EU Regulatory Update - c.ymcdn.com · B.I.a.2.c - Change in manufacturing process of the active substance B.I.a.2.c The change refers to a biological / immunological substance or

An agency of the European Union

EU Regulatory Update Peter Richardson Head of Quality Specialised Scientific Disciplines Department, European Medicines Agency

Content

• Re-organisation of the EMA

• Validation guideline – Biological active substances

• Quality by Design

• Variations (Post approval changes)

• Biosimilars

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Re-organisation of the EMA

• Management Positions defined – 16th September

• Focus on how to better:

• support the scientific work of the of the EMA committees;

• share the knowledge and information the Agency holds throughout the EU medicines regulatory network;

• meet the need of the Agency’s stakeholders and partners.

• Therapeutic area Offices lead Product Teams.

• Additional functions – Offices / Services support to procedures and processes.

• Effort to rationalise activities where possible.

• Administrative / procedural aspects separated from scientific – regulatory support.

• Quality Office : further integration of chemicals and biologicals.

• Implementation in progress following redesign of the processes.

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http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/09/news_detail_001886.jsp&mid=WC0b01ac058004d5c1

New EMA Structure

Management structure: Divisions / Departments / Offices

Human Medicines Research and Development Support Division,

Human Medicines Evaluation Division,

- Scientific and Regulatory Management Department

- Specialised Scientific disciplines Department

- Quality Office (Chemicals and biologicals)

Procedure Management and Business Support Division

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http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000112.jsp&mid=WC0b01ac0580028c2c

Content





• Biosimilars

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Concept Paper

Why develop this ?

- active substance focus

● Gaps to be filled: process- and product-related impurity clearance (e.g. host cell proteins, DNA),

column/membrane sanitization and life time, hold time, reprocessing, pooling of intermediates and

selection of batches to be included in evaluation/validation studies.

● Evolution of concepts already outlined in ICH 8 -11 do not provide practical recommendations on the

necessary evaluation/validation studies to be filed on these specific aspects.

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Validation Guideline Workshop

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http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/events/2013/01/event_detail_000693.jsp&mid=WC0b01ac058004d5c3

Workshop - Remarks

Acknowledgement:

K. Ho (ANSM / Roche)

BWP and industry

participants

A. Ganan (EMA)

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Critical Process Parameters:

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Process Verification

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Data overview

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Product Validation

• Draft (QWP) guideline finalised.

• Principles applicable to biologicals.

(addresses continuous process

verification)

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Content





• Biosimilars

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• FDA – QbD parallel

assessment.

• Focus: chemicals

(affects biologicals).

• Outcomes – Q&A.

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Perjeta - (informal) parallel assessment

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QbD Approach:

QbD Workshop - Jan 2014

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Content





• Biosimilars

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Variations Regulation

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Procedural guideline

Variation classification guideline

• in force since Jan 2010

• medicinal products authorised via centralized (CP), mutual recognition (MRP) and decentralized

• in force since Nov 2012 • extend the scope -> medicinal products

authorised at national level

• Changes in decision making process for product involving a CP

• EC decision only for type II variations favourable & affecting annexes, acc. to Art 2.3.1(a)

Variation to all MAs in EU subject to the same rules Earlier implementation for most Quality changes for CPs -> as no EC decision needed.

Regulation (EC) No 1234/2008

Regulation (EC) No 712/2012

Revision of classification guideline

Updated guidleine published on EC website on 16th May 2013.

Published in Official Journal of EU. Entered into force on 04 August 2013,

Main Revisions in the guideline:

•New Pharmacovigilance legislation;

•Other changes to reflect experience;

•Outcome of Art. 5 recommendations

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Revision of Classification guideline

Overview of Quality related changes

• New scopes:

– As result of Art 5 (e.g. stability protocol)

– From frequent questions to CA / Clarification purposes

(e.g. WCB storage)

– Align requirements (e.g. consistency between active and product)

– In relation to enhanced development (QbD) (e.g. changes to

change management protocols)

– relevant to biological products e.g. inclusion of finished product

design space, adventitious agents safety, batch control/testing sites.

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Important changes for biologicals -

Classification Guideline

B.I.a.2.c - Change in manufacturing process of the active substance

B.I.a.2.c The change refers to a biological / immunological substance or use of a different chemically derived

substance in the manufacture of a biological/immunological substance, which may have a significant

impact on the quality, safety and efficacy of the medicinal product and is not related to a protocol

B.I.b.2.d Change in test precedure for the active substance

B.I.b.2.d Substantial change to or replacement of a biological/ immunological/ immunochemical test method or

a method using a biological reagent for a biological active substance.

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Variations – Web Link Categorisation Guideline:

http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2013:223:FULL:EN:PDF

Content





• Biosimilars

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Evolution of Biosimilars in the EU

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2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

First biosimilars authorised –

Omnitrope and Valtropin

First biosimilar epoetins

authorised

First biosimilar filgrastims authorised

Legislation Guidance

Product evaluation

Directive 2001/83/EC


Overarching guideline

Product-class specific guidelines

Quality guideline Non-clinical/Clinical guideline

First biosimilar mAbs authorised


Guideline Revision /

Update

Biosimilar product experience in EU Marketing Authorisation

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26 MAAs reviewed

18 Positive 1 Negative 7 Withdrawn

14 Valid MAs

2 Withdrawn

28 MAAs submitted

2 MAAs under review

Follitropin alfa (1) Insulin glargine(1)

Somatropin (1) Epoetin (5) Filgrastim (6) Infliximab (2)

Filgrastim (1) Somatropin (1)

Interferon alfa Insulin (6) Epoetin (1)

2 DMP

Filgrastim (1) Follitropin alfa (1)

Guidelines for biosimilars

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Overarching Guideline (CHMP/437/04) “Guideline on Similar Biological Medicinal Products”

Defines principles

Draft GL : May 2013

Quality Guideline Non-clinical/clinical Guideline

General Guidelines on Q/S/E

Final GL 1Q2104

Insulin Somatropin G-CSF Epoetin LMWH IFN-α IFN-β mAbs Follitropin alfa

Class-specific Guidelines: non-clinical/clinical aspects

Overarching Guidelines:

Draft GL : June 2013

2006 Rev 2012

2006 2006 2006 Rev 2010

2009 Rev 2013

2009 2013 2012 2013

30 Jun 2013

31 Jul 2013

Implementation 1 Sep 2013

Biosimilars Workshop

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INN Aspects

• EMA uses INN according to WHO policy

• Biosimilar can use Reference Product INN

• EMA: robust assessment of biosimilarity

• WHO Consultation – 2006 / 2013

• What can be expected from INN ?

• When to use INN ?

• Coding of active substance in biosimilar ?

- TGA / (WHO Draft Policy ?):

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EC: Market access to biosimilars

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• Sep 2010 project launch

• Review availability of biosimilars in EU markets

• Define the necessary conditions for patient access

– Current experience with access and uptake of biosimilars

– Effects and consequences from the uptake of biosimilars

– How to promote uptake of biosimilars

• Deliverables -> 22th April 2013

– Consensus doc: “What you need to know about Biosimilars”

– Information on reimbursement in EEA countries

– Study on “biosimilar market access” prepared by IMS

– Survey conducted by EGA to identify good practices, obstacles related

to biosimilar uptake

http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_report_en.pdf

1st Biosimilar Mab - Remsima

• Remsima (duplicate Inflectra) : first biosimilar mAbs to be approved in Europe. European Commission

Decision – 10th September 2013.

• Active substance: INN infliximab

• Reference product Remicade (authorised 1999).

• Further details – see comprehensive EPAR.

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Remsima Comparability (physicochemical)

33 Table continued in EPAR

Remsima Comparability (bioactivity)

34 Table continued in EPAR

Remsima - Learnings

• Extensive comparability exercise: quality and non-clinical (in-vitro).

This provides robust assurance on clinical performance and the

extrapolation of indications.

• Difference in quality profile - reduced afucosylation, translating into a

lower binding affinity towards specific FcγRIIIa receptors→ lower

ADCC activity ? Resolved by extended testing and consideration of

mechanism of action.

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Thank you

Peter Richardson

Head of Quality

Specialised Medicines Department

European Medicines Agency [email protected] http://www.ema.europa.eu

mailto:[email protected]

http://www.ema.europa.eu/

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EU Regulatory Update - c.ymcdn.com · B.I.a.2.c - Change in manufacturing process of the active substance B.I.a.2.c The change refers to a biological / immunological substance or