Last update: October 5th, 2018

Quality Guidelines

NOTE: This document should only be used as a first orientation and was created with utmost caution and great care. However, we
do neither claim completeness nor timeliness of data published (yearly update). For further information visit the EMA website:
http://www.ema.europa.eu/ema/. This document contains links to external websites no liability for any content of any external
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Pharmaceuticals Biological and Biotechnological Products

GMP • GMP for active pharmaceutical ingredients (ICH Q7) CPMP/ICH/4106/00
General consideration • Guideline on pharmaceutical development (ICH Q8 (R2)) EMA/CHMP/ICH/167068/2004
• Note for guidance on development pharmaceutics CPMP/QWP/155/96
• Guideline on quality risk management (ICH Q9) EMA/CHMP/ICH/24235/2006
• Guideline on pharmaceutical quality system (ICH Q10) EMA/CHMP/ICH/214732/2007
• Guideline on development and manufacture of drug substances (ICH Q11) EMA/CHMP/ICH/425213/2011 (Q&A document
regarding selection and justification of starting material ICH Q11 Q&A)
• Note for guidance on quality of water for pharmaceutical use CPMP/QWP/158/01 Revision

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 Pharmaceuticals Biological and Biotechnological Products
General consideration • Guideline on the requirements to the chemical and • Guideline on the requirements for quality documentation
pharmaceutical quality documentation concerning IMPs in concerning biological IMPs in clinical trials
clinical trials EMA/CHMP/QWP/545525/2017 EMA/CHMP/BWP/534898/2008 rev. 1
• Development pharmaceutics for biotechnological and
biological products (Annex to note for guidance on
development pharmaceutics) CPMP/BWP/328/99

Active Substance • Guideline on summary of requirements for active • Guideline on the use of starting materials and
substances in the quality part of the dossier intermediates collected from different sources in the
CHMP/QWP/297/97 Rev 1 corr manufacturing of non-recombinant biological medicinal
• Reflection paper on the chemical structure and properties products EMA/CHMP/BWP/429241/2013
criteria to be considered for the evaluation of new active
substance (NAS) status of chemical substances
EMA/CHMP/QWP/104223/2015
• Reflection paper on the requirements for selection and
justification of starting materials for the manufacture of
chemical active substances
EMA/CHMP/CVMP/QWP/826771/2016 - Corr. 1
• Guideline on active substance master file procedure
CHMP/QWP/227/02 Rev 3/Corr*
• Guideline on the chemistry of new active substances
EMA/454576/2016
• Investigation of chiral active substances 3CC29A

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 Pharmaceuticals Biological and Biotechnological Products
Manufacturing • Note for guidance on manufacture of the finished dosage form EMA/CHMP/QWP/245074/2015
• The use of ionising radiation in the manufacture of medicinal products 3AQ4a
• Annex 12 Use of ionising radiation in the manufacture of medicinal products
• Comparability of biotechnological/biological products
subject to changes in their manufacturing process
(ICH Q5E) CPMP/ICH/5721/03
• Guideline on the quality of biological active substances
produced by stable transgene expression in higher plants
EMEA/CHMP/BWP/48316/2006
• Guideline on human cell-based medicinal products
EMEA/CHMP/410869/2006
• Guideline on quality of biological active substances
produced by transgene expression in animals
EMA/CHMP/BWP/151897/2013
• Position statement on the use of tumourigenic cells of
human origin for the production of biological and
biotechnological medicinal products CPMP/BWP/1143/00
Specifications • Evaluation and recommendation of pharmacopoeial texts for use in the ICH regions (ICH Q4B)
EMEA/CHMP/ICH/222007/2006
• Specifications: Test procedures and acceptance criteria for • Specifications: Test procedures and acceptance criteria for
new drug substances and new drug products: Chemical biotechnological/biological products (ICH Q6B)
substances (ICH Q6A) CPMP/ICH/367/96 CPMP/ICH/365/96
Process Validation • Guideline on process validation for finished products - • Guideline on process validation for the manufacture of
information and data to be provided in regulatory biotechnology-derived active substances and data to be
submissions EMA/CHMP/CVMP/QWP/BWP/ 70278/2012- provided in the regulatory submission
Rev1, Corr.1 EMA/CHMP/BWP/187338/2014

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 Pharmaceuticals Biotechnological Products
Impurities • Guideline on impurities: Guideline for residual solvents (ICH Q3C (R5)) EMA/CHMP/ICH/82260/2006 + Annexes
• Guideline on elemental impurities EMA/CHMP/ICH/353369/2013
• Guideline on the limits of genotoxic impurities EMEA/CHMP/QWP/251344/2006 (Q&A document
EMA/CHMP/SWP/431994/2007 Rev. 3)
• Guideline on elemental impurities (ICH Q3D (R1)) EMA/CHMP/ICH/353369/2013
• Impurities in new drug substances (ICH Q3A (R2)) • Guideline on setting specifications for related impurities in
CPMP/ICH/2737/99 antibiotics EMA/CHMP/CVMP/QWP/199250/2009 corr
• Impurities in new drug products (ICH Q3B (R2)) • Viral safety evaluation of biotechnology products derived
CPMP/ICH/2738/99 from cell lines of human or animal origin (ICH Q4A (R1))
CPMP/ICH/295/95
• Position statement on DNA and host cell proteins
impurities (HCP), routine testing versus validation studies
CPMP/BWP/382/97
Adventitious Agents • Guideline on virus safety evaluation of biotechnological
IMPs EMEA/CHMP/BWP/398498/2005
• 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
• Guideline on the use of bovine serum in the manufacture
of human biological medicinal products
EMA/CHMP/BWP/457920/2012 rev 1
• Guideline on the use of porcine trypsin used in the
manufacture of human biological medicinal products
EMA/CHMP/BWP/814397/2011

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 Pharmaceuticals Biological and Biotechnological Products
Adventitious Agents • Guideline on the investigation of manufacturing processes
for plasma-derived medicinal products with regard to
variant Creutzfeld-Jakob disease risk
CPMP/BWP/CPMP/5136/03
• Note for guidance on minimising the risk of transmitting
animal spongiform encephalopathy agents via human and
veterinary medicinal products EMA/410/01 rev. 3
Analytical Procedure • Validation of analytical procedures: Text and methodology (ICH Q2 (R1)) CPMP/ICH/381/95
• Quality of biotechnological products: Analysis of the
expression construct in cell lines used for production of
r-DNA derived protein products (ICH Q5B)
CPMP/ICH/139/95
• Quality of biotechnological products: Derivation and
characterisation of cell substrates used for production of
biotechnological/biological products (ICH Q5D)
CPMP/ICH/294/95
Excipients • Guideline on excipients in the dossier for application for marketing authorisation EMEA/CHMP/QWP/396951/2006
• Note for guidance on inclusion of antioxidants and antimicrobial preservatives in medicinal products
CPMP/CVMP/QWP/115/95
Adjuvants • WHO Guideline on nonclinical evaluation of vaccine adjuvants and adjuvanted vaccines
https://www.who.int/biologicals/areas/vaccines/TRS_987_Annex2.pdf
• EMA Guideline on Adjuvants in Vaccines for human use CHMP/VEG/134716/04
https://www.ema.europa.eu/en/adjuvants-vaccines-human-use
Packaging • Guideline on plastic immediate packaging materials CPMP/QWP/4359/03
Stability • Stability testing of new drug substances and products (ICH • Stability testing of biotechnological/biological products
Q1A (R2)) CPMP/ICH/2736/99 (ICH Q5C) CPMP/ICH/138/95

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 • Photostability testing of new drug substances and
medicinal products (ICH Q1B) CPMP/ICH/279/95
• Evaluation of stability data (ICH Q1E) CPMP/ICH/420/02
Pharmaceuticals Biological and Biotechnological Products
Stability • Stability data package for registration in climatic zones III
and IV (ICH Q1F) CPMP/ICH/421/02
Qualified Person • Guidance for the template for the QP’s declaration concerning GMP compliance of active substance manufacture
EMA/196292/2014
• The QP declaration template EMA/334808/2014

Additional Guidelines:

Manufacture, characterisation and control of the active substance

• ICH considerations: Oncolytic viruses EMA/CHMP/ICH/607698/2008

• Allergen products: Production and quality issues EMEA/CHMP/BWP/304831/2007
• Development and manufacture lentiviral vectors CHMP/BWP/2458/03
• Development, production, characterisation and specification for monoclonal antibodies and related products EMA/CHMP/BWP/532517/2008
• Gene therapy product quality aspects in the production of vectors and genetically modified somatic cells 3AB6a
• Production and quality control of animal immunoglobulins and immunosera for human use EMA/CHMP/BWP/3354/1999 rev.1
• Production and quality control of medicinal products derived by recombinant DNA technology 3AB1a
• Quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells EMA/CAT/GTWP/671639/2008
(Note: currently under revision EMA/CAT/424191/2017)
• Quality, non-clinical and clinical aspects of gene therapy medicinal products EMA/CAT/80183/2014
• Xenogeneic cell-based medicinal products EMEA/CHMP/CPWP/83508/2009

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Stability

• Stability testing for new dosage forms (ICH Q1C) CPMP/ICH/280/95

• Bracketing and matrixing designs for stability testing of drug substances and drug products (ICH Q1D) CPMP/ICH/4104/00
• Note for guidance on in-use stability testing of human medicinal products CPMP/QWP/2934/99
• Guideline on stability testing: Stability testing of existing active substances and related finished products CPMP/QWP/122/02, rev 1 corr
• Maximum shelf-life for sterile products for human use after first opening or following reconstitution CPMP/QWP/159/96 corr

Analytical Validation

• ICH Q4B Annex 1: Residue on ignition/sulphated ash CHMP/ICH/222063/06

• ICH Q4B Annex 2: Test for extractable volume in parenteral preparations CHMP/ICH/559409/2007
• ICH Q4B Annex 3: Test for particulate contamination: Sub-visible particles CHMP/ICH/561176/2007
• ICH Q4B Annex 4A: Microbiological examination of non-sterile products: Microbial enumeration tests CHMP/ICH/308671/07
• ICH Q4B Annex 4B: Test for microbiological examination of non-sterile products: Tests for specified microorganisms CHMP/ICH/308817/07
• ICH Q4B Annex 4C: Test for microbiological examination of non-sterile products: Acceptance criteria for pharmaceutical preparations and substances
for pharmaceutical use CHMP/ICH/308867/08
• ICH Q4B Annex 5: Disintegration test CHMP/ICH/308895/08
• ICH Q4B Annex 6: Uniformity of dosage units EMA/CHMP/ICH/645408/2008
• ICH Q4B Annex 7: Dissolution test CHMP/ICH/645469/08
• ICH Q4B Annex 8: Sterility test CHMP/ICH/645592/08
• ICH 4 QB Annex 9: Tablet friability CHMP/ICH/379801/09
• ICH Q4B Annex 10: Polyacrylamide gel electrophoresis CHMP/ICH/381133/09
• ICH Q4B Annex 11: Capillary electrophoresis CHMP/ICH/730028/09

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 • ICH Q4B Annex 12: Analytical sieving CHMP/ICH/730028/09
• ICH Q4B Annex 13: Bulk density and tapped density of powders CHMP/ICH/405290/10
• ICH Q4B Annex 14: Bacterial endotoxins tests CHMP/ICH/529785/10

Adventitious Agents

• Guideline on the adventitious agent safety of urine-derived medicinal products EMA/CHMP/BWP/126802/2012