Good Manufacturing PracticeGood Manufacturing PracticeTrends – Industry side of viewTrends – Industry side of view

in European Union

and and

in Pharmaceutical Inspections Cooperation Scheme (PIC/S)

Dr.Vee RevithiROCHE, PTQG – External Relations Europe

August 2014

European Union28 Member States / 508 million people

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CROATIA joined EU as the 28th M-S in 1 July 2013

Greece / ELLAS, my country, where Princess Europe was kidnapped by Zeus as a bull from Phoenice (now Lebanon) to Crete

Member states of the European Union

Candidate and potential candidate countries

Principles

Detailed Guidelines

Part I GMP Med. Products Part II GMP Active substances

Supplementary Guidelines Annexes 1 to 19 of EC GMP Guide

Part III : Collection of GMP related documents, to clarify regulatory expectations

European regulatory structure in the GMPs

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Directives 2001/83 & 82Manufacturing and Wholesale Authorisation

Directives 2003/94/EC & 91/412/EEC EC GMP Guide Basic Requirements

GDPs for Med. ProductsGDPs for APIs

Revision Procedure in EU and PIC/S

The procedure to change GMPs is continuous, as new technologies and new data and legislation come about, or problems come up and have to be addressed. The industry continuously sets in questions, proposals, improvements, new ideas etc.

The fora of the technical discussion among national authorities are:• In EU, at the EMA, Inspections Working Group (GMDP IWG)• In PIC/S, at the PIC/S Committee of Officials (PIC/S CoO)

These two Groups cooperate closely and work in parallel on the GMP Guidelines. There exists an agreement on the procedure used and the changes are happening almost simultaneously. To note that 28 of the 46 Authorities within PIC/S are EU authorities

In practical terms PIC/S and EU influence each other and adopt the same requirements in GMPs

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Revision Procedure in EU and PIC/SEffort for parallel paths

(usually takes about 2 years for a document)

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©2011 EDQM, Council of Europe, All rights reserved

Timeframes: In EU, it may take from 12 months to more than 2 yearsDuring the EU procedure period, the PIC/S authorities are informed and are welcome to comment as well. They are encouraged to participate in the drafting groupsIn PIC/S, the procedure starts usually after the EU and it takes longer, as the non-EU member authorities follow each one their own consultancy and decision making procedure.Usually there is a time gap between the adoption by EU and PIC/S of about 6 months to 1 year.

©2011 EDQM, Council of Europe, All rights reserved

Revision Procedure in EU and PIC/SEffort for parallel paths

GMPs in EU PART Ι Basic Requirements for MPs (9 Chapters)

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CHAPTER TITLE DATE of issue

1 Pharmaceutical Quality System 31-1-2013

2 Personnel 16-2-2014

3 Premises and Equipment 1998 (under revision)

4 Documentation June 2011

5 Production (1998) (under revision)

6 Quality Control (from 1-10-2014 on)

7 Outsourced Activities 31-1-2013

8 Complaints & Product Recall 1998 (under revision)

9 Self Inspections 1998

Blue – recently revised Green – under revision

GMPs in EU

PART ΙΙ Basic Requirements for APIs (July 2010)

Identical to ICH Q7

PART ΙΙΙ GMP related guidance documents

1. Site Master File (November 2010)

2. Q9 Quality Risk Management (31-1-2011)

3. Q10 Note for guidance on Pharmaceutical QS (31-1-2011)

4. MRA (Mutual Recognition Agreement) Batch Certificate (31-1-2011)

5. Template for the “Written Confirmation” for APIs exported to the EU for MPs (2-7-2013)

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GMPs in EU GMP Annexes (19, one blank)

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ANNEX Nr TITLE DATE

1 Manufacture of Sterile MPs 1-3-2009

2 Manufacture of Biological APIs & MPs 31-1-2013

3 Manufacture of radiopharmaceuticals 1-3-20094 Manufacture of Veterinary MPs other than

Immunological Veterinary MPs1998

5 Manufacture of Immunological Veterinary MPs 31-7-2010

6 Manufacture of Medicinal Gases 31-7-2010

7 Manufacture of Herbal MPs 1-9-20098 Sampling of starting and packaging materials 1998

9 Manufacture of creams, liquids and ointments 1998

10 Manufacture of pressurized MD Aerosol Preparations for inhalation

1998

Blue – recently revised Green – under revision

GMPs in EU GMP Annexes

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ANNEX TITLE DATE

11 Computerised Systems 30-6-2011

12 Use of ionizing radiation in the manufacture of MPs 1998

13 Manufacture of Investigational MPs (IMPs) 31-7-2010

14 Manufacture of MPs /Human Blood/Plasma 30-11-2011

15 Qualification & Validation 2001 (under revision)

16 Certification by a QP and Batch Release 2002 (under revision)

17 Parametric Release 2002 (under revision)

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19 Reference and Retention Samples 1-6-2006

Blue – recently revised Green – under revision

Comparing GMPs & GDPs in EU/EEA and PIC/S

GΜPs in ΕU 3 Parts and 19 Annexes

PART Ι Basic Requirements for MPs PART ΙΙ Basic Requirements for APIs PART ΙΙΙ GMP related guidance & 19 Annexes of GMPs (18 is blank)

& GDPs in EU

GΜPs in PIC/S (PE 009-11):

PART Ι Basic Requirements for MPs PART ΙΙ Basic Requirements for APIs

No Part III 19 Annexes of GMPs (16 and 18 blank)

& GDPs in PIC/S

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EMA GMDP Inspectors Working Group

EMA GMDP IWG

• GMDP Inspectors from 28 member states of EU (43 authorities) and from EEA countries and Switzerland meet regularly at the EMA (London), 4 times per year for 3.5 days each time. MRA partners and EU candidates may participate as well.

• They discuss and propose on the GMPs and GDPs, on technical guidance and any other relevant document to the EU Commission.

• They meet with Industry Representatives at least once a year as a group.

• The meetings are supported, coordinated and chaired by the EMA.

• A representative (or sometimes two) from each authority is participating.

• Sub and working groups are often organized on special topics ad hoc.

• Most of the EU Authorities are PIC/S members as well (only Luxembourg, Bulgaria and Croatia are not PIC/S members).

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PIC/S Committee

• Heads of GMDP Inspectorates (or senior Inspectors) from 46 actually Authorities/members meet regularly 2x per year, once in Geneva and once in a host country for 1.5 days each time. Partners (EMA, WHO, UNICEF, EDQM) and PIC/S candidates participate as well.

• They discuss and propose on the GMPs and GDPs, on technical guidance and any other relevant document.

• They meet and organize training events with Professional Associations (PDA, ISPE etc).

• The meetings are supported by the PIC/S Secretariat.

• A representative (or sometimes two) from each authority is participating.

• Sub-committees and Expert circles are organized on special topics.

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How EMA and PIC/S cooperate

Since 8 May 2012 EMA and PIC/S signed an agreement to “Harmonize the Consultation Procedure “ for all GMP documents.

The agreement provides that: The GMP Guide and related documents should be harmonized between

PIC/S and the GMDP IWG (they need NOT be identical) to keep the regulatory environment equivalent between the different regions.

an effective and co-operative exchange of information, including drafts and proposals, exists between EMA Inspectors Group and PIC/S.

a list of documents subject to harmonization is established and will regularly up-date their status

Mutual participation in drafting groups is encouraged Effort should be there for common implementation dates.

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Actually harmonisation exists as follows:

GMPs Chapters

EU Status

Chapter 1 Jan 2013 Sept 2009 On going at PIC/S

Chapter 2 Feb 2014 Mar 2009 On going at PIC/S

Chapter 3 1998 Sept 2009 OK, undergo parallel change

Chapter 4 June 2011 Jan 2013 OK

Chapter 5 1998 Sept 2009 OK, undergo parallel change

Chapter 6 Oct 2014 Sept 2009 On going at PIC/S

Chapter 7 Jan 2013 Sept 2009 On going at PIC/S

Chapter 8 1998 Sept 2009 OK, undergo parallel change

Chapter 9 1998 Sept 2009 OK

Harmonization - EU & PIC/S

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Actually harmonisation exists as follows:

GMPs Annexes

Status

Annex 1 March 2009 Sept 2009 OK

Annex 2 Jan 2013 Mar 2014 OK

Annex 3 March 2009 Sept 2009 OK

Annex 4 1998 Sept 2009 OK

Annex 5 1998 Sept 2009 OK

Annex 6 July 2010 Jan 2013 OK

Annex 7 Sept 2009 Jan 2013 OK

Annex 8 1998 Sept 2009 OK

Annex 9 1998 Sept 2009 OK

Harmonization - EU & PIC/S

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Actually harmonization exists as follows:Harmonization - EU & PIC/S

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GMPs Annexes

Status

Annex 10 1998 Sept 2009 OK

Annex 11 Jan 2010 Jan 2013 OK

Annex 12 1998 Sept 2009 OK

Annex 13 July 2010 Jan 2013 OK

Annex 14 Nov 2011 Mar 2014 OK

Annex 15 Sept 2001 Sept 2009 OK, undergo parallel change

Annex 16 Jan 2002 ___ Not existing in PIC/S, under revision in EU

Annex 17 Jan 2002 Sept 2009 OK, undergo parallel change

Annex 18 _______ ________ _________

Annex 19 June 2006 Sept 2009 OK

Actually harmonization exists as follows:

Status

GMP Guide Part II (APIs)

July 2010 Mar 2014 OK

Site Master File

Nov 2010 Nov 2013 OK

Inspection Report format

May 2006 Sept 2007 OK

Harmonization - EU & PIC/S

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GDP Guide for Finished products

November 2013

June 2014 OK

Future Global Harmonisation

As PIC/S is actually under a dynamic expansion in all the continents, with 46 Authorities / members and soon to reach 50, it has become a very important international forum where discussions among regulatory authorities are held and harmonization in GMPs and GDPs is achieved through consensus, mutual understanding and confidence.

In the present globalized environment, the goal of Harmonization is supported by both the Authorities and the Industry as it provides consistency and homogeneity in the GMPs and GDPs, higher quality and efficiency and keeps resources available.

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Benefits of PIC/S Membership

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Benefits of PIC/S Membership

What is the pathway usually GMP Inspectorates follow?

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Oh, no more resources!

Industry express often concern about the increasing number of foreign inspections at the sites. They burden the normal manufacturing activity and divert valuable resources to service Inspection needs. They put additional pressure, physical and psychological to the personnel involved.

Inspectors from different authorities use often different methodology and request various levels of detail in documentation and SOPs. Lack of harmonization between Inspectorates is often observed and the Industry struggles to comply with different standards.

But, it should be considered that Industry has in mind also that: more inspections raise the probability of more observations (more inspectors

in site, more detailed monitoring).

Sometimes, inspection sharing between authorities is not really in favour of the Industry, since it reveals observations that other inspectors might not find.

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Why Inspection Harmonization & Coordination benefit the Industry?

YES, despite some drawbacks in cases, the benefits are definitely essential and important.

The HARMONIZATION (from greek word Αρμονία: music that sounds well) means that the GMPs & GDPs will evolve to an internationally accepted and applied common regulation and all authorities will inspect in the same or equivalent way.

The COORDINATION means that Authorities will respect other authorities’ Inspection reports and will not perform new inspection for the same reason (for a manufacturing authorization, surveillance inspection etc).

Ideally, for a large site, without any big changes in production, we could have 1 general GMP surveillance inspection every 2 to 3 years!

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So, does Industry really favor Inspection Harmonization & Coordination?

How realistic can this vision be? Which are the “tools”?

ICH is working steadily in producing commonly accepted technical guidance.

PIC/S is the main “tool” of Authorities towards harmonization. Most authorities wants to join!In 2014, PIC/S has 46 authorities with almost all EU, US, Canada, Australia, Argentina, South Africa, Ukraine and some ASEAN countries among many others. Since 2002, 23 authorities have joined.By 2017, Brazil, Turkey, Mexico & Iran will likely join to raise the number over 50.By 2020, Russia and China will likely have applied in PIC/S. India will take longer. Probably some African countries like Uganda and Nigeria and Arab countries like Saudi Arabia too.

So, by 2020, Harmonization and Coordination will be in a very good path globally

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Is really a vision that can come true?And when will that happen?

Industry : to understand and acknowledge the reasons of expansion of Foreign Inspections, connected to Public Health concerns.

Industry & Agencies : to realize that ALL will benefit by a proper Foreign Inspections Coordination and ALL will save resources.

Agencies : to realize the benefits of joining global organizations and the value of the “sharing of information” and of “sharing inspection Reports” in protecting public health.

Agencies : to realize the importance of cooperation, of confidence building and of using common methodology.

Industry : to support the global forums for activities like training and communication among authorities.

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How can Industry & Agencies support the Inspection Methodology Harmonization

Doing now what patients need next