CRED Getting the CMC Dossier Right 2024

CRED Getting the CMC Dossier Right

4 – 5 September 202 4

©The Organisation for Professionals in Regulatory Affairs 202 4 Presentations are supplied to delegates for their personal reference and are the copyright of the speaker and The Organisation for Professionals in Regulatory Affairs. The presentations must not be copied, stored in a retrieval system or transmitted in any form without prior permission from TOPRA. Agreement must be reached with TOPRA before any part of this material is reproduced, abstracted, stored in a retrieval system or transmitted in any form by any means – that is, electronic, mechanical, photocopying, recording or otherwise.

CRED Getting the CMC Dossier Right, 4 September 2024 Day 1 Programme: Drug Substance Chair: Vimal Patel, Regulatory CMC Expert

Time (BST) Activity

Presenters

09:00 Registration/Registration online 09:15 Welcome from TOPRA

Vimal Patel Regulatory CMC Expert

09:20

Welcome •

Overview of the day

09:30 Introduction to Preparing the Perfect Common Technical Document (CTD) Module 3 Part ‘S’ • Origin of the Common Technical Document • Overview of CTD structure - where drug substance data fits (Module 3.2.S) • Different routes to incorporate drug substance data into 3.2.S: originator data, DMF or CEP • Due Diligence Tips

Chris Carr Bio Products Laboratory Ltd.

10:15 Break 10:45 Control of Drug Substances • Regulations and Guidelines •

Bethany Jackson AstraZeneca, UK

Critical Quality Attributes and Specifications • Analytical Methodology and Validation • Reference standards

11:30 Data Requirements and Practical Guidance for Drug Substance Development • Challenges of drug development and the role of the regulatory team member • Drug development - the objective and supporting guidelines; Control strategy and Quality by design • Regulatory starting materials • Specifications • Stability • Drug Substance Lifecycle challenges.

Olivier Dirat Pfizer

12:15 Lunch

Vimal Patel Regulatory CMC Expert

13:15 Case study introduction and set-up

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Time (BST) Activity

Presenters

13:30 Case study

Tea/coffee to be taken in case study groups

14:30 Feedback on Case Study Session

Bassel Odeh Medicines and Healthcare products Regulatory Agency (MHRA)

Regulatory Agency’s Perspective on the Drug Substance Section of Marketing Authorisation Applications (MAAs) • Potential pitfalls and practical issues experienced with the active drug substance section of an MAA • An agency perspective on common findings arising during regulatory review • Current experience and advice on preparation of the drug substance section of the CTD • Quality Overall Summary –what reviewers want to see • Falsified Medicines Legislation • Inspection issues for drug substance manufacturers

15:00

16:00 Q&A

Vimal Patel Regulatory CMC Expert

17:00 Chairman’s Review of the Day

17:30 Close

Delegates will be encouraged to ask questions throughout the day so as to ensure the meeting is as interactive as possible.

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CRED Getting the CMC Dossier Right, 5 September 2024 Day 2 Programme: Drug Product Chair: Sargon Daniel, Regulatory Affairs Director, VIR Biotechnology, Inc

Time (BST)

Activity

Presenters

09:00 Registration/Registration online 09:30 Chairperson’s Welcome • Overview of the day

Sargon Daniel VIR Biotechnology, Inc Christian Monnerjahn Eckert & Ziegler Radiopharma GmbH

09:45 Introduction to Preparing the Perfect Common Technical Document (CTD) Module 3 Part ‘P’ • Overview of Module 3.2.P CTD structure and key guidelines for content • Considerations for data presentation in the sections of 3.2.P • Due diligence tips • Approaching the Quality Overall Summary 10:30 Break 11:00 Data Requirements and Practical Guidance for Medicinal Product Development • Issues faced at different phases of development o The need to agree the specific product type required o Medicinal product production, scale up from development to production batches o Process validation requirements for different dosage forms o Stability programmes and data requirements • When/how to deal with changes during development to ensure this does not invalidate any of the clinical/other data already generated. • Specific data requirements for and issues associated with different dosage forms ICH Q8 and QBD

Sharon Page Pfizer

11:45 Control of Medicinal Product •

Paul Marshall Jazz Pharmaceuticals

How specifications for finished product are set and maintained • Review and development of specifications • Analytical Procedures/Validation of analytical procedures and justification of specifications

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Time (BST)

Activity

Presenters

• Application of ICH General Concepts in setting and reviewing of specification • Roles of competent authorities and pharmacopoeias in controlling the quality of medicinal product • Introduction to universal and specific tests/criteria for different dosage forms

12:45 Lunch 13:45 Regulatory Agency’s Perspective •

Alejandro Montón Silva Medicines Evaluation Board (MEB)

Potential pitfalls and practical issues experienced with the medicinal product section of an MAA o An agency perspective on common findings arising during regulatory review for a range of product formulations o Current experience and advice on preparation and presentation of the medicinal product section of the CTD • Quality Overall Summary – what reviewers want to see

14:30 Introduction and Preparation for the Case Study

Sargon Daniel VIR Biotechnology, Inc

Christian Monnerjahn Eckert & Ziegler Radiopharma GmbH

Case Study Tea/coffee to be taken in case study groups

14:45

15:45 Feedback on Case Study Session

Sargon Daniel VIR Biotechnology, Inc

16:15 Chairperson’s Review of the Day

16:45 Close

Delegates will be encouraged to ask questions throughout the day so as to ensure the meeting is as interactive as possible.

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Speaker Biographies Vimal Patel Vimal started his career in 1981 with Glaxo in pharmaceutical research and development working on various dosage forms and taking these from“bench to production”. In 1997, Vimal moved over to regulatory working on CMC changes on established products. Vimal then took on the project management of the regulatory activities for site rationalisation projects with subsequent transfer of products to alternative sources. In 2005 Vimal joined Pharmalink Consulting Ltd and worked on various regulatory projects with several large pharmaceutical companies whilst managing a large team of regulatory consultants. In 2010 Vimal joined Reckitt Benckiser to head up a global compliance project working on over 5000 SKUs supplied to over 100 markets resulting in filings of over 2000 variations worldwide in order to bring product documentation and manufacturing practices back into compliance. In 2016 Vimal worked independently for GSK and Theramex on a consultancy basis on established products in the CMC area. Vimal is a Fellow member of TOPRA and a lead volunteer for one of the CMC CRED areas. Vimal was also a member of the Life-Long Learning Committee which was formed by TOPRA to address and capture the training and continuous development of regulatory professionals. Vimal is also a volunteer with St Johns Ambulance and helped to vaccinate in local pharmacies and mass vaccination centres during the Covid pandemic. Sargon Daniel Sargon has gained over 25 years of Regulatory Affairs experience in the industry and CROs, working for both several Bio-Pharmaceutical companies and CROs. Nowadays Sargon mainly focuses on Phase 1 to Phase 3 strategic development of medicines for infectious disease. He currently works at Vir Biotechnology. Chris Carr Chris is a highly experienced regulatory affairs professional with almost 20 years in the industry, working as a regulator; in the pharmaceutical industry across multiple regulatory areas from product development through to post marketing; consulting and most recently held the post of head of regulatory affairs for the Cell and Gene Therapy Catapult.

Bethany Jackson Bethany is an Associate Principal Scientist within Chemical Development at AstraZeneca, a global, science led, patient focused pharmaceutical company. Bethany has 10 years of experience in drug substance development and has been lead author of multiple regulatory submissions. Olivier Dirat Olivier completed his PhD in organic chemistry at Paris University, followed by a post-doctoral position at Stanford University. Olivier has over 20 years of industrial experience in discovery and late-stage API process development at Merck and Pfizer and currently holds the position of Senior Director within Pfizer Global Regulatory Sciences CMC Advisory Office where he provides technical and regulatory guidance and direction to teams on a wide array of topics, including CMC regulatory strategies, the development and articulation of control strategies, impurities management, N-nitrosamines, continuous manufacturing, starting materials, ADCs, mRNA vaccine lipids and other special cases. He chairs one of Pfizer’s Impurities Councils, a multidisciplinary council that provides advice to teams regarding impurities from safety, quality and regulatory perspectives. External to Pfizer, Olivier is involved with ICH as PhRMA deputy topic lead for ICH Q13 IWG, IQ consortium Board of Directors, co-chairs the regulatory advisory committee and also on N-nitrosamines, starting materials, ADCs, and EFPIA on N-nitrosamines, ICH M7, ICH M4Q and ICH Q6. Olivier is based in Sandwich, UK. Bassel Odeh Dr Bassel Odeh has a PhD in Clinical Pharmacy and MSC in Pharmaceutical Sciences from Kingston University and over 20 years of experience in the pharmaceutical industry. Dr Odeh is currently the Head of New Active Substances Team at the Medicines & Healthcare products Regulatory Agency and he is part of the Innovative Medicines and Population Health senior leadership team. He provides operational management support to one of the multidisciplinary teams that evaluate marketing authorisation applications and variation applications for chemical new active substances. Dr Odeh has also worked as a Leading Senior Pharmaceutical Assessor at the Agency where he conducted pharmaceutical assessments, prepared and presented objective assessments and scientific papers to expert advisory committees, and provided regulatory and scientific advice to stakeholders through company meetings and written procedures. Prior to this role, he worked as a Senior Formulation Scientist where he conducted pre-formulation and formulation characterisation studies and supported drug product development, validation, and transferring into GMP manufacturing. Christian Monnerjahn Christian is a biologist by education. After some academia roles, he moved into the pharma industry starting at Salutas Pharma, a Sandoz affiliate. From here he joined the DRA world at the time CTD was introduced. Christian’s role grew from being Germany-focussed to EU to almost global regulatory CMC management for small molecule generics in various dosage forms. In

addition, he has participated in several cross-divisional/ cross-functional project teams and DRA-coordination groups in Sandoz. From 2009 until 2015, Christian spent much time for the TOPRA Master in Regulatory Affairs. In 2022, Christian left the generics world and joined Eckert & Ziegler Radiopharma GmbH as Regulatory Affairs Manager for established and new radiopharmaceutical precursor products Sharon Page Sharon Page has more than 25 years of experience in the pharmaceutical industry covering drug product development and regulatory sciences. She is based in the United Kingdom and has global responsibilities for Chemistry, Manufacturing and Control (CMC), from IND/IMPD at First in-Human through registration (NDA/MAA) and post approval for life cycle maintenance. She is also responsible for engaging with regulatory authorities, developing CMC strategies, and maintaining alignment with quality, compliance, and regulatory guidance. Additionally, she holds expertise in dosage form commercial nomination, process development and scale up, with a particular focus on biopharmaceutics and age-appropriate dosage form design. She has a BSC (hons) in Biochemistry and is an active member of MTOPRA and the International Consortium for Innovation and Quality in Pharmaceutical Development, API sub team. Paul Marshall Paul is a Director of Global Regulatory Affairs CMC at Jazz Pharmaceuticals, working in early phase development and commercial, and is a Commissioner at the British Pharmacopoeia, chairing Medicinal Chemistry Expert Advisory Group 1 and Radioactive Materials and Excipients Panels. He is a Fellow of TOPRA. Paul is a former Senior Pharmaceutical Assessor in the MHRA Licensing Division for over 10 years. He supported the CEP scheme as an Expert Assessor for 6 years and member of EDQM Technical Advisory Board for 3 years. Paul chaired the CHMP/CMDh working group on ASMF procedures and was integral in developing the worksharing procedure. He has worked in the pharmaceutical industry as a regulatory and pharmaceutical consultant and senior formulation scientist for over 15 years. Paul has published chapters on product stability and stability testing of in Aulton's Pharmaceutics: The Design and Manufacture of Medicines and common deficiencies in the stability dossier and ways to improve in Methods for Stability Testing of Pharmaceuticals. Paul read pharmacy for his graduate degree and researched the internal properties of the bioadhesive bond for his doctorate thesis, both at the School of Pharmacy, University of Nottingham. Alejandro Monton Silva Alejandro Montón Silva’s PhD and Postdoc positions were related to antibiotic development and antibiotic resistances. He has been with the MEB for 3.5 years as their Quality Assessor. Prior to this, Alejandro was a Product Regulatory Affairs Specialist at Smit & Zoon in the Netherlands.

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Introduction to Preparing the Perfect

Common Technical Document (CTD)

Module 3 Part ‘S’

Chris Carr

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Learning Objectives

• Origin of the Common Technical Document (CTD)

• Overview of CTD structure - where drug substance data fits (Module 3.2.S) • Different routes to incorporate drug substance data into 3.2.S: originator data, ASMF (or DMF) or CEP

• Overview of variations in the EU

Due-Diligence Tips

•

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Some Common Abbreviations

ASM

Active Substance Manufacturer

ASMF

Active Substance Master File

CEP

Certificate of Suitability to the monograph of the European Pharmacopoeia

CTD

Common Technical Document

DS

Drug Substance

(E)DMF

(European) Drug Master File (syn. for ASMF)

EDQM

European Directorate for the Quality of Medicines

eCTD

Electronic Common Technical Document

ICH

International Conference on Harmonisation

NCE

New Chemical Entity

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Why are there Regulations?

Government must decide whether the benefit to the population is commensurate with the

Patients and Prescribers must have access to safe and effective medicines

potential risk and increasingly cost

Is the potential risk to the patient outweighed by the potential benefit??

Industry and academia must have a clear understanding of what is required

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Brief History of Regulations...

• Historically, regulation has been introduced as reactions to events such as the European Thalidomide tragedy causing birth defects and the Elixir Sulphanilamide disaster which killed over 100 people in the US • 1906 - Public Pressure in the USA lead to the Pure Food and Drug act which prevents interstate trade in adulterated food, drugs and drinks • 1910 - Introduction of arsphenamine (anti syphilitic organic arsenical) let to the UK Therapeutic Substances Act • 1927 - Introduction of Elixir Sulfanilamide in the USA led to the USA Food, Drug and Cosmetic Act (1938)

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Brief History of Regulations... (cont)

• 1957 - Introduction of Thalidomide in Led to a number of new Laws: • USA Kefauver-Harris Drug Amendments (1962) • UK Committee on Safety Drug (1963) • UK Medicines Act (1968) • Today Advancing scientific Knowledge is the key driver for legislation changes and increasing R&D costs

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The Need to Harmonise

• Prior to 1990s, proliferation in national laws and guidelines as a result of various safety incidents

• Increasing globalisation, yet drug regulatory technical requirements were diverging globally

• Costly duplication of tests to differing standards

Lengthy approval delays

•

• Budgetary restrictions on rising healthcare costs

• Ethical considerations of animal drug testing and duplicated human clinical data

• Access to medicines for patients in more geographies

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ICH and development of CTD

• European Union progress towards a single market in 1980s showed harmonisation was possible • Trilateral harmonisation discussions launched 1990 – US, Japan & Europe – birth of International Conference on Harmonisation (ICH) • Industry representatives are equal partners with Regulatory Agencies • Topics for harmonisation divided into Quality (Q), Safety (S), Efficacy (E) & Multidisciplinary (M) • ICH M4 - the Common Technical Dossier - agreed Nov 2000, implemented simultaneously July 2003

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Common Technical Dossier (CTD)

• CTD – common format for submissions to regulatory authorities in EU, Japan, US • Mandatory format for new drug applications in EU, Japan and US, mandatory for INDs in US

• EU: CTD format → adopted as Notice to Applicants Vol 2B of Eudralex

• Content → legally defined in Annex 1 of Directive 2001/83 as amended by 2003/63.

• eCTD – an electronic version can be produced following guideline ICH M8 – separate guideline

• CTD format divides information into 5 Modules

• (Module 1 is specific to each region – not part of CTD)

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The CTD (ICH M4)

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Role of the Quality section

• Quality topics located in two sub-sections of ICH M4:

• Module 3 Quality & Module 2.3 Quality Overall Summary

• ICH M4Q gives detailed breakdown of heading for both these

• Format applies to New Chemical Entities and Biotech drug substances and corresponding finished products

• The purpose of the Quality information is to:

• Provide assurance of the identity, purity, potency and other standards of quality in the drug substance and drug product (ICH Q6A and Q6B)

• To ensure the critical quality attributes are met using critical manufacturing parameters (ICH Q8)

• Provide science – and risk-based assessments of the quality of the pharmaceutical (ICH Q9)

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CTD Quality Structure of Module 3

3.1 Table of Contents

•

3.2 Body of Data

•

•

3.2.S Drug Substance Data

•

3.2.P Drug Product Data

3.2.A Appendices

•

• 3.2.A.1 Facilities and Equipment (Biotech)

• 3.2 A.2 Adventitious Agents Safety Evaluation

• 3.2.A.3 Novel Excipients (as per 3.2.S headings)

3.2.R Regional Information

•

3.3 Literature References

•

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Module 3.2.S Drug Substance

Section Title

Functional Area

3.1

Table of Contents

3.2

Body of Data

3.2.S

Drug Substance

3.2.S.1 General Information

Chemistry

3.2.S.2 Manufacture

Manufacturing

3.2.S.3 Characterisation

Chemistry

3.2.S.4 Control of Drug Substance

Control

3.2.S.5 Reference Standards

Control

3.2.S.6 Container Closure System Manufacturing

3.2.S.7 Stability

Control

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General points on content

• Neither the type nor extent of specific supporting data is addressed in ICH M4 – both may depend on regional guidance (“For example” used)

• Harmonised Content is not available for all sections – cross referenced to existing ICH guidelines where they exist. If not, check regional (EU/US).

• Section 3.2.R (Regional Information) provides examples of where content is not harmonised (e.g. Executed Batch Records – US only)

• When more than one drug substance used in a product – generally present one complete drug substance section followed by another – but- • Separate sections warranted when single drug substance made at two different manufacturing sites • Multiple references proposed within CTD – Q for Polymorphism, Particle size and Impurities

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3.2.S.1 General Information

• Nomenclature (INN, non-proprietary, compendial, CAS)

• Structure (stereochemistry, biotech – schematic amino acid sequence) • General properties (physicochemical, biological activity for biotech)

• Reference: ICH Guidelines: Q6A and Q6B

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3.2.S.2 Manufacture

• Manufacturer(s): all sites of manufacture including testing

• Description of Manufacturing Process and Process Controls: flow diagram and narrative. Q5A, Q5B, Q6B • Control of Materials: Q6A, Q6B. Biologically sourced – details in 3.2.A.2. Cell bank – Q5A,B,C,D

• Control of Critical Steps and Intermediates: Q6A, Biotech Q6B and Q5C

• Process Validation/Evaluation: aseptic processing and sterilisation validation, justify in-process controls all cases • Manufacturing Process Development: include history of development of the drug substance NCE- Q3A, biotech - Q6B, relevant batch information on drug substance batches manufactured and their use

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3.2.S.3 Characterisation

• Elucidation of Structure: NCE – include potential for isomerism, polymorphism -Q6A. Biotech- include desired product and product-related substances- Q6B • Impurities: Discussion of impurities and information on their qualification (impurities will also be referred to in 3.2.S.4.1 through 3.2.S.4.5)

References to ICH guidelines as appropriate for drug-type: Q3A, Q3C, Q5C, Q6A and Q6B

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3.2.S.4. Control of Drug Substance

• Specification: Q6A, Q6B, the new genotoxic guideline ICH M7 and links to finished product ICH Q3D (elemental)

• Analytical Procedures: Q2A, Q6B

• Validation of Analytical Procedures : Q2A, Q2B, Q6B

• Batch Analyses: Q3A, Q3C, Q6A, Q6B

• Justification of Specification: Q3a, Q3C, Q6A, Q6B

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3.2.S.5 Reference Standards

• Provide information on reference standards used for testing of drug substance Q6A, Q6B

3.2.S.6 Container Closure System

• Primary packaging components: identity of materials of construction and their specification • Non-functional secondary packaging components: only a brief description • Suitability should be discussed: e.g. protection from moisture/light, compatibility with drug substance – sorption, leaching, safety

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3.2.S.7 Stability

• Stability Summary and Conclusions: types of studies, protocols, summary results, forced degradation studies, conclusions re storage and shelf-life, re-test date Q1A, Q1B, Q5C, CHMP guideline for established DS

• Post-approval Stability Protocol & Stability Commitment: Q1A, Q5C

• Stability Data: results in appropriate format, analytical methods used, validation of analytical procedures

Q1A, Q1B, Q2A, Q2B, Q5C

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3.2.R Regional guidance

Any additional drug substance information specific to each region is provided here

For EU*:

• Certificates of Suitability (CEP)

• Statement of Compliance to Annex 1 of Directive

2001/83/EC Part 1, module 2, paragraph 3.2(9) i.e. specific measures concerning the prevention of transmission of TSE

* Qualified person declarations for GMP of active substances are located in annex 5.22 to Module 1

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Feasible ways to submit DS data

Guideline on Summary of Requirements for Active substances in the Quality part of the Dossier (CHMP/QWP/297/97) – depending on the classification i.e.

New active substances

•

• Existing active substances not described in Ph. Eur. or member state pharmacopoeia, or • Existing active substances described in Ph. Eur. or member state pharmacopoeia, and the nature of drug, i.e. organic, inorganic, herbal, the required data may be submitted in one of three ways

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Feasible ways to submit DS data (cont …)

3 main ways to submit Drug Substance data:

1. Full details of manufacture: originator proprietary data or via cross-referral to another application 2. Active Substance Master File (ASMF): (commonly referred to as a DMF - Drug Master File). ● Applicant files Applicant’s (Open) part ● Manufacturer files both Closed (confidential) and Applicant’s parts.

3. Certificate of Suitability to the monograph of the European Pharmacopoeia (CEP)

● Data assessed by EDQM, CEP is issued and this is filed in dossier ● Replaces many sections of 3.2.S

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ASMF procedure

• Full details of chemistry, manufacturing process, quality control submitted to regulatory authority by holder of the ASMF according to Guideline

• Active Substance Master File Procedure (CPMP/QWP/227/02 or EMEA/CVMP/134/02)

• Applicant’s Part included in Marketing Authorisation (MA) Application

• Letter of Access (original) permitting reference to the ASMF by each applicant required to be filed by ASM and copy included in MA dossier • Emphasis on demonstrating that all potential impurities from synthesis can be controlled

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CEP Certificate of Suitability

• European Directorate for the Quality of Medicines (EDQM), a body of European Pharmacopoeia, assesses the drug substance and methods proposed for control for their suitability. May inspect manufacturers at company request. • CEP issued by EDQM and updated periodically on database – withdrawals, suspensions all publicly listed.

• Applicant files latest CEP to Health Authority

• CEP may not address all relevant parameters e.g no re-test period and thus applicant must supply drug substance stability data justifying proposed re-test period.

• European validity but may be accepted in other countries

CERTIFICATION OF SUBSTANCES FOR PHARMACEUTICAL USE - FAQs Home - FAQs (edqm.eu)

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ASMF versus CEP

CEP

ASMF

• No further assessment in EU

• Assessed by each regulatory body

• a certificate of suitability is valid 5 years

Applicant responsible for co ordination

•

• CEP renewed once, and then it is valid for an unlimited period, provided it is kept up to date by the holder.

• Frequent filing of updates required

May be used globally

•

• Minimises additional routine testing

Valid for EU

•

• Acceptable in some markets globally

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Quality Overall Summary: Module 2.3

• Module 2 summaries are key documents for reviewers

• QOS has a combined function as both summary and an “Expert Report” in EU

• Discuss and critique critical key data

• Opportunity to explain any deviations from guidelines

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QOS vs Module 3.2.S

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Variations

Revised Commission Variation Guidelines (May 2013): EUR-Lex - 52013XC0802(04) - EN - EUR-Lex (europa.eu)

A- Administrative Changes

• E.g. change in the name of the active substance 1AIN

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Variations (cont …)

B. Quality Changes

I. Active Substance

Manufacture

•

Control of active substance

•

Container Closure system

•

Stability

•

• Design Space and post approval change management protocol

Examples of Changes:

• Type 1A (B.I.a.2a) Change in the manufacturing Process of the API

• Type 1B (B.I.d.1.b.3) Change in the storage conditions of an API

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Variations (cont …)

III CEP/TSE/Monograph

• Submission of a new CEP for an active or an update to an already approved CEP • Changes to comply with Ph. Eur. or national pharmacopeia of a member state

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Variations to the CEP

• Holders of a Certificate of Suitability to the monographs of the European Pharmacopoeia (CEPs) must inform the EDQM of any change(s) to the information provided in the initial application.

• GUIDELINE ON REQUIREMENTS FOR REVISION/RENEWAL OF CERTIFICATES OF SUITABILITY TO THE EUROPEAN PHARMACOPOEIA MONOGRAPHS - European Directorate for the Quality of Medicines & HealthCare (edqm.eu)

• Applicants should send the following documentation to the Certification of Substances Division (DCEP) of the EDQM:

• a completed application form, which includes your invoicing details

• data supporting the request for revision

• update of the relevant section(s) of the dossier.

• If the change impact information on the CEP a new CEP will be issued, otherwise EDQM will simply assess without any update required

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Due-Diligence Tips - CEP

• Applicants should check if a re-test date has been included in the CEP and if not request the corresponding stability data from the supplier. • Check for TSE certification, i.e. has this been included in the CEP if not is a declaration required? • Has an update to the CEP been issued, which should be submitted instead? • KNOWLEDGE Database - European Directorate for the Quality of Medicines & HealthCare (edqm.eu) • Are there any analytical method and specifications included as conditions of the CEP?

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Due-Diligence Tips - ASMF

• Is the document consistent across all sections?

• Does the ASMF include all the data required as stated in relevant ICH guidelines?

• Are there discrepancies between the applicant’s part and the ASMF. Is the same re -test date being quoted? Are any additional tests being done by the applicant?

• Is there any further processing of the API after it is obtained from the supplier?

• Has the relevant data been included in the applicant’s part?

• Was stability performed in the Container Closure System as it is to be supplied?

• In the case of different API suppliers, is a common spec being used or are different specifications and methods being used?

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Due-Diligence Tips – full Module 3.2.S (and ASMFs)

• Have all manufacturing sites been listed (including milling sites)? Does the information on the GMP certificate match the eAF application form?

• Has the specification been appropriately justified?

• Are stability results within spec and has the correct spec been used. If not have there been changes in the spec which need to be explained? • Have non-pharmacopeial methods been appropriately validated?

• The QOS should be aligned to module 3.2.S.

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Learning Objectives

• Origin of the Common Technical Document

• Overview of CTD structure - where drug substance data fits (Module 3.2.S) • Different routes to incorporate drug substance data into 3.2.S: originator data, ASMF or CEP

• Overview of variations in the EU

Due-Diligence Tips

•

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Thank You

Questions ?

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Control of Active Drug Substances

Bethany Jackson

Associate Principal Scientist

Chemical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, UK

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Learning Objectives

⚫ Regulations and Guidelines

⚫ Critical Quality Attributes and Specifications

⚫ Analytical Methodology and Validation

⚫ Reference standards

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Regulations and Guidelines

Summary of Requirements for Active Substances in the Quality Part of the Dossier (CHMP/QWP/297/97) Feb 2005 ● New active drug substances ● Existing active drug substances – Pharmacopoeial – Non-pharmacopoeial

Guideline on the chemistry of active substances • EMA/454576/2016

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Regulations and Guidelines

Directive 2003/63/EC (amending Dir 2001/83/EC) ● Module 3 requirements

Directive 2009/120/EC (more requirements on Mod 3) ● Advanced therapies – Gene therapy – Somatic cell therapy Directive 2004/24/EC (amending 2001/83/EC) ● Herbal medicinal products – Definition – Simplified registration procedure

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Sources of Active Drug Substances

Sources of Active Drug Substances are many and varied: ● Chemical (organic and inorganic) ● Plants (herbal products and herbal extracts) ● Homeopathic Stocks ● Animals and Humans (tissues, fluids, extracts) ● Fermentation (antibiotics, vaccines) ● Biotechnology (proteins)

Wide range of different complexities - some can present a significant challenge to analyse, fully characterise and establish a specification

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Critical Quality Attributes – ICH Q11

● A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. ● CQAs can be modified as drug substance knowledge and process understanding increase. ● CQAs typically include those properties or characteristics that affect identity, purity, biological activity and stability. – Impurities are an important class of potential DS CQAs; potential to direct impact on drug product safety ● When physical properties are important with respect to in vivo performance or drug product manufacture, these can be designated as CQAs.

● Biotechnological/biological products, most of the CQAs of the drug product are associated with the drug substance ... are a direct result of the design of the drug substance or its manufacturing process.

The identification of CQAs is vital for all active drug substances

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Specifications - ICH Q6A and Q6B

● A specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria which are numerical limits, ranges, or other criteria for the tests described.

● It establishes the set of criteria to which a drug substance......should conform to be considered acceptable for its intended use.

● “Conformance to specification” means that the drug substance ....., when tested according to the listed analytical procedures, will meet the listed acceptance criteria.

● Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval.

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Establishing a Specification

Is there a universal set of tests for drug substances?

Some specification tests are required for all substances

● Many additional tests are drug product specific based on developed understanding of CQAs https://upload.wikimedia.org/wikipedia/commons/thumb/d/d5/Archery_Target_80cm.svg/220px-Archery_Target_80cm.svg.png

ICH Guidelines for specifications

● See detailed slide in back ups

Key data to consider

● Prior knowledge / Development data ● Representative manufacturing data ● Drug substance control strategy

Specification very likely to change as development progresses

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Specification Tests Overview

Universal Tests:

● Description

● ID

● Assay/potency

● Impurities

Specific Tests (defined by DS + requirements of DP):

● Physico-chemical properties

● Particle size

● Polymorphic forms

● Chirality

● Microbial limits

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Drug Substance – Quality Attributes

Description

● Visual test ● Appearance

Identification ● Specific tests to discriminate between related compounds of similar structure (validated)

● Typically IR spectroscopy, compare spectra to Reference Standard ● HPLC RT not sufficient (combined RT plus orthogonal test is acceptable) ● If a salt, ID for the salt itself ● Confirmation of chirality (if appropriate)

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Assay/potency ● Validated method specific for drug substance ● Controls purity level (upper and lower limits) ● Stability indicating ● Non-specific methods can be justified if combined with other specific methods for impurities Drug Substance – Quality Attributes

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Drug Substance – Quality Attributes

Impurities (ICH Q3A) ● From synthetic route; – starting materials

– intermediates/by-products – enantiomers (chiral compounds) – elemental impurities (ICH Q3D) – residual solvents (ICH Q3C) ● Degradation products ● Mutagenic impurities (ICH M7)

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Drug Substance – Quality Attributes

Specification should address

• Each specified identified impurity

• Each specified unidentified impurity

• A clause to capture any unspecified impurity with potential to be present

• Total impurities

Typical Early specification

Typical Late/commercial specification

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Drug Substance – Quality Attributes

Impurities (ICH Q3A)

Specified impurities should be limited based on understanding of safety i.e., Impurities should be suitably qualified

Qualification

The process of acquiring and evaluating data that establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified.’

Thresholds

ICH Q6A Decision trees give guidance on acceptance criteria

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Drug Substance – Quality Attributes

Residual Solvents (ICH Q3c)

Control of solvents according to ICH Q3C is vital

Solvents divided in 4 classes:

• Class 1: Solvents to be avoided (Avoid / fully justify)

• Class 2: Solvents to be limited (Fully justify)

• Class 3: Solvents with low toxic potential (Favoured)

• Class 4: Solvents with no safety data (A challenge!)

Exposure limits determined using:

• Option 1 (Concentration - ppm) - Favoured option!

• Option 2 (Permitted Daily Exposure – PDE – mg/day)

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Mutagenic Impurities • ICH – S2(R1): Guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use – S9(R1): Nonclinical Evaluation for Anticancer Pharmaceuticals. – M7 on Assessment and control of DNA reactive impurities Drug Substance – Quality Attributes

• ICH M7 holds primacy

Supersedes EMEA/FDA/Ph.Eur guidances

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N Nitrosamines • Originally identified as a result of detection of simple dialkyl N-Nitrosamines in the active the issue has expanded and is now dominated by complex API like Nitrosamines – referred to as Nitrosamine Drug Substance related impurities (NDSRIs). Drug Substance – Quality Attributes

• NDSRIs form where the drug is a secondary amine through interaction with nitrites present in common excipients

• Cannot eliminate nitrites in excipients

• Unlike the initial simple di-alkyl N-Nitrosamines for which there is considerable carcinogenicity data that allows limits to be set – there are no carcinogenicity data for NDSRIs.

• Recently an entirely new concept and process has been established to address this problem

• Despite this issues remain

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Drug Substance – Quality Attributes

Mutagenic Impurities (ICH M7)

“ Threshold of Toxicological Concern” (TTC) based on a 10 -5 cancer life time risk

Impurities assessment in drug substance and product

Hazard Assessment/classification of impurity structures • Role of QSAR and Ames

Risk characterisation • Limits MIs to 1.5  g / day for >10years dosing (plus higher durational limits) • Compound specific limits (see ICH M7 addendum) • Multiple MI’s

Control strategy •

Multiple options for control strategy in API • Including; specifications (API/intermediates/SM), IPCs/processing parameters, implicit in design of manufacturing process • Purge factors • Quantitative assessment of potential carry-over of a MI (Based on understanding of physicochemical properties of the MI relative to the process conditions. Covers both clinical and marketed products

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Drug Substance – Quality Attributes Elemental Impurities • Pre-2014 regulatory position

Metal catalysts: Pd, Pt, Rh, Ru, etc...

• Control of metal catalysts only.

• Current regulatory position - ICH Q3D

• Three classes of Elemental impurity

• See excellent ICH Q3D training package

Metal catalysts: Pd, Pt, Rh, Ru etc... AND Environmental impurities: As, Cd, Pb, Hg V, Ni, Co etc…

http://www.ich.org/products/guidelines/quality /article/quality-guidelines.html

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Elemental Impurities – USP 232/233 & ICH Q3D a) Move to risk based control strategies that consider all potential sources of metal impurities in drug products b) decrease in some permitted daily exposure (PDE) limits c) limits for some ‘new’ elements d) updated analytical technology Drug Substance – Quality Attributes

Manufacturing equipment *

Drug Substance

Metal Catalysts

Inorganic Reagents

Manufact. Equipment

Elemental impurities in drug Product

Elemental Impurities in DS

Primary Container Closure

Processing Aids

Organic Materials

Solvents

Water **

Container Closure System

Excipients

Water

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Drug Substance – Quality Attributes

Physico-chemical properties

● Defined by the characterisation of DS + needs of DP – pH – Melting point (range) – Solubility + permeability (NB: BCS classification/biowaivers) – Refractive index – Visicocity

Understanding physico-chemical properties informs development of correct formulation and delivery of the drug.

● Generally “direct” methods. No validation

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Drug Substance – Quality Attributes

Particle size

● For DP pharmaceutical forms that are solid/suspensions ● Will it impact; – Dissolution of DP (BCS/biowaiver) – DP processing/manufacture – DP content uniformity – Stability ● Decision tree from ICH Q6A very useful to define impact and guide development ● Control limits typically established based on clinical precedence but what of modelling the impact of PSD?

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Drug Substance – Quality Attributes

Polymorphic forms ● Different crystalline forms? ● Solvation or hydration products? ● Amorphous forms? ● Transformation between forms

Do forms have different properties? ● Solubility? ● Stability?

● Decision Trees in ICH Q6A very useful to define impact and guide development

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Drug Substance – Quality Attributes

Chiral compounds

● Ensure have correct enantiomer – Different biological properties therefore different/undesired performance ● Can control – in specification by chiral specific assay/impurity limit – during manufacture by testing starting material/intermediate and no further racemisation or change ● ID test must prove have correct enantiomer

● Stability studies to prove no change during storage of chirality ● Atropisomerism – planar chirality/racemisation by bond rotation

● Decision Trees in ICH Q6A very useful to define impact and guide development

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Drug Substance – Quality Attributes

Microbial limits

● DS capable of supporting growth - Water activity determination

● Synthetic route has steps which reduce micro-organisms?

● If need a spec, use pharmacopoeial limits

● Can justify no testing or periodic testing

(ICH Q4B Annex 4 A, B, C)

Sterility

● Ph.Eur. 2.6.1. Sterility, JP 4.06 Sterility Test, USP <71> (ICH Q4B Annex 8)

● Decision Trees in ICH Q6A very useful to define impact and guide development

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Analytical Methodology

No universal list of ‘acceptable’ methods

Techniques can be divided into

● Qualitative (Meets test)

● Semi ‐ quantitative (Limit tests)

● Quantitative (Reports a numerical value or quantity)

All analytical methods should be scientifically sound/fit for purpose

- Supporting development understanding or specification control

- Appropriately validated – increasing rigour as development progresses to full ICH validation at time of NDA

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Analytical Methodology - Early Development

Molecular characterisation of the drug substance and related substances:

• Structure [NMR, IR, MS, X-ray crystallography]

• Assay [HPLC, GC, UV/Vis]

• Impurities [HPLC, GC]

• Solvents, catalysts [GC, AAS, ICP]

Control of DS and intermediates

Method and validation summaries presented in the clinical application – not for all territories.

• Increasing detail as progress through development phases.

Important to gather valid data throughout development

• understand CQAs and control strategy

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Analytical Methodology – Regulatory Validation (ICH Q2A / Q2B)

Data submitted in MAA/NDA

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