comparative study requirements for the submission of generic drug us eu

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

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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 EMEA2 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 Procedures3.

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 ICH4 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.

http://www.ordonearresearchlibrary.com/

http://www.ich.org/


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the efficiency in the FDA review process5,6. CTD is common technical documents7 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 1st 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 modules8. 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

http://www.fda.gov/


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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

studies9 (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 FDA11.

In European Union, the expert reports and tabulated summaries12 were recommended n Europe before the

recommendation of CTD as shown in Figure 3. Likewise, In Japan, GAIYO format13 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


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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

199217.

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 Europe11

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 exclusivity18.

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.


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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

Statement20) 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 Certification21 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


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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) impurities23.

(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 changes25.


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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.

NeeS21 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.


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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.


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Figures:

CTD TRIANGLE

Figure 1: CTD TRIANGLE: Diagrammatic representation of the Organization of CTD10

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


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Figure 2. USFDA Drug Registration Triangle14

Figure 3. European Drug Registration Triangle14


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Figure 4. Japan Drug Registration Triangle14

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comparative study requirements for the submission of generic drug us eu

Documents

technical requirements

regional requirements

different requirements

application of drug

ajpsr volume

ctdectd format sukesh

regulatory agency

drug products