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 - IVExam No.: 76

Objectives & Plan of workReview of LiteratureIntroductionWork AccomplishedConclusionReferences

STREAM OF PRESENTATION

Tuesday, April 18, 2023 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.Tuesday, April 18, 2023 M.Pharm (PMRA), KBIPER 5

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

M.Pharm (PMRA), KBIPERTuesday, April 18, 2023 10

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

IANot 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 CMSsValidation 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 andCo-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 pack2. 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/368314/Pre-submission_checklist.pdf

REFERENCES


3) Volume 2A, Notice to Applicants, Procedure for Marketing Authorisation, 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_guidance/Application_for_MA/DCP/CMDh_078_2005_Rev05_01_2014_clean_a.pdf

5) Volume 2A, Notice to Applicants, Procedure for Marketing Authorisation, 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.pdfTuesday, April 18, 2023 M.Pharm (PMRA), KBIPER 44

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_guidance/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/con063041.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/369095/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