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Guideline on Development, Production, Characterisation and Specification for Monoclonal Antibodies and Related Products

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Guideline on Development, Production, Characterisation and Specification for Monoclonal Antibodies and Related Products 21 July 2016 EMA/CHMP/BWP/532517/2008 Committee for medicinal products for human use (CHMP) Guideline on development, production, characterisation and specification for monoclonal antibodies and related products 3R’s technical update January 2016 Agreed by Biologics Working Party January 2016 Adopted by CHMP July 2016 Date for coming into effect September 2016 * This is a technical update to reflect current best practice with regard to implementation of 3Rs approaches and it is not intended as a full revision of this guideline (only sections 1, 5.3 and 6.3 are affected). In addition, minor changes have been introduced to reflect the new Agency templates, for example addition of an Executive Summary. All these changes are considered to be minor and uncontroversial and consequently a consultation phase was considered to be unnecessary. This guideline replaces the guideline on “Production and quality control of monoclonal antibodies” (3AB4A). This guideline replaces the quality requirements for monoclonal antibodies set forth in the guideline on “Radiopharmaceuticals based on monoclonal antibodies” (3AQ21A). This guideline replaces “Guideline on development, production, characterisation and specification for monoclonal antibodies and related products” (EMEA/CHMP/BWP/157653/2007). Keywords Monoclonal antibody, recombinant proteins, quality, characterisation, specification, hybridoma 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. Guideline on development, production, characterisation and specification for monoclonal antibodies and related products Table of contents Executive summary ..................................................................................... 3 1. Introduction (background) ...................................................................... 3 2. Scope....................................................................................................... 3 3. Legal basis .............................................................................................. 4 4. Development of the monoclonal antibody ................................................ 4 5. Production of monoclonal antibodies ....................................................... 5 5.1. General considerations .......................................................................................... 5 5.2. Platform manufacturing ......................................................................................... 5 5.3. Viral safety and Transmissible Spongiform Encephalopathy (TSE) ............................... 6 6. Characterisation of monoclonal antibodies .............................................. 7 6.1. Physicochemical characterisation ............................................................................ 7 6.2. Immunological properties ...................................................................................... 8 6.3. Biological activity ................................................................................................. 8 6.4. Purity, impurity and contaminants .......................................................................... 8 6.5. Quantity .............................................................................................................. 9 7. Specifications .......................................................................................... 9 7.1. Identity ............................................................................................................... 9 7.2. Purity and impurities ............................................................................................. 9 7.3. Potency ............................................................................................................. 10 7.4. Quantity ............................................................................................................ 10 7.5. General tests ..................................................................................................... 11 8. Monoclonal antibody-related products .................................................. 11 References ................................................................................................ 12 Annex - suggested list of human tissues to be used for immunohistochemical or cytochemical investigations of cross reactivity of monoclonal antibodies............................................................................... 13 Guideline on development, production, characterisation and specification for monoclonal antibodies and related products EMA/CHMP/BWP/532517/2008 Page 2/13 Executive summary This guideline addresses quality aspects of monoclonal antibodies for human use in the context of a marketing authorisation application. Guidance is provided in relation to development, production, characterisation and control for this class of products. The concept of platform manufacturing is presented in the guideline to support the use, where appropriate and justified, of data derived from relevant experience. The guideline explains the importance of characterisation and control of relevant glycosylation structures and biological activity. This guideline does not include requirements regarding the use of specific analytical methods in order to allow flexibility in the selection of methods and take into account future technology evolutions. However, references to relevant European Pharmacopoeia monographs are present. 1. Introduction (background) This guideline lays down quality requirements for monoclonal antibodies. Monoclonal antibodies are immunoglobulins (Ig) with a defined specificity derived from a monoclonal cell line. Their biological activities are characterised by a specific binding characteristic to a ligand (commonly known as antigen), and may be dependent on immune effector function such as antibody- dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Monoclonal antibodies may be generated by recombinant DNA (rDNA) technology, hybridoma technology, B lymphocyte immortalisation or other technologies (e.g. display technology, genetically engineered animals). This guideline covers principles and general requirements for development, production, characterisation and specifications for monoclonal antibodies to be used as, or in the production of, human medicinal products. In accordance with the provisions of the European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes and Directive 2010/63/EU on protection of animals used for scientific purposes, the 3R principles (replacement, reduction and refinement) should be applied to production and control testing of medicinal products. 2. Scope This guideline addresses quality issues for the marketing authorisation of monoclonal antibodies derived from a monoclonal cell line, and intended for therapeutic and prophylactic use (including ex vivo application), and in vivo diagnostic use. The principles described in this document apply to monoclonal antibodies used as reagents, as well as monoclonal antibody-related products, such as fragments, conjugates, and fusion proteins. However, their applicability will be determined on a case-by-case basis, based on their specific properties, and may be addressed in specific annexes. Polyclonal antibodies (fractionated or recombinant) are outside the scope of this guideline, although its principles should be applied where appropriate. Guideline on development, production, characterisation and specification for monoclonal antibodies and related products EMA/CHMP/BWP/532517/2008 Page 3/13 The scope of this guideline does not include: • Monoclonal antibodies to be used for diagnostic purposes in vitro; • Monoclonal antibodies used in clinical trials. However, the principles described in this document should be taken into account in the production and control of monoclonal antibodies in clinical trials, and their applicability will be determined on a case-by-case basis. 3. Legal basis This guideline should be read in conjunction with the introduction and general principles and Part 2 of Annex I of Directive 2001/83/EC, as amended. This guideline replaces the guideline on "Production and quality control of monoclonal antibodies" (3AB4a). This guideline replaces the quality requirements for monoclonal antibodies set forth in the guideline on “Radiopharmaceuticals based on monoclonal antibodies” (3AQ21A). This guideline replaces “Guideline on development, production, characterisation and specification for monoclonal antibodies and related products” (EMEA/CHMP/BWP/157653/2007). This guideline should be read in conjunction with all other relevant guidelines, especially those pertinent to the production and quality control of rDNA products. Furthermore, reference is made to the Ph. Eur. monograph on “Monoclonal antibodies for human use” (2031). 4. Development of the monoclonal antibody The structure of the monoclonal antibody should be justified with respect to its mechanism of action, biological activity and stability. This justification should at least include discussion on the suitability of the product’s immunochemical properties (e.g. affinity, cross-reactivity, isotype, allotype) and the importance and integrity of effector function. Furthermore, the risk of inducing antibody
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