Exam no. 76 ashma

“MARKETING AUTHORISATION & POST APPROVAL
CHANGES (VARIATION) OF MEDICINAL PRODUCTS IN UK.”
INSTITUTIONAL GUIDE:
Prof. K. M. Patel,
HOD - PMRA,
KBIPER, Gandhinagar.
INDUSTRIAL GUIDE:
Mrs. Sonal G. Pujara,
B.Pharm, IPR
Head Regulatory Affairs,
Stallion Laboratories. Pvt.
Ltd., Ahmedabad
PRESENTED BY:
Ms. Ashma R. Tirmizi,
M.Pharm (PMRA) Sem - IV
Exam No.: 76

Objectives & Plan of work
Review of Literature
Introduction
Work Accomplished
Conclusion
References
STREAM OF PRESENTATION
Tuesday, May 12, 2015 M.Pharm (PMRA), KBIPER 2

 The main purpose of this present work is to represent the Marketing
Authorisation procedure & Variation requirement for Marketing Authorisation
Application (MAA) of a medicinal product in UK.
 This presentation will be helpful for industry, academicians & pharma health
professionals.
PLAN OF WORK
 Selection of market for filling MAA
 Filling procedure for MAA in Member States
 Implementation of changes for post approval filing
OBJECTIVES & PLAN OF WORK

REVIEW OF LITERATURE
Sr. No. Title Reference No.
1 Marketing Authorization of Human Medicinal Products
to European Union/European Economic Area
8
2 Marketing Authorisation Application (MAA) for Europe
Market
9
3 Procedure for securing a marketing authorisation in UK 10
Articles Referred
(8), (9),(10)

 A marketing authorisation lays down the terms under which the marketing of
a medicinal product is authorized in the UK.
 A marketing authorisation is composed of:
(i) A decision granting the marketing authorisation issued by the relevant
authority; and
(ii) A technical dossier with the data submitted by the applicant.
INTRODUCTION
WHAT IS MARKETING AUTHORIZATION?
(1)

"Marketing Authorisation Holder" can be a physical or legal entity.
It is noted:
 Applicants and marketing authorisation holders belonging to the same company group or that
are controlled by the same physical or legal entity are to be considered as one entity.
 The marketing authorisation holder must be established within the European Economic Area.
MARKETING AUTHORISATION PROCEDURES FOR UK
(UNITED KINGDOM):
MARKETING AUTHORIZATION HOLDER
Mutual Recognition Procedure
Decentralised Procedure
Centralised Procedure
1
2
3
(1)
(3), (4), (5), (6)

 In mutual recognition procedure, where the applicant seeks approval in
additional member states (concerned member states) for a product already
approved in an initial member state (the reference member state), the RMS
prepares an assessment report, which the CMS must approve or reject within 90
days.
 Assessment report contains Recommendation, Executive Summary, Scientific
Overview, Benefit - Risk Assessment, Recommended conditions for marketing
authorisation & product information.
The DCP cannot be used for products, which are authorized via CP, but it can be
used for duplicate applications and extension applications of products originally
approved by the Mutual Recognition Procedure. It can be used for generic
products for which the reference product was authorized via CP.
1. Mutual Recognition Procedure
2. Decentralised Procedure

Mutual Recognition Procedure & Decentralised Procedure cannot be applied
for following products:
 Homeopathic products
 Special, simplified registration of traditional herbal medicinal products
The main difference between MRP and DCP is the fact that the initial MA is not
submitted and issued for the RMS alone. Instead of this, the MAA dossier is
submitted to the RMS and the CMS in parallel. A statement that the identical dossier
is submitted to RMS and CMS is submitted together with the MAA dossier. The
RMS will prepare a draft assessment report in consultation with the CMS. This
Assessment Report is the basis for the RMS and CMS to agree the terms for the
MA.

A marketing authorisation granted under the centralised procedure is valid for
the entire Community market, which means the medicinal product may be put
on the market in all Member States.
Centralised Procedure can be applied for following products:
High-tech and biotechnology-derived products & Biosimilar Products
Product used for the rare diseases (so called orphan products), as well as for
products treating Acquired Immune Deficiency Syndrome (AIDS), cancer,
Diabetes Mellitus & neurodegenerative disorders like life-threatening diseases.
For authorisation of products with new active substances.
3. Centralised Procedure

WHAT ARE POST APPROVAL CHANGES ?
Synonym: Variations
 Once the drug product is in the market after authorisation
& MAH wants to do some changes in the approved Drug
product then MAH send application for post marketing
authorization to MHRA along with the supporting
documents.
 After getting approval of changes for a drug product, it
can be marketed.
(11), (15)

Variation
Minor
Major
 Tell, Wait & Do procedure
 Significant impact on Quality, safety or efficacy.
 Require prior approval before implementation
( “prior authorization procedure”)
Type I A
 Do & tell procedure
 Do not require prior
approval before
implementation
`
Type I B
 Tell, Wait & Do procedure
 Must be notified before implementation.
 Do not require prior approval.
 MAH must wait for a period of 30 days to ensure whether it is acceptable or not
IA IN
Require immediate notification following implementation
IA
Not requiring immediate notification .May be submitted
in 12 months after implementation (annual reporting)

Characteristics Type I A Type I B Type II
Procedure Do & Tell Tell, Wait & Do Tell, Wait & Do
Synonym Minor Minor Major
Processing of
application
30 Days 30 Days 30, 90, 120 Days
depending on urgency
Approval from
authority
Do not require
prior approval
before
implementation
Do not require
prior approval
before
implementation
Require prior approval
before implementation
Role of MAH
MAH should
implement the
change before
notifying MHRA
MHRA must be
notified before
implementation of
change
MHRA must be
notified before
implementation of
change

Documents required for submission of Variation Application:
Sr. No. Documents
1 Cover Letter
2 Completed Application Form
3 Updated product information: SmPC, PIL, other labelling (packaging)
details.
4 Fees
5 A contents page listing all documents included in submission
6 A new or updated addendum to the ‘quality overall summary’, clinical
and non-clinical overviews

CTD – Common Technical Document
 The CTD is an internationally agreed format for the preparation of
applications to be submitted to regulatory authorities. It is intended to save time
and resources and to facilitate regulatory review and communication. The CTD-
presentation will be applicable for all types of marketing authorisation
applications irrespective of the procedure (CP, MRP, DCP or national).
Preparing and Organizing the CTD
 Throughout the CTD, the display of information should be transparent. Text
and tables should be prepared using margins that allow the document to be
printed on A4 paper. The left-hand margin should be sufficiently large that
information is not obscured through binding.
Font sizes for text and tables should be of a style and size that are large enough
to be easily legible, even after photocopying. Times New Roman, 12-point font
is recommended for narrative text.
(16)

CTD is organized into five modules:
Module 1 Administrative Information and Prescribing Information
Module 2 Summaries
Module 3 Quality
Module 4 Non – clinical Study Reports
Module 5 Clinical Study Reports

Marketing Authorisation Pre – submission Checklist:
WORK ACCOMPLISHED
Application Requirements Confirm
Format
Proof of Payment
Fee
SmPC & Label & Leaflet
(2)

Application form section 1 – Type of Application Confirm
Orphan Designation
Article of Submission
Data Protection period
Reference Medicinal Product
Application form section 2 – MAA Particulars Confirm
Invented names
Pharmacovigilance System Summary
Risk Management Plan
ASMF
Application form section 4 – Other MAA Confirm
Pending applications in other Member States

Applicant
Requests RMS to update Assessment Report (AR) and allocate
procedure number.
Submits the dossier to CMS. RMS circulates the AR including SPC,
PL and labelling to CMSs. Validation of the application in the CMSs.
Day -14
Approx. 90 days before
submission to CMS
1. Mutual Recognition Procedure
(3)

RMS starts the procedure
CMSs send their comments to the RMS and applicant
Applicant sends the response document to CMSs and RMS
RMS circulates their assessment of the response document to CMSs.
CMSs send their remaining comments to RMS and applicant.
Day - 0
Day - 50
Day - 60
Until Day 68
Day 75 to 85
Role of RMS & CMS:

CMSs notify RMS and applicant of final position
If consensus is reached, the RMS closes the procedure.
If consensus is not reached, the points for disagreement submitted by CMS(s)
are referred to CMD (h) by the RMS within 7 days after Day 90.
Applicant sends high quality national translations of SPC,
PL and labelling to CMSs and RMS.
Granting of national marketing authorisations in the CMSs
subject to submission of acceptable translations.
Day 90 to 150
5 Days after close of procedure
30 Days after close of procedure

Applicant
Discussions with RMS. RMS allocates procedure number. Creation in
CTS.
Submission of the dossier to the RMS and CMSs
Validation of the application
Day -14
Before Day -14
2. Decentralised Procedure
STEP 1: PRE – PROCEDURAL STEP
(4)

RMS starts the procedure
RMS forwards the Preliminary Assessment Report (PrAR),SPC , PL and
labelling to the CMSs
CMSs send their comments to the RMS
Consultation between RMS, CMSs and applicant.
Applicant sends the final response document to the RMS and CMSs
within a recommended period of 3 months, which could be extended if
justified.
Day - 0
Day - 70
Until Day 100
Until Day 105
Clock – Off Period
Role of RMS & CMS: STEP 2: ASSESSMENT STEP - I

Valid submission of the response of the applicant received. RMS restarts
the procedure.
RMS updates PrAR to prepare DAR, draft SPC, draft labelling and draft
PIL to CMSs.
RMS may close procedure if consensus reached. Proceed to national 30
days step for granting MA.
Day - 106
Day 106 to 120
Day - 120
STEP 2: ASSESSMENT STEP - I

If consensus not reached RMS sends the DAR, draft SPC, draft labelling
and draft PIL to CMSs
CMSs sends final comments to RMS
RMS may close procedure if consensus reached.
Proceed to national 30 days step for granting MA
If consensus is not reached by day 150, RMS to communicate
outstanding issues with applicant, receive any additional clarification and
prepare a short report for discussion at Coordination Group.
Day - 120
Day - 145
Day - 150
Until Day 180
STEP 3: ASSESSMENT STEP - II

Breakout Group of involved Member States reaches consensus on the matter
Closure of the procedure including CMSs approval of assessment report,
SPC, labelling and PIL, or referral to Co-ordination group. Proceed to
national 30 days step for granting MA.
Final position adopted by Co-ordination Group with referral to
CHMP/CVMP for arbitration in case of unsolved disagreement
Until Day 205
Day - 210
Day - 270
STEP 3: ASSESSMENT STEP - II

Applicant sends high quality national translations of SPC,
labelling and PIL to CMS and RMS
Granting of national marketing authorisation in RMS and
CMSs if positive conclusion by the Co-ordination group
and no referral to the CHMP/CVMP.
Day – 110/125/155/215/275
Day – 135/150/180/240/300
STEP 4: NATIONAL STEP

Start of the procedure
Receipt of the Assessment Report(s) from Rapporteur and Co-Rapporteur(s)
by CHMP members and EMEA
Rapporteur, Co-Rapporteur, other CHMP members and EMEA receive
comments from Members of the CHMP
Receipt of draft list of questions from Rapporteur and Co-Rapporteur,
CHMP members and EMEA.
CHMP adopts the list of questions as well as the overall conclusions and
review of the scientific data to be sent to the applicant by the EMEA. Clock
Stop.
Day - 1
Day - 80
Day - 100
Day - 115
Day - 120
3. Centralised Procedure
(5)

Joint response Assessment Report from Rapporteur and Co-Rapporteur received
by CHMP members and the EMEA.
Deadline for comments from CHMP Members to be sent to Rapporteur and
Co-Rapporteur, EMEA and other CHMP Members.
Submission of final inspection report to EMEA, Rapporteur and Co-Rapporteur by
the inspections team. Clock Stops.
Day - 121
Day - 150
Day - 170
Day - 180
Submission of the responses, including revised summary of product characteristics
labelling and package leaflet texts in English, and restart of the clock.
After receipt of the responses, the CHMP will adopt a timetable for the evaluation of the
responses. In general the following standard timetable will apply:

Final draft of English summary of product characteristics, labelling and
package leaflet sent by applicant to the Rapporteur and Co-Rapporteur,
EMEA and other CHMP members.
Adoption of CHMP Opinion + CHMP Assessment Report
Applicant provides the EMEA with summary of product characteristics,
labelling and package leaflet in the different languages acc. to language of
MS. EMEA circulates draft translations to Member States for review.
Applicant provides EMEA with final translations of summary of product
characteristics, Annex II, labelling and package leaflet in the different
languages, taking account comments received from Member States by
Day 229.
Day 181 to 210
Day - 210
Day - 215
Day - 181
Day - 232
Restart the clock and oral explanation
After adoption of a CHMP opinion, the preparation of the annexes to the
Commission Decision is carried out in accordance with the following timetable:

Transmission of Opinion in all languages to applicant, Commission, and
Members of the Standing Committee.
Applicant provides EMEA with one final full colour 'worst-case' mock-
up of outer and inner packaging for each pharmaceutical form.
Day - 237
Day - 246

Scope of changes in variation
 ADMINISTRATIVE CHANGES
 QUALITY CHANGES
 Manufacture
 Description and composition
 Control of active substance
 Control of excipients
 Control of finished product
 Container closure system
 Stability
 SAFETY EFFICACY PHARMACOVIGILANCE CHANGES
(15)

Type of Variations Example
Type I A Variation Change in the composition of finished product,
Addition of Batch Size,
Replacement or addition of packaging site,
Addition of supplier for packaging components
Type I B Variation Addition of test method for Assay during Inprocess test of finished product,
Change in test procedure for the finished product,
Shelf-life Extension,
Change in pack size of Finished Product
Type II Variation Change in the specification parameters of Finished Products,
Addition of new manufacturer for API
Administrative
changes
Change in address of MAH,
Change in invented name of product,
Change in name of excipient,
Change in name of the MAH,
Change in ATC Code
Different Types of Variation (Examples)
(15)

Reason for Variation Filing: Based on manufacturer’s requirements
STEPS INVOLVED IN SUBMISSION:
1. Application Form
Selection of change code from variation classification guideline.
2. Conditions & supporting documents which are mandatory to submit variation
application as per variation guidance:
B.II.b.4 Change in the batch size (including batch size
ranges) of the finished product
Procedure
type
a) Up to 10-fold compared to the originally approved batch size IA
ADDITION OF BATCH SIZE
(15)

2.1 Conditions:
Sr. No. Conditions
1 The change does not affect reproducibility and/or consistency of the product.
2 Any changes to the manufacturing method and/or to the in-process controls are
only those necessitated by the change in batch-size, e.g. use of different sized
equipment.
3 Validation scheme is available or validation of the manufacture has been
successfully carried out according to the current protocol with at least three
batches at the proposed new batch size in accordance with the relevant guidelines.
4 The batch size is within the 10-fold range of the batch size foreseen when the
marketing authorisation was granted or following a subsequent change not agreed
as a Type IA variation.

2.2 Supporting Documents:
3. Submission to the respected agency
4. Time line
It is Type IA variation. So timeline to submit variation application is 30 days.
Sr. No. Documents
1 Amendment of the relevant section(s) of the dossier.
2 Where relevant the batch numbers, corresponding batch size and the
manufacturing date of batches (≥3) used in the validation study should be
indicated or validation protocol be submitted.

Reason for Variation Filing: Based on market requirements
1. APPLICATION FORM
2.1 Conditions:
Here change code B.II.e.5. (a) is found for variation so required condition not
found within the reference variation guideline.
B.II.e.5 Change in pack size of the finished product Procedure type
a) Change in the number of units (e.g. Tablets, ampoules, etc.) in a pack
2.Change outside the range of the currently approved pack sizes
IB
CHANGE IN PACK SIZE OF FINISHED PRODUCT
(15)

4. Time line
It is Type IB variation. So timeline to submit variation application is 30 days.
Sr. No. Documents
1 Amendment of the relevant section(s) of the dossier including revised product
information as appropriate.
2 Justification for the new/remaining pack-size, showing that the new/remaining
size is/are consistent with the dosage regimen and duration of treatment as
approved in the summary of product characteristics.
3 Declaration that stability studies will be conducted in accordance with the relevant
guidelines for products where stability parameters could be affected.

Reason for Variation Filing: Based on manufacturer’s requirements
1. Application Form
2.1 Conditions:
Here change code B.II.d.1.(e) is found for variation so required condition not
found within the reference variation guideline.
B.II.d.1 Change in the specification parameters and/or limits of the
finished product
Procedure type
e)Change outside the approved specifications limits range II
CHANGE IN THE SPECIFICATION PARAMETERS OF FINISHED PRODUCT
(15)

4. Time line
It is Type II variation. So timeline to submit variation application is 30, 60, or 90
days.
Sr. No. Documents
1 Cover letter
2 Application Form
3 Finished Product Specification
4 Analytical Procedure

Reason for variation filing: Based on MAH’s requirements.
1. Application form:
Selection of change code from variation classification guideline:
A.1 Change in the name and/or address of the marketing authorisation
holder
Procedure type
IAIN
CHANGE IN NAME OF THE MAH
(15)

2.1 Conditions:
2.2 Supported Documents:
4. Time line
It is Type IA IN variation. So timeline to submit variation application is 30 days.
Sr. No. Documents
1 A formal document from a relevant official body (e.g. Chamber of Commerce) in
which the new name or new address is mentioned.
2 Revised product information.

The most important traits that have to be considered by MAH while applying for
MA & variation application are listed:
 Developmental studies during process and formulation development and
appropriate corresponding stability studies can save a significant amount of
resources down the road.
Systematic filing of marketing authorisation leads to speedy approval of
process.
Data to be generated and submitted should remain the same.
Equipment, suppliers, components, raw materials and processes will change
and impact the drug product.
Administrative changes like change in name of product, excipient or change in
Name & Address of MAH will lead to variation.
CONCLUSION

1) Volume 2A, Notice to Applicants, Procedure for Marketing Authorisation,
Chapter 1 Marketing Authorisation, edition June 2013 (Accessed on 18/11/2014)
Available on:
http://ec.europa.eu/health/files/eudralex/vol-2/a/vol2a_chap1_2013-06_en.pdf
2) Marketing Authorisation Pre-submission checklist (Accessed on 18/11/2014)
Available on:
https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/36
8314/Pre-submission_checklist.pdf
REFERENCES

Chapter 2 Mutual Recognition, edition February 2007 (Accessed on 18/11/2014)
Available on:
http://ec.europa.eu/health/files/eudralex/vol-2/a/vol2a_chap2_2007-02_en.pdf
4) Decentralised Procedure, Member States’ Standard Operating Procedure,
CMDh, edition January 2014 (Accessed on 25/12/2014)
Available on:
http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/procedural_g
uidance/Application_for_MA/DCP/CMDh_078_2005_Rev05_01_2014_clean_a
.pdf
Chapter 4 Centralised procedure, edition April 2006 (Accessed on 25/12/2014)
Available on:
http://ec.europa.eu/health/files/eudralex/vol-2/a/chap4rev200604_en.pdf

6) Assessment Report – Mutual Recognition Procedure, Guidance Document
(Accessed on 25/12/2014)
Available on:
http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/procedural_g
uidance/Application_for_MA/MRP/2006_09_ARctd_guidance_Rev3.pdf
7) MHRA FEES 2014/2015 for Marketing Authorisation (Accessed on
25/12/2014)
Available on: https://www.gov.uk/government/publications/mhra-fees-
201415/mhra-fees-201415
8) Santosh Kumar Narla, Marketing Authorization of Human Medicinal Products
to European Union/European Economic Area (Accessed on 17/01/2015)
Available on:
http://globalresearchonline.net/journalcontents/volume10issue1/Article-001.pdf
International Journal of Pharmaceutical Sciences Review & Research, Volume
10, Issue 1, September- October 2011

9) Bhave C, Dolhare N, Badjatya J.K., Marketing Authorisation Application
(MAA) for Europe Market (Accessed on 17/01/2015)
Available on: http://www.ijdra.com/images/ijdra%20160.pdf
International Journal of Drug Regulatory Affairs, Volume 3, Issue 1, JAN-MAR
2015
10) Procedure for securing a marketing authorisation in UK (Accessed on
17/01/2015)
Available on: http://www.taylorwessing.com/synapse/regulatory_procedure.html
11) Apply for changes to your marketing authorisation, including minor
variations type IA and IB, major variations type II and extensions. (Accessed on
16/02/2015)
Available on:
https://www.gov.uk/medicines-apply-for-a-variation-to-your-marketing-
authorisation

12) UK National MA Variations guidance (Accessed on 16/02/2015)
Available on:
http://www.mhra.gov.uk/home/groups/pla/documents/websiteresources/con06304
1.pdf
13) MHRA Fees for Variation (Accessed on 16/02/2015)
Available on:
https://www.gov.uk/government/publications/mhra-fees-201415/mhra-fees-
201415#variation
14) Marketing Authorisation Variations - Supplementary Guidance (Accessed on
18/03/2015)
Available on:
https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/36
9095/Common_Scenarios_-_Supplementary_Guidance.pdf

15) 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, edition May 2013
(Accessed on 18/03/2015)
Available on:
http://ec.europa.eu/health/files/eudralex/vol-2/2013_05_16_c2804_en.pdf
16) Volume 2B, Notice to Applicants, Medicinal products for human use,
Presentation and format of the dossier Common Technical Document (CTD),
edition June 2010 (Accessed on 18/03/2015)
Available on:
http://ec.europa.eu/health/files/eudralex/vol-2/b/update_200805/ctd_05-
2008_en.pdf

Special thanks to K.M.Patel Sir,
Priyank Sir, my friends & Classmates.
“No matter who says what, you should
accept it with a smile and do your own
work.” – Mother Teresa

Exam no. 76 ashma

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