14/15 December 2023
On 23.June 2017, the Committee for Medicinal Products for Veterinary Use (CVMP) of the European Medicines Agency (EMA) has published a new Questions and Answers (Q&A) document. It represents the first European guidance ever relating to stem cell-based medicines for veterinary use. The document focusses on the concerns of manufacturers as well as authorities on the sterility of allogenic stem cell therapies in the veterinary sector. In their announcement the EMA stated:
"Allogenic stem cell-based veterinary medicines originate from tissues (such as bone marrow or fat) from a donor from the same species of animal, not from the recipient of the cells. These products are manufactured in large batches which need to be sterile as they are administered by injection directly into the body. Microbiological contamination can occur at various steps, from the initial sampling of the cells and tissues, up to the final product packaging into containers such as vials, syringes or bottles. A crucial step is the sourcing and collection of the stem cells as it is not always possible to fully implement aseptic techniques at this stage. Control for the absence of microorganisms is also key in manufacturing process controls and quality controls of cell preparations at selected stages of production. The guidance provides answers to eight main issues identified by ADVENT to support manufacturers in ensuring sterile and safe stem cell-based therapies for veterinary use.
Until now, no specific guidance on stem cell-based medicines for veterinary use was available from EMA. The CVMP identified the sterility of allogenic stem cell therapies as one of the priority areas where it would be useful and necessary to develop guidance, following a review of the scientific evidence, such as published literature, available guidance on stem cells for medicines for human use, experience gained by the CVMP through scientific advice and public consultations. More guidance concerning cell based products and other priority areas such as monoclonal antibodies is under development.
Interest and research activities into novel therapies such as stem cell or gene therapy has gathered speed over the last few years. ADVENT, a group mandated by the CVMP and composed of senior regulatory experts, brings together wide knowledge and expertise on the scientific aspects of veterinary medicines and also on their regulation. It was set up by EMA to provide general guidance on the requirements for authorisation of novel veterinary medicines and engages additional specific expertise for the development of such guidance.
Novel therapies are therapies entirely new to the veterinary sector either because they are genuinely new and have not been previously used in animals, or new only to the veterinary domain, although well known in the context of human medicines."
Relating to the fact, that a contamination with microorganisms can occur in various steps during the manufacturing process, such a guidance document will be helpful for manufacturers as well as for authorities. Especially sourcing and collection of stem cells is not always possible under aseptic conditions and techniques. Additionally, the raw material can be a source of contamination and the in vitro processing can be risky too.
Moreover the control of absence of microorganisms and their degradation products like Endotoxins and Pyrogens, in selected stages of the production and/or in the final stem cell-based product is an important concern. But testing is often not easy which is related to limited suitability of the common methods - especially for products with a short shelf life - or to masking effects of endotoxins. For that, the document refers in its introduction to the relevant documents of the Pharmacopoeias like European Pharmacopoeia chapter
In the general text 5.14 on ‘Gene transfer medicinal products for human use’ the Ph. Eur. advises to test genetically modified cells for specific characteristics (sterility, mycoplasma, endotoxin).
Guidance on raw materials of biological origin has been recently developed by the Ph. Eur. 5.2.12 ‘Raw materials of biological origin for the production of cell-based and gene therapy medicinal products’ .
The United States Pharmacopeia (USP) has established a specific chapter <1046> addressing ‘Cellular and Tissue-based Products’ , which gives information on sterility, mycoplasma and endotoxin testing, amongst other things.