-based medicinal products” (EMEA/CHMP/410869/2006), EMA describes CBMPs as heterogeneous and considers that product-specific case-by-case testing strategies are needed, rather than conventional non-clinical pharmacology and toxicology studies. It further recommends early presentation of these individual, risk-based strategies for preclinical evaluation to the drug registration authorities for discussion. With our long-standing expertise in preclinical testing of new drugs, including safety-relevant studies according to GLP, we are in a position to adequately support our clients in all contexts of preclinical testing of heterogeneous cell-based therapies. This includes initial consulting to set up an appropriate testing strategy and early interaction with the competent authorities to ensure regulatory compliance of the developed strategy. The complex assays and studies are then validated and performed according to the relevant quality standards.

Immunohistochemical detection of hematopoietic stem cells and induced pluripotent stem cells

A core area of our research in the field of biodistribution of cell therapies is immunohistochemical detection of hematopoietic stem cells and induced pluripotent stem cells in tissues and whole-organ slices of laboratory animals, even if the number of cells distributed throughout the body is low. For this purpose, a broad spectrum of antibodies is established at Fraunhofer ITEM. In view of safety aspects and registration, histopathology and immunohistochemistry are performed under GLP conditions.

A risk of stem cell therapies is the formation of teratomas. These  germ cell tumors can be induced by injection of pluripotent stem cells into immunodeficient mice. During tumor growth, the injected stem cells differentiate into cell types from all three germ layers, reflecting embryonic development to a certain degree. With the broad range of methods we have at our disposal, teratoma formation can be assessed as an endpoint in toxicology studies.

© Fraunhofer ITEM
Immunohistochemical analysis of teratoma sections. IHC staining for CD34+ and CD31+ cells, representing hemogenic endothelium (A; scale bar 50 µm). Exemplary result of IHC for hCD90, hCD34 and human nuclei in a teratoma section, arrows indicate CD34+/CD90+ cells (B; scale bar 20 µm).


Henning Weigt

Contact Press / Media

Dr. Henning Weigt

Head of Staff Group Institute Strategy and Communication

Phone +49 511 5350-329