Guidelines relevant for advanced therapy medicinal products

The European Medicines Agency develops scientific guidelines to help pharmaceutical companies and individuals to prepare marketing-authorisation applications for human medicines. This page lists relevant guidelines for applicants for advanced therapy medicinal products.
Human Advanced therapies Regulatory and procedural guidance Research and development

All of the below listed guidelines are available on the Agency's scientific guidelines pages as well as in the European Pharmacopoeia database and are listed because of their relevance to:

Please note that this list is not exhaustive and is only intended as guidance.


Gene therapy medicinal products

Web page Relevant guidelines
Gene therapy
  • ICH guideline S12 on nonclinical biodistribution considerations for gene therapy products - Step 2b (EMA/CHMP/ICH/318372/2021)
  • Questions and answers on comparability considerations for advanced therapy medicinal products (ATMP) (EMA/CAT/499821/2019)
  • The overarching guideline for human gene therapy medicinal products is the Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products (EMA/CAT/80183/2014​​)
  • Questions and answers on gene therapy (EMA/CAT/80183/2014)
  • Guideline on scientific requirements for the environmental risk assessment of gene therapy medicinal products (CHMP/GTWP/125491/06)
  • Reflection paper on design modifications of gene therapy medicinal products during development (EMA/CAT/GTWP/44236/2009)
  • Reflection paper on quality, non-clinical and clinical issues relating specifically to recombinant adeno-associated viral vectors (CHMP/GTWP/587488/07)
  • ICH Considerations - Oncolytic Viruses (EMEA/CHMP/ICH/607698/2008)
  • Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells (CAT/CHMP/GTWP/671639/2008)
  • Guideline on the non-clinical studies required before first clinical use of gene therapy medicinal products (EMEA/CHMP/GTWP/125459/2006)
  • Guideline on non-clinical testing for inadvertent germline transmission of the gene transfer vectors (EMEA/273974/2005)
  • Reflection paper on management of clinical risks deriving from insertional mutagenesis (CAT/190186/2012)
  • Guideline on follow-up of patients administered with gene therapy medicinal products (EMEA/CHMP/GTWP/60436/2007)
  • Guideline on safety and efficacy follow-up and risk management of advanced therapy medicinal products (EMEA/149995/2008)
Biologicals: drug product
  • Guideline on environmental risk assessments for medicinal products consisting of, or containing, genetically modified organisms (GMOs) (EMEA/CHMP/BWP/473191/2006)
  • Guideline on the use of bovine serum in the manufacture of human biological medicinal products (CPMP/BWP/1793/02)
  • Development pharmaceutics for biotechnological and biological products (CPMP/BWP/328/99)
  • Annex to Note for guidance on development pharmaceutics (CPMP/QWP/155/96)
  • The design, contribution and interpretation of studies validating the inactivation and removal of viruses (CPMP/BWP/268/95 or 3AB8A)
  • Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (EMEA/410/01)
  • CHMP/CAT position statement on Creutzfeldt-Jakob disease and advanced therapy medicinal products (CHMP/CAT/BWP/353632/2010)
Biologicals: drug substance
  • Position statement on the use of tumorigenic cells of human origin for the production of biological and biotechnological medicinal products (CPMP/BWP/1143/00)
  • Use of transgenic animals in the manufacture of biological medicinal products for human use (3AB7A)
  • Guideline on development and manufacture of lentiviral vectors (CHMP/BWP/2458/03)
  • Tests on samples of biological origin (3AB11A)
Quality: ICH
  • ICH Q5B Analysis of the expression construct in cell lines used for production of r-DNA derived protein products (CPMP/ICH/139/95)
  • ICH Q5D Derivation and characterisation of cell substrates used for production of biotechnological/biological products (CPMP/ICH/294/95)
  • ICH Q5A Viral safety evaluation of biotechnology products derived from cell lines of human or animal origin (CPMP/ICH/295/95)
  • ICH Topic Q5E Comparability of biotechnological/biological products (CPMP/ICH/5721/03)
  • ICH 5QC Stability testing of biotechnological/biological products (CPMP/ICH/138/95)
  • ICH Q6B Specifications: Test procedures and acceptance criteria for biotechnological/biological products (CPMP/ICH/365/96)
  • ICH Q7 Good manufacturing practice for active pharmaceutical ingredients (CPMP/ICH/4106/00)
  • ICH Q8 (R2) Pharmaceutical development (CHMP/ICH/167068/04)
  • ICH Q9 Quality risk management (EMA/CHMP/ICH/24235/2006)
  • ICH Q10 Pharmaceutical quality system (EMA/CHMP/ICH/214732/2007)
Safety and efficacy: Biostatistics
  • Guideline on clinical trials in small populations (CHMP/EWP/83561/2005)
ICH: efficacy
  • ICH E1 The extent of population exposure to assess clinical safety (CPMP/ICH/375/95)
  • ICH E3 Structure and content of clinical study reports (CPMP/ICH/137/95)
  • ICH E4 Dose response information to support drug registration (CPMP/ICH/378/95)
  • ICH E6 (R1) Good clinical practice (CPMP/ICH/135/95)
  • ICH E7 Geriatrics (CPMP/ICH/379/95)
  • ICH E8 General considerations for clinical trials (CPMP/ICH/291/95)
  • ICH E11 Clinical investigation of medicinal products in the paediatric population (CPMP/ICH/2711/99)
ICH: considerations
  • General principles to address the risk of inadvertent germline integration of gene therapy vectors (CHMP/ICH/469991/2006)
  • General principles to address virus and vector shedding (EMEA/CHMP/ICH/449035/2009)
Clinical safety and efficacy
  • Existing clinical guidance for the studied indication(s) should be consulted
Cell therapy and tissue engineering
  • Guideline on potency testing of cell based immunotherapy medicinal products for the treatment of cancer (EMEA/CHMP/BWP/271475/2006)
Vaccines
  • Guideline on quality, non-clinical and clinical aspects of live recombinant viral vectored vaccines (EMA/CHMP/VWP/141697/2009)
European Pharmacopoeia

The following monograph from the European Pharmacopoeia (Ph. Eur) should be considered, where relevant:

  • Ph.Eur. monograph 5.14 Gene transfer medicinal products for human use (01/2010:51400)

Cell-therapy and tissue engineering

Web page Relevant guidelines
Cell-therapy and tissue engineering
  • The overarching guideline for human cell- based medicinal products is the guideline on human cell-based medicinal products (EMEA/CHMP/410869/2006)
  • Reflection paper on stem cell-based medicinal products (EMA/CAT/571134/2009)
  • Reflection paper on in-vitro cultured chondrocyte containing products for cartilage repair of the knee (EMA/CAT/CPWP/568181/2009)
  • Guideline on xenogeneic cell-based medicinal products (EMEA/CHMP/CPWP/83508/2009)
  • Guideline on potency testing of cell based immunotherapy medicinal products for the treatment of cancer (CHMP/BWP/271475/06)
  • Reflection paper on clinical aspects related to tissue engineered products (EMA/CAT/573420/2009)
  • Guideline on safety and efficacy follow-up and risk management of advanced therapy medicinal products (EMEA/149995/2008)
Gene therapy
  • Questions and answers on comparability considerations for advanced therapy medicinal products (ATMP) (EMA/CAT/499821/2019)
  • Quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells (CHMP/GTWP/671639/2008)
Biologicals: drug product
  • Guidance on the use of bovine serum in the manufacture of human biological medicinal products (CPMP/BWP/1793/02)
  • Minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (EMA/410/01)
  • CHMP/CAT position statement on Creutzfeldt-Jakob disease and advanced therapy medicinal products (CHMP/CAT/BWP/353632/2010)
  • Position Paper on Re-establishment of working seeds and working cell banks using TSE compliant materials (EMEA/22314/02)
  • Guideline on the use of porcine trypsin used in the manufacture of human biological medicinal products (EMA/CHMP/BWP/814397/2011)
Biologicals: drug substance
  • Note for guidance on plasma derived medicinal products (CPMP/BWP/269/95)
Quality: Excipients
  • Guideline on excipients in the dossier for application for marketing authorisation of a medicinal product (EMEA/CHMP/QWP/396951/2006)
Quality: ICH
  • ICH Q2 (R1) Validation of analytical procedures: text and methodology (CPMP/ICH/381/95)
  • ICH Q5A (R1) Viral safety evaluation of biotechnology products derived from cell lines of human or animal origin (CPMP/ICH/295/95)
  • ICH Q5C Stability testing of biotechnological/biological products (CPMP/ICH/138/95)
  • ICH Q5D Derivation and characterisation of cell substrates used for production of biotechnological/biological products (CPMP/ICH/294/95)
  • ICH Q5E Comparability of biotechnological/biological products (CPMP/ICH/5721/03)
  • ICH Q7 Good manufacturing practice for active pharmaceutical ingredients (CPMP/ICH/4106/00)
  • ICH Q8 (R2) Pharmaceutical development (CHMP/ICH/167068/04)
  • ICH Q9 Quality risk management (EMA/CHMP/ICH/24235/2006)
  • ICH Q10 Pharmaceutical quality system (EMA/CHMP/ICH/214732/2007)
Safety: ICH

For non-clinical specific guidance, see

  • ICH S6 (R1) Preclinical safety evaluation of biotechnology-derived pharmaceuticals (CHMP/ICH/731268/1998)
Safety and efficacy: Biostatistics
  • Guideline on clinical trials in small populations (CHMP/EWP/83561/2005)
  • Points to consider on applications with 1. Meta-analyses; 2. One pivotal study (CPMP/EWP/2330/99)
Efficacy: ICH
  • ICH E1 The extent of population exposure to assess clinical safety (CPMP/ICH/375/95)
  • ICH E3 Structure and content of clinical study reports (CPMP/ICH/137/95)
  • ICH E4 Dose response information to support drug registration (CPMP/ICH/378/95)
  • ICH E6 (R1) Good clinical practice (CPMP/ICH/135/95)
  • ICH E7 Geriatrics (CPMP/ICH/379/95)
  • ICH E8 General considerations for clinical trials (CPMP/ICH/291/95)
  • ICH E11 Clinical investigation of medicinal products in the paediatric population (CPMP/ICH/2711/99)
Clinical safety and efficacy
  • Existing clinical guidance for the studied indication(s) should be consulted.
European Pharmacopoeia

The following monographs from the European Pharmacopoeia (Ph. Eur) should be considered, where relevant:

  • Ph.Eur. monograph on human haematopoietic stem cells (Cellulae stirpes haematopoieticae humanae) Version 7.2
  • Ph.Eur. monograph on Method of analysis (2.7.23.) Numeration of CD34/CD45+ cells in haematopoietic products. Version 7.2
  • Ph.Eur. monograph on Method of analysis (2.7.28.) Colony-forming cell assay for human haematopoietic progenitor cells. Version 7.2
  • Ph.Eur. monograph on Nucleated Cell Count and Viability (2.7.29.)
  • Ph.Eur. monograph on Nucleic Acid Amplification Techniques (2.6.21.)
  • Ph.Eur. monograph on Flow Cytometry (2.7.24.)
  • Ph.Eur: (2.6.27) Microbiological control of cellular products
  • Ph.Eur: (2.6.1.) Sterility
  • Ph.Eur: (5.1.6) Alternative methods for control of microbiological quality
  • Ph.Eur. monograph Mycoplasmas (2.6.7.)
  • Ph.Eur. monograph on Bacterial endotoxins (2.6.14.)
  • General chapter 5.2.12 Raw materials for the production of cell-based and gene therapy medicinal products

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