FILING

VARIATIONS
SUMAIYA PATEL
NOVEMBER 2017

Private & Confidential

 AIMS & OBJECTIVES

Aim: An overview and/or refresher of Filing Variations and

the regulatory requirements strategy on maintaining product
through lifecycle.

Key Objectives:

To provide an understanding and awareness of the key

regulations, classification of variations, variations procedures
and impact and data requirements when planning a
submission.
Please, note I will not being going through all the slides some
are for information only.
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GROUP INTRODUCTION & BACKGROUND

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 PROGRAMME
Day 1 Day 2

•Basis of Regulations 1234/2008 and 712/2012 •Type II variations

in Europe.
•Extension applications
•Practical exercise: Analysing and classifying •Data requirements
the different changes.
•Article 5 procedures
• Timelines for variations
•Centralised-MRP-DCP-national submissions
•Urgent safety restrictions
•Experience with real life variations
•Grouping and worksharing
•Electronic submissions
•Practical exercise: CMC case.
•Several practical Exercises
•Filing tips

•Practical session

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TIMELINES FOR DRUG DEVELOPMENT

Title of document goes here 5

BASIS OF REGULATIONS 1234/2008 AND
712/2012 IN EUROPE

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VARIATION –NEED FOR CHANGE TO REGULATIONS PRE 2008

➢ Number of variations being handled by Regulators escalating.

Economic situation making for even greater numbers.

➢ Delays being experienced by MAHs in Approval timings.

Consequent delays to implementation.

➢ Majority of MAAs are National.

Some illogical differences between Member States in classification.
Differences between National, MR and Centralised products.

Duplication of assessment of National Variations is not best use of Regulatory

resources.
Same information assessed many times.

Delays are not in the best interests of the patient.

Quality changes are often improvements.
Information changes are usually enhancements or safety changes.
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VARIATION –LEGISLATION 1234/2008

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VARIATION REGULATION-1234/2008

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VARIATION REGULATION-1234/2008

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VARIATION REGULATION-1234/2008

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VARIATION REGULATION-1234/2008 STRUCTURE

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VARIATION REGULATION-1234/2008 STRUCTURE

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VARIATION REGULATION-1234/2008 STRUCTURE & ANNEXES

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VARIATIONS

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 VARIATIONS

➢ What is a Variation….?
A variation to the terms of a marketing authorization is an amendment to the contents of
the documents of the approved dossier.
Variations in European Union (EU) are regulated by following regulations and Guidelines:
Commission Regulation (EC) No. 712/2012 of 3 August 2012 amending Regulation (EC) No. 1234/ 2008
concerning examination of variations to the terms of marketing authorisations for medicinal products
for human use and veterinary medicinal products.
Annex I – Extensions of marketing authorisations.
Annex II – Classification of variations.
Annex III – Cases for grouping variations.
Annex IV – Elements to be submitted.
Annex V – Variations concerning a change to or addition of therapeutic indication, addition of
non-food producing target species, replacement or addition of a stereotype, strain, antigen etc.
Guidelines of 16.05.2013 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.

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 VARIATIONS

Variations are
classified into three
types

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VARIATION CLASSIFICATIONS-REGULATIONS 1234

Type IB
(Minor
variation)

Type IA Type II
(Minor Variations (Major
variation) variation)

Extension
(new
application)

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VARIATION CLASSIFICATIONS-REGULATIONS 1234

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VARIATION CLASSIFICATIONS-REGULATIONS 1234

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VARIATION CLASSIFICATIONS-GUIDELINES STRUCTURE

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REVIEW OF REGULATION 1234/2008 ARTICLE 4(2)

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INTRODUCTION OF REGULATION 712/2012

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INTRODUCTION OF REGULATION 712/2012-OBJECTIVE

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INTRODUCTION OF REGULATION PREVIOUS TO CURRENT

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EU VARIATION PROCEDURE NATIONAL ADOPTION

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ADDITIONAL READING

MHRA FAQs for variations submitted after 1 January 2010:

http://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/Marketingauthorisations/Varia
tionstolicences/FAQsforvariationssubmittedafter1January2010/Administrativechanges/
MHRA Variations to licences: Administrative FAQs:
http://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/Marketingauthorisations/Varia
tionstolicences/FAQsforvariationssubmittedafter1January2010/Administrative/index.htm
MHRA Variations to licences: Quality changes FAQs:
http://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/Marketingauthorisations/Varia
tionstolicences/FAQsforvariationssubmittedafter1January2010/Qualitychanges/index.htm
MHRA Variations to licences: MHRA experiences:
http://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/Marketingauthorisations/Varia
tionstolicences/Experiencetodate/index.htm
MHRA Variations to licences: Grouping & work-sharing:
http://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/Marketingauthorisations/Varia
tionstolicences/QualityAuditReportofNewTIANotifications/index.htm
CMDH Variation Procedure:
http://www.hma.eu/96.html
EMEA post authorisation Question & Answers:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000019.jsp&
mid=WC0b01ac0580023b12

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BREAK

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EUROPEAN VARIATION
CLASSIFICATIONS

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VARIATION CLASSIFICATION

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VARIATION CLASSIFICATION

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VARIATION CLASSIFICATIONS

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TYPES OF VARIATION

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CLASSIFICATION -HIERARCHY

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 TYPE IA VARIATIONS

➢Type lA variations: Type lA variations are the minor variations which have only a
minimal impact or no impact at all, on the quality, safety or efficacy of the medicinal
product, and do not require prior approval before implementation ("Do and Tell"
procedure).

Such a minor variations are “classified” two subcategories, which impact on their
submission:

Type lA variations requiring immediate notification (‘IA IN‘)

Type lA variations NOT requiring immediate notification (‘lA’) (Variations which do not
require immediate notification may be submitted by the marketing authorisation
holder (MAH) within 12 months after implementation).

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 TYPE IA VARIATIONS

➢Why certain minor variations of Type IA require immediate notification ?

Certain minor variations of Type IA require immediate notification after
implementation, in order to ensure
the continuous supervision of the medicinal product.

➢When should I submit my Type IAINvariation?

This should be submitted immediately and generally within 2 weeks of implementation
of the change.

➢What is meant by 'implementation' for Type IA variations?

For quality changes, implementation is when the company makes the change in its
own quality system.

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 EXAMPLE OF TYPE IA VARIATIONS

Type IA Changes - Only a minimal impact or no impact at all, on the quality,

safety or efficacy of the medicinal product ("Do and Tell" procedure ):
➢Examples of Type IAIN variation:
▪Change in the name and/or address of the marketing authorisation holder
▪Change in the name and/or address of a manufacturer/importer of the finished
product (including batch release or quality control testing sites)
▪Changes in imprints, bossing or other markings
▪Change in the shape or dimensions of the pharmaceutical form perticularly
Immediate release tablets, capsules, suppositories and pessaries.

➢Examples of Type IA variation:

▪Addition of physico-chemical test in specification.
▪Deletion of non-significant test (ex: Identification test in Stability study).
▪Tightening of specification limits (ex: Tightening of test limit for water content,
Residual solvents and Related substances..etc.
▪CEP updates/renewal.
▪API and FP Batch size increase/decrease within 10 fold.
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 TYPE IB VARIATIONS

Commission Regulation (EC) No 1234/2008 ('the Variations

Regulation') defines a minor variation or Type 1B as a variation
which is neither a Type lA variation nor Type II variation nor an
Extension.

Such minor variations must be notified to the National Competent

Authority/European Medicines Agency by the Marketing
Authorisation Holder (MAH) before implementation.

However, the MAH must wait a period of 30 days to ensure that the
notification is acceptable by the Agency before implementing the
change (Tell, Wait and Do procedure).

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 EXAMPLE OF TYPE IB VARIATIONS

Type IB Changes - Min to moderate impact on product

quality (Tell, Wait and Do procedure):

➢Major change the approved Analytical method

➢FP Mfg. site changes
➢Shelf-life extension
➢Change in storage condition
➢Minor changes to approved manufacturing process
➢Change in batch size beyond 10 fold category
➢SmPC /PIL changes in-line with innovator product

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 EXAMPLE OF TYPE II VARIATIONS

Type II Changes (Significant impact on product quality,

safety & efficacy):

➢Addition of alternate/new API DMF supplier

➢Relaxation of approved specification
➢Major change in approved manufacturing process
➢Major change in approved composition
➢.

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 EXTENSION APPLICATIONS
Definition for Extension of marketing authorisation:
Changes to a marketing authorisation listed in Annex I of Commission Regulation (EC) No
1234/2008 are regarded as "extensions" of the marketing authorisation.
Examples of extension changes:
1. Changes to the active substance(s)
- replacement of a chemical active substance by a different salt/ester
complex/derivative. with the same
therapeutic moiety, where the efficacy/safety characteristics are not significantly
different;
2. Change to strength, pharmaceutical form, route of administration
Change of bioavailability;
Change of pharmacokinetics e.g. change in rate of release;
Change or addition of a new strength/ potency;
Change or addition of a new pharmaceutical form;
Change or addition of a new route of administration.

Such applications will be evaluated in accordance with the same procedure as for the
granting of the initial marketing authorisation to which it relates.
The extension can either be granted as a new marketing authorisation or will be included in
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the initial marketing authorisation to which it relates.
CLASSIFICATION: SUMMARY OF KEY CHANGES IN 1234/2008

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HOW TO CLASSIFY VARIATION

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CLASSIFICATION: DIVISION OF CHANGES

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CLASSIFICATION: GUIDELINES C2804

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VETERINARY CLASSIFICATION: GUIDELINES C2804

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CLASSIFICATION GUIDELINES –OTHER PLACES TO FIND INFORMATION

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CLASSIFICATION GUIDELINES –APPLYING THE GUIDLINES

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CLASSIFICATION GUIDELINES –APPLYING THE GUIDELINES

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LEGISLATION ALLOWS FOR UPDATING
CLASSIFICATION GUIDLINES

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CLASSIFICATION REVIEW 2012 –UPDATES

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N0 CLASSIFICATION SECTION IN REGULATIONS 1234

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EMA TYPE IB PRE NOTIFICATION CHECKLIST

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TYPE 1A VARIATIONS

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TYPE IA VARIATIONS

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TYPE IA VARIATIONS-CONDITIONS AND DATA

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TYPE IA VARIATIONS-CONDITIONS AND DATA

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APPLICATION FORMS

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AGENCY PERSPECTIVE-TYPE IA VARIATIONS

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AGENCY PERSPECTIVE-TYPE IA VARIATIONS

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AGENCY PERSPECTIVE-TYPE IA VARIATIONS

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AGENCY PERSPECTIVE-TYPE IA VARIATIONS

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AGENCY PERSPECTIVE-COMMON REFUSALS

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EMA PRE NOTIFICATION CHECKLIST

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CLASSIFICATION GUIDELINES FROM2013

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PRACTICAL EXERCISE: ANALYSING AND
CLASSIFYING THE DIFFERENT CHANGES.

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EUROPEAN VARIATION PROCEDURES

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LEARNING OBJECTIVES

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EUROPEAN PROCEDURES

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EUROPEAN PROCEDURES-NATIONAL GUIDANCE

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EUROPEAN PROCEDURES-DCP/MRP GUIDANCE

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CMD (H) GUIDANCE- HEAD OF MEDICINE AGENCY

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CENTRALISED PROCEDURE GUIDANCE

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GROUPING AND WORK SHARING
PROCEDURES

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GROUPING AND WORK SHARING

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GROUPING AND WORK SHARING

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GROUPING

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 GROUPING

It is possible to group variations of different categories the same marketing

authorisation (MA) and submit them in one submission, under a single application
form, to the same relevant authority. This is permissible where variations are
covered under the cases listed in Annex Ill to the variations regulation.
Examples are any group of lA changes, a group comprising a Type IB or Type II
change plus one or more of the same or lower category which are consequential
to the first, and a group of administrative changes to labelling.
If a projected group is not listed in Annex Ill, the regulation and supporting
guidances permit the MAH to request agreement of the relevant authority(ies) to
grouping of related changes where a single data package and evaluation are
meaningful.
14 cases of Groupings listed in Annex Ill
CMDh Guidance for Examples for Acceptable and Not-Acceptable Groupings for
MRP/DCP Products -Doc. Ref: CMDh/173/2010/Rev.10 July 2013

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GROUPING

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GROUPING

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GROUPING

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GROUPING

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GROUPING

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GROUPING

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GROUPING

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GROUPING VARIATIONS- RULES FOR OTHER GROUPINGS

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GROUPING VARIATIONS- OTHER GUIDANCE

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ACCEPTABLE GROUPING –CLINICAL EXAMPLE

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GROUPING

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GROUPING EXERCISE

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WORK SHARING PROCEDURES

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 WORK SHARING

Article 14-18 Centralised Procedure

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WORK SHARING

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WORK SHARING

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WORK SHARING

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WORK SHARING

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WORK SHARING

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WORK SHARING

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WORK SHARING

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WORK SHARING

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WORK SHARING

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WORK SHARING

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WORK SHARING

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WORK SHARING- WHAT CAN I WORK SHARE

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WORK SHARING- WHAT CAN I WORK SHARE

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WORK SHARING- ADVANTAGES

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VARIATION TIMELINES

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TIMELINES

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TIMELINES

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TIMELINES

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TIMELINES

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TIMELINES

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TIMELINES

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TIMELINES

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VARIATION PLANNING

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VARIATION PLANNING

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VARIATION PLANNING

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VARIATION PLANNING

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VARIATION PLANNING

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VARIATION PLANNING

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VARIATION PLANNING

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VARIATION PLANNING

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VARIATION PLANNING

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VARIATION PLANNING

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VARIATION PLANNING

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VARIATION PLANNING

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URGENT SAFETY RESTRICTIONS

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USR

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USR

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USR

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USR

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USR

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USR-HOW TO DEAL WITH ONE

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USR-HOW TO DEAL WITH ONE

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USR-HOW TO DEAL WITH ONE

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USR-EXAMPLES

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USR

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DAY 2

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ARTICLE 5

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ARTICLE 5

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ARTICLE 5

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ARTICLE 5

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ARTICLE 5

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ARTICLE 5

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ARTICLE 5

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ARTICLE 5

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ARTICLE 5

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ARTICLE 5

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ARTICLE 5

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ARTICLE 5

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ARTICLE 5

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TYPE II VARIATIONS

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TYPE II VARIATIONS

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TYPE II VARIATIONS

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TYPE II VARIATIONS

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TYPE II VARIATIONS

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TYPE II VARIATIONS

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TYPE II VARIATIONS

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TYPE II VARIATIONS

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TYPE II VARIATIONS

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TYPE II VARIATIONS-SUPPORTING TYPE II VARIATIONS

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TYPE II VARIATIONS-SUPPORTING TYPE II VARIATIONS

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TYPE II VARIATIONS-SUPPORTING TYPE II VARIATIONS

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TYPE II VARIATIONS-SUPPORTING TYPE II VARIATIONS

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CASE STUDY 2

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TYPE II VARIATIONS-SUPPORTING TYPE II VARIATIONS

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TYPE II VARIATIONS-SUPPORTING TYPE II VARIATIONS

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TYPE II VARIATIONS-SUPPORTING TYPE II VARIATIONS

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TYPE II VARIATIONS-SUPPORTING TYPE II VARIATIONS

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TYPE II VARIATIONS-SUPPORTING TYPE II VARIATIONS

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TYPE II VARIATIONS-SUPPORTING TYPE II VARIATIONS

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TYPE II VARIATIONS-SUPPORTING TYPE II VARIATIONS

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DESIGN SPACE

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EUROPEAN VARIATIONS –CENTRALISED
& DCP MRP & NATIONAL

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CENTRALISED & DCP MRP & NATIONAL

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CENTRALISED

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CENTRALISED

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CENTRALISED

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CENTRALISED

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CENTRALISED

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CENTRALISED

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CENTRALISED

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CENTRALISED

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MRP/DCP PROCESS

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MRP/DCP PROCESS

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MRP/DCP PROCESS

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MRP/DCP PROCESS

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MRP/DCP PROCESS

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MRP/DCP PROCESS

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MRP/DCP PROCESS

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MRP/DCP GUIDANCE

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TIPS & RFI

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 TIPS AND RFI’S

Tips for applicants submitting a variations

As an example the UK authority MHRA’s Process Licensing Team (PCL) typically

receives around 840 manufacturing authorisation related applications per year, so
that’s around 70 per month. Unfortunately, around 30% of all applications result in
Requests for Further Information (RFI) before they can be accepted for processing. So
that’s around 251 applications each year requiring follow-up before the detailed
assessment work can get underway!

The purpose of these slides is to help reduce the number of applications requiring
RFIs, by raising awareness of the common mistakes. RFIs will delay the application
process and can be costly in terms of time and effort to resolve. They cause
frustration for applicants as well as assessor/staff, but in most cases they are
avoidable!

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 TIPS AND RFI’S

1. Incomplete Applications

A very basic but common mistake is that applicants do not complete all of the
required fields in the application form or fail to attach supporting documentation, e.g.

Supporting documentation such as CVs, QP eligibility certificates should be included

with applications
Individual Personnel forms (e.g. 15V) should be completed and signed by each named
person and the applicant
Applications for Site Functions (or variations to) should be supported by the correct
Site Type and vice versa
Make sure you read the application form and check that the required documents are
attached when you submit your application.

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 TIPS AND RFI’S

2. Know your limits

The activities you are requesting to be included on the variation should reflect
current reality and not future aspirations! The Inspector will expect to see that you
have the necessary procedures, control systems, equipment and expertise to
support the range of products and activities you are proposing to include on the
licence

Activities that you do not have capability to perform will need to be removed from
the application before it can be approved. Such changes create extra work and
result in delays in processing applications.

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 TIPS AND RFI’S

3. Nominating Site Personnel – QP, PM, QC

Key personnel who do not have product specific experience and knowledge of the
site’s or Product and operations or product recalls represent a risk to GMP
compliance. Key personnel are therefore important to address concerns with
appropriate knowledge

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 TIPS AND RFI’S

4. Requests for activities that do not need to be licensed – QC laboratories

You only need to name contract laboratories on the manufacturing authorisation if they are
performing an inspectable activity. UK guidance on when a contract laboratory must and
should not be named on a manufacturing authorisation has been published by MHRA, but
applicants are still wasting time and money submitting unnecessary applications, which in
turn takes up PCL and Inspectorate time to process and review before the application is
withdrawn.

Contract laboratories only need to be named if they are undertaking the testing of
medicinal products or an investigational medicinal product for human use:

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 TIPS AND RFI’S

Applicants are strongly advised to use the pre-submission checklist which will
reduce likelihood of the submitted application being invalidated or rejected.

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EXPERIENCE

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EXPERIENCE

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EXPERIENCE

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EXPERIENCE

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EXPERIENCE

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EXPERIENCE

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EXPERIENCE

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EXPERIENCE

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EXPERIENCE

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EXPERIENCE

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EXPERIENCE

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EXPERIENCE

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EXPERIENCE

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EXPERIENCE

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EXPERIENCE

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EXPERIENCE

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EXPERIENCE

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EXPERIENCE

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EXPERIENCE

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EXPERIENCE

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EXPERIENCE

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EXPERIENCE

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QUESTIONS

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THANK YOU

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