Comparative Study Requirements For The Submission of Generic Drug Us Eu

Sukesh Bhardwaj et al. / AJPSR volume 1 issue 5, Oct.
2011

1
Sukesh Bhardwaj et al. / AJPSR volume 1 issue 5, Oct 2011

Available online at www.ordonearresearchlibrary.com ISSN 2249-4898

ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES AND RESEARCH
COMPARATIVE STUDY: REQUIREMENTS FOR THE SUBMISSION OF GENERIC DRUG
APPLICATION ACROSS US AND EU IN CTD/ECTD FORMAT
Sukesh Bhardwaj, Vikaas Budhwar, Vipul K. Gupta
Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak (Haryana).

Received: 27 Aug. 2011; Revised: 24 Sep. 2011; Accepted: 21 Oct 2011; Available online: 25 Nov 2011

INTRODUCTION
Food Drug and administration
[1]
is the regulatory agency of the United States and the European Union consists
of about 27 countries, each nation has its own regulatory agency but EMEA
2
is the centralized regulatory
authority applicable to whole Europe. In order to get the approval of the drug product in the particular country
by their regulatory authorities, complex procedures had been followed. In Europe, there are three procedures
mainly used for filing a drug application, such as, Centralized, decentralized/MRP and National Procedures
3
.
There were lots of problems occur for the translation according to the regional language of a same application
and are generally very time consuming process. To overcome such problems, a concept of ICH
4
was declared in
1990. This was declared by the cooperation of the three regions US, EU and Japan; which are known as
tripartite regions of the ICH. ICH was organized with a major objective to draft, approve and implementation of
the guidelines which are accepted throughout the tripartite regions. Such guidelines are made covering all the
aspects and parameters related to the drug products i.e. purity, quality, safety, and efficacy point of view.
Hence, the guidelines prepared by the ICH are known as tripartite guidelines. According to ICH, all the
technical requirements for the application of drug approval were harmonized in CTD format which are
scientifically more elaborate by USFDA in Quality Overall Summary (QOS) and Overall efficacy (includes
clinical overview and clinical summary). This way of presentation of the registration documents has increased
Review Article
ABSTRACT
The major pharmaceutical markets in the world are United States and European Union, have different requirements
for the registration of a pharmaceutical product. To harmonize the requirements as per the regulatory agencies, a
concept of common technical and its electric version was implemented by ICH. As the CTD consists 5 modules;
some modules are common to all regions. But there are still some differences in the requirements in the common
modules as per the regional requirements. In this competitive world of Pharma generics, an attempt is made to
highlight the difference between the two major countries registration requirements through CTD and eCTD format
in this article.
Key words: CTD, eCTD, ANDA, Generic drugs etc.

Sukesh Bhardwaj et al. / AJPSR volume 1 issue 5, Oct. 2011

2

the efficiency in the FDA review process
5,6
. CTD is common technical documents
7
which is a major project of
the ICH to avoid the duplication and translation into regional language work of a single application. Through
this, an applicant can file one single application to more than one country at a time for the registration of their
drug product.
The main Areas of Harmonization for CTD are:
Safety Pharmacology
Clinical pathology
Immunotoxicology
Juvenile toxicity studies
Statistical methods in certain studies like mutagenecity, carcinogenicity and toxicokinetic studies during
the 1
st
phase of ICH. So far, this has not been discussed in any ICH EWG and could be considered as a
future topic.
Recommendations for additional/ alternative methods of testing carcinogenicity.
The Common Technical Document is organized into five modules
8
. The contents of Module 1 are different
according to the competent authorities of the United States (FDA), the European Agency for the Evaluation of
Medicinal Products (EU). The modules are present in the triangular format as shown in the Figure 1 in which all
the modules are the part of CTD except module 1 which is not the part of CTD and is different for different
country. The different modules are as follows:
Module 1: It is related to submit the regional and administrative information to the national regulatory agencies
in which an applicant desires to file a market approval application as per their regulatory guidelines. Prescribing
informations (such as labeling and package inserts) also come under this module. It is totally different for
different country. The list of requirements fir module 1 is enlisted in the Table 2 for US and EU.
Module 2: It consists of the overviews and overall summaries related to the chemistry, manufacture, control
(CMC), non-clinical, and clinical studies results conducted to prove the quality, safety and efficacy of the drug
product. This module includes the summaries of module 3, 4, and 5.
Module 3: Quality - It covers the complete pharmaceutical and technical aspects which can affect the quality of
the drug product. From the formulation and development department (pharmaceutical development report) to
the manufacturing (GMP), analysis and testing (GLP), packaging, storage conditions, stability studies of the
drug product. The main differences as per the regulatory requirements are given in the Table 3.
Module 4: Non-clinical study reports it covers the complete pharmacological, toxicological study reports and
informations equivalent to the quality of the drug to provide the evidence of the safety of the drug product.
Module 5: Clinical study Reports The clinical trials and their reports carried out on the human beings to list
the desired effect of the drug product are included in this section. It is to provide to the regulatory authority

3

containing the informations which prove the efficacy of the drug. For generic drugs, the applicant only has to
prove the bioavailability similar to that of innovator or branded drug only. To conduct such bioequivalence
studies
9
(BA-BE), healthy volunteers are selected and to be conducted in a controlled manner.
Before CTD/eCTD application for the submission of a drug application, the procedure was different as per the
country wise. In US, NDA, ANDA, BLA, Integrated summary of Safety (ISS), integrated summary of Efficacy
(ISE) was submitted for the approval of the product as shown in the Figure 2, so many duplicate copies were
required to make according to the FDA
11
.
In European Union, the expert reports and tabulated summaries
12
were recommended n Europe before the
recommendation of CTD as shown in Figure 3. Likewise, In Japan, GAIYO format
13
was followed for the filing
of the regulated drug application as shown in the Figure 4.
The tables given below consist of the possible regulatory requirements for the registration application as per US
and European regulatory guidelines:
Comparison between US eCTD and EU eCTD

Table 1: General
CTD/eCTD
UNITED STATES EUROPE
General
1. FDA is the sole regulatory authority for
controlling and regulating the food and drugs.

2. The eCTD is mandatory for the submission
of the drug applications (NDA/ANDA)

3. US FDA guidance (CFR) documents and
FDA sections (e.g. 505 (b) for NDA and 505(j)
for ANDA)
15
are followed for the preparation
1. EMEA is the centralized authority and many
CPMP, MHRA, CHMP etc. country wise for the
approval of the market authorization application in
whole Europe.

2. The eCTD is not fully mandatory but NeeS is
submitted along with the paper submission for
MAA till end of December 2009.

3. Expert reports and Directives (e.g. Directive
2001/83/EC-Article 8(j))
16
drafted are followed in
making the dossiers for market authorization

4

of the dossier for the drug approval
applications.

4. The applications are different e.g.
For new drug- NDA
For generic drug ANDA
For biological application BLA

5. The application is directly submit to the
FDA by the applicant or through any approved
contact agent for whom a certification is
provided to the agency according to the GDEA
1992
17
.

6. The technical data about drug substance or
API is known as DMF (Drug Master File Type
II) and is submitted in the eCTD in Module 2
(2.3.S) and 3 (3.2.S).

7. CFN (Central file no.) or FEI no. is
submitted to FDA which is issued by the
district government.
application.

4. Only single type of application is applicable for
each new drug, generic drug etc is MAA (Market
Authorization Application).

5. Three processes for drugs approval are
applicable in Europe
11

A) Centralized procedure (CP)
B) Decentralized procedure (DCP)/
Mutual Recognition procedure(MRP)
C) National procedures

6. The technical data about drug substance
submitted with the dossier in 2.3.S and 3.2.S part
of the eCTD is known as ASMF (Active
Substance Master File).

7. No any CFN or FEI no. is submitted to the
agency.


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Table 2: Module 1
Module 1:Regional information
i. Administrative information is different
i.e. cover letter, forms (356h),
application information, field copy
certification, debarment certification,
financial certification, Patent information
and exclusivity
18
.

ii. The paper size for the submission is
Letter size (8.5x11 inches) with font size
12 in times new roman format. The
tables and figures have small font size
i.e. 8 to 10.

iii. Package inserts are provided for drug
product in labeling.

iv. Proposed Labels and cartons with proper
dimensions similar to that of the RLD
labels are provided.

v. The information about the clinical
investigators is provided in the Module 5
and in financial disclosure Statement
section of this module.

i. Administrative information such as cover
letter specified for the particular country,
application form applicable in that
country, exclusivity statement, proof of
payment to clinical investigators, proof
of establishment of the applicant in EEA.

ii. A4 (8.27x11.69inches) paper size is used
for the dossier preparation with font size
12 in times new roman format.

iii. SPC (summary of product
characteristic)
19
is provided about the
drug product in labeling.

iv. Mock ups and specimens of labels and
cartons sent with the application as
appropriate. Braille is used for the
labeling conditions on the labels.

v. The information (curriculum vitae) of the
experts (Quality and Clinical) is
provided.


6

vi. Request for waiver of in-vivo BE studies
is provided in the module 1.

vii. Annotated draft labeling (side by side)
for labels and cartons compared with the
RLD with proper annotation is provided.

viii. The EAS (Environment Assessment
Statement
20
) for categorical exclusion
certification in compliance with the law of
EPA of US is provided.

ix. Risk management Plans section is for
the post marketing surveillance and
controlling the adverse effects of the drugs
by proper management. This is the part of
Clinical Trial Phase IV.

vi. Request for waive is not provided in the
module 1.

vii. No annotation (side by side) for labeling
is provided. Everything is provided in the
SPC and package inserts.

viii. Environ risk Certification
21
is given with
the information for GMO or Non -
GMO. The fresh/new certificate is
provided.

ix. A separate additional section is provided
for the pharmacovigilance system for
surveying and controlling the post
approval undesired effects of the drug.

Table 3: Module 3
Module 3
Module 3.2.R
(i) The executed batch records for manufacturing
and packaging are provided in Module 3.2.R for
only single batch.

(ii) The declaration is given for the residual
solvents limits used or present in the drug
Module 3.2.R
(i) The three executed batch records for
manufacturing and packaging for process
validation schemes are provided in Module
3.2.R.

(ii) The declaration is given for the residual

7

substance and excipients according to the USP
<467>
22
.

(iii) Information on components including the
name and address of the supplier or
manufacturer of the raw material, package
material etc provided in the 3.2.R.

(iv) Letter of Access is not mentioned in 3.2.R.

(v) TSE and BSE certificates are not attached in
this section whereas submit in DMF.

(vi) Certificate of suitability (CEP certificate) is
not applicable.

(vii) Comparability protocols are not attached for
both the drug substance and drug products.

solvents limits used or present in the drug
substance and excipients accordance with the
ICH limit mention in the Q3C (R3) impurities
23
.

(iii) information in components employed in the
drug product formulations is generally not
provided in the module 3.2.R

(iv) Letter of access to Active substance master
file of drug substance is provided for the agency.

(vi) TSE and BSE certificates are attached for
drug substance and excipients.

(vii) The latest Certificate of suitability (CEP)
24

obtained from the EDQM Europe for each drug
substance and excipients are attached.

(vii) Comparability protocols are attached.
A comparability protocol prospectively specifies
the tests and studies that will be performed,
analytical procedures that will be used, and
acceptance criteria that will be achieved to
assess the effect of CMC changes
25
.


8

Table 4: Other differences
Other Differences
(i) The stability data for accelerated studies are
submitted for three months at the time of
original submission.

(ii) Node extension is not allowed in the eCTD
XML in software.

(iii) Structured product labeling (SPL)
26
and
study tagging file (STF)
27
is mandatory by
the USFDA in eCTD of a drug registration
application. Paper CTD format is not
accepted by FDA at all.
(i) The stability data for accelerated studies are
submitted for complete 6 months at the time
of original submission.

(ii) Node extension can be permissible.

(iii)SPL and STF are not applicable in
European eCTD dossier preparation
because it not fully mandatory in Europe.
NeeS
21
format is submitted in place of
eCTD along with paper CTD dossier.

SOME MERITS AND DEMERITS OF CTD
MERITS
Enables the ease and fast submission.
Easily approachable and loadable from the industry to regulatory agency.
Pictures, images resolution is increased through jpeg, gif etc. files.
Available in various formats like pdf, xml and word files.
Most frequently it is being adopted by the pharmaceutical industries and research on a large
scale.
It is multidisciplinary so widely acceptable.
The labeling based on the SPL (structured product labeling) format makes easy, clear, and
readable fastly according to the particular sections.
Granularity in the whole document is increased.
Easy navigation by the XML (extensible markup Language) index throughout the document.

9

In case of any discrepancies in particular page of any section, only that page can be replaced in
spite of replacing the complete section.
STF makes the filing very easy.
The electronic software helps in creating the STFs (Study Tagging Files) in order to correlate the
case report forms with the study files.
DEMERITS

It is far easier to prepare paper submission (CTD) than to build electronic submissions (eCTD)
expertise in-house Since it is fully electronic, it requires full skills and knowledge about the
software and other technologies.

Extensive retraining of staff is usually needed: It is based on the XML format; therefore the
person involved in the eCTD compilation must be trained.

The eCTD requires more attention as a single minor mistake can create a deficiency in the whole
application. Therefore it is not fully mandatory in the world. It is mandatory in USA whereas in
EU it is accepted along with the paper submission.

CONCLUSION:
It is concluded that though the CTD is the common format but it was found that still some differences are there
in the regulatory requirements. Like for residual solvents, in US USP<467> limits are followed but for EU, ICH
Q3C residual solvent limits are incorporated. The two major pharmaceutical markets are involving in the
generic Pharma field as no. of the patents are going to be expired in future. Due to this, many generic applicants
are keeping busy themselves in the finding the patent claims loop holes and paragraph certification filing to
achieve the market as first as possible. For this electronic version of the CTD is being used. Non eCTD
electronic submission (NeeS) is mandatory in EU in place of eCTD up to December 2009 where as it is purely
mandatory by USFDA. There is further need of the harmonization in the regional requirements in the common
technical documents.


10

Figures:
CTD TRIANGLE

Figure 1: CTD TRIANGLE: Diagrammatic representation of the Organization of CTD
10

The diagrammatic or CTD triangle for the three different countries which are the tripartite countries of ICH is
given below as provided in the triangle:

The registration triangles for the US and EU below:

Module 1
Module 2
Module 3
Module 4 Module 5
Quality
Nonclinical
Study
Reports
Clinical
Study
Reports
Regional
Administrative
Information
Nonclinical
Summary
Clinical
Summary
Nonclinical
Overview
Clinical
Overview
Quality
Overall
Summary
Not
part
of
CTD
CTD
Table of Contents
&
Introduction

11

Figure 2. USFDA Drug Registration Triangle
14

Figure 3. European Drug Registration Triangle
14


12

Figure 4. Japan Drug Registration Triangle
14

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13

11. Guideline On The Use Of The CTD Format In The Preparation Of A Registration Application For
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24. European Directorate for the Quality of Medicines & HealthCare http://www.edqm.eu/en/Revisions-
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