Revision of EU GMP Annex 2 – Update and Key Issues · PDF fileRevision of EU GMP Annex 2...

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Safeguarding public health

Revision of EU GMP Annex 2 –Update and Key Issues

Ian ReesRapporteur, EU GMP Annex 2 Revision

21st March 2011

Date: 21st March 2011Name: Ian Rees

Presentation title: Annex 2 revision, EBE / CASS

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Presentation Outline

• Abbreviation glossary

• Background information

- revision process / drafting group

• Revision overview / drivers of change

• Public consultation 2010 overview

• Key areas of Annex 2

• Next steps



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Abbreviation Glossary

• ATMP - Advanced Therapy Medicinal Product• AS - Active Substance (Active Pharmaceutical Ingredient)• BWP - Biotechnology Working Party• CAT - Committee for Advanced Therapy• EC - European Commission• EUTCD- EU Tissue and Cells Directive (2004/23/EC)• GP - Good Practice (Blood & EUTCD)• IWG - GMP GDP Inspectors Working Group• QRM - Quality Risk Management (ICH Q9, Chapter 1 GMP)• RP - Responsible Person (Blood & EUTCD)• QP - Qualified Person (Medicinal Products Directive)



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Background - EMA Revision Process

Problem Statement Concept Paper Public consultation

(3 months)

Review comments, text revision

Public consultation (3 or 6 months)

Review comments, text revision

Final text adopted by IWG

Final text adopted by EC

Publish, time to come into effect

Second public consultation



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Background - Drafting Group

• Members:- Ian Rees, MHRA - Sinead Masterson, IMB- Anette Bjerregaard, DMA - Sonja Otten, PEI- Marie-Thérèse Duffour, AFSSAPS

• ATMP :- Maria Christina Galli, Istituto Superiore di Sanità- Dominique Labbe, AFSSAPS- Augustinus Bader, BBZ, University of Leipzig



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Consultation 1Consultation 2

Revision overview

EU GMP changes

Annex 2 revision

Part A

New legislation Advances in science

ATMP Regulation

Part I -Chapter revisions

Part II –ICH Q7

Annex revisions

EUTCD

Part B Glossary

2009/120/ECGCP

Re-draft

PV Other documentsGMP

TechnologyProducts

Hospital Exemption

Blood Directive

Final textPublish

Part III –Guidance

documents



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Drivers of change – science

• Drafted in late 1980’s / early 1990’s

• Many changes in science:- Range of product types- Manufacturing and testing technology



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Drivers of change – new legislation: ATMP Regulation 1394/2007

• Adds to main medicines directive (2001/83/EC)• Meet requirements of Article 5:

- ‘The Commission shall, after consulting the Agency [EMA], draw up guidelines in line with the principles of good manufacturing practice and specific to advanced therapy medicinal products.’

• Requirements of Article 15:- Traceability including materials in contact with the tissues- Minimum 30 year record retention after product expiry

• Consistency with requirements of 2009/120/EC- Provides further ATMP details, e.g.

· Definitions of starting materials, AS, finished product· MA dossier requirements



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Drivers of change – new legislation:Tissue and Cells Directive 2004/23/EC

• Recital 6 / Article 2:- ‘Tissues and cells intended to be used for industrially manufactured

products, including medical devices, should be covered by this Directive only as far as donation, procurement and testing are concerned, where the processing, preservation, storage and distribution areregulated by other Community legislation.’

- ‘The further manufacturing steps are covered by Directive 2001/83/EC’

• Starts traceability requirement, continued by Medicines / ATMP Regulation

• Quality System is called ‘Good Practice’, text being developed• Annex 2 clarifies transition from EUTCD to medicinal product

manufacture (RP/ QP)



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Drivers of change – new legislation: Blood and Blood Components 2002/98/EC

• Scope (Recitals 4 and 5 / Article 2):- Cover the entire supply chain for transfusion - Collection & testing only for starting materials for medicinal products.

• Starts traceability requirement, RP / QP• Quality System is called ‘Good Practice’:

- Text being developed- To be aligned with Council of Europe’s ‘Guide to the preparation, use

and quality assurance of blood components’• Borderline between Blood Directive and medicinal products:

- GMP Annex 14 for blood products (fractionated products, e.g. albumin, immunoglobulin)

- Guidance on blood-derived ATMPs is in Annex 2



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ATMPs - linking the regulatory stages

Marketing AuthorisationCentralised licence (MA)

EMA

CommercialClinical TrialsPhase I, II, III

Pre-clinical

Safety

Clinical Trialsnational licence (CTA)

NCA

Dossier

EUTCDor

Blood Directive

Donation, procurement

& testing

Unlicensed (Hospital Exemption)

Cert. of Quality & non-clinical data

EMA

GP GMPMIA(IMP)

GMP

GMPMIA

GLP

DossierDossier

Transplants or TransfusionsProcessing, preservation, storage, distributionGP

Borderline



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Drivers of change – general EU GMP changes

• Large number of changes that do not impact Annex 2

• EU changes that do have an impact:- Restructure of EU GMP following ‘2001 review’:

· Mandatory application of GMP to APIs (Part II)- Dedicated facilities:

· Align with text being amended in Chapter 3/5 revision- QRM principles in Chapter 1

• Other guidance documents / regulatory perspectives:- ICH Q8 / 9 / 10 → all chapter & annexes- Alignment with other regulators’ requirements,

· e.g. FDA on live vaccines and spore forming organisms



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Drivers of change – non GMP changes

• EU Better Regulation: protect public safety and welfare, adapt to pace of change in technology, foster innovation

EU Pharma

Regulation



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Public consultation 2010 overview

• Respondents – 18, from EU, Switzerland, USA• Range of respondents – pharma, ATMP organisation and

individuals, (c.f. previous consultation)• Broad range of comments:

- Scope - principally on start point of GMP (Part II)- Depth of guidance- Interface with EUTCD- Confusion on intent of reference to GMP Annex 1- Dedicated facilities- Glossary entries



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Key areas - Scope

• In line with ‘Introduction’ in Eudralex Volume 4 – provides supplementary guidance to that in other areas of GMP

• Covers:- All biological/biotech products - All stages

• Title change:- Manufacture of Biological Medicinal Substances and Products

for Human Use• Table 1 provides illustrative guide, not precise scope



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Key areas – Scope: Table 1

Type and source of material Example product Application of this guide to manufacturing steps shown in grey

1. Animal or plant sources: non-transgenic

Heparins, insulin, enzymes, proteins, allergen extract, ATMPs immunosera,

Collection of plant, organ, tissue or fluid

Cutting, mixing, and / or initial processing3

Isolation and purification Formulation, filling

2. Virus or bacteria / fermentation / cell culture

Viral or bacterial vaccines; enzymes, proteins

Establishment & maintenance of MCB, WCB, MVS, WVS

Cell culture and/or fermentation Inactivation when applicable, isolation and purification

Formulation, filling

3. Biotechnology -fermentation/ cell culture

Recombinant. products, MAb, allergens, vaccines Gene Therapy (viral and non-viral vectors, plasmids)

Establishment & maintenance of MCB and WCB, MSL, WSL

Cell culture and / or fermentation Isolation, purification, modification


4. Animal sources: transgenic

Recombinant proteins, ATMPs Master2 and working transgenic bank

Collection, cutting, mixing, and / or initial processing

Isolation, purification and modification


5. Plant sources: transgenic

Recombinant proteins, vaccines, allergen

Master and working transgenic bank

Growing, harvesting Initial extraction, isolation, purification, modification


6. Human sourcesUrine derived enzymes, hormones

Collection of fluid Mixing, and/or initial processing Isolation and purification Formulation, filling

7. Human and / or animal sources

Gene therapy: genetically modified cells

Donation, procurement and testing of starting tissue / cells

Manufacture vector and cell purification and processing,

Ex-vivo genetic modification of cells, Establish MCB, WCB or primary cell lot


Somatic cell therapy Donation, procurement and testing of starting tissue / cells

Establish MCB, WCB or primary cell lot or cell pool

Cell isolation, culturepurification, combination with non-cellular components

Formulation, combination, fill

Tissue engineered products Donation, procurement and testing of starting tissue / cells

Initial processing, isolation and purification, establish MCB, WCB, primary cell lot or cell pool

Cell isolation, culture, purification, combination with non-cellular components

formulation, combination, fill

I n c r e a s i n g G M P r e q u i r e m e n t s



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Key areas - Structure

• Part A- Modified version of current Annex 2- General guidance for biological products

• Part B – specific guidance on selected product types:- Animal sourced products - Allergens - Animal immunosera - Vaccines - Recombinant - Monoclonal Antibody - Transgenic animal products - Transgenic plant products- SCT and TE products - GT products

• Glossary: only for terms used in the Annex



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Key areas – Start Point of GMP

• GMP principles at:- cell bank establishment - vector manufacture- animal sourcing

• ATMPs: - Follows on from ‘GP’ of EU licensed sites under EUTCD / Blood

Directive - Sources outside EEA need to operate to equivalent standards



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Key areas - Reference to GMP Annex 1

• Title does not reflect entire content of Annex 1: - ‘Manufacture of sterile medicinal products’

• But:- Annex 1 is the only guidance on all classified rooms (grade A –

D) in EU GMP

• Use guidance in the appropriate section(s) of Annex 1

• No new expectations for sterile manufacture beyond that in Clinical Trial Authorisation or Marketing Authorisation



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Key areas - Facility / Equipment Dedication

• Aim: to minimize opportunities for cross-contamination and mix-up• Use of control strategy concept, based on QRM principles

- Net effect is relaxations from most current prescriptive measures (apart from pathogenic organisms)

• Level of segregation based on:- Nature of product and engineering solutions - Other specific considerations

• Aligned with approaches of:- IWG Chapter 3 / 5 revision and relevant ICH principles- FDA on requirements for live vaccine processing and spore

forming organisms



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Key areas - Short Shelf Life Products

• Text drawn from recently revised Annex 3 (Manufacture of Radiopharmaceuticals)

• Draw assurances from the following to facilitate batch certification and release:- Facilities / equipment / process validation- Staff training- Change management / identification of incidents- Availability of relevant information for QPs- Other considerations - rapid micro tests

• Primary requirements in Clinical Trial Authorisation or Marketing Authorisation



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Next Steps

• Await comments from IWG• Finalise text• Share text with CAT and BWP for information• Submit to European Commission for adoption • Consider whether there is a need for supplementary

information on the ‘Frequently asked Questions’ section of the EMA website

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