Regulatory Affairs Related Project

1. Challenges In Regulatory Filing Of Generic
Products In Europe & Malaysia
Under the guidence:
K.Nagamani,Msc(Bio-chemistry)
Deputy Manager
Regulatory Affairs,
Sanzyme (P) Ltd,
Hyderabad
Presented By
B.Ramakrishna, M.pharm.
Department of Regulatory Affairs,
Sanzyme (P) Ltd,
Hyderabed.

2. CONTENTS
Ø AIM & OBJECTIVE
Ø INTRODUCTION
Ø DIFFERENCE BETWEEN INNOVATOR & GENERIC PRODUCT
Ø GENERIC DRUG REQUIREMENTS
Ø GENERIC DRUG DEVELOPMENT
Ø FILING A GENERIC DRUG APPLICATION
Ø MARKETING AUTHORIZATIONOF GENERICS IN EUROPE
Ø EUROPEAN FILING PROCEDURE
Ø REGISTRATION PROCEDURE IN EU

3. CONTENTS
ACTD
ORAGANIZATION OF ACTD
DIFFERENCE BETWEEN CTD & ACTD
ACTD TABLE OF CONTENTS
LIST OF DOCUMENTS REQUIRED
DEFINITION OF GENERIC PRODUCTS
INNOVATOR Vs GENERIC
ACTD REGISTRATION FOR PHARMACEUTICALS
REGISTRATION PROCESS & CONDITIONS
POST-REGISTRATION
REFERENCE

4. AIM & OBJECTIVE
The main aim of this topic is facing challenges and overcoming when filling
Generic Products.
The objective of this topic is to review and compare generic drug filing process
along with their challenges in different countries.
Examples
Generic drug filling process in USA is ANDA(Abbreviated New Drug
Application).
Generic drugs are filled seperately through EMA (European Medical Agency)
in Europe.
In India generic drugs are filled to Drug Controller General of India (DCGI).

5. INTRODUCTION
●
The pharmaceutical industry is one of the highly regulated industries, with
many rules and regulations enforced by the government to protect the health and
well-being of the public.
●
Therefore, the aim of the pharmaceutical industry is to identify and develop a
generic drug product which can be tailor made to meet the diverse market
requirements

6. As per global market trend, it is estimated that approximately $150 billion worth
of drugs will be off-patented during the period 2010 to 2017, which will serve as a
platform for pharmaceutical companies to develop generic drugs.
[1] The pharmaceutical industry in India has shown a remarkable growth which in
turn has risen the economy of India.
[2] After the introduction of the product patent regime in India, there was a need
for pharmaceutical companies both in India and abroad to explore newer markets.

7. DEFINITIONS
Generic Product
A generic drug is a
pharmaceutical drug that is
equivalent to a Innovator
product in dosage, strength,
route of administration, quality,
performance and intended use,
but does not carry the brand
name. ... A generic drug must
contain the same active
ingredients as the original
brand-name formulation.
Innovator product;
An innovator drug is
the first drug created
containing its specific active
ingredient to receive approval
for use. It is usually the
product for which efficacy,
safety and quality have been
fully established. When a new
drug is first made, drug patent
usually will be acquired by
the founding company

8. Difference between Innovator & Generic Product
Innovator Product
➔
Initially Marketed as New
Chemical Entities
➔
First version sold by the
innovotor manufacturer is
know as the reference
product.
➔
Eg. IND (Investigational
New Drug Application),
NDA (New Drug
Application) etc.
Generic Product
➔
Copies of Innovator.
➔
Produced after the original
patent Expires.
➔
Eg. ANDA for USFDA,
➔
MAH (Marketing
Authorization Holder) for
Europe and JANDA for
Japan etc.

9. GENERIC DRUG REQUIRMENTS
It must be same active Ingredient(s), same route of administration, same dosage
form, same strength, same indication, same container, same pharmacological
action in terms of efficacy with the already approved drug product.
A suitable manufacturing site/plant to manufacture the drug product and with a
suitable clinical laboratory for conducting clinical trails. Both sites must holds
site approvals from regulatory authorities.

10. GENERIC DRUG DEVELOPMENT
To make a generic product, formulator must know in detail the exact regulatory
requirements of each concerned country where the drug is intended to be filed.
Generic drug product development uses a different approach and strategy
compared to that used to develop an innovator drug product containing a new
chemical entity.
Generic drug product manufacturers must formulate a drug product that will have
the same therapeutic efficacy, safety, and performance characteristics as of its
branded counterpart.

11. ●
The key factor is that the generic drug product must meet all the necessary criteria
to be therapeutically equivalent to the innovator drug product.
●
Therapeutically equivalent means that the drug product shows pharmaceutical
equivalence as well as bioequivalence.

12. Therapeutic Equivalence
Therapeutic Equivalence includes:
 Pharmaceutically Equivalent (PE)
● Same active ingredient(s)
● Same dosage form
● Same route of administration
● Identical in strength or concentration
● May differ in characteristics such as shape, excipients, packaging...
 Bioequivalent (BE)
● Two drugs demonstrate same rate and extent when they become available at
the site of drug action

13. A generic drug is considered
to be bioequivalent to the brand name
drug if :
The rate and extent of absorption do
not show a significant difference
from the innovator drug , or
The extent of absorption does not
show a significant difference and
any difference in rate in intentional
or not medically significant .
Bioequivalence
13

15. FILING A GENERIC DRUG APPLICATION
When a dossier is ready as per the regulatory requirement of
the respective country, it is submitted to the regulatory
agency of that country. Various regulatory agencies
worldwide are tabulated in the below table .

16. ●
FDA:Food and Drug Administration (USA)
●
EMA: European Medicines Agency (EUROPE)
●
PMDA: Pharmaceutical and Medical Devices
Agency(JAPAN)
●
TGA: Therapeutic Goods Administration(AUSTRALIA)
●
MCC: Medicines Control Council (South Africa)
●
TFDA: Tanzania Food and Drugs Authority (AFRICA)
●
ANVISA: Agencia Nacional de Vigilância Sanitária
(National Health Surveillance Agency)(BRAZIL)
●
CIS: Common wealth Independent States (RUSSIA)
●
DOH: Department of Health
●
GCC: The Gulf Co-Operation Council

17. MARKETING
AUTHORIZATION
OF GENERICS IN
EUROPE

18. MARKETING AUTHORIZATION OF GENERICS IN EUROPE
European Medical Agency:
Ø
EMA is the regulatory agency / decentralized body its mainly
responsible in the protection and promotion of public and animal health,
through the evaluation and supervision of medicines for human and veterinary
use. The EU has one of the most highly regarded regulatory systems in the
world.
Ø
EU consists of 27 member states:
Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia,
Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania,
Luxemburg, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia,
Spain, Sweden, and the United Kingdom and three countries which are member of
European Free Trade Agreement (EFTA) Iceland, Norway, and Liechtenstein.
18

19. EUROPEAN FILING PROCEDURE
EU establishes 4 different drug approval processes:
1. Centralized Procedure
2. Decentralization Procedure
3. National Procedure
4. Mutual Recognition Procedure
All medicines must be authorized before they can be marketed and made
available to patients.
In Europe Union (EU), there are two main routes for authorized
medicines:
A centralized route
A national route.

20. CENTRALIZED PROCEDURE
The centralized procedure is one which allows applicants to obtain a
marketing authorization that is valid throughout the EU.
Timeline: EMA opinion issued within 210 days, and submitted to European
Commission for final approval.
Centralized process is compulsory for:
Those medicines which are intended for the treatment of Cancer,
HIV/Aids, diabetes, neurodegenerative disorders or autoimmune diseases
and other immune dysfunctions.

21. 21

22. DECENTRALIZED PROCEDURE
Ø
Simultaneously authorized in numerous countries in the EU.
Ø
More efficient than National Authorization.
Ø
Applicant can select which countries to apply to; does not have to be all EU
countries.
Ø
Based on the assessment report which prepared by the RMS & any comments
made by the CMS, marketing authorization should be granted in accordance
with the decision taken by the RMS & CMS in this decentralized procedure.
Ø
Generally used for those products that has not yet received any authorization
in an EU country.
Ø
Time line: 210 days
22

23. Applicant submits application to the RMS & CMS
RMS & CMS Validates the application
RMS distributes the preliminary assessment report
to the CMS
RMS sends preliminary assessment report & all
comments of the CMS to the applicant
Clock stops, applicant responds, clock runs
RMS sends draft assessment report to the CMS &
Applicant
CMS approve the assessment report
Marketing Authorization in RMS & each of the CMS
70 Days
35 Days
15 Days
90 Days or less
DECENTRALIZED PROCEDURE

24. Applicant submits application to the RMS & CMS
RMS Validates the application
RMS distributes assessment report to the CMS
CMS validates the application
CMS approves the assessment report
Marketing authorization in each of the CMS
90Days
90Days
MUTUAL RECOGNITION PROCEDURE (MRP)

25. NATIONALIZED PROCEDURE
Ø
The National procedure is one which allows applicants to obtain a marketing
authorization in one member state only.
Ø
In order to obtain a national marketing authorization, an application must be
submitted to the competent authority of the Member State.
Ø
New active substances which are not mandatory under Centralized procedure
can obtain marketing authorization under this procedure.
Ø
Timeline for this procedure is 210 Days.

26. 26

27. ASEAN COUNTRIES

29. ACTD
•ASEAN abbreviates Association of South East Asian Nations.
•Established in 08 August 1967
•Ten (10) Member states are Brunei, Cambodia, Indonesia, Lao, Malaysia,
Myanmar, Philippines, Singapore, Thailand, Viet Nam.
•The ASEAN Common Technical Document is organized into four parts. The
ACTD consists of Parts I to IV whereas ICH –CTD has 5 Modules. The
administrative data of Part I is part of ACTD whereas Module 1 of ICH –CTD is
purely country specific.The summaries of the quality (Part II), nonclinical (Part III)
and clinical (Part IV) are located at the beginning of each part of the ACTD. The
ICH –CTD dedicates these summaries in a separate Module 2. As the ACTD does
not have such summary part, it consists of only 4 Parts and not 5.

30. ORGANIZATION OF ACTD

31. ORGANIZATION OF ACTD
ACTD documents comprises following parts;
●PART I:Table of contents, Administrative Data & Product
Information(Applicable)
●PART II:Quality Documents(Applicable)
●PART III:Non Clinical Documents(Not Applicable for generic products)
●PART IV:Clinical Documents(Not Applicable for generic products some
exception may apply)

32. DIFFERENCE BETWEEN CTD & ACTD

35. ACTD Table of Content

36. ORGANIZATION OF ACTD….Content
Part I : Table of Content Administrative Information and Prescribing
Information
Section A: Introduction
Section B: Overall ASEAN Common Technical Dossier Table of Contents
Section C: Documents required for registration (for example, application forms,
labeling, Product Data Sheet, prescribing information)
Part II : Quality Document
Section A: Table of Contents
Section B: Quality Overall Summary
Section C: Body of Data

37. Part III : Nonclinical Document
Section A: Table of Contents
Section B: Non clinical Overview
Section C: Nonclinical Written and Tabulated Summaries
1. Table of Contents
2. Pharmacology
3. Pharmacokinetics
4. Toxicology
Section D: Nonclinical Study Reports
1. Table of Contents
2. Pharmacology
3. Pharmacokinetics
4. Toxicology

38. Part IV:ClinicalDocument
SectionA:Table of Contents
SectionB:Clinical Overview
SectionC:Clinical Summary
1.Summary of Bio pharmaceutics and Associated Analytical Methods
2.Summary of Clinical PharmacologyStudies
3.Summary of Clinical Efficacy
4.Summary of Clinical Safety
5.Synopses of Individual Studies
SectionD:Tabular Listing of All Clinical Studies
SectionE:Clinical Study Reports
SectionF:List of Key Literature References

39. List of Documents Required
List of documents required for Part I Administrative section writing:
1. Application form (details to be filed in)
2. Letter of Authorization
3. Certifications
i. Manufacturing license
ii. Certificate of Pharmaceutical Product
iii. GMP certificate of the Manufacturer
iv. Site Master File of manufacturer
4. Labeling
i. Mock-up for Inner Carton
ii. Mock-up for outer carton
iii. Mock-up for Label

40. 5. Product Information
i. Package Insert
ii. Summary of Product Characteristics (Product Data Sheet)
Summary of Product Characteristics is required for NCE and Biotechnology
products.
iii. Patient Information Leaflet (PIL)
PIL is required for Over-the-Counter Products Product Information

41. List of documents required for Part II Quality section writing:
1. DMF of API
2. BMR Finished product
3. BPR Finished product
4. Critical manufacturing steps and justifications
5. Process validation protocol and report
6. Flow chart (Detailed and simple)
7. Process development report
8. Impurity profile with justifications
List of Documents Required

42. 9. Excipient details :
–Specification and testing method
–COA
–TSE/BSE declaration from supplier/manufacturer.
10. Specification and method of Analysis (MOA)
–Intermediates and in-process specification & MOA
–Finished product release specification & MOA
–Finished product Stability specification & MOA
–API specification & MOA from finished product manufacturer.
–Packaging material (primary, secondary and tertiary)

43. 11. Analytical method validations at release and stability (if different methods are
used)
–Assay
–Related substance
–Dissolution (if applicable)
–Preservative content (if applicable)
–Sterility (if applicable)
–Endotoxin(if applicable)
–MLT
–Forced degradation

44. 12. COA’s
–API (3 consecutive batches) from FP manufacturer
–All the raw material (excipients and coating materials)
–Reference and working standards
–Impurity standards
–Packaging material (primary, secondary and tertiary)
13. IR spectra of PVC/PVDC sheets and aluminum foil if used
14. Soft copy of labels (PDF)
15. Food grade certificate from primary packaging material manufacturer
for its primary packaging material

45. 16. Preparation of reference standard in brief
17. Stability protocol
18. Stability data and Photo stability data (if applicable)
19. Bioequivalence study (if applicable)

46. MALAYSIA
GENERIC DRUG
FILING PROCEDURE

47. DEFINITION : GENERIC PRODUCTS
A product that is essentially similar to a currently registered product in Malaysia.
•The term generic is not applicable to biological & biotechnology products.
•Active ingredient previously approved.
•Product information previously approved.
•Route of administration, strength and dosage form equal to those of previously
approved product.

48. •Usually intended to be interchangeable with the innovator product.
•Manufactured without a license from innovator company.
•Marketed after expiry of patent or other exclusivity rights.
•Marketed either under the approved non-proprietary name or under a brand name
(proprietary name)

49. INNOVATOR Vs GENERICS
Criteria Innovator Generic
Registration by DCA yes yes
Procedures Online/Manual Online
Processing Fee RM4000-RM5000 RM2200-RM3000
Requirements Quality,Safety
Efficacy(Animal And
Clinical Study)
Quality,Safety
Efficacy(BE study)
Processing Time 245 W.d 210 W.d
Validity Of Registration 5 years 5years
PMS & ADR Monitoring Yes yes
GMP Facilities Yes Yes
Finished Produccts QC Yes Yes
Stability Data Yes Yes

50. Types of Generic Applications
Full Evalution Abridged Evaluation
Scheduled
Poison
OTC / Non Scheduled Poison
*Categories
Generic pharmaceutical Products
210 Days 80 Days

51. •Scheduled Poison(s) Products
Pharmaceutical products which contain scheduled poison(s) as defined in the First
Schedule under POISON ACT 1952.
•E.g. Atenolol, Ibuprofen, Lisinopril, Cimetidine, Dextromethorphan, etc
Non-Scheduled Poison(s) Products (Over-the-Counter (OTC))
•Pharmaceutical products which do not contain scheduled poison(s), other than
health supplements or natural medicines or cosmetics.
•E.g. Paracetamol, Simethicone, Aspirin, Clotrimazole, etc.

52. •Non-Scheduled Poison(s) Products (Over-the-Counter (OTC))
•Includes, but not limited to the following :
•Antiseptics / skin disinfectants;
•Locally-acting lozenges / pastilles;
•Topical analgesics / counter-irritants;
•Topical nasal decongestants;
•Emollient / demulcent / skin protectants;
•Keratolytics;
•Anti-dandruff;
•Oral care;
•Anti-acne;
•Medicated plasters / patch / pad; and
•Topical antibacterial

53. PART-I:Adiministrative Data & Product Information
THE ASEAN COMMON TECHNICAL DOSSIER (ACTD) FOR THE
REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE
Section A Product Particulars
Product name,name & Strength of active ingredients(s), Product
Description
,Indication,Dosage,Contra indications, Warning & Precautions,Storage
Condictions & Shelf life.
Section B Product Formula
Section C Particulars of Packing
Section D Label & Package Insert
Section E
Supplementary Documentation
Letter of Authorisation, Certificate of Pharmaceutical Product, CFS, GMP

54. Part-II:Quality
a)Part S-Drug substance
THE ASEAN COMMON TECHNICAL DOSSIER (ACTD) FOR THE
REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE
General Information Nomenclature
Structure
General Properties
ManufaCturer
Contro of Drug
Substance
Specification
Certificate of Analysis(CoAs)

55. Part II: Quality
b)Part P-Drug Product
THE ASEAN COMMON TECHNICAL DOSSIER (ACTD) FOR THE
REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE
P1
Description & Composition
P2 Pharmaceutical Development
Justification of overages, selection of preservative, formula
development summary
P3 Manufacturer
Batch Manufacturing Formula, Manufacturing & Packaging Process, Control of Critical
Steps & Intermediates, Process Validation
P4 Control of Excipients
Specifications

56. P5
Control of Finished Product
Specification, Certificate of Analysis (CoAs)
P8
Stability
Real time & accelerated stability report
P9
Product Interchangeability / Equivalent Evidence
BE Report – applicable only for listed generic oral solid immediate release
dosage form
Bioavailabiliy Report – applicable for all modified-release/extended-
release/sustained release product

57. Application Submission
Application Screening
Application Evaluation
Regulatory Decision
Approval
Rejected
Appeal
Registration Process
Application
Rejected

58. REGISTRATION CONDITIONS
Registration no: MAL07021234A
•Product registration is for a period of 5 years
•Updating of product information / amendments / variations is allowed through
proper application - any changes that would affect the quality, safety and efficacy
of product will not be allowed
•Renewal of registration is required for maintenance on the register ( to be notified
by holder within 6 months before registration expires)
•Post Market Surveillance, Adverse Drug Reaction Monitoring and investigation
on complaints AT ALL TIME.

59. REGISTRATION CONDITIONS
•The DCA wishes that all medical practitioners, health professionals, consumers
and the public report any complaints regarding the quality of medicines
particularly if they experience adverse reactions or any other problems with
these medicines.
•DCA will not hesitate to suspend, cancel, recall unsafe or substandard products
from the market.

60. OBJECTIVES OF CENTRE FOR POST-REGISTRATION OF
PRODUCTS
•Ensure that drugs registered for use in Malaysia comply in terms of quality,
efficacy and safety.
•Ensure that product labeling (inserts, labels, indications and claims) of registered
products are as approved by Drug Control Authority.
•Monitor the safety profile of marketed drugs in order to
Take the necessary actions to minimize risks to consumers
Reevaluate the risks-benefits ratio of marketed products

61. POST-REGISTRATION
● Routine surveillance
Market Sampling
Laboratory Analysis
Label Monitoring
● Investigations of product complaints
Quality defects
Safety & efficacy issues
● Safety profile monitoring of products
Adverse Drug Reactions (ADR) Monitoring
Review of Periodic Safety Update Reports (PSUR)

62. POST-REGISTRATION
● Routine surveillance
Market Sampling
Laboratory Analysis
Label Monitoring
● Investigations of product complaints
Quality defects
Safety & efficacy issues
● Safety profile monitoring of products
Adverse Drug Reactions (ADR) Monitoring
Review of Periodic Safety Update Reports (PSUR)

63. Challenges in Malaysia and Europe
● Overcoming the Price tag between Branded and generic drugs
● Quality generic products can be access to remote and rural areas
than branded drugs.
● By assessing the drug product and manufacturing processes of the
product it is possible to apply a Specific Customs procedure to
minimize or eradicate duties payable
Eg:high-value biologic API's being shipped into Europe by US clients
Charge Duties are High
● Multiple languages on packaging requirements.
● To ensure all drug products reach the end user in optimum condition
customized configurations validations etc are performed.

64. Filing Review
● Filing review is conducted to determine whether
the application is sufficiently complete to permit
a substantive review.
● Acceptance/Refuse to Receive (RTR) letter is
issued based on completeness of the ANDA.
● Updating the regulatory filing checklist on a
quarterly basis (calendar year) and on an as
needed basis.

65. Conclusion
Although there is a continuous process of harmonization taking place all
around the world, still we see a huge challenge, which is yet to be overcome
by the Pharmaceutical industry in case of generic drug development and filing.
This is due to the heterogeneity in the regulatory landscape of the various
countries. Therefore, to meet these challenges, a lot of strategic planning is
required before the development of any generic drug product.

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