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16 June 2016 EMA/CVMP/ADVENT/174610/2016 Committee for Medicinal Products for Veterinary Use (CVMP)

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Stem cell -based products for veterinary use: Specific questions on extraneous agents to be addressed by ADVENT

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Draft

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Draft agreed by Ad Hoc Expert Group on Veterinary Novel Therapies (ADVENT)

May 2016

Adopted by CVMP for preparation of a Question and Answer document

16 June 2016

Start of public consultation

27 June 2016

End of consultation (deadline for comments)

30 September 2016

8 Comments should be provided using this template. The completed comments form should be sent to [email protected] 9 10

30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact

An agency of the European Union

© European Medicines Agency, 2016. Reproduction is authorised provided the source is acknowledged.

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Background

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Cell-based medicinal products (CBMP) are heterogeneous with regard to the origin and type of cells

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and to the complexity of the product.

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Cells may be self-renewing stem cells, more committed progenitor cells or terminally differentiated

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cells exerting a specific defined physiological function.

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Stem cell -based products (SCP) and animal stem cell -based products (ASCP) are a subset of cell-

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based medicinal products containing, consisting of or derived from cells such as stem cells, progenitor

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cells, precursor cells, stem cell -like cells, reprogrammed cells, and other cell types with similar

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properties.

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The term “stem cell” means a non-terminally differentiated, self-renewing cell that harbours the ability

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to produce mature, differentiated daughter cells. Stem cells serve to regulate or participate in normal

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tissue homeostasis and embryonic and foetal development.

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The use of stem cell -based products in the veterinary sector, mainly for horses and dogs, is increasing

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and is raising questions for manufacturers, authorities and users.

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A critical aspect under discussion concerns the freedom of extraneous agents of the stem cell -based

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product. Freedom from extraneous agents is a high priority for any veterinary medicinal product,

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including therefore stem cell -based products veterinary medicinal products to be administered

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parenterally, and the requirement to test veterinary medicinal products for potential infectious

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contaminants is specified in Directive 2001/82/EC and in the European Pharmacopoeia (Ph. Eur.).

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Contamination could originate from the starting or raw materials, or adventitiously introduced during

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the manufacturing process. Differentiation between the cell sourcing steps, which include donor/tissue

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screening for extraneous agents (viruses, bacteria, protozoa), and the process thereafter during

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manufacture where typical microbiological contamination (not related to donor/tissue) might occur

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(viruses, bacteria, mycoplasma) is reasonable.

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Freedom of extraneous agents is crucial when donor animals need to be qualified as source of

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tissues/fluids/cells which contain the stem cells wanted.

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Defining freedom from extraneous agents poses a real challenge taken into account that the ideal

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absolute freedom from extraneous agents or residual pathogenicity is neither possible nor realistic. The

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detection of extraneous agents depends on the amount of agent present in the raw material as well as

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the methods used for sampling and detection.

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The manufacture of stem cell -based products usually does not include terminal sterilisation of the

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product or removal or inactivation steps for viruses and parasites. Therefore it is crucial to define

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acceptance criteria for starting and raw materials derived from human or animal origin taking into

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consideration the intended use.

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Animal stem cells must be sourced from donor animals which are appropriately screened and tested for

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the absence of extraneous agents. Risk control for extraneous agents includes control of sourcing,

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testing of starting materials of animal origin and/or subjecting them to validated inactivation

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procedures, validation of the capacity of the manufacturing process of the product to remove and/or

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inactivate viruses, and, if deemed necessary, testing of the final product.

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Currently no specific guidance is available for stem cell -products for veterinary use. Guidance

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documents have been established for human cell-based products (CHMP Guideline on human cell-

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based products, EMA/CHMP/410869/2006 and CAT Reflection paper on stem cell -based medicinal Stem cell -based products for veterinary use: Specific questions on extraneous agents to be addressed by ADVENT EMA/CVMP/ADVENT/174610/2016

Page 2/4

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products, EMA/CAT/571134/2009). The CHMP Guideline on human cell-based products describes the

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general procedure to ensure quality during collection of source material and manufacturing process.

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The EU Guide to good manufacturing practice - GMP (provided in Eudralex Volume 4) covers in Part I

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basic GMP principles for the manufacture of human and veterinary medicinal products. Annex 2 to this

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guide covers the manufacture of human biological products including advanced therapy medicinal

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products (ATMP). The principle provisions laid down in that Annex are considered to be applicable also

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to stem cell -products for veterinary use.

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Safety aspects of extraneous agents with regard to veterinary medicinal products are included e.g. in

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the following documents:

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The table of extraneous agents to be tested for in relation to the general and species-specific

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guidelines on production and control of mammalian veterinary vaccines should be taken into

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consideration for viral safety testing of materials of animal species (Eudralex Vol. 7, Blm10a). This

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table is intended to be replaced by the CVMP guideline on the requirements for the production and

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control of immunological veterinary medicinal products (Annex 2- The approach to demonstrate

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freedom from extraneous agents as part of the production and control of immunological veterinary

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medicinal products for mammalian species and fish). (EMA/CVMP/IWP/206555/2010-Rev.1, under

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development)

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71 72 73 74

Note for Guidance on minimizing the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (EMA/410/01 rev.3).



The position paper of the Coordination Group for Mutual Recognition and Decentralised Procedures - Veterinary (CMDv/POS/001) on requirements for starting material of animal origin.

Principles on viral safety are also laid down in the European Pharmacopoeia (Ph. Eur.) (e.g. Chapter

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5.2.5:Substances of animal origin for the production of veterinary vaccines’; Chapter 5.1.7: Viral

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safety; Chapter 5.2.8: Minimising the risk of transmitting animal spongiform encephalopathy agents

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via human and veterinary medicinal products).

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The European Pharmacopoeia has recently adopted the general chapter on microbiological products:

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Chapter 5.2.12: Raw materials of biological origin for the production of cell-based and gene therapy

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medicinal products which will be published in the 9th edition (July 2016) and will come into force 01

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January 2017.

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The United States Pharmacopeia (USP) has established a specific chapter 1046 addressing cellular and

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tissue-based products, which gives information on several aspects of CBMPs, including freedom from

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extraneous agents.

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Following a review of the scientific information relating to extraneous agents of stem cell –products for

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veterinary use, a number of areas have been identified that would benefit from further consideration

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by relevant experts and, where appropriate, the elaboration of specific guidance in the form of

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question and answer (Q&A).

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Three specific questions for further consideration have been identified. These questions, together with

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a brief comment outlining the background, are presented below.

Stem cell -based products for veterinary use: Specific questions on extraneous agents to be addressed by ADVENT EMA/CVMP/ADVENT/174610/2016

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Questions

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Freedom from extraneous agents of stem cell -products

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Freedom from extraneous agents is a crucial aspect of quality evaluation of stem cell -based

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preparations and therefore appropriate acceptance criteria for starting and raw materials derived from

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human or animal origin need to be established.

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Question 1: Is the currently available guidance on demonstration of freedom from viruses and

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bacteria (list of viruses and bacteria which must be taken into account) appropriate and sufficient for

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stem cell -based products intended for use in horses and dogs?

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If not, would it be beneficial to elaborate further specific guidance and appropriate requirements for

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stem cell -products intended for use in horses and dogs?

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Question 2: As no EU guidance is currently available on demonstration of freedom from parasites,

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especially protozoa, which protozoa should be specifically taken into account for stem cell -based

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products intended for horses and dogs?

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Question 3: Are there (would you have) any recommendations regarding other aspects or approaches

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to be taken into account (risk control, risk analysis, risk mitigation, risk management) concerning the

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freedom of extraneous agents of stem cell- based products for horses and dogs?

Stem cell -based products for veterinary use: Specific questions on extraneous agents to be addressed by ADVENT EMA/CVMP/ADVENT/174610/2016

Page 4/4

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