Manufacturing Binding Text and Guidance

Binding EU Text: 

• Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (Text with EEA relevance), OJ L 324, 10.12.2007, p. 121–137, CELEX number: 32007R1394 
  • Original text 
  • PDF Original text 
  • Consolidated text 
  • PDF Consolidated text 
  • Document summary 

• Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, OJ L 311, 28.11.2001, p. 67–128, CELEX number: 32001L0083 
  • Original text 
  • PDF Original text 
  • Consolidated text 
  • PDF Consolidated text 
  • Document summary 

• Commission Directive (EU) 2017/1572 of 15 September 2017 supplementing Directive 2001/83/EC of the European Parliament and of the Council as regards the principles and guidelines of good manufacturing practice for medicinal products for human use (Text with EEA relevance), C/2017/6127, OJ L 238, 16.9.2017, p. 44–50, CELEX number: 32017L1572 
  • Original text 
  • PDF Original text 
  • Original text In EU languages 

• Commission Delegated Regulation (EU) 2017/1569 of 23 May 2017 supplementing Regulation (EU) No 536/2014 of the European Parliament and of the Council by specifying principles of and guidelines for good manufacturing practice for investigational medicinal products for human use and arrangements for inspections (Text with EEA relevance), C/2017/3368, OJ L 238, 16.9.2017, p. 12–21, CELEX number: 32017R1569 
  • Original text 
  • PDF Original text 

• Commission Delegated Regulation (EU) No 1252/2014 of 28 May 2014 supplementing Directive 2001/83/EC of the European Parliament and of the Council with regard to principles and guidelines of good manufacturing practice for active substances for medicinal products for human use Text with EEA relevance, OJ L 337, 25.11.2014, p. 1–7 
  • PDF Original text-English 
  • Original text in all EU languages 

• Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products (Text with EEA relevance), OJ L 91, 9.4.2005, p. 13–19, CELEX number: 32005L0028 
  • Original text 
  • PDF Original text 

• Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use (Text with EEA relevance), OJ L 262, 14.10.2003, p. 22–26, CELEX number: 32003L0094 
  • Original text 
  • PDF Original text 
  • Document summary 

Guidelines Specific to ATMPs: 

• European Commission, Guidelines on Good Manufacturing Practices specific to ATMPs, C(2017) 7694 final, 22 November 2017
• EMA, CAT, Questions and answers on comparability considerations for advanced therapy medicinal products (ATMP), EMA/CAT/499821/2019, 6 December 2019
• EMA, Inspections, Human Medicines, Pharmacovigilance and Committees Division, Questions and answers on the exemption from batch controls carried out on ATMPs imported into the European Union from a third country, EMA/354272/2019, 12 July 2019
• EMA, CAT, Questions and answers on the use of out-of-specification batches of authorised cell/tissue-based advanced therapy medicinal products, EMA/CAT/224381/2019, 24 April 2019
• EMA, Inspections, Human Medicines, Pharmacovigilance and Committees Division, Questions and answers on the principles of GMP for the manufacturing of starting materials of biological origin used to transfer genetic material for the manufacturing of ATMPs, EMA/246400/2021, 24 February 2021
• EMA, Guide on Advanced Therapy Medicinal Products- Quality flowchart and checklist, 29 November 2021  

For GTMP:

• EMA, CAT, Quality, preclinical and clinical aspects of gene therapy medicinal products, EMA/CAT/80183/2014, 22 March 2018
• EMA, CAT, Quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells, EMA/CAT/GTWP/671639/2008 Rev. 1 – corr, 12 November 2020  
• EMA, CHMP, Potency testing of cell-based immunotherapy medicinal products for the treatment of cancer, EMA/CHMP/BWP/271475/2006 rev.1, 21 July 2016 
• EMA, CHMP, Development and manufacture of lentiviral vectors, CHMP/BWP/2458/03, 26 May 2005    
• EMA, CHMP, Guideline on quality, non-clinical and clinical aspects of live recombinant viral vectored vaccines, EMA/CHMP/VWP/141697/2009, 24 June 2010   
• EMA, CHMP, Guideline on development and manufacture of lentiviral vectors, CHMP/BWP/2458/03, 26 May 2005
• EMA, CPMP, ICH Q5B Analysis of the expression construct in cell lines used for production of r-DNA derived protein products, CPMP/ICH/139/95, July 1996 
• EMA, CPMP, CPMP position statement on DNA and Host Cell Proteins (HCP) impurities, routine testing versus validation studies, CPMP/BWP/382/97, 10 June 1997 
• EMA, CPMP, Note for guidance on virus validation studies: The design, contribution and interpretation of studies validating the inactivation and removal of viruses, CPMP/BWP/268/95 or 3AB8A, 14 February 1996
• Ph.Eur chapter 2.6.16. Tests for extraneous agents in viral vaccines for human use (01/2011:20616)
• Ph.Eur. General chapter 5.1.7 on viral safety (01/2008:50107)
• Ph.Eur. General chapter 5.2.3 on cell substrates for the production of vaccines for human use (01/2017:50203)
• Ph.Eur. General chapter 5.2.12. on raw materials of biological origin for the production of cell based and gene therapy medicinal products (01/2017:50212)
• Ph.Eur. General chapter 5.14 on Gene transfer medicinal products for human use (01/2010:51400)
• Ph.Eur. General chapter 5.15. Functionality-related characteristics of excipients (07/2017:51500)  

For Cell Therapy and Tissue Engineered Products:

• EMA, CAT, Quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells EMA/CAT/GTWP/671639/2008 Rev. 1 – corr, 12 November 2020
• EMA, CHMP, Human cell-based medicinal products, EMEA/CHMP/410869/2006, 21 May 2008 
• EMA, CHMP, Guideline on Potency testing of cell-based immunotherapy medicinal products for the treatment of cancer, EMA/CHMP/BWP/271475/2006 rev.1, 21 July 2016 
• EMA, CHMP, Xenogeneic cell-based medicinal products, EMEA/CHMP/CPWP/83508/2009, 22 October 2009
• EMA, CAT, Clinical aspects related to tissue engineered products, EMA/CAT/573420/2009, 19 September 2014   
• EMA, CAT, In-vitro cultured chondrocyte containing products for cartilage repair of the knee, EMA/CAT/CPWP/568181/2009, 8 April 2010
• EMA, CAT, Stem cell-based medicinal products, EMA/CAT/571134/2009, 14 January 2011
• 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

Guidelines on Medicinal Products Potentially Applicable to ATMPs:

• EMA, CHMP, Guideline on the use of bovine serum in the manufacture of human biological medicinal products, EMA/CHMP/BWP/457920/2012 rev 1, 30 May 2013
• EMA, CHMP, Guideline on the use of porcine trypsin used in the manufacture of human biological medicinal products, EMA/CHMP/BWP/814397/2011, 20 February 2014
• EMA, Guideline on Use of transgenic animals in the manufacture of biological medicinal products for human use, 3AB7A, December 1994
• EMA, CPMP, ICH Q2 (R1) Validation of analytical procedures: text and methodology, CPMP/ICH/381/95, June 1995
• EMA, CPMP, ICH Q5A (R1) Viral safety evaluation of biotechnology products derived from cell lines of human or animal origin, CPMP/ICH/295/95, October 1997
• EMA, CPMP, ICH Q5C Stability testing of biotechnological/biological products, CPMP/ICH/138/95, July 1996
• EMA, CPMP, ICH Q5D Derivation and characterisation of cell substrates used for production of biotechnological/biological products, CPMP/ICH/294/95, March 1998  
• EMA, CPMP, ICH Q5E Comparability of biotechnological/biological products, CPMP/ICH/5721/03, June 2005
• EMA, CPMP, ICH Q6B Specifications: Test procedures and acceptance criteria for biotechnological/biological products, CPMP/ICH/365/96, September 1999
• EMA, CPMP, ICH Q7 Good manufacturing practice for active pharmaceutical ingredients, CPMP/ICH/4106/00, November 2000
• EMA, CHMP, ICH Q8 (R2) Pharmaceutical development, CHMP/ICH/167068/04, 22 June 2017
• EMA, CHMP, Draft ICH guideline Q9 (R1) on quality risk management, Step 2b, EMA/CHMP/ICH/24235/2006, 16 December 2021
  • currently under consultation 
• EMA, CHMP, ICH Q9 Quality risk management – Step 5, EMA/CHMP/ICH/24235/2006, September 2015
• EMA, CHMP, ICH Q10 Pharmaceutical quality system, EMA/CHMP/ICH/214732/2007, September 2015
• EMA, CPMP, CVMP, Position Paper on Re-establishment of working seeds and working cell banks using TSE compliant materials, EMEA/22314/02, 10 September 2002
• EMA, CPMP, Position statement on the use of tumorigenic cells of human origin for the production of biological and biotechnological medicinal products, CPMP/BWP/1143/00, 1 March 2001

Manufacturing Authorisation

This section is in development.

Good Manufacturing Practice

• European Commission, Guidelines on Good Manufacturing Practices specific to ATMPs, C(2017) 7694 final, 22 November 2017
• European Commission, EU guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 2 - Manufacture of biological active substances and medicinal products for human use, 2018
• European Commission, EU guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, ENTR/F/2/AM/an D(2010) 3374, Annex 13 - Manufacture of investigational medicinal products, 3 February 2010 
• European Commission, EU guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Ref. Ares(2015)4234460, Annex 16 - Certification by a qualified person and batch release, 12 October 2015

Selection of GMP cell line 

Process Validation 

Generation of Master and Working Cell Banks 

Development of Standard Operating Procedures (SOPs) 

GMP Training – Validation and Execution 

CMC (Chemistry, Manufacturing, and Controls) 

Release Testing 

European Pharmacopeia

This section is in development.

Investigational Medicinal Products Dossier

This section is in development.

Capability

This section is in development.

Scalability

This section is in development.

Packaging and Labeling

Binding EU Text

• Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, OJ L 311, 28.11.2001, p. 67–128, CELEX number: 32001L0083. See Title V, Articles 54 to 69 on packaging and labelling. 
  • Current version including last amendments 
  • Original document summary 
• Directive 2001/83/EC has been amended regarding packaging and labelling by the following legal texts: 
• Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use (Text with EEA relevance), OJ L 136, 30.4.2004, p. 34–57, CELEX number: 32004L0027 
  • Original text 
• Directive 2011/62/EU of the European Parliament and of the Council of 8 June 2011 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use, as regards the prevention of the entry into the legal supply chain of falsified medicinal products (Text with EEA relevance), OJ L 174, 1.7.2011, p. 74-87, CELEX number: 32011L0062 
  • Original text 
• Commission delegated regulation (EU) 2016/161 of 2 October 2015 supplementing Directive 2001/83/EC of the European Parliament and of the Council by laying down detailed rules for the safety features appearing on the packaging of medicinal products for human use, OJ L 32, 9.2.2016, pp. 1–27. 
  • Original text
• Regulation (EU) no 1027/2012 of the European Parliament and of the Council of 25 October 2012 amending Regulation (EC) No 726/2004 as regards pharmacovigilance, OJ L 316, 14.11.2012, pp. 38–40. 
  • Original text 
• Commission Implementing Regulation (EU) No 198/2013 of 7 March 2013 on the selection of a symbol for the purpose of identifying medicinal products for human use that are subject to additional monitoring, OJ L 65, 8.3.2013, p. 17–18. 
  • Original text 
• Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (Text with EEA relevance), OJ L 324, 10.12.2007, p. 121–137. 
  • Current version with last amendments 
  • Original document summary 
• Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004, OJ L 378, 27.12.2006, pp. 1–19. 
  • Current version with last amendments 
  • Original document summary 

EMA Guidelines

• EMA, CAT, Guideline on core SmPC, labelling and package leaflet for advanced therapy medicinal products (ATMPs) containing genetically modified cells, EMA/CAT/CHMP/158266/2021, 16 June 2021,  
• EMA, Implementation plan for the introduction of the safety features on the packaging of centrally authorised medicinal products for human use, 2017 
• QRD product-information annotated template v.10.2 rev.1 (applicable as of January 1st, 2021) (Especially pages 14 to 24) 
• QRD annex A template  
• Guideline on 'Excipients in the labelling and package leaflet of medicines for human use' and its annex 
• In addition, for Advanced Therapy Medicinal Products containing genetically modified cells: Guideline on Core SmPC, labelling and package leaflet for Advanced Therapy Medicinal Products (ATMPs) containing genetically modified cells 

Relevant European Medicines Agency guidance 

• Recommendations for the implementation of the exemption to the labelling and package-leaflet obligations in the centralised procedure 
• Contact details of national competent authorities for requests of translation exemptions falling under Art. 63.3 of Directive 2001/83 EC and cases of shortages 
• Labelling-exemption requests under Art. 63 of Directive 2001/83/EC examined by the QRD group 

Relevant European Medicines Agency’s guidelines on checking process 

• Checking process of mock-ups and specimens of outer/immediate labelling and package leaflets of human medicinal products in the centralised procedure 
• Standard operating procedure for checking of mock-ups and specimens for new applications and extensions 
• Standard operating procedure for checking of mock-ups and specimens for renewals 
• Standard operating procedure for checking of mock-ups and specimens for transfer of marketing authorisation 
• Standard operating procedure for checking of mock-ups and specimens for all post-authorisation procedures other than new applications, line extensions, renewals and transfers 
• Contact details of national competent authorities for requests to use a sticker to place the Unique Identifier on the outer/immediate packaging of centrally approved products 
• To go further: detailed checking process of mock-ups and specimens in the centralised procedure available here. 
• Relevant European Medicines Agency’s guidelines 
• Linguistic review process:  
  • Linguistic review process of product information in the centralised procedure 
  • Checklist for the submission of Day 215 product information annexes for a post-opinion linguistic review 
  • Member states contact points for translations review 
  • Practical information on translations for referral procedures (human) 
• Provision of final language versions: 
  • User guide on how to generate PDF versions of the product information - human 
  • Submission of day +25/235 final product information annexes (human and veterinary) 
  • Quality review of Documents (QRD) convention to be followed for the EMA QRD templates 
• Standard operating procedures: 
  • Standard operating procedure for Product information Quality/Quality review of Documents pre-opinion review of product information for renewal procedures 
  • Standard operating procedure for Quality Review of Documents post-opinion review of product information for initial applications and annex-II applications 
  • Standard operating procedure for Quality Review of Documents post-opinion review of product information for post-authorisation procedures affecting the annexes, excluding annex II applications 
  • Standard operating procedure for handling of financial compensation for checking of product information by the Member States