variations - ages.at · „cmdh questions & answers qp declaration“ variations examples for...

Mag. Caroline Kleber

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Vienna, 9. 11. 2017

AGES MEA-LCM-QUAL

Variations

Variations

Regulatory Background

Commission Regulation (EC)

No 1234/2008,

amended by No 712/2012

Guidelines of 16.05.2013 on the details of the various categories of variations, on the operation of

the procedures laid down in

Chapers II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 of

25 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 persuant

to those procedures C (2013) 2804

CMDh Best Practice Guides (BPGs) for the Submission and Processing of Variations in the

Mutual Recognition Procedure,

CMDh/CMDv Q & A, …

2

Minor variations of type IA:

„Do and Tell“

→minimal impact, or no impact at all on the quality, safety or

efficacy of the medicinal product concerned

Type IAin: Notification immediately after implementation

Type IA: Notification within 12 months

→ within 30 days following receipt CA takes appropriate

measures („Acknowledgement of an acceptable notification“)

Variations Classification of Variations

3

Major variations of type II:

„Tell and wait for Approval before Implementation“

→significant impact on quality, safety or efficacy of the

medicinal product concerned

→ Prior approval necessary

Extension of a marketing authorisation

→a Variation which is listed in Annex I


4

Minor variation of type IB:

„Tell, Wait and Do“

→neither a minor variation of type IA nor a major variation of

type II nor an extension

→if 30 days following acknowledgement of receipt of a valid

notification CA has not sent unfavourable opinion, notification

is deemed accepted.


5

Article 7: Grouping of Variations

IAs of one or more marketing authorisations owned by the same

holder

Several variations of the same marketing authorisation according

Annex III

Several Variations of the same marketing authorisation not

inaccordance with Annex III but Agency agrees

National:

Grouped applications only in one member states, otherwise

worksharing

One or several variations to several purely national MAs in one MS

Facilitate review and reduce administrative burden

Variations Grouping

6

Article 20: Worksharing procedure

Type IB, Type II, Grouping to several MA owned by the same

holder

National: Type IB, Type II, Grouping to one MA owned by the same

holde in more than one member states

Assessment report will always be prepared

avoid duplication of work

Variations Worksharing

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A. Administrative changes

B. Quality changes I. Active Substance

a) Manufacture

b) Control of active substance

c) Container closure system

d) Stability

e) Design Space and post approval change management protocol

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

Variations Guideline of 16.5.2013

8

III. CEP/TSE/monographs

IV. Medical Devices

V. Changes to a marketing authorisation resulting from other regulatory

procedures

a) PMF/VAMF

b) Referral

c) Other changes to the quality dossier requested by the competent authority

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

II. Veterinary medicinal product – specific changes

D. PMF/VAMF

Variations Guideline of 16.5.2013

9

TYPE IB unforseen

→ a type IB variation where a „z“category is ticked and which

has not been classified as „z“-category following Article 5

recommendation

Article 5: Recommendation of unforseen variation

→ holder may request a recommendation on the classification

of the variation

„CMDh Recommendation for classification of unforeseen

variations according to Article 5 of Commission

Regulation (EC) No 1234/2008“

Variations Unforseen Variation

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GL: Changes to a Marketing Authorisation:

Addition, Replacement, Deletion of Data – Variation necessary

Editorial Changes:

- no separate Variation necessary

- can be included in a Variation

- clearly identified in the Application form

- Justification as why to consider editorial

Variations Editorial changes

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Q&A 3.16: Under which classification category can

editorial changes be submitted?

• Editorial changes of the SmPC, updates in line with QRD, etc.

without changing the content

→ included in TYP IB, TYP II under Chapter C

• Modul 3,4,5

→ see EMA Guidance

CMDh/CMDv: Q&A – List for the submission of variations according to Commission Regulation(EC) 1234/2008


13

EMA: Human post-authorisation Q&A

4.1. What can be considered an editorial change and how

can it be submitted as part of a type IA/IB/II variation?

Editorial: adding headers, reordering of existing information,

grammar/orthographic corrections

Not considered editorial changes: removal of specification parameters or

manufacturing description, update of information to bring the dossier in line

with the current manufacturing process, etc.

Included in sections up to the fourth level of the eCTD: Variation in 3.2.S.2.1 –

editorial changes in 3.2.S.2.1 to 3.2.S.2.7


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Application Form

Precise Scope and Background

• State changes

• Explanation why change is required

• Justificiation for Grouping

• Justification for Classification of Type IB if „z“ category is ticked

Present/Proposed Table

• Precise present and proposed content

„EMA/CMDh Explanatory notes on variation

application form“

Variations Examples for correct submissions

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Q&A 3.4: Update of an ASMF/Modul 3.2.S

• Grouped variation according to the highest type of single change

• Substantial changes: B.I.z Type II

Present/Proposed section filled out completely

CMDh/CMDv: Q&A – List for the submission of

variations according to Commission Regulation(EC)

1234/2008


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Submission of Updated CEPs (Classification Category

B.III.3)

• Each CEP Update submitted as variation scope

• More than one CEP version - Grouping

• Revisions of CEPs can be omitted – Confirmation that the

substance form the omitted CEP Version was not used in the FP

during validity of this CEP

EMA: Human post-authorisation Q&A (2.4)


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Brexit:

• Batch releaser

• New summary of Pharmacovigilance system

• Change in name

• ……

→Grouping possible

„CMDh/CMDv Examples of acceptable and not acceptable

groupings for MRP/DCP Products“


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New finished product bulk manufacturing site

• Changes in manufacturing process

• Changes in batch size

• Changes in in-process controls

……to adapt to the new manufacturing site settings

→Single type II under B.II.b.1 (clearly identified in the

Application form)

Changes in Excipients, specification parameters, container closure

system

→ Additional scopes in a grouped application

„CMDh/CMDv Examples of acceptable and not acceptable

groupings for MRP/DCP Products“

Variations

Examples for correct submissions

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Update Dossier in preparation of a RUP/MRP:

• Changes or addition of Braille, User Test, ERA, summary of

pharmacovigilance system, RMP, QPs declaration, updated

confirmatory stability data, updated clinical and non-clinical

overviews, summaries or Expert reports based on already

submitted or approved data

→ C.I.z TYP II

CMDh/CMDv: Q&A – List for the submission of

variations according to Commission Regulation(EC)

1234/2008 (4.12)


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QP Declarations

• New active substance manufacturer:

→QP Declarations from each finished product manufacturer and

batch release sites

• New finished product manufacturer (no batch release):

→QP Declaration from the new finished product manufacturer (if

located in the EU/EEA)

→QP Declaration from at least one batch release sites

„CMDh Questions & Answers QP Declaration“


21

Questions ?

Variations

22

BASG -

Austrian Federal Office for Safety in Health Care

www.basg.gv.at

Traisengasse 5

1200 Vienna

MEA – LCM - QUAL

T : +43 (0) 50555 - 36578

[email protected]

Mag. Caroline Kleber

variations - ages.at · „cmdh questions & answers qp declaration“ variations examples for...

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