Spring Intro 2023

Programme

The TOPRA 45 th Spring Introductory Course:

Introduction to Pharmaceutical Regulatory Affairs

28-31 March 2023

Coppid Beech Hotel, Bracknell, Berkshire, UK

Day 1 28 March 2023 Chairperson: Morning: Claire Beggs, Jazz Pharma, Afternoon: Zena Smith, Jazz Pharma Day Co-ordinator: Dima Al-Hadithi, Minaret Consulting Limited **All timings presented are BST

08:00

Registration

08:30

Welcome & Introduction to the course Claire Beggs, Jazz Pharma

08:45

New Product Development, The European Regulatory Environment & the Role of Regulatory Affairs Steve Brookes, Biogen

09:45

Overview of the MAA Jenny Lamport, 1st Regulatory Ltd.

10:45

Break

11.00

Chemical Development/Quality Brian Corrigan, MSD

12:00

Lunch

12:45

Pharmaceutical Development/Quality Brian Corrigan, MSD

Module 3. An Agency Perspective Mirza Ćatibušić , Health Products Regulatory Authority (HPRA)

13:45

14:45

Panel Q&A and Closing Remarks Zena, Smith, Jazz Pharma , Claire Beggs, Chair

15:00

Case Study 1 Introduction and break

15:30

Case Study 1. Chemistry & Pharmacy Zena Smith, Jazz Pharma

17:00

End of day 1

19:00

Dinner

Day 2 29 March 2023 Chairperson: Xavier Luria, VERISTAT Day Co-ordinator: Bob Ibbotson, Shionogi BV

**All timings presented are BST

08:30

Understanding the Need for Non-Clinical Safety Studies Chris Powell, Cambridge Biopharma Consultants

09:30

The Importance of Pharmacokinetics & Pharmacodynamics in Drug Development Helen Walker, HW ClinPharm Ltd

10:30

Tea/ coffee break

The Components of the Non-Clinical Section of a Marketing Authorisation Application David Jones, Consultant

10:45

11:35

Non-Clinical Panel Discussion and Questions

12:00

Clinical Drug Development, Paediatric Investigation Plans & the link with Regulatory Affairs Steve Pinder, Envestia Ltd

13:00

Lunch

13:45

The Regulation of Clinical Trials in Europe – An Agency Perspective Gunilla Andrew Nielsen, MPA

14:40

The European Clinical Trials Process – Industry Perspective Shaila Choi, Seagen Ltd

15:15

Tea/Coffee Break

15:25

The MAA – the perspective of an EU Regulatory Authority Clinical Assessor Jan Span, Medicines Evaluation Board (MEB)

16:10

Clinical Panel Discussion and Questions

16:30

Case Study 2. Non-Clinical & Clinical Development Ming Ewe , Smarter Biotech Solutions Limited

18:30

End of day 2

19:00

Dinner

Day 3 30 March 2023

Chairperson: Niamh Lawler Turner, University of Limerick Day Co-ordinator: Ming Ewe, Smarter Biotech Solutions Limited **All timings presented are BST

08:45

The Centralised Procedure – Practical Industry Experience Will James, Pfizer

09:45

The Mutual Recognition Procedure & the Decentralised Procedure – Practical Industry Experience Stephen Thompson , S-Cubed

10:45

Break

11:00

Generics Andrew Modley, Teva

12:00

Lunch

13:00

Regulatory Strategy Session Part 1: 1. Initial considerations for Strategic Thinking 2. Think Global – Key considerations for Worldwide Markets 3. Regulatory/HTA Advice 4. Paediatric Development and PIPs David Kane, Vertex / Neil Roberts , Gilead

14:15

Break

Regulatory Strategy Session Part 2: 5. Orphan Disease Considerations 6. Accelerating Access (Expedited Pathways) 7. Tradename 8. IP and Exclusivity Considerations David Kane, Vertex / Neil Roberts , Gilead

14:30

15:45

Closing remarks of the day Niamh Lawler-Turner, University of Limerick

16:00

Case Study 3. Regulatory Strategy David Kane, Vertex

17:30

End of day 3

19:00

Dinner

Day 4 31 Mar 2023

Chairperson: Gwenaelle Pemberton, Syncona Ltd Day Co-ordinator: Susanna Dean, Apothecom Ltd **All timings presented are BST

Opening and learning objectives presentation Gwenaelle Pemberton, Syncona Ltd

08:30

Lifecycle Management – Quality Richard Keane, Biogen Idec Ltd.

08:40

09.40

Lifecycle Management – Safety & Efficacy Kay Martin, Biogen

10:40

Break

10:55

Product Information – Regulation of the SmPC, PIL & label Julia Coombes, MHRA

12:10

Q&A session Panel: Richard Keane, Kay Martin, Julia Coombes

12:30

Lunch

13:15

Case Study 4: Variations Jenny Davies, Haleon

14:30

Break

14:45

Health Technology Assessment: Why and where does the regulatory professional become involved? Sara Lopes, Shionogi BV

15:15

An Introduction to Biotechnology & Advanced Therapy Medicinal Products Paul Smith, MetisRA Consulting Ltd

16:15

The Future ahead in Regulatory Affairs: What to expect next L aura Liebers, Vertex Pharmaceuticals

16:45

Closing remarks Gwenaelle Pemberton

17:00

End of day 4

First Name

Last Name

Company

Country

Teodora

Andrian

Eli Lilly & Co

United Kingdom United Kingdom United Kingdom

Antonina

Barna

Vertex Pharmaceuticals (Europe) Ltd

Inci Aya

Bastaci Arpaci

Teva UK Ltd MediWound

Ben Yaakov

Israel

Prachi James

Bhargava

Zentiva Pharma UK Limited

United Kingdom United Kingdom

Boss

Aspire Pharma Ltd

Guy

Byrne

Torbay PMU South Devon Healthcare Trust United Kingdom

Victoria Kathryn Simran Hasan Mirrin Rachel Martin Suman Manali

Clark

DLRC Ltd

United Kingdom United Kingdom United Kingdom United Kingdom United Kingdom United Kingdom United Kingdom United Kingdom United Kingdom United Kingdom United Kingdom United Kingdom United Kingdom United Kingdom Germany

Costelloe

ProPharma Group UK

Damija

Boehringer Ingelheim Ltd

Gaffar-Karim

Gillespie

Sanofi Reading

Ingram

Regeneron UK Ltd

Jäger

Lilly Deutschland GmbH

Jhand

DLRC Ltd

Kadam

Teva UK Ltd

Rose

Khan

Fresenius Kabi Ltd Aspire Pharma Ltd Chemidex Pharma Ltd

Gurtek

Landa

Yenny

Lee

Ruth Ruth

Lloyd-Williams

MHRA

McDowall Mirfattahi

AbbVie Ltd

Rouzbeh

Reckitt

Patrick

Murphy

Bayer

Ireland

Kasim

Naeem

AstraZeneca - MACCLESFIELD

United Kingdom

Kate

O'Donnell

Organon Pharma (Ireland) Limited Gilead Sciences International Ltd (Cambridge)

Ireland

Leah

Parcell

United Kingdom United Kingdom United Kingdom United Kingdom

Deanna

Patmore

Crescendo Biologics Ltd

Carolane

Preel

AbbVie Ltd

Jessica

Quilter

Janssen-Cilag Ltd

Actelion, A Janssen Pharmaceutical Comapany of Johnson & Johnson

Gloria

Schneider-Ferrer

Switzerland

Lily

Sears

AstraZeneca - Cambridge

United Kingdom

Ingrid

Sterrenburg-Verhaart Baggerman Farma Consult

Netherlands

Matthew

Wilkins

Jenson R+ Ltd - East Bridgford

United Kingdom United Kingdom

Danhui

Zhu

DLRC Ltd

03/03/2023

TOPRA Introductory Course

New Product Development, the EU Regulatory Environment & the Role of Regulatory Affairs

Steve Brookes, Senior Director, Regulatory Sciences & RnD Project Lead, Biogen

Disclaimer: Content reflects my personal views

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

1

Learning outcomes

New Product Development ● Overview of the environment & process The EU Regulatory Environment ● The history & pharmaceutical legislation ● Evolution & decision makers The Role of Regulatory ● The perception ● Its importance & where it fits ● The various roles of a Regulatory Professional ● The rewards

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OVERVIEW OF NEW PRODUCT DEVELOPMENT

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Pharmaceutical R&D highest level of industry investment in the world

Pharmaceutical R&D Industrial Sector Comparison:

17.0%

Computer Software & Services

10.5%

Electrical & Electronics

8.4%

7.8%

Office Equipment & Services

5.3%

Telecommunications

Leisure Time Products

4.7%

Automotive

3.9%

Aerospace & Defense

3.8%

1.2%

Metals & Mining

0.73%

Paper & Forest Products

All Industries

3.9%

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Drug development costs

$1100 M

$2600 M

$500 M

$125 M

$54M

1977

2007

2019

1987

1997

5

Drug discovery and development process

File Patent

Years

5

14 15

0

6 7

9

12 13

DISCOVERY

Candidate Nomination

TOX

Idea

I

II

PK & Safety

III

Initial Efficacy

Full Development Comparative Agents

Filing

Approval Process

Registration (Approval)

Nonclinical

Clinical

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3

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An overview of discovery research

7

Target Product Profile (TPP): Links development strategy and market

8

4

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Small molecules – Nonclinical safety

Initial Safety Batch Development Batch Using Clinical Synthesis

First Dose in Man

Development

Initial Safety

Development Track

Safety Assessment Lead

Total 19 (21) Months

3 Months

4 Months

3 Months 7 Months (9 months for 13 wk) 2 Months

Toxicology for IND/CTA

Initial Safety Assessment

IND/CTA Regulatory Submission/ Approval

Acute Rodent (2, 4, or 13 Week) Non-Rodent (2, 4 or 13 Week) Non-Rodent CV Safety Pharm Rodent CNS, Resp. Safety Pharm In Vivo Mouse Micronucleus

Rodent RF 5-14 Day (+Histo) Screening Ames

Non-Rodent RF 5-14 Days (+Histo)

In vitro Ames, Chromo Ab

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To proceed - appropriate safety profile and ideally: ● Target organs identified ● Methods identified for monitoring toxicity and blood drug levels in clinic ● Type of toxicity observed in animals is predictive of toxicity in human ● There are adequate exposure and dose safety margins for patient population and for indication involved – No observed adverse effect level (NOAEL) – Minimum anticipated biological effect level (MABEL) – Target engagement and receptor occupancy Nonclinical safety evaluations

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5

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Clinical development

Non-clinical Safety Evaluation

Clinical Evaluation

Pivotal/Phase III Patients 1000's

PoC/Phase II Patients 100's

Phase I Healthy Volunteers 10's

Confirmatory Efficacy, Safety, Claims, Comparators, Health Economics

Preliminary Efficacy, Side Effects, Safety, Dose Selection/Regimen

Regulatory Filing

Safety ADME

1 yr

1 yr

2 yrs

3 yrs

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CTD structure of the MA submission…

Module 1 – Administrative data + Regional information

1.0

TOC

Module 2: Summaries

2.2 Introduction

2.6 Summary 2.4 Overview

2.5 Overview

2.3 QOS

2.7 Summary

Modules 3,4,5: 3. Quality 4. Nonclinical 5. Clinical

4 Non clinical

3 Quality

5 Clinical

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Registration and approval

Establish Quality, Safety & Efficacy  Approval!! ● Global Regulatory Strategy – Optimise development leading to approvals (time, resources, procedures) ● Simultaneous submissions in key regions? i.e. US, EU, JPN; UK, CAN, SWZ, CHN, BRZ, SA, AUS/NZ ● Meetings with regulatory authorities (from Phase II or earlier – “PRIME”), seek national and CHMP Scientific Advice, HTA input, minimise questions & surprises!

13

Outcomes research (pharmaco-economics)

Measures economic and quality of life implications of medicines – “Effectiveness of product” Data used in ‘value for money’ driven healthcare markets to: ● Secure reimbursement & justify pricing – Health Technology Assessment (HTA) e.g. NICE, IQWIG/GBA ● Support marketing ● Get on formularies Endpoints included in Phase III (or II) studies ● Consider parallel HTA/regulatory agency advice/consultation

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LCM - adding value to established products

Additional indications, manufacturing sites, forms, strengths, delivery devices ● Grow Brand (e.g. Enbrel in EU $0.1B to $1.4B from 2001 to 2005) ● Extra data exclusivity/protection (sig indication+1 year, PIP +6 months Supp Patent Cert) ● Maintain profile in disease area/management

To maintain income at time of patent expiry ● Introduce new indication tied to new patentable formulation ● New patentable formulation offeringmedical or commercial advantage

15

Lack of Harmonisation – ICH (?)

Different standards of medicine in the US, Europe and Japan complicate clinical trials: ● Choice of comparators: US-placebo; EU-comparator drug and placebo ● EU is not one country; which comparator? ● Comparative effectiveness and social need must now be established for new drug (EU, US?); no longer just quality, safety and efficacy ● Support pricing strategy with clinical trial data ● Differing expectations for risk/benefit (US “substantial evidence of efficacy” EU “Positive benefit:risk”) ● Clinical Trial Regulation - EU regulations harmonized but Ethics? ● Japan - Japanese monkey study request???

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How could all this affect you?

• Entering industry when very difficult and very expensive to get new products on the market • Navigate many hurdles where there is often no obvious answer • Know your area of expertise very well • In this environment – you are expected to give quick and accurate answers • Your advice could be of high value or high cost depending on how well you do your job (no pressure!!)

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THE EU REGULATORY ENVIRONMENT

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Content

• A little history ● …why does Regulatory Affairs as a discipline/ function exist? • Pharmaceutical legislation • Evolving EU Regulatory environment • The EU Regulatory procedures & decision makers

19

A little history....

• First Pharmacopoeias and formularies - Europe appeared in C15th / C16th: ● Henry VIII enacted the first English law to control medicines (following pressure from the College of Physicians) in 1540 ● The first Spanish Pharmacopoeia issued in 1581 ● The London Pharmacopoeia in 1618 • Many centuries of updating……

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More recent history….

• Medicinal regulation developed across Europe at the same time as the European Economic Community was being born

• The first European Directive on pharmaceuticals was issued on 26th January 1965 (65/65/EC)

• The primary purpose of all medicines regulation worldwide is:

THE SAFEGUARDING OF PUBLIC HEALTH

21

How the regulations arose

• As with most laws, the rules that govern them are often written or tightened in response to one or more disasters e.g. • US – Elixir of Sulfanilamide (1930s) ● A solution formulated with diethylene glycol, tested for flavour appearance and fragrance only, without toxicology testing ~ 100 deaths

● Food and Drugs Act, (FDA) (1938) – Introduced pre-market drug review – Manufacturers needed to present evidence of the drug’s SAFETY • UK – Thalidomide (1960s) ● UK Committee on Safety of Drugs (1963) ● UK Medicines Act (1968) ● Product Licensing in the UK became mandatory from 1971

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EU legislative categories

• Regulations – Binding completely on all Member States (MSs) • Directives – binding with respect to result but method of achieving result left to each MS • Commission Decision – Binding in their entirety • Guidelines – Persuasive but not binding, justification required if you do not follow • Scientific advice recommendations and opinions – Persuasive, “morally binding”, very good justification required if you do not follow “Don’t ask - if you won’t act”

23

Pharmaceutical legislation What do we mean by regulation?

• Product acceptability (Quality, Safety, Efficacy)

• Process Integrity (GXP) (Audit trails)

• Environmental protection

• Animal welfare

• Promotional/advertising material

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EU Current Legislation

• Current EU Legislation was published after a review in 2000/01 – implemented in 2005 ● Regulation EC no 726/2004 (New Centralised Procedure Regulation) ● Directive 2004/27 (amending Directive 2001/83/EC) • Covering multitude of areas e.g. ● Benefit-Risk, Marketing Authorisations, Generic Products, Mutual Recognition Procedure and new Decentralised Procedure, Referrals, GMP, Labelling, Leaflets ● The changes in legislation were as a result of scientific and technical progress and feedback from stakeholders

25

Beyond Regulation 726/2004

• Orphan Drugs (Regulation (EC) 141/2000) • Advanced Therapy Medicinal Products (ATMP) (Regulation (EC) 1394/2007) • Paediatric (Regulation (EC) 1901/2006) • Variations (Regulation (EC) 1234/2008) • Pharmacovigilance (Regulation (EC) 1235/2010) • Clinical Trials (Regulation (EC) 536/2014) • Keep up-to-date…proposals to revise the legislation proposed in 2023 (if not adopted, next opportunity likely in 5 years). ● http://www.ema.europa.eu/ ● http://ec.europa.eu/health/human-use ● http://www.hma.eu

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What are the Current Regulatory Procedures for the Approval of Products in Europe?

• Centralised Procedure (CP) – All or nothing ● Single application, single evaluation, ● single EU community authorisation • Decentralised Procedure (DCP)/Mutual Recognition Procedure (MRP) ● All EU agencies are equal and hence they should all recognise each others’ approvals ● One agency should be able to perform the review for the whole of the EU • National Procedures ● Older products, Switzerland, UK (bar NI) post Brexit Procedures will be discussed in detail on Day 3

27

EU Regulatory Decision Makers

CVMP

PRAC

CAT

EMA

COMP

HMPC

PDCO

CHMP

SAWP, QWP, EWP, BWP, etc.

SAG, iNRG

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14

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Conclusions on Drug Development & Regulatory Environment

• Environment is very challenging and always changing • Drug development is most costly, risky and lengthy endeavour in industry • R&D costs  , but so are returns to successful projects • Pay-offs for continuous improvements in bringing new, different and better treatments to patients are significant •  Complexity = Regulatory professionals needed now more than ever! (Generalists or niche, e.g. orphan, device, biotech, GTx, TA, CMC) You are a key player – you can make a difference! Let’s look at how and the role of regulatory

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The role of regulatory

PERCEPTION IMPORTANCE VARIOUS ROLES REWARDS

30

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Perception of regulatory

• People in isolation • ‘Regularly awkward’ • ‘You’re just a bunch of form-fillers’ • Inflexible • Unapproachable • Studious ... ‘geeks’

31

Definition of 'geek' Microsoft (UK); English (noun)

Somebody awkward Considered unattractive & socially awkward (insult) Obsessive computer user COMPUTING – somebody who enjoys or takes pride in using computers, or other technology, often to what others consider an excessive degree (informal) Outrageous sideshow performer ARTS – a sideshow performer whose act consists of outrageous feats such as biting the heads off live animals

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Is this the person perceived as a regulatory professional?

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IMPORTANCE OF THE REGULATORY FUNCTION

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Q. When are regulatory involved? A. Throughout development –unique!

Nonclin

Phase 1 Phase 2 Phase 3

Post-approval

MAA Submission

Agency meetings/ Scientific advice

Approve promotional activities

Life-cycle management

Submission planning

Clinical trial applications

Clinical trial applications

Approval (MA)

Choice of Nonclinical studies

Finalise filing plans

MA variations

Pre-submission meetings

Labelling development (Target Product Profile)

Draft responses & Labelling fallbacks

Pricing & reimbursement activities

Labelling development

Final labelling

Most of this will be covered, day-by-day, as you go through the course

Response to questions

CHMP/CMDh/SAG Meetings, OE

The regulatory continuum – We are the only function involved throughout development and life cycle

35

Main responsibilities of regulatory are to:

 Advise on product development, probability of regulatory success  Obtain approvals (e.g. CTAs, PIPs, ODDs, MA, Var) & agency advice for development  Provide mitigations & solutions – creativity! Obtain MAs for medicinal products ● In line with company objectives (as soon as possible) ● With a competitive label (label as driver)

Maintain & grow the MA ● Post-approval commitments

● Line extensions, new indications etc. ● Evolving benefit/risk (PSUR, PBRER) ● The involvement continues until the product is removed from the market Keep the company in compliance

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"Regulatory are like the 'White Knights'* of the Company"

Champions of development, product approvals and protecting the company

• To protect patients • To liaise and assist the regulatory bodies • To remain honest, trustworthy and reliable citizens

* From mythology

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Common perception of regulatory activity related to sales

MA

Sales

Regulatory Activity

Pre-launch

Post-launch

2007

2008

2009

2014

2010

2011

2012

2013

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A more realistic picture of regulatory activity

MA

Regulatory Activity

Sales

Pre-launch

Post-launch

2008

2009

2014

2007

2010

2011

2012

2013

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Various roles of the regulatory professional

Dependent on business, location/organisational structure: ● Ethical (small molecule/biotech)/Generic ● Head Office ● Local Operating Company ● Global structure/aligned to business units ● EU/regional offices ● Manufacturing facilities (CMC regulatory) ● CRO/Contractor/Consultant

40

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Regulatory interactions

Drug Safety

Formulation

Clinical Research

Quality

Regulatory

Sales & Marketing

Manuf & Operations

Non-clinical, Pharmacol, Tox

Internal customers

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Role of regulatory

Can the other functions do anything without regulatory affairs? Can they be left in charge of drug development? Who do they turn to when things go wrong?

‘Ah yes, this is a question for regulatory...’

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Operations Manager

Clinical Development Lead

Commercial Lead

Product Team Leader

Patents Lawyer

Drug Safety

Project Manager

Pharm Development

Ad Hoc member

Clinical Research

Regulatory Affairs

43

Role of regulatory – external interactions

Health Technology Agencies

Regulatory Agencies

CROs

Regulatory

Other Pharmaceutical Companies

Trade Assoc

Consultants Key opinion leaders

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• Reputation and perception • The most feasible / optimal drug development path • Linking development to the “labeling” • Commercially focused life cycle opportunities • ‘Low maintenance’ documentation • Better allocation of resources • Speed to market What can an effective regulatory function add?

Strategic Regulatory Leadership

45

The role of regulatory

THE REWARDS

46

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Regulatory Ju-Jitsu …….

“Have you got a new medicine approved yet?”

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Leading the approval of new medicines for European patients

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Minimising the risks for European patients

You?

Progressive Multifocal Leukoencephalopathy (PML) •More frequent abbreviated MRIs (every 3 to 6 mo) in high risk patients •Risk is low at JCV index ≤ 0.9 & increases substantially above 1.5

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Putting something back…..

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50

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Conclusion

• An integral part of a company • Interaction at all levels • Speed to market, onus on quality • Wherever the future, a major role

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You are the face of regulatory… keep calm & carry on smiling!

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New Product Development ● Overview of the environment & process  The EU Regulatory Environment ● The history & pharmaceutical legislation  ● Evolution & decision makers  The Role of Regulatory ● The perception  ● Its importance & where it fits  ● The various roles of a Regulatory Professional  ● The rewards  Learning objectives for this presentation were:

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Jenny Lamport

Overview of the MAA

Jenny Lamport – 1st Regulatory Ltd

The Organisation for Professionals in Regulatory Affairs

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Agenda

Marketing authorisation applications ● Legislative background ● Format and data content – Common technical document (CTD) ● Types of application

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Jenny Lamport

Principal EU legislation

 Directive 2001/83/EC 6 November 2001 ● ……….. as amended by multiple Directives

– 2002/98/EC, 2003/63/EC – 2004/24/EC, 2004/27/EC – 2008/29/EC, 2009/53/EC, 2009/120/EC, – 2010/84/EU, 2011/62/EU, 2012/26/EU, 2019/1234………….

[Regulations ….. – eg 726/2004, 141/2000, 1901/2006, 1394/2007 as amended]

https://ec.europa.eu/health/documents/eudralex/vol-1_en

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e.g. SE: Medicinal Products Act (SFS 2015:315) Medicinal Products Ordinance (SFS 2015:458) IE: Medicines Board Act 1995 (as amended) [UK previously: Human Medicines Regulations SI 2012/1916 ] Member state legislation enacting the Directive

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Jenny Lamport

Requirements for format and data content

Notice to applicants CHMP/ICH guidelines ● CHMP - Committee for Medicinal Products for Human Use ● ICH - The International Council on Harmonisation

– organisational changes following 25 years of harmonisation – global initiative, expanding beyond the previous ICH members – Health Canada, European Commission, Ministry of Health Labor and Welfare/Pharmaceuticals and Medical Devices Agency (Japan), Swissmedic, FDA …….20 members, 36 observers – more stable operating structure through the establishment as a legal entity under Swiss law – over-arching Assembly governing body instrumental in facilitating future growth through the participation of new members

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EUDRALEX

Volume 1

Legislation

Volume 2

Notice to Applicants

A Procedures B Content of the dossier C Regulatory guidelines

Volume 3

Scientific guidelines (links back to EMA site)

Volume 4

GMP …………….

Volume 9

Pharmacovigilance

Volume 10

Clinical trials

https://ec.europa.eu/health/documents/eudralex_en

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Notice to applicants volume 2B

 Harmonised view of Member States on how the legal requirements can be met

 No legal force ● latest version May 2008

https://health.ec.europa.eu/system/files/2016-11/ctd_05-2008_en_0.pdf

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Guidelines

CHMP

ICH

Safety

Quality

Efficacy Biotechnology Operational

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Jenny Lamport

Data content of MAA

Efficacy Clinical

Quality Chemistry & Pharmacy

Safety Preclinical

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The CTD format

Common technical document ● ICH guideline M4 ● Common presentation format for EU, Japan, USA – Also adopted by other countries ● 5 modules

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Jenny Lamport

ICH CTD guidelines

 M4 organisation  M4Q quality (rapporteur: EU)  M4S safety (rapporteur: MHLW)  M4E efficacy (rapporteur: FDA)  e CTD (rapporteur: FDA)

Q & A Guidance's

https://www.ich.org/page/ctd

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Implementation in the EU….

Implementing legislation ● Directive 2003/63/EC of 25 June 2003 – Applicable from 1 July 2003 – Revised Annex 1 to 2001/83/EC …CTD format THEREFORE… ● Centralised applications: – 1 July 2003 ● National and new MRP applications: – 31 October 2003

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Jenny Lamport

CTD structure of the MA submission…

Module 1 – Administrative data + Regional information

1.0

2.2 Introduction TOC

Module 2: Summaries

2.4 Overview

2.7 Summary 2.5 Overview

2.3 QOS 2.6

Summary

Modules 3,4,5: Quality Nonclinical Clinical

3 Quality

4 Non clinical

5 Clinical

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Format of the CTD

….designed to accommodate e-submissions ● Modular structure – Self-contained pieces of data ● Logical hierarchy of information ● Simple numbering system

……….ONE SIZE FITS ALL

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Jenny Lamport

Format of the CTD

ICH organisation guideline….. ● Sections

● Sub-sections ● Sub-headings ● Documents …….

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CTD Granularity

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Jenny Lamport

CTD format - Module 1

Administrative information and prescribing information – 1.1 Overall table of contents – 1.2 Application form – 1.3 Product information (SmPC, labelling and leaflets) – 1.4 Information about the experts – 1.5 Specific requirements for different types of application – 1.6 Environmental risk assessment

– 1.7 Information on orphan market exclusivity – 1.8 Information relating to pharmacovigilance - Pharmacovigilance system - Risk Management Plan (RMP) – 1.9 Information relating to clinical trials – 1.10 Information relating to paediatrics

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 Fees, declaration and signature  Type of application  Name of product and active ingredient, ATC code  Pharmaceutical form and strength  Route of administration  Container, pack size, shelf life, storage conditions  Legal status  Names and addresses  Qualitative and quantitative composition  Scientific advice, paediatric development programme  Other MA applications/approvals  Appended documents Application form

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Names and addresses

 Applicant  Communication during assessment  Communication post approval  Manufacturer of the finished product  Manufacturer/importer responsible for batch release and actual site(s) of control/testing  Manufacturer of active substance  Contract companies for bioavailability/bioequivalence (BAV/BEQ) studies

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Application form

Name of persons responsible for ● Pharmacovigilance QPPV

● Scientific services ● Defects and recalls

Attached documents eg - Manufacturers authorisation - Declaration signed by the Qualified Person that the active substance is manufactured in accordance with GMP

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 Trade name  Qualitative and quantitative composition  Pharmaceutical form  Clinical particulars ● Indications, dosage & administration, contraindications, warnings & precautions, interactions, pregnancy & lactation, effects on ability to drive, side effects, overdose  Pharmacological properties ● Pharmacodynamics, pharmacokinetics, preclinical safety data  Pharmaceutical particulars ● Excipients, incompatibilities, shelf life, storage precautions, container, instructions for use  MA holder and number  Date of first authorisation/renewal  Date of revision of text Summary of product characteristics

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Expert declaration (Module 1.4)

Information about the expert ● According to his/her respective qualifications the undersigned expert declares hereby to have performed the duties set out in Article 12 and in accordance with Annex I Part I 1.4 of Directive 2001/83/EC as amended ● Name and address of expert: – Address: – Date: – Signature: – Brief information about the educational background, training and occupational experience

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Directive 2001/83/EC Article 12.1 as amended  ‘The necessary technical or professional qualifications which shall be set out in a brief curriculum vitae’  Article 2: of original Directive 2001/83: ● ‘The analyst’ ● ‘The pharmacologist or the specialist with similar experimental competence’ ● ‘The clinician’ Who is an expert?

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CTD format – Module 2

Summaries

– 2.1 Table of contents – 2.2 Introduction – 2.3 Quality overall summary – 2.4 Nonclinical overview – 2.5 Clinical overview – 2.6 Nonclinical summary ) – 2.7 Clinical summary )

written and tabulated

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The purpose of module 2

To provide an OVERVIEW of the CTD for each of the Reviewers ● Modules 3, 4 and 5

– QUALITY OVERALL SUMMARY – NONCLINICAL OVERVIEW – CLINICAL OVERVIEW

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The quality overall summary

 ‘Normally’ not more than 40 pages ● Excluding tables / graphs

 Function: ● Emphasise critical key parameters ● Justify where guidelines have not been followed ● Discuss key issues – Including those that integrate with other modules

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Nonclinical overview

 ‘In general’ not more than 30 pages

 Function: ● To provide an INTEGRATED and CRITICAL assessment: – Pharmacology – Pharmacokinetics – Toxicology

 Nonclinical summary is factual

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Clinical overview

 ‘About’ 30 pages

 Function: ● To provide a critical analysis of the clinical data – Present the conclusions and implications ... not recapitulate them – Clinical summary is factual

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CTD – Module 3 quality

 3.1 Module 3 table of contents  3.2 Body of data ● 3.2.S Drug substance ● 3.2.P Drug product ● 3.2.A Appendices ● 3.2.R Regional information  3.3 Literature references

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CTD – Module 3.2.S

3.2.S.1 General information 3.2.S.2 Manufacture 3.2.S.3 Characterisation 3.2.S.4 Control of drug substance 3.2.S.5 Reference standards or materials 3.2.S.6 Container closure system 3.2.S.7 Stability

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Module 3.2.S – Options

All relevant data in 3.2.S

Drug Master File ● Means of protecting confidential know how of third party manufacturer ● ‘Open’ part in 3.2.S ● ‘Open’ and ‘closed’ parts + QOS submitted to authorities by third party ● Letter of access ● Agreement to notify changes to MA holder

https://www.ema.europa.eu/en/active-substance-master file-procedure

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Module 3.2.S – Options

Certificate of Suitability ● Ph Eur drug substances ● 3.2.S + QOS submitted to EDQM – Evidence to show that the Ph Eur monograph can adequately control quality – Typically 12 month procedure – Certificate or Certificate Plus granted ● CEP referenced in Module 3 in lieu of data

EDQM = European Directorate for the Quality of Medicines & Healthcare

https://www.edqm.eu/en/certification

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CTD – Module 3.2.P

3.2.P.1 Description and composition of the drug product 3.2.P.2 Pharmaceutical development 3.2.P.3 Manufacture

3.2.P.4 Control of excipients 3.2.P.5 Control of drug product 3.2.P.6 Reference standards or materials 3.2.P.7 Container closure system 3.2.P.8 Stability

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CTD – Module 3.2

3.2.A Appendices ● 3.2.A.1 Facilities and equipment ● 3.2.A.2 Adventitious agents safety evaluation

● 3.2.A.3 Novel excipients 3.2.R Regional information ● Process validation scheme ● Medical device ● Certificate of suitability ● TSE information 3.3 Literature references

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CTD – Module 4 Nonclinical study reports

4.1 Module 4 table of contents  4.2 Study reports ● 4.2.1 Pharmacology

● 4.2.1.1 Primary pharmacology ● 4.2.1.2 Secondary pharmacology ● 4.2.1.3 Safety pharmacology ● 4.2.1.4 Pharmacodynamic drug interactions

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CTD – Module 4

4.2.2 Pharmacokinetics ● 4.2.2.1 Analytical methods and validation reports

● 4.2.2.2 Absorption ● 4.2.2.3 Distribution ● 4.2.2.4 Metabolism ● 4.2.2.5 Excretion

● 4.2.2.6 Pharmacokinetic drug interactions ● 4.2.2.7 Other pharmacokinetic studies

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4.2.3 Toxicology ● 4.2.3.1 Single dose toxicity ● 4.2.3.2 Repeat dose toxicity ● 4.2.3.3 Genotoxicity ● 4.2.3.4 Carcinogenicity ● 4.2.3.5 Reproductive and developmental toxicity ● 4.2.3.6 Local tolerance ● 4.2.3.7 Other toxicity studies 4.3 Copies of literature references CTD – Module 4

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CTD – Module 5 Clinical study reports

5.1 Table of contents for clinical study reports ● 5.2 Tabular listing of all clinical studies ● 5.3 Clinical study reports ● 5.3.1 Reports of biopharmaceutic studies ● 5.3.2 Reports of studies pertinent to pharmacokinetics using human biomaterials

● 5.3.3 Reports of human pharmacokinetic studies ● 5.3.4 Reports of human pharmacodynamic studies ● 5.3.5 Reports of efficacy and safety studies ● 5.3.6 Reports of postmarketing experience ● 5.3.7 Case report forms and individual patient listings 5.4 Literature references

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Overall content…

 Trying to fit information on some products to all areas of the CTD format can lead to a lot of repetition, and a larger dossier than necessary

 Ensure that sections are linked and consistent

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Types of application

Full applications

● Complete information

‘Abridged’ applications ● Cross-reference to information submitted previously

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Types of application

Full applications (i.e. complete dossier) ● New or known active substances – Article 8(3) – Company data (+ published data) ● Well established use – Article 10a – Published data

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New active substance

 ‘First’ EU application  Starts the ‘global marketing authorisation’ ● Relevant for data exclusivity and market protection

● https://ec.europa.eu/health/sites/health/files/files/eudralex/vol 2/vol2a_chap1_en.pdf [Annex I gives definition of new active substance}

● Also reflection paper https://www.ema.europa.eu/en/chemical-structure-properties-criteria-be considered-evaluation-new-active-substance-nas-status

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Types of applications

‘Abridged’ applications ● Known active substance ● ‘Second’ or subsequent applications ● Reduced data requirements – Cross reference to fulfil requirements

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‘Abridged’ applications

Generic products ● Article 10(1) ● Article 10(3)

– Hybrid (product not essentially similar to originator) – Differences supported by data ● Article 10(4) – Similar biological product [Informed consent ● Article 10c]

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Conclusions

 Plan the structure of the CTD as early as possible

 This can be done before actual data are available

 Optimise granularity for the future

 Consider all uses of the document

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Topics covered

Marketing authorisation applications ● Legislative background ● Format and data content – Common technical document (CTD) ● Types of application

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Questions

Questions?

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03/03/2023

Module 3: An Agency Perspective TOPRA - An Introduction to Regulatory Affairs

Mirza Ćatibušić, Senior Pharmaceutical Assessor, HPRA

28 th March 2023

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Learning objectives

• Where to find information? • How and what to submit? • Introduction

• Understand the most common deficiencies identified during assessment of the DS and DP sections of MAAs • Brief overview of QbD / PAT • What do regulators expect to see in Module 3?

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First marketed in 1957 in West Germany ( Contergan) . Primarily prescribed as a sedative or hypnotic, thalidomide also claimed to cure "anxiety, insomnia, gastritis, and tension". Afterwards, it was used against nausea and to alleviate morning sickness in pregnant women. Thalidomide became OTC in West Germany in October 1957. Shortly after around 7,000 infants were born with phocomelia (malformation of the limbs). Only 40% survived. Throughout the world, about 10,000 cases were reported of infants with phocomelia due to thalidomide; only 50% of the 10,000 survived. Negative effects of thalidomide led to the development of more structured drug regulations and control over drug use and development.

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HPRA Vision and Mission

• The vision of the HPRA is ‘to be recognised as a centre of excellence for both the quality and scientific rigour we bring to the work we do and the efficient manner in which it is completed.’ • The HPRA’s mission statement is ‘to protect and enhance public and animal health through the regulation of medicine, medical devices and healthcare products.’

Common Deficiencies in CMC

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Marketing Authorisations (MA)

• Directive 2001/83/EEC, Article 8:

• In order to obtain a marketing authorisation (MA) to place a medicinal product on the market an application shall be made to the competent authority of the Member State concerned. • Only when a MA has been issued by the competent authority can a medicinal product be placed on the market of a Member State of the European Union. • MA granted initially for a period of 5 years • 1 renewal  indefinite validity

Common Deficiencies in CMC

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Introduction

• Quality/Safety/Efficacy-3 legs of the licensing process • Quality is an inherent

objective in itself as well as a determinant of safety and efficacy considered as a continuum from development through marketing and beyond 2001/83/EC as amended requires a commitment to continuous improvement (manufacturing and analytical procedures).

• Quality should be

efficacy

safety

• Article 23 of Directive

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Introduction

• Quality cannot be “tested in” to a product • Quality assurance embraces product design

• Total quality strategy involves • Product development

• Manufacturing process optimisation • GMP conformance • Compliance with specifications/pharmacopoeias • Stability testing • Good distribution, transport, storage and dispensing practices

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Introduction

• Control of product quality throughout the product life cycle • Pre-approval

• clinical studies • scientific advice • Marketing authorisation dossier review • Application of GMP

• Role of the Qualified Person • Post Marketing surveillance

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Where to find information?

• EMA pre-authorisation procedural advice for users of the centralised procedure • Harmonised Guidance for eCTD submissions in the EU • EU Legislation – Eudralex Volume 1 to 10

The body of European Union legislation in the pharmaceutical sector is compiled in Volume 1 and Volume 5 of the publication "The rules governing medicinal products in the European Union": • Volume 1 - EU pharmaceutical legislation for medicinal products for human use • Volume 5 - EU pharmaceutical legislation for medicinal products for veterinary use The basic legislation is supported by a series of guidelines that are also published in the following volumes of "The rules governing medicinal products in the European Union": • Volume 2 - Notice to applicants and regulatory guidelines for medicinal products for human use • Volume 3 - Scientific guidelines for medicinal products for human use • Volume 4 - Guidelines for good manufacturing practices for medicinal products for human and veterinary use • Volume 6 - Notice to applicants and regulatory guidelines for medicinal products for veterinary use • Volume 7 - Scientific guidelines for medicinal products for veterinary use • Volume 8 - Maximum residue limits • Volume 9 - Guidelines for pharmacovigilance for medicinal products for human and veterinary use • Volume 10 - Guidelines for clinical trial • Medicinal products for paediatric use, orphans, herbal medicinal products and advanced therapies are governed by specific rules. 03/03/2023 10

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Application dossier - Common Technical Document (CTD)

CMC / Quality Module 3

CTD

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Where to find information? How and what to submit?

– Volume 2B Notice to Applicants • Medicinal products for human use Presentation and format of the dossier (CTD)

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Module 2 - What needs to be submitted? • Information required detailed in ‘Notice to applicants Volume 2b’. – Sufficient information should be included from each section to provide the quality reviewer with an overview of Module 3. • A quality overall summary is always required (separate open and restricted QOS needed if ASMF is used) • OBSERVED DEFICIENCIES – Information in module 2 differs to module 3 (module 3 / ASMF updated, but module 2 still refers to previous version) – No comment on QOS results presented in Module 3 – QOS on restricted part of ASMF not provided (the ASMF Holder)

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What do regulators expect to see in Module 3? • Quality requirements are laid down by Directives and Regulations – These are mandatory legally binding texts • However they are high level and generally non specific, provide a regulatory framework only • More detail is spelled out in non-mandatory guidelines , which provide flexibility, and advise on how and what data to generate Unlike legislation or pharmacopoeial monographs, guidelines are not mandatory, but need to be followed unless justified – Represent an agreed position – For industry give protection - an agreed, but not the sole approach – For Regulators - should not question the agreed approach – Avoid “checklist mentality” – Good science should always prevail!

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