CRED Managing Variations Effectively

CRED Managing Variations Effectively 7 June 2018

CRED Managing variations effectively 7 June 2018, TOPRA, 6th Floor, 3 Harbour Exchange, South Quay, London, E14 9GE Chair: Shilpa Jain, TEVA Time Activity Speaker 09.00 Registration

Welcome from TOPRA

Samantha Alsbury Head of Professional Development TOPRA

09.30

Chairperson’s Introduction

Shilpa Jain Specialty European Regulatory Affairs Manager - Respiratory TEVA Richard Keane Associate Director, Global Regulatory CMC Biogen Idec

09.35

Principles of Variations Regulations and Guidelines • Introduction to Variations • Legal Basis of Variations • Introduction to Classification of Variations • Unforeseen variations • Introduction to Grouping and Work-sharing, • Practical issues for submissions Introduction to Classification – CMC/ Clinical/ PhV Variations • Overview of the categorisation annex of the variation guideline • Type IA/IAIN, Type IB and Type II variations • Variations relating to the quality dossier • Variations relating to safety/efficacy/PV • Handling of variations by EMA • Feedback from usage of the system from a Regulatory Authority perspective (for centralised submissions) Procedures & their impact on regulatory strategy and implementation • Grouping, Work-sharing • Submission strategy • Feedback from usage of the system from a Regulatory Authority perspective. • MRP/DCP considerations Tea/ coffee break Panel session Lunch

09.40

10.15

Alberto Ganan Jimenez Head of Procedure Management Service D in the Medicines Evaluation Division, and Jaime Oliva Procedure Manager EMA

10.30

11.45 12.05

All

Krystyna Fielden Manager, Product Lifecycle Assessment Team 2 (Dermatology, Respiratory, Sensory & Endocrine Medicines) MHRA

12.50

14.05

Introduction to Case Study

Time

Activity

Speaker

Case study Tea/ coffee to be taken in syndicate groups Case study feedback and discussions Agency feedback on real Type IA rejections • Discussion on recent real examples

Lorraine Marsh Pharma Now Ltd.

14.15

15.30

Elena Razzano Pharmaceutical Assessor MHRA

16.05

16.35

Panel session

All

Chair person’s conclusion

Shilpa Jain Specialty European Regulatory Affairs Manager - Respiratory TEVA

16.55

17.00

Close

CRED Variations

Principles of Variations Regulations and Guidelines 7 June 2017

Richard Keane PhD, Associate Director, Global Regulatory CMC, Biogen Idec Ltd, UK

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

Learning Outcomes

 Definition of What is a Variation  Legal Basis of Variations  Classification of Variations  Procedures: Introduction to Grouping and Worksharing  Practical issues for submissions and data requirements

Changes to Marketing Authorisations Marketing Authorisation Application

Approved MA 1.Authorisations are legally binding 2.All aspects of

Module 1

Health Authority Approval

Module 2

medicine on market must comply with the MA

Module 3, 4, 5

The Importance of Compliance The lack of compliance is a risk to the entire company, and can lead to: • Increase of product complaints and recalls • Risk to patient safety and potential for product withdrawal • Trigger for unexpected inspections • Failure of GMP • Potential manufacturing site closure • Lost reputation with regulators and physicians/patients • Application Rejections

COMPLIANCE IS KEY FOR YOUR SUCCESS

Definition of a Variation? • A change to the previously approved content of the Marketing Authorisation • Filing variations ensures continued compliance

New indication, New population

New warnings, Side effects

Safety

Indication

Quality

Admin

Name changes, Pack removal

New process, New site

Some Variations Can be Avoided

 Post-approval changes to a product often require the submission of a variation, but not always  Amount of detail put into Module 3 at time of MAA submission will determine the number of variations  Need to maintain a balance between: 1. The amount of data required for assessor review to ensure a product of consistent and appropriate quality is manufactured vs. 2. What is required to be maintained in the Company’s Quality Systems (e.g. GMP info)  It is in the interest of both the MAH & CA to avoid unnecessary variations

Reducing Post-Approval Regulatory Burden….Some top tips ● Avoid unnecessary levels of detail or use flexible wording when describing e.g: – Manufacturing process – Apparatus – Methods of analysis ● Avoid repeat of information in different files, to avoid need to maintain several sections, which increase chances of missing updates resulting in inconsistencies in the file ● Avoid GMP type info: e.g. testing of incoming drug substance at DP site, stability protocols for annual testing of GMP batches ● You should include any aspect which may impact on Quality, Safety or Efficacy

Is a Variation Required? ● Look at ICH Q12 for “established conditions” - identify certain CTD components as the “registered details” requiring maintenance – For example, P.2 and P.3.5 are historical data and may not need updating ● Am I adding detail versus amending detail? E.g. – Introduction of additional IPC’s to be considered as in- house measurements – Addition of internal action limits to a specification ● Are the changes covered by other legislation? E.g. – Reprocessing for NCE’s is allowed under GMP regulations provided it only occurs on an infrequent basis (ICH Q7)

Legal Basis of Variations - a brief history

• EU Variations Regulation (1234/2008) came into force on 01 January 2010 and replaced Regulations 1084/2003/EC and 1085/2003/EC • Regulation 1234/2008 only concerned variations handled via CP, MRP or DCP • Was amended by Regulation (712/2012) and includes national authorisations • Provide additional details on variation procedures and classifications outlined in Chapters II, IIa, III and IV of Regulation 1234/2008 • These guidelines are updated regularly to take into account scientific advances, industry trends, etc. • Current revision published in 2013

Variations Regulation (1234/2008) as amended by (712/2012)

Variations Guidelines

(2013/C 223/01)

Regulation Structure (1234/2008) Chapter Article Content I: General provisions 2 Definitions 3

Classification of variations (also see Annex II)

4 5 7

Guidelines

Procedure for unforeseen variations Grouping (also see Annex III)

II: Variations to Marketing Authorisations IIa: Variations to Marketing Authorisations - National III: Centralized Marketing Authorisations IV: Section 1 Special Procedures Section 2: Amendment to decisions

8-13 Variation Procedures covering

MRP/DCP/Centralised (also see Annex VI)

13a-f

Variation Procedures covering National (also see Annex VI)

14-18

19 20 22 24

Extensions (also see Annex I)

Worksharing

Urgent Safety Restriction Implementation of Variations

IV: Final provisions

25-28

Differences in Processing Variations

● All variation procedures share a fairly common process (submission, validation, (questions), approvals) but there are differences – Centralised Licences (See EMA Website – e.g. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation /q_and_a/q_and_a_detail_000019.jsp&mid=WC0b01ac0580023b 12 ) – MRP/DCP Licences (CMDh - http://www.hma.eu/96.html ) – National Licences – refer to local legislation/guidance and national agencies websites (e.g. MHRA - https://www.gov.uk/guidance/medicines-apply-for-a-variation- to-your-marketing-authorisation ) ● Ultimately you want to seek to avoid delays in approval caused by administrative errors

Variations Guidelines – Classification of variations ● Variation guideline classifies many types of common changes: – >90 types of change/variation are listed. – Each change is assigned a classification category – Exact category is dependent on the type of change, type of product and whether certain pre-defined conditions can be met – Time for assessment, required supporting documentation and fee are dependent on category assigned ● Variation guideline covers: – Administrative changes – Quality changes (Drug substance, Drug product, Devices, CEP) – Safety, efficacy, pharmacovigilance changes – PMF/VMF

• The classification of a variation is defined by impact of the change on the quality, safety or efficacy of product • Classification of changes might differ between countries

Line extension

Major Variation – Type II

Minor Variation – Type IB

Minor Variation – Type IA

Risk of potential to impact Quality/Safety or Efficacy Level of data and or justification to support change Times of review from agencies

Definition of Classifications

– Type IA – “Do and tell” for changes implemented in previous 12 months – Type IA IN - “Do and tell” and requires immediate notification after implementation – Type IB – “Tell, wait and do” and requires notification before implementation (wait 30 days after notification) – Type II – More detailed changes (“Tell and do”) and requires approval before implementation (usually 60 day review; range 30-90 days) – Extension applications – e.g. additional strengths, pharmaceutical form and route of administration (up to 1 year review)

Can submit these changes as a type-IB ‘unforeseen’: ● When the change is not specifically classified as a major variation of Type II or an Extension (and not covered by an Article 5 recommendation) (submit using as “z” – other variation category e.g. B.I.a.2.z ) - TIP: tick “Type IB” Unforeseen in application form ● These are often changes not precisely covered by the guidance but that require a modest technical and risk assessment (largely quality changes) ● The agency may re-classify to a Type II unforeseen (or even a Type IA) during validation of a Type IB What is an Unforeseen Variation? Despite >90 variations being defined in Guidance, there are still many changes being identified that don’t ‘fit’ within the current categories Other uncategorised Type-IB ‘default’ variations: ● When one or more of the conditions established in the Classification Guideline for a Type IA variation are not met (use Type IA category number, e.g. B.I.a.2.a , but note exception to conditions) - TIP: tick “Type IB” in application form

Example of Type IB ‘Default’ Variation

Variation Proposed Variation Type

Category Rationale for category/Grouping

Section 3.2.S.2.2 Adjustment of target flow rates for chromatography columns for a biologic

IB B.I.a.2.a Condition 5 is not fulfilled. Amend registered details to a different target flow rate, within the currently assigned operating range, to ensure that the pressure within the respective columns prevents risk of the column pack being compromised. Column flow rates are considered as non- critical parameters, and the changes do not impact safety or quality.

Article 5 Recommendations

Aim of Article 5: To provide advice on classification of unforeseen variations in a harmonised way across EU ● If not already listed, MAH/MS can request a recommendation on unforeseen category from CMDh or EMA: – Official Article 5 request, via specific procedure: Agency can take up to 45 days to assess category – TIP: Template for request available from CMDh and EMA – No appeal process and publically published – Can be used to apply to products with same change – Go to CMDh or EMA website for published recommendations: CMDh Recommendation for classification of unforeseen variations according to Article 5 of Commission Regulation (EC) 1234/2008 (March 2017) http://www.hma.eu/

Article 5: Extract of Published Recommendations

Relevant part of Classification Guideline

Proposed Change Proposed

Classification Proposed Conditions

1. There should at least remain one manufacturing process, as previously authorised. 2. The deletion should not be due to critical deficiencies concerning manufacturing See corresponding change for the active substance: B.I.b.2.a

Deletion of one manufacturing process of the drug substance manufacturing processes

IA

B.I.a.2.z

Minor change of an analytical procedure for an in-process control.

B.I.a.4.z

IA

Extensions - Fundamental changes to MAA  Extensions are classified as per Annex I of EU Regulation (1234/2008) 1. Significant changes to the Active Substance that do not lead to significant differences in safety/efficacy:  Different salt/ester  Replacement by different isomer(s), or mixture vs single isomers  Biological with slightly different molecular structure  New master cell bank  New ligand for Radiopharmaceuticals 2. Changes to the strength, pharmaceutical form and route of administration, causing changes in:  Bioavailability  Pharmacokinetics  New strength  New form  New route of administration

 Outlined in Article 19 of Regulation 1234/2008  Extension Applications follow the same procedure and timelines as for granting new MAA  Guideline on the Categorisation Of Extension Applications (EA) versus Variations Applications (V) OCTOBER 2003 ● Provides clarification on the classification of extension applications (e.g. defining pharmaceutical form and strength) ● See EDQM Guidance: Standard terms Extensions – Points to Consider

Grouping of Variations

Change 4 (Type IA)

Change 2 (Type IB)

Change 1 (Type IA)

Change 5 (Type IA)

Change 1 (Type IA)

Change 3 (Type II)

Single Filing for Product A

Single Filing for Products A and B

Option 1: Same Product (all strengths/forms); >1 related changes

Option 2: Multiple Products ; ≥1 identical changes

 Must make sense!  Must be from same MAH  Agreement from CA/EMA may be obtained in advance, including justification for grouping  Usually one discipline only (e.g. not mixed Quality and Clinical)

What can be Grouped? Variations can be grouped together into bundles ● There are no conditions for the grouping of Type IA or IA IN variations (but need to consider if immediate notification) ● Groups containing Type IB or higher (Type II or extensions) need to be justified (see Annex III of Regulation 1234/2008) – Must be related changes, e.g. change to a method that affects the release specification – OR Needs to be confirmed by Agency; present justification for grouping in correspondence for agreement/confirmation ● Will follow the review timelines of the highest category change ● TIP: Cover letter templates available from CMDh and EMA Potential to use enquiry emails – EMA Procedure Management Team mailboxes ( IAquery@ema.europa.eu or IBquery@ema.europa.eu ) ● Need to provide your company position in the correspondence ● Benefits of doing this are early review and pre-agreed classification so goes through validation quicker

23

Example of Grouping

Variation Proposed

Variation Type

Category Rationale for Category/Grouping

S.2.1 - Change of Site name

IA IN

A.1 Change in the name of the Drug

Substance manufacturing site, used to manufacture five different drug substances used in five different MAs

Worksharing

Change 2 (Type IB)

Applies to: Multiple Products ; ≥1 identical changes • Only applicable to Type IBs and IIs (however IAs can be grouped with the IB or II) • Extensions excluded

Change 1 (Type IA)

Change 3 (Type II)

Single Filing for Products A and B

 Apply where there is more than one CA to assess a variation  Useful for mixed national and/or MRP procedures. One authority (the ‘reference authority’) is chosen to examine the variation on behalf of the other concerned authorities. Will avoid different outcomes from individual authorities  Can apply for single or grouped variations from same MAH  Letter of intent to be submitted 2 months prior to variation application - TIP: LoI and Cover letter templates available from CMDh and EMA  Generally will follow a 60 day review (similar to Type II)

Example of Worksharing

Variation Proposed

Variation Type

CategoryRationale for category/Grouping

Product Information. Addition of safety information.

IB

C.1.z Same single variation affecting two products. Updates to the product information have been made based on a PRAC recommendation to include a specific adverse reaction for this class of product. Identical wording used for both products.

27 Documentation to Support Variations 1. Cover letter (templates available from CMDh and EMA) 2. Application form – (use standard form otherwise fail validation!) ● Scope and background ● Present and proposed table is critical ● Implementation dates • Type IAs must be within the last 12 months (unless grouped with higher category variation) • Type IAINs must be notified (submitted) immediately following implementation • Type IBs must be in the future 3. Copy of relevant pages of Commission Guideline showing conditions and documentation requirements are met for Type IA and Type IB (or copy of Article 5 recommendation received) 4. Supporting data/documentation • Amended CTD components where relevant • TIP: Generate CTD components with tracked changes first, to aid completion of the application form’s “present and proposed” section • For Type II variations need an updated Mod 2 QOS or an addendum to the QOS • Note: The supporting data does not always need to be incorporated into CTD components, and may need to make a judgement call on how to present (based on future life cycle flexibility).

Example of Documentation Requirements

Practical Aspects of Submission: Application Form Electronic application form is mandatory for applications via all procedures (Centralised, MRP/DCP and National)

Important Notes • Use a valid version of the form (there are frequent updates!) • Check how the electronic application form can be managed in publishing software • TIP: Once ‘signed’, the form is locked. Take a copy prior to Signature in case changes are needed later! • Guidance available: • Questions and answers relating to practical and technical aspects of the Electronic Application Forms (Human and Veterinary), June 2016 - EMA/167541/2016 • Practical User Guide for Electronic Application Forms (eAF) for human and veterinary medicinal products in the EU. Version 1.6, December 2017 • EMA/CMDh Explanatory Notes On Variation Application Form (Human medicinal products only) CMDh/EMA/133/2010/Rev.7 - Dec 2014 • European Medicines Agency practical guidance on the application form for centralised type IA and IB variations EMA/233564/2014 Rev.2 – June 2017

Learning Outcomes: Recap

 Definition of What is a Variation  Legal Basis of Variations  Classification of Variations  Procedures: Introduction to Grouping and Worksharing  Practical issues for submissions and data requirements

Important references • Notice to Applicants, Volume 2A, Chapter 5 Variations / Chapter 7

• CMD(h) Best Practice Guides (BPG) for the Submission and Processing of Variations in the Mutual Recognition Procedure (also applies to national only procedures; April 2013 and subsequent chapter updates) • European Medicines Agency post-authorisation procedural advice for users of the centralised procedure • Guideline on the Categorisation of Extension Applications vs. variation applications F2/AW D(2002) - October 2003 • EMEA Procedural advice on recommendations on unforeseen variations according to Article 5 of Commission Regulation (EC) No 1234/2008 EMEA/588416/2008

List of abbreviations

AR CA

Assessment Report Competent Authority

CMD(h)

Coordination Group of Mutual Recognition and Decentralised Procedures (Human)

CMS

Concerned Member State Centralised procedure Decentralised Procedure

CP

DCP

DMF EEA

Drug Master File

European Economic Area European Medicines Agency

EMA

EU MA

European Union

Marketing Authorisation MAH Marketing Authorisation Holder MRP Mutual Recognised Procedure PI Product Information PRAC

Pharmacovigilance Risk Assessment Committee

Q

Quality

RMS

Reference Member State

RSI

Request for Supplementary Information

Introduction to Classification of CMC (Quality)/Clinical/PhV Variations

Life Cycle Management – Variations TOPRA CRED Variations, 7 th June 2018

Presented by Alberto Ganan Jimenez (Head of Evaluation Procedures Service D) & Jaime Oliva (Procedure Manager Service B) European Medicines Agency (EMA)

An agency of the European Union

Agenda

1. Introduction to classification of variations 2. Structure of the Classification Annex of the variations guidelines 3. Handling variations in the centralised procedure 4. EMA guidance

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations 34

1. Introduction to classification of variations

Simply put, a variation is any change to the dossier supporting the marketing authorisation The need for classification of such changes stems from the fact that not all changes have the same level of complexity nor require the same level of assessment (scrutiny) before approval. Additionally, different variation types requires different expertise (Quality, Non-Clinical, Clinical, Pharmacovigilance) for their assessment. Finally, classification allows reporting on volumes of variations (e.g. to ascertain the impact of legislation changes).

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations 35

How are variations classified?

• Extensions [changes to active substance, new strength/pharm form/route of administration, addition of food-producing target species (vet area)]* • Major variation of type II, i.e. with significant impact on quality, safety and efficacy • Minor variation of type IA, i.e. no or minimal impact on quality, safety and efficacy • Minor variation of type IB, i.e. minor impact on quality, safety and efficacy a variation, as defined in the Classification Guideline. Also: • Variation that is neither a type IA nor a type II (default variation for unforeseen variations); • Type IA variation where at least one of the conditions is not met.

* Refer to Annex I of the Variations Regulation

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations 36

Where can I learn more?

In the classification guidelines 1 which are procedural guidance to • Facilitate interpretation and application of the Variation Regulation • Inform on relevant procedural steps for type IA, IB and II variation • Provide details of classification of variations types (Annex) • Inform on the conditions to be fulfilled and the scientific data in support of specific variation applications (Annex)

1 Guidelines on the details of the various categories of variations , on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations 37

Information on variation types in the Annex of the classification guidelines

Type IA: Conditions & documentation listed

Type IB: Default category >> Only documentation listed (no conditions)

Type II: No conditions or documentation requirements

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations 38

Classification Decision tree for a specific change

Extension application

Is it an Extension?

Yes*

No

IA IN

– Immediate notification

Does it meet Type IA (cond.) requirements?

Yes

IA – notification ≤12 months Submit as a Type II

No

Is it listed as a Type II?

Yes

No

Submit as a Type IB

Type IB unforeseen? No Is it listed as a Type IB?

Yes

Submit as a Type IB or II

* Annex I of Variations regulation , EMA post-authorisation guidance on Extension applications , Guideline on the categorisation of new applications versus variation applications

39 Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

Implementation of variations

- Type IA: implementation up to 12 months prior submission - Type IA IN : implementation immediately prior submission - Type IB: implementation after favourable notification (e.g. next production run, within 6 months) - Type II: implementation after favourable opinion - Non-immediate Commission Decision: implementation after favourable opinion - Immediate Commission Decision: implementation after Commission Decision

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations 40

Numbering of variations

Variation Numbering structure

B.II.a.2

Var. No.

Chapter

Section Subsection

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations 41

2. Structure of the Annex of Variations guidelines

A. Administrative changes B. Quality changes

B. I. Active Substance B. II. Finished product B. III. CEP / TSE / Monographs B. IV. Medical Devices B. V. Dossier changes due to other regulatory procedures

C. Safety, Efficacy and PhVig changes D. PMF / VAMF

42 Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

A. Administrative Changes

These involve: • Change in the name and/or address of the marketing authorisation holder, manufacturers of active substance/finished product • Change in the (invented) name of the medicinal product / active substance /excipient • Change in ATC Code / ATC Vet Code • Deletion of manufacturers

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations 43

Chapter A – example

Proposal: to delete two manufacturing sites [sites of drug product testing (sterility)] for a medicinal product available as solution for injection (prefilled syringe). It is proposed to delete these sites as they have not been and will not be used.

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations 44

Chapter A – example cont.

A. Administrative changes A.1 Change in the name and/or address of the MAH

A.2 Change in the (invented) name of the medicinal product A.3 Change in name of the active substance or of an excipient

A.4 Change in the name and/or address of: a manufacturer (including where relevant quality control testing sites); or an ASMF holder; or a supplier of the active substance, starting material, reagent or intermediate used in the manufacture of the active substance (where specified in the technical dossier) where no Ph. Eur. Certificate of Suitability is part of the approved dossier; or a manufacturer of a novel excipient (where specified in the technical dossier)

A.5 Change in the name and/or address of a manufacturer/importer of the finished product (including batch release or quality control testing sites)

A.6 Change in ATC Code / ATC Vet Code A.7 Deletion of manufacturing sites for an active substance, intermediate or finished product, packaging site, manufacturer responsible for batch release, site where batch control takes place, or supplier of a starting material, reagent or excipient (when mentioned in the dossier)

A.8 Changes to date of the audit to verify GMP compliance of the manufacturer of the active substance

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

45

Chapter A – example cont .

Procedure type

A.7 Deletion of manufacturing sites for an active substance, intermediate or finished product, packaging site, manufacturer responsible for batch release, site where batch control takes place, or supplier of a starting material, reagent or excipient (when mentioned in the dossier)*

Conditions to be fulfilled

Documentation to be supplied

1, 2

1, 2

IA

Conditions

1. There should at least remain one site/manufacturer, as previously authorised, performing the same function as the one(s) concerned by the deletion. Where applicable at least one manufacturer responsible for batch release that is able to certify the product testing for the purpose of batch release within the EU/EEA remains in the EU/EEA 2. The deletion should not be due to critical deficiencies concerning manufacturing.

Documentation

1. The variation application form should clearly outline the “present” and “proposed” manufacturers as listed in section 2.5 of the application form for marketing authorisations. 2. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate), including revised product information as appropriate. * Note: Where notice has been given by the authorities of the intention to perform an inspection, the deletion of the relevant site shall be notified immediately.

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

46

Chapter A – example cont.

Proposal: to delete two manufacturing sites [sites of drug product testing (sterility)] for a medicinal product available as solution for injection (prefilled syringe). It is proposed to delete these sites as they have not been and will not be used.  A.7 (type IA)

47 Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

Chapter A - Remarks (I)

• Changes in section A are of administrative nature. • Scope A.1

 Changes of address of MAH (e.g. relocation, change of name of street/post code)  Change of the name of MAH but the MAH remains the same legal entity (e.g. “Generics Pharma B.V.” to “Generics B.V.”) If the legal entity changes (i.e. the marketing authorisation of the medicinal product is transferred from MAH1 to MAH2), this variation does not apply. In this case, a “MAH transfer” procedure applies, which is not a variation procedure.

48 Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

Chapter A - Remarks (II)

Scopes A.4 & A.5 • Changes of address or name of a manufacturing site or a site performing quality control (e.g. rename of the street or change of post code, administrative change of the name); • This scope cannot be used for a site transfer. In this case the relevant scopes under section B apply (e.g. B.I.a.1, B.II.b.1, B.II.b.2).

49

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

B. Quality Changes

I. Active Substance II. Finished Product III. CEP/TSE/monographs IV. Medical Devices V. Changes to a marketing authorisation resulting from other regulatory procedures ( changes affecting information provided in Module 3 of the dossier)

50

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

B. Quality Changes

I. Active Substance (AS) Within this section, the following changes are classified: a) Manufacture: addition of new manufacturing site, changes to manufacturing process of AS, in-process controls; b) Control of the active substance: changes in the specifications of AS & intermediates; c) Changes in the container closure system of AS; d) Stability of the AS (e.g. retest period or storage conditions); e) Design space and post-approval change management protocol (PACMP) and implementation .

51

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

B. Quality Changes

II. Finished product (FP) Within this section, the following changes are classified: a) Changes to description and composition of the finished product; b) Manufacture: new manufacturing or quality control sites, changes to manufacturing process of FP, in-process controls; c) Control of excipients; d) Control of the FP: changes to the specification of FP; e) Changes in the container closure system of FP; f) Stability of the FP (e.g. shelf life or storage conditions); g) Design space and post-approval change management protocol (PACMP) and implementation.

52

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

B. Quality Changes

III. CEPs / TSE monographs 1. New/updated CEPs & TSE CEPs, 2. Changes to comply with Ph. Eur. or Ph. From a Member State

IV. Medical devices – Changes to integrated / non-integrated medical device

V. Changes to the dossier due to other regulatory procedures – 2 nd step of PMF / VAMF, – Update of Module 3 following a referral

53

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

Chapter B – example

Proposal: WonderPil strength 200mg has currently authorised the following pack sizes:  7 tablets and 28 tablets. The MAH wants to introduce two additional pack sizes of 14 and 84 tablets, to be

consistent with the recently approved posologies: “one tablet to be taken once daily for 14 days.” “one tablet to be taken once daily for up to 3 months.”

54 Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

Chapter B – example cont.

B. Quality changes I. Active Substance II. Finished Product III. CEP/TSE/monographs IV. Medical Devices V. Changes to a marketing authorisation resulting from other regulatory procedures

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

55

Chapter B – example cont.

B. Quality changes II. Finished Product a) Description and composition b) Manufacture c) Control of excipients

d) Control of finished product e) Container closure system f) Stability g) Design Space and post approval change management protocol h) Adventitious Agents Safety

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

56

Chapter B – example cont.

B. Quality changes II. Finished Product e) Container closure system 1 Change in immediate packaging of the finished product

2 Change in the specification parameters and/or limits of the immediate packaging of the finished product

3 Change in test procedure for the immediate packaging of the finished product

4 Change in shape or dimensions of the container or closure (immediate packaging)

5 Change in pack size of the finished product

6 Change in any part of the (primary) packaging material not in contact with the finished product formulation (such as colour of flip-off caps, colour code rings on ampoules, change of needle shield (different plastic used))

7 Change in supplier of packaging components or devices (when mentioned in the dossier)

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

57

Chapter B – example cont.

B.II.e.5 Change in pack size of the finished product

Conditions to be fulfilled

Documentation to be supplied

Procedure type

a) Change in the number of units (e.g. tablets, ampoules, etc.) in a pack 1. Change within the range of the currently approved pack sizes

1, 2

1, 3

IA IN

1, 2, 3

IB

2. Change outside the range of the currently approved pack sizes

b) Deletion of pack size(s)

3

1, 2

IA

c) Change in the fill weight/fill volume of sterile multidose (or single-dose, partial use) parenteral medicinal products, including biological/ immunological medicinal products.

II

d) Change in the fill weight/fill volume of nonparenteral multi- dose (or single-dose, partial use) products

1, 2, 3

IB

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

58

Chapter B – example cont.

Proposal: In addition to the only currently approved pack size (7 and 28 tablets), the proposed new pack sizes 14 and 84 tablets should be submitted as two variations.  B.II.e.5.a.1 (type IA IN ) -> to add pack size of 14 tablets  B.II.e.5.a.2 (type IB) -> to add pack size of 84 tablets These variations should preferably be submitted as a grouping with Annexes reflecting both presentations.

59 Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

Chapter B – Post approval change management protocol

Examples of CMP submissions received: • Introduction of additional manufacturing site for FP/ AS, • Introduction of a new purification cartridge • Changes in reprocessing of certain steps in manufacturing process of AS • Scale up of manufacturing of Active substance (biological) • Changes to in-process control testing strategy

Protocol included in 3.2.R

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations 60

Chapter B – Post approval change management protocol

Module 3 section modified in the implementing variation

61

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

Chapter B – Post approval change management protocol An approved CMP can be modified before implementation through a Type II/IB variation

Example 1: (Biological mAb)

• Type II B.II.g.2: To introduce a PACMP for the new manufacturing site 1 for pre-filled syringes (PFS) • Type IB B.II.g.5.b): To register Manufacturing Site 1 • Type IB B.II.g.4.b): To adapt the PACMP for introduction of Manufacturing site 2 for PFS • Type IB B.II.g.5.b): To register Manufacturing Site 2

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations 62

C. Safety, Efficacy, Pharmacovigilance

I. Human and Veterinary medicinal products II. Veterinary medicinal product – specific changes  Changes affecting Modules 4/5 of the CTD for human medicinal products  Part III (Safety) or Part IV (Efficacy) of the dossier for veterinary products in analogy

63 Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

Chapter C – Most commonly used scope categories

Changes to SmPC (and Package Leaflet): • affecting indication: C.I.6 (and C.I.2 for generics) • non-indication changes at MAH’s initiative: C.I.4 • non-indication changes at regulator recommendation (PASS or paediatric art 45 or 46): C.I.3 (from signal assessment: C.I.z ) No changes to SmPC • Changes to RMP (and other conditions): C.I.11 • Submission of final study results: C.I.13

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64

Chapter C – Pointers on most commonly used scope categories

Changes to SmPC (and Package Leaflet): • C.I.6 : additional submission requirements (see next slide) • C.I.4 : number of scopes equals number of changes • C.I.3 : copy of prior assessment to be included in submission No changes to SmPC

• C.I.11 : minor changes qualifying as IA/IB scopes if submitted alone can be included as minor changes in a type II variation, clinical overview expected • C.I.13 : number of scopes equals number of studies submitted, clinical overview expected and clinical summary updates expected if relevant

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65

Chapter C – Submission requirements

All variation types CTD Module 1 cover letter, application form, reference to prior assessment product information and/or RMP (non)clinical expert statement and CV clinical trials statement: new studies CTD module 2 (non)clinical overview (non)clinical summaries: new studies CTD module 4/5 studies/reports/literature

Extension of indication (additional requirements) orphan aspects (similarity) paediatric aspects User Testing (of package leaflet) Environmental Risk Assessment Risk Management Plan

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66

Chapter C – 1 st example (I)

Proposal: Revision of SmPC section 4.5 ‘Interaction with other medicinal products and other forms of interaction’, based on the results of a clinical study that has revealed a clinically relevant drug- to-drug interaction between eslicarbazepine acetate and rosuvastatin. Proposed additional wording: Rosuvastatin There was an average decrease of 36-39% in systemic exposure in healthy subjects when co-administered with eslicarbazepine acetate 1,200 mg once daily. The mechanism for this reduction is unknown, but could be due to interference of transporter activity for rosuvastatin alone or in combination with induction of its metabolism. Since the relationship between exposure and drug activity is unclear, the monitoring of response to therapy (e.g., cholesterol levels) is recommended.

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67

Chapter C – 1 st example cont .

C. Safety, Efficacy, Pharmacovigilance changes I. Human and Veterinary medicinal products II. Veterinary medicinal products – specific changes

68 Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

Chapter C – 1 st example cont.

C. Safety, Efficacy, Pharmacovigilance changes I. Human and Veterinary medicinal products 1 Change(s) in the SmPC, Labelling or Package Leaflet to implement a Union referral procedure 2 Change(s) in the SmPC, Labelling or Package Leaflet of a generic/hybrid/biosimilar medicinal products following assessment of the same change for the reference product 3 Change(s) in the SmPC, Labelling or Package Leaflet of human medicinal products intended to implement PSUR or PASS outcome, or following assessment under Articles 45 or 46 of Reg 1901/2006 4 Change(s) in the SmPC, Labelling or Package Leaflet due to new quality, (pre-)clinical, or PhV data 5 Change in the legal status of a medicinal product for centrally authorised products 6 Change(s) to therapeutic indication(s) 7 Deletion of a pharmaceutical form or strength

8 Introduction of, or changes to, a summary of PhV system for medicinal products for human use 9 Change(s) to an existing PhV system as described in the detailed description of the PhV system (DDPS) 10 Change in the frequency and/or date of submission of PSUR for human medicinal products 11 Introduction of, or change(s) to, the obligations/conditions of a marketing authorisation, incl the RMP 12 Inclusion/deletion of black symbol & explanatory statements for products subject to additional monitoring 13 Other variations not specifically covered elsewhere in this Annex which involve the submission of studies

69 Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

Chapter C – 1 st example cont.

C.I.4 Change(s) in the Summary of Product Characteristics, Labelling or Package Leaflet due to new quality, preclinical, clinical or pharmacovigilance data.

Conditions to be fulfilled

Documentation to be supplied

Procedure type

II

70 Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

Chapter C – 1 st example cont.

Proposal: Revision of SmPC section 4.5 ‘Interaction with other medicinal products and other forms of interaction’, based on the results of a clinical study that has revealed a clinically relevant drug-to-drug interaction between eslicarbazepine acetate and rosuvastatin

 C.I.4 (type II)

71 Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

Chapter C – 2 nd example

Proposal: Update of sections 4.1, 4.2, 4.4, 4.8, 5.1, 5.2 and 5.3 of the SmPC in order to extend the indication of Revolade in patients with chronic hepatitis C infection for the treatment of thrombocytopenia to enable the initiation of interferon- based therapy and during interferon-based therapy. The proposed starting dose is 25 mg once daily to be adjusted as necessary up to a maximum dose of 100 mg once daily. Therefore, two new tablet strengths (75 mg and 100 mg) are proposed to be introduced as well.  Extension application!!!!  Grouped with a variation (????)

72 Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

Chapter C – 2 nd example cont.

C. Safety, Efficacy, Pharmacovigilance changes I. Human and Veterinary medicinal products 1 Change(s) in the SmPC, Labelling or Package Leaflet to implement a Union referral procedure 2 Change(s) in the SmPC, Labelling or Package Leaflet of a generic/hybrid/biosimilar medicinal products following assessment of the same change for the reference product 3 Change(s) in the SmPC, Labelling or Package Leaflet of human medicinal products intended to implement PSUR or PASS outcome, or following assessment under Articles 45 or 46 of Reg 1901/2006 4 Change(s) in the SmPC, Labelling or Package Leaflet due to new quality, (pre-)clinical, or PhV data. 5 Change in the legal status of a medicinal product for centrally authorised products 6 Change(s) to therapeutic indication(s) 7 Deletion of a pharmaceutical form or strength

8 Introduction of, or changes to, a summary of PhV system for medicinal products for human use 9 Change(s) to an existing PhV system as described in the detailed description of the PhV system (DDPS) 10 Change in the frequency and/or date of submission of PSUR for human medicinal products 11 Introduction of, or change(s) to, the obligations/conditions of a marketing authorisation, incl the RMP 12 Inclusion/deletion of black symbol & explanatory statements for products subject to additional monitoring 13 Other variations not specifically covered elsewhere in this Annex which involve the submission of studies 73

Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

Chapter C – 2 nd example cont.

C.I.6 Change(s) to therapeutic indication(s)

Conditions to be fulfilled

Documentation to be supplied

Procedure type

a) Addition of a new therapeutic indication or modification of an approved one b) Deletion of a therapeutic indication

II

IB Note: Where the change takes place in the context of the implementation of the outcome of a referral procedure, or -for a generic/hybrid/biosimilar product- when the same change has been done for the reference product, variations C.I.1 and C.I.2 apply, respectively

74 Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

Chapter C – 2 nd example cont.

Proposal: Update of sections 4.1, 4.2, 4.4, 4.8, 5.1, 5.2 and 5.3 of the SmPC in order to extend the indication of Revolade in patients with chronic hepatitis C infection for the treatment of thrombocytopenia to enable the initiation of interferon- based therapy and during interferon-based therapy. The proposed starting dose is 25 mg once daily to be adjusted as necessary up to a maximum dose of 100 mg once daily. Therefore, two new tablet strengths (75 mg and 100 mg) are proposed to be introduced as well.  Extension application  Grouped with a variation (the new indication also applies to existing strengths) C.I.6.a (type II)

75 Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

Chapter D – PMF / VAMF

• This section includes changes applicable to a PMF (Plasma master file) & VAMF (Vaccine antigen master file). • PMF is certified by EMA and contains all the information of quality and safety of blood used as starting material of plasma derived medicinal products. • The plasma master file (PMF) is a compilation of all the required scientific data on the quality and safety of human plasma relevant to the medicines that use human plasma in their manufacture. These data cover all aspects of the use of plasma, from collection to plasma pool. • It includes information on collection centres, testing of donations /pools, containers, storage, transport . • This section does not apply to dossiers of medicinal products.

76 Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

3. Handling of variations in the centralised procedure

Validation of documentation (IA) / Assessment phase (IB, II)

Submission

Start

Notification / CHMP Opinion

Pre-submission queries service (PQS): For IA/IBs

Procedure Manager (PM) - oversees all aspects of the management of procedure;  first point of contact with MAHs and Rapporteurs Procedure assistant (PA) – supports PM and MAH (Annexes, EPAR updates) For IBs, MAH informed of PM at start of procedure or during validation phase (if RSI during validation)

IAquery@ema.europa.eu IBquery@ema.europa.eu For Type IIs /other: Procedure designated PM

77 Introduction to Classification of CMC (Quality) / Clinical / PhV Variations

Submission due date

Validation

Procedure

Rapp involvement

IA

No

No

Notification in 30 days Notification in 30 days 1 RSI 60 day default timetable

No

IB

Only when linguistic review

Yes

Yes

II

Weekly / monthly submission due dates monthly submission due dates

Yes

Yes

II- Extension of Indication

Yes

90 days default timetable

Yes (co-Rapp on case by case basis)

78 Introduction to Classification of CMC (Quality) / Clinical / PhV Variations