“REGULATORY ENVIRONMENT OF DIFFERENT COUNTRIES ON THE BASIS OF E CTD”

GE-International Journal of Management Research

© Associated Asia Research Foundation (AARF)

“REGULATORY ENVIRONMENT OF DIFFERENT COUNTRIES ON

THE BASIS OF E CTD”

Lincy Joseph*1, Mathew George 2Sachin Lawania, 3 Anjana .M.N4

1

Professor, Department of Pharmachemistry, 2 Professor, Department of Pharmacology, 4 Asst. Professor, Department of Pharmaceutics. Pushpagiri College of Pharmacy,

Medicity Campus, Peruthuruthi P.O, Thiruvalla- 689107 Kerala, India.

ABSTRACT

Regulatory Affairs refers to the interaction of the company with the regulatory authorities,

internal departments of the organization and interaction throughout the life cycle of a

product, from conceptualization to marketing of it. Since it is the world of competition and

due to the expiration of the numerous patents of the branded drugs in the coming year may

lead to encourage the various generic companies. The every generic applicant wants to

launch the drug into market as soon as possible the project firstly and gets the 180 days

market exclusivity period to exclude the other generic applicants to market their products.

Objective of the present study is to study the regulatory requirements for the submission of an

eCTD for generic drugs on global basis,to find out the effectiveness and awareness of an e

CTD ,to study the modules of various countries and to comparative study of an e CTD in US

and EU.Since e CTD is an international initiative,it is belived that the e CTD will be globally

recognized submission format for several years. The e CTD is the preferred format for

regulatory submissions to FDA and offers considerable strategic be befits to sponsor

organisations.For many sponsors, outsourcing offers a compelling option to achieve the

benefits of e CTD while significantly lowering the cost ,effort and risk barriers. Overall, this

and business requirements forces agencies to consider changes in their systems, guidelines

and processes to make development more efficicent and cost effective.

KEYWORDS: eCTD, FDA, Regulated product Submission, Regulatory affairs, Modules

Introduction

Drug Regulatory /Regulatory Affair [1]

Regulatory affairs refer to the interaction of the company with the regulatory authorities,

internal departments of the organisations and interaction throughout the life cycle of the

product, from conceptualization to marketing of it. Drug regulatory affairs are a dynamic,

rewarding field that embraces both scientific and legal aspects of drug development. Drug

affairs provide an in depth overview of the full spectrum of drug development, from clinical

trials to marketing to post approval activities. As members of the development team

regulatory affairs professionals play a very important role in new approvals. Despite the

existence of standards for drug regulation now at least 50 years, there are still many problems

with regard to the safety and quality of medicines, in both developing and developed

countries. The primary aim of drug regulation is protection of public health. Medicines are

not normal commodities, they meet fundamental health needs, and access to essential

medicines, according to the WHO.[2]

Common Technical Documents

Common technical document is an internationally agreed formal for the preparation of

application to be submitted to regulatory authorities in the three ICH regions of Europe, USA,

Japan. [3]The CTD indicates an appropriate format for the data that have been required in an

application. Applicants should not modify the overall organization of the common technical

document as outlined in the guideline. However in the non clinal summaries, applicants can

modify individual’s formats if needed to provide the best possible tabulated presentation of

the technical information, in order to facilitate the understanding and evaltion of the results.

[4]

Electronic Common Technical Documents:

eCTD is the electronic version of CTD,CTDis the harmonized format for submission of

make a product.The LCHM2EWG has defined the specification for the eCTD. [5] It is

defined asan interface for industry to agency transfer of regulatory information while at the

same time taking into consideration the facilitation of the creation,review ,life cycle

management and archiving of the electronic submission.[6].For 10 years ICH has set about

achieving a common format for the dossier that must be submitted to gain approval for

medicinal products in all three ICH regions, Europe, USA and Japan. The aim of the CTD

was to provide a common format for the preparation of the documentation to support a

marketing authorization appilication, that would be submitted to the regulatory

authorities.[7,8] The survey showed the similar results in the two regions Europe, as a large

continent consists of many countries and different languages are generally used for the

marketing authorization in different countries. In order to market the same product ion other

country with Europe and long hypothetical procedure was followed and firstly the complete

registration application had to convert into the regional language according to the regional

guidelines.CTD which meansthe document containing the complete information regarding

chemistry,biochemistry,microbiology ,pharmacological ,clinical ,pre

clinical,pharmaceuticaland manufacturing,product characteristics,labelling and packaging

details etc.A CTD cou;ld thus bring real savings by minimizing the time and resources

required for preparing different submissions for different regulatory agencies.[7,8]

Area of Harmonization for CTD[7,8]

 Safety Pharmacology, Clinical Pathology, Immuno toxicity ,Juvenile toxicity studies

 Stastical methods in certain studies like mutagenecity,carcinogencity,and

toxicokinetic studies during first phase of ICH.

 Recommendations for additional/alternative methods of testing carcinogenicity.

The common technical document is organized into five modules.The content of module 1

is different according to the competent authorities of the united states,the European

agency for the evalution of Medicinal products and Japan but the structure of module

2.3.4 they are common for all ICH regions.

Modules [9]:The electronic technical document is divided into 5 modules.

 Administrative and prescribing information.

 Safety

 Efficacy

Administrative and prescribing information: Including the granularity document that provides

guidance on document location and paginations. The common technical document provides

for a harmonized structure and format new product applications.

Quality: The section of the application covering chemical and pharmaceutical data including

data for biological /biotechnological products. The quality section of the CTD provides a

harmonized structure and format for presenting CMC information in a registration dossier.

The table of contents includes sections on drug substance and drug product. There are

sections for regional specific information as well as some appendices.

Safety: Non-Clinical Study reports: The CTD guideline delineates the structure and format of

the non clinical summaries in Module 2 of the common technical document, and provides the

organization of Module 4,the non clinical study reports. The non clinical overview should

present an integrated and critical assessment of the pharmacologic, pharmacokinetic and

toxicological evalution of the pharmaceutical and generally should not exceed 30 pages.

Efficacy: Clinical Study reports: CTD efficacy describes the structure and format of the

clinical data in an application including summaries and detailed study reports. There are two

M high level clinical summaries in Module 2 of the CTD, the clinical overview,a short

document that provides a critical assessement ofthe clinical data ,and the clinical summary,a

longer document that focuses on data summarization and integration.Clinical study repots and

raw data are included in module 5 of the CTD.

MERITS AND DEMERITS OF e CTD [9]

The experience to help to move confidently into electronic submissions and Ectd:The FDA

and EMEA are both encouraging and in some cases, already requiring the use of electronic

submission. Many companies are post ponding the transition to electronic filing because it

requires new infrastructure, procedures and concepts.

Major Challenges which are required to be faced in implementing e CTD

 Business process needs revision

 Personal needs to be trained

 High investment and maintenance cost in purchasing and adopting the system.

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 files.

 Available in various formats like pdf, xml and org files

 Most frequently it is being adopted by the pharmaceutical industries and research on a

large scale

 It is multi dispinary so widely acceptable.

 The labelling based on SPL format makes easy ,clear and readable fastly according to

the particular sections.

 Granularity in the whole document is increased.

 Easy navigation by the XML index throughout document.  STF makes the filling very easy.

 The electronic software helps in creating the STF in order to correlate the case report

forms with the study files.

Demerits

 It is far easier to prepare paper submission than to build electronic submissions (e

CTD ) 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 usaually needed.It is based on the XML

format,therefore the person involved in the e CTD compilation must be trained.

 The e CTD requires more attention as asingle minor mistake can create a deficiency in

the whole appilication.

Many softwares are being used by the pharmaceutical companies for filling e-dossiers to the

regulatory authorities in order to fulfill the regulatory requirements with the prescribed time

to get approval as soon as possible. A variety of software products which being used by the

companies are available to facilitate viewing and or creating e CTD publications. For an

visibility into the entire regulatory document management form document creation to the

regulatory submission. It facilities

 Submission roadmap/Structure creation  Document assembly

 Work in progress/Final preview  Interview review

 Sequential/Parallel approval cycles  Compilation

 Publishing

The objective of this present study is

 To study the regulatory for the submission of an e CTD for generic drugs on global

basis.

 To study the Module 1 of various countries in order to facilitate the administrative and

prescribing information.

 To find out the effectiveness and awareness of an eCTD.  To study the status of eCTD worldwide

 To provide the comparative study of an eCTD in US,and EU, two major

pharmaceutical markets in this world.

The primary focus of the present study on eCTD is to provide data in interchange information

between the industry and regulatory agencies.The industry initiates the process by creating

intial submissions in terms of an electronic CTD.Throughout the lifecycle of this process by

creating initial submissions in terms of an electronic CTD through out the lifecycle of this

process,additional information will be submitted to update or modify the information.

Methodology

The module 1 of the common technical document or electronic common technical document

is specifically for the regional information which are applicable to that country created by

their own regulatory agencies.Also dexcribe the prescribing information which is provided

for labelling and packaging inserts for the drug products. Frequently ,the module 1 is

different for the different countries whereas the rest of the module 2 to 5 are common for all

the ICH regions.As the CTD became mandatory ,when implemented by the Multidisciplinary

concept e CTD implemented by ICH M2 EWG mainly for the e-submissions and become

more important topic than any other project. It describes the full content for the dossier for

the submission of marketing authorization application to the respective agency. Module 1

includes all administrative documents (forms and certifications) and labelling, including the

documents described in regional guidance. Not all regionally specific documents are included

in regional guidance. Not all regionally specific documents are included in module

1.Technical reports required for a specific region should be placed in modules 2 to 5.

United States: e CTD Module 1[10]

The US module 1 consists ToC sections containing the administrative and regional

information applicable in ITS only.

Cover Letter [11]:It is optional for the e-submission while mandatory for the paper

submissions.It is required to submit the purpose of submission and type of submission,

original/amendment/supplement/annual report/resubmission etc.The following

information should be included in the cover letter.

 Description of the submission including approximate regulatory information.

 Description of the submission including appropriate size of the submission, volumes of the document,the format used for DLT tapes and the type and number

of electronic media used.

 Statement that the submission is virus free with a description of the software ,used

to check the files for viruses.

 Regulatory and technical point of contact for the submission.

FDA Form 3674: Certificate of compliance of PHS Act Requirement of Clinical Trials[12]

A separate form 3674,in pursuant of section 505 (j) of the Federal Food Drug and Cosmetic

Act, the appilicant or generic manufacturer herewith submits as ANDA for the product in

order to support the FDA requirements, section 42 (j) of public Health and service Act, this

form 3654 is enclosed for conducting the BE studies of the generic drug product.

Administrative Information:Applicant Information/Contact/Sponsor: The name of the generic

drug manufacturer or applicant for e CTD submission for generic drug, company name,

case of any change in address, sponsor or contact agent the upto date information should be

provided to FDA.

Field Copy Certification [13]:Not applicable for e-submissions. It is only for the paper

submission because in paper submission, there are four copies to be submitted to FDA,

archival copy, review copy, review copies for CMC section and bioequivalence study section,

and field report review copy.

Deparment Certification: Generic Drug Enforcement Act 1992[14]

Federal Food Drug and Cosemetic Act as amended by the GDEA 1992, the generic drug

manufacturer certifies that the company did not and will not use in any capacity, the services

of any person debarred under subsections or of the GDEA 1992 in connection with the

ANDA.

Financial Certification Disclosure:This section provides the certification to the FDA that the

clinical investigators involved in carrying out the bioequivalence studies are not the member

of any other finance form 3454 anf form 3455 are prescribed in order to provide this

certification.

Patent Information:According to the information published in the approved drug products

with therapeutic equivalence evaluations,(orange book) [15] the information of unexpired

patents/expired patents for the drug product in the orange book database for which ANDA

filing is submitted.

Patent Certification [16]:In accordance with the Food DRUG and Cosemetic Act , as

amended and with the final regulations effective pursuant therefore Patent certification is

provided for the Abbreviated New DRUG Appilication for the Generic drug product.

Para 1 Certification: When patent information is not present or exits. This certification is

made when ANDA applicant is aware that there may be patent in force that may cover RLD,

but the NDA holder has whatever reason decided not to list the patent with agency.If ANDA

appilant makes a Para certification, the FDA may approve its appilication immediately as

long as the FDA determines that the ANDA otherwise meets the approval requirements.

Para11 Certification: A paragraph II certification is appropriate when there is a patent listed

has expired, and provides the patent no and date of the patent expiration. An ANDA

containing certification is eligible for immediate effective approval if the ANDA applicant

has otherwise met the FDA approval requirements.

Para III Certification: Apara III certification acknowledges that there is a listed patent on the

RLD that has not expired and the applicant does not plan to market its product prior to the

expiration of the patent. In this instance, the law precludes the FDA from approving until the

patent has expired. The applicant gets the tentative approval if all the information provided to

the agency is in compliance with the regulatory guidelines.

Para IV Certification: An applicant containing a paragraph IV certification signifies that the

ANDA applicant plans to challenge one or more of the listed patents.The ANDA holder once

claims that the patent is invalid, or will not be infringed by the manufacture, use or sale of the

generic product. A generic applicant makes a para Iv certification only when its intent is to

market the drug product prior to the expiration of the patent.After submitting the para IV

certification, FDA reviews the application and notifies the applicant.After getting the

response by the agency, within 10 days ,the generic applicant sends a letter to the patentee

and agency also .If the patentee suits in court within 45 days of receipt of the letter ,30

months long duration is applied.

Exclusivity Certification :In accordance with the food, drug and Cosmetic Act as well as with

21 CFR314.94(a)(3)(ii) and information published in orange book, it should be provided that

the RI.Dis not covered by ant kind of exclusivity under 505 (j)(4)(d) of the food, Drug and

Cosemetic Act.

Letter For Authorization For DMF: This is the letter provided by the API manufacturer.

Excipient supplier, packaging material manufacturer, to the USFDA along with the CTD in

favor of the applicants product for the reference with the DMF no, with updated information

and appropriate volumes. It is also declared that there has not been any change in the DMF

and will not be change without the permission or approval of FDA.

US Agent Letter of Authorization [17]:This letter will serve to advise the CDER that the

applicant has appointed the following named company as a U.S agent for the submission of

Basis for ANDA Submission; A reference is given of RLD against which the application is

filling.The information provides in this section is different for different countries for the

ANDA submission as follows.

Reference Listed Drugs: ABC talets with all strengths,name of the innovator company as

published in Approved Drug Products with Therapeutic Equivalence Evaluations ,commonly

known as the Orange book and the listing of the above is enclosed for ready reference for the

agency.

Patent and Exclusivity: According to the details about the drug inorange book,it is required to

provide the patent number with date of expiration and statement for clearing any kind of

exclusivity.

Active Ingredient:It is provided that the generic drug product contains the similar active

ingredient to that of RLD in all dosage unit,strength,indications and route of

administration.The current labelling information of the RID is provided and the reviewer is

requested to refer the section 1.14.1/3 of this eCTD for the annotated labelling of the

applicants generic product.Rute of administration dosage form and strength of generic

version is sameas that of the reference listed drug.

Bioequivalence Data: The complete bioequivalence report is attached in Module 5 section of

the abbreviated New Drug Application for ready reference to prove both generic drug and

reference listed drug against which the ANDA is filling are bioequivalent in all manners.

Comparison between Generic Drug and RLD

The comparison is mainly on the basis of the following points:

Conditions of Use: The conditions of use prescribed recommended or suggested in the

labelling proposed for generic drug is similar to the conditions in the labelling proposed for

generic drug is similar to the conditions in the labelling of the RLD.

Active Ingredient: are similar in all fashion to the brand or patented drug as per 21CFR314.94

(a)(5)(i).Inactive Ingredients: All the inactive ingredients should be in the IIGlimit.All

ingredients are identified and represented in the components and composition statement in

Section 3.2.P.1 of the ANDA .Route of Administration, Dosage form and Strength must be

Environmental Impact consideration: Claim of Categorical Exclusion: An environmental

assessment report is provided containing the matter in order to prove that the ANDA for drug

product which will not be administered at a higher dosage level for a longer duration or

different indications that were previously in effect or mentioned. It is also certified that the

drug product is not toxic to organisms in the environment.

Waiver Request for Bioeuivalence Studies: Provisions for waivers of in vivo BA/BE under

certain conditions is provided at 21 CFR 320.22.According to the Biopharmaceutics

Classification System (BCS)[18] ,three major factors that govern the rate and extend of

absorption are dissolution,solubility,and intestinal permeability.According to the BCS drug

substance are classified as follows.

 Class I:High solubility-High Permeability

 Class 2:Low Solubility-High Permeability

 Class3:High Solubility-Low Permeability

 Class 4:Low solubility-Low permeability

The drug substance for which a waiver is being requested should be highly soluble and highly

permeable.Hence the biowaiver request is easily applicable for class 1.Sponsorsrequesting

biowaivers based on the BCS should submit the following information to the agency.

 Drug Supporting High Solubility  Drug supporting High Permeability

 Data Supporting Rapid and Similar Dissolution  Additional Information.

In case of many dosage form if the in vitro dissolution studies of all strength are comparable

then a waier request for in vivo studies is addressed for the lower strength and the invivo

studies will be carried out at highest strength of the generic drug against the lower strength

the R.I.D.

Labelling [19]

Labelling of Reference Listed Drug: A copy of the currently approved labelling is enclosed in

Proposed Generic Drug Product Labels and Labelling: The draft copies of the proposed

Generic Drug product container labels and package insert labelling of GD are attached in this

section and the inactive ingredients of generic drug product are specified in the description

section of the package insert. All ingredients of generic drug wil be mentioned in the formula

composition statement provided in module .Labelling Similarity Statement: Generic

Applicant proposed labelling for their generic drug will be same as the labelling for RID

expect for the difference annotated and explained in subsection.Side by side Labelling

Comparison (Annotated):An annotated side by side comparison of the labelling for GD

versus RLD is provided in which the similar difference numbered once and go on increasing

naturally for the different difference.

SPL(Structured Product Labelling)[20]:The structured product labelling is a document mark

up standard approved by health level seven and adopted by FDA as a mechanism for

exchanging medication information. A new automated system, BLIPS, to process, reviews,

and archives the content of labelling using SPL standard. An SPL document can be created

using a variety of possible tools, ranging from a general purpose word processor or XML

editor to an specific editing tool.SPL is a standard for exchanging the information in product

labelling using XML in electronic submissions. An SPL document consists conceptually of

two sections, a header and a body. The body comprises the content of labelling and includes

the human readable text and the data elements .The human readable text includes the text,

tables and figures found in the package insert.SPL document contain oth the content of

labelling along with additional machine readable information. Drugs listing data elements

include information about the product.

Discussion:

Overall summaries is common for all the ICH regions Europe, United States and Japan and

all the other countries which are accepting common technical document either in electronic or

paper version. Canada and Australia follows the guidelines for e CTD submission for module

2 of EU and US respectively. For the ASEAN countries, this module is not submitted as in

place of modules, parts are applicable in ASEAN countries Singapore, Malaysia. This

module mainly concerns with the three topics (i) Quality overall summaries and

Quality Overall Summary: The QOS is a summary that follows the scope and the outline of

the Body of Data in Module 3.The QOS should not information, data or justification that is

not already included in Module 3or in other parts of the CTD. The QOS should sufficient

from each section to provide the quality reviewer with an overview of Module 3.TheQOS

should also emphasis critical key parameters of the product and provide, for instance,

justification in cases where guidelines are not followed. The QOS should include sufficicent

information from each section to provide the Quality reviewer with an overview of Module 3.

Non-Clinical Overview [21]:The Non Clinical Overview should provide an integrated overall

analysis of the information in the Common Technical Document (CTD)/eCTD.

Clinical Overview [22]:The Clinical Overview is intended to provide a critical analysis of the

clinical data in the electronic common technical document.Specifically ,the Clinical

Summary should provide a detailded factful summarization of the clinical information in the

CTD ,and the clinical overview should provide a succinct discussion and interpretation of

these findings together with any other relevant information.

Non Clinical Summary [21]:This section provides the non clinical and tabulated summary of

Module 4of the common technical document for the pharmacology,pharmacokinetics and

toxicological reports conducted on animals.This section is submitted for the NDA or new

chemistry entity registration application but not applicable for ANDA/MAAsubmission for

generic drugs or abridged applications.

Clinical Summary [22]:The clinical summary is intended to provide a detailed,factual

summarization of all the clinical information in the Common Technical Document.The

summary of bioequivalence studies which have conducted under the module 5 in the facilities

according in this module.

Quality [23]:This section is the main part ofthe complete dossier ,relates to the quality of the

drug substance and drug product along with the CMC of the drug substance ,excipients or

products ,validation and control ,container and closure system,packaging material drug

master files ,stability studies .This module is common for ICH guidelines regions of

US,Japan,Europe and other countries like Canada,Australia etc.In ASEAN countries in place

of module which are the part of e CTD of CTD parts are used, Part II is used for the quality

Body of Data: The body of data in the dossier merely indicates where the information should

be located in the CTD.

Drug Substance: This section contains the complete information of active pharmaceutical

ingredient.All the detils about the API ie, nomenclature,Structure,Properties of drug

substance,Manufactures,Description of manufacturing process,Characterization,Validation of

Analytical proceduresReference standards or materials ,Stability,Stabilty

protocols,Composition of drug product,Excipients,formulation development,Container

closure system,Innovator characterization,Compatability should be mentioned in detail.[24]

Non Clinical Study Reports [25, 26]:This module mainly focus the safety study reports of

the new active pharmaceutical ingredient which has been performed on animals but not

submitted in e CTD dossier for the generic drugs abridged drugs for all the ICH tripartite and

other countries a of the world. As the gereric application or abridged applications are totally

based on the already approved listed drug, hence by following the Hatch Waxman Act., this

section is by passed and directly leads to the waier of the long and tedious animal studies or

pre-clinical or non –clinical studies. The reports from the RLD are assumed that the safety of

drug is proved and hence on the basis of the new drug pre-clinical data, the generic drug file.

Management and handling of granular clinical study reports

In Europe, node extensions should be used to group together individual files.STF s from

submissions in the US are not required but a submission will not be rejected if they are

included. If a US/NDA/ANDA is repurposed for submission in the EU, the study content

should be placed under a node extension. The STF xml file itself and any content not usually

provided in Europe should be removed. In order to keep the cumulative and current dossier

views of the e CTD consistent, the node extension are used for all clinical study reports,

regardless of the granularity of the content.

Provisions for CRF s and data when requested [27]:If case report forms and individual

patient data listing are submitted they should be placed in the same order as the clinical study

reports appearing in m535 and should be indexed by study.The bookmarks will not be

required as there will be no further internal structure in this section.

Common Technical Document In India:In India, CTD is being used by ,many importers of

act 1040 and rules there under 1945.Intitially the CTD was not being used by the importers

who imported the drgs and cosmetics fromforeign countries ,but as the interest of the global

countries to export their products in to India,The DCGI makes the rules and regulations to

control the import of the drug products in order to ensure the quality,safety,and efficacy of

the product for their registration in India.

New Registration Document List [28]:It consists of many sections but not as much complex

format applicable for the ICH countries. The CTD of India does not sectioned in modules.

The parts of CTD for the registration of the active pharmaceutical ingredients in India

according to the guidelines and regulations of the DCGI are as follows. It consists of many

sections but not as much complex format applicable for the ICH countries the CTD OF India

does not sectioned in modules. The parts of CTD for the registration of the active

pharmaceutical ingredients in India according to the guidelines and regulations of the DCGI

are as follows:

Cover Letter: This is prepared by the registration agents who are appointed by the exporting

countries to launch or register their drug substance in India.

Form 40: This is submitted by the agent /applicant to apply for the issuing of the import

license from the licensing authority constituted by the DCGI.

Schedule D1 and DII Certification: provided bt the importer to the DCGI in which the list of

the drugs is mentioned which are exempted from the special provisions or conditiond of the

import under D &C Act.

Plant Master File:It is provided by the exporting country /supplier about the complete detils

of their manufacturing plant by providing the certificates issued by their governments to

maintain the quality of the drug substance.

Drug Master File:The detail is discussed as per the requirements by DCGI earlier and present

time.

Business License/Manufacturing Licence: It is provided by the supplier or exporter with drug

WHO/GMP Certificates: Also provides by the exporter with the complete details of product

mane duly issued by the food and drug administration or national regulatory authority with

validity details.

Certificates of drug exportation: provided by the exporter according to the WTO conditions.

Power of Attorney: It is an important certificate which is duly signed by the Indian Embassy

and provides by the manufacturer with his stamp and sign to the agent appointed to clear that

the agent is not debarred or blacklisted in the sight of Indian Government.

Material Safety Data Sheet: AS per the import conditions mentioned under D& C Act of

India, the safety study details if the product is generic and available in India more than 4

years already but if it is new and less than 4 years, the permission shall be granted by the

DCGI to conduct the safety and efficacy studies on the bases of the pre-clinical study reports

provided by the manufacturer in India according to the guidelines given in Schedule Y under

Drug and Cosmetic Act.

Samples: Three samples of the drug substance with their certificate of analysis carried out by

the manufacturer or exporter provided to the custom collector. Such samples are further send

to CDTI, situate in Mumbai, Chennai as a subsidiary unit of CDL, Kolkata for testing and

safety and quality clarification form adulterated, misbranded and spurious drugs and

cosmetics.

Declaration is required for the countries which are exporting with any complaint received for

sub-standard quality of products if any.

Two main documents of the CTD submitted to the DCGI are

 Plant Master File

 Drug Master File

Plant Master File OR Site Master File [29]:The license shall prepare a succinct document in

the form of Site Master File containing specific and factual GMP about the production and

/or control pharmaceutical manufacturing preparation carried out at the licensed premises.

Drug Master File:The information to be furnished in the DMF of a bulk drug shall include

following minimum information chronogically arranged and submitted to the drugs

the drug substance or product in Indian market.[30] .DMF must be notarized by the authority

from the country of origin. Earlier information for DMF was not in CTD format but presently

only CTD format is accepted by the DCGI.

e CTD Soft Ware Arena [30]

Many software products are being used by the pharmaceutical companies for filling of

e-dossiers to the regulatory authorities in order to fullfill the regulatory requirements with the

prescribed time to get the approval as soon as possible.I n this competitive world, everyone

wants to achieve the target firstly to earn the profit and growth of the organisation. eCTD

software for regulatory submission isa powerful feature packed document /knowledge

management solution that does virtually everything from store to organize to share to manage

the e CTD documents quickly,efficiently,reliably and above all securely.e CTD software

helps pharmaceuticals companies to create ,update store and publish the complete set of

dissier documents and manage,compile, review, register and acheive e CTD submission to

regulatory agencies like US FDA and UK MHRA etc. E CTD submissions software also

helps in copying the relevant portion of previous submission to avoid duplication of work.

Pharma ready DMS is a web based document management system that automates and

seamlessly manages your document control process to ensure compliance with International

regulatory authorities like FDA, EMEA, Health Canada, TGA, and HSA.

Services provided by the Pharma Ready are as follows: Some of the main services are in

compliance with FDA services, E submissions to FDA spl Conversion services, European –

EMEA services ,Health Canada Services, Trial Master Management Services and Validation

Services.

DMS –Document management system-Efficiently manage SOPs,work instructions and other

documents within regulated business areas.

e CTD-Electronic Common Technical Document –Easily submit in the FDA-recommend

XML format while supporting submissions lifecycle management,role based authoring and

intuitive electronic content assembly processes.

SPL-PLR-Structured Product Labeling-Achieve immediate compliance as well as improve

TRMS-Training Record Management-Seamlessly manages technical training and maintains

of training records.

Pharma Ready Hosting-Pharma ready on Demand Minimize start up costs with nothing to

install on the site. No customer hardware or software is required. For an e CTD filing the

pharma ready providing the seamless visibility into the entire regulatory document

management from document creation to the regulatory submission. It facilitates:

 Submission road map

 Document Assembly

 Work in Progress

 Internal Review

 Sequential /Parallel approval cycles

 Compilation

 Publishing

 Archiving

 Seamless collaboration

Some of the e CTD features which pharma ready provides during the submission are given

below.

 Intuitive electronic content assembly processes.

 Integrated document management and publishing features.

 Support for all major regional templates.

 Submission life cycle management and consolidated submission reviews.

 Role based document authoring and access management for multi user electronic

submission, authoring and publishing.

 Automatic creation of validated ,submission ready package that includes the index

XMLback bone ,regional XMLback bone and associated leaf documents.

 Module 1-Regional templates for US,Europe,Canada readily available facilities easy

cloning for other regions.

 CTD Module 2 to Module 5 can be independenly assembled based on the submission type and module requiorements.

 Pre-built document templates with corresponding CTD sections- Drastically reduce

 Pre-assembled document templates in appropriate CTD sections enable regulatory affairs personnel to:

 Drastically reduce assembly/document CTD section association

lime,effort and cost.

 Create standardized submission dossiers across different product

applications.

Free e CTD S oftware

In regulatory publishing,intelligence and intellectual property solutions,the availability of free

e CTD software products are very essential which are approved by the who,that automatically

generates all required XML files from an e CTD ready file/folder structure ,for solving such

needful task,liquent,Inc.,the global leader in regulatory field provides e CTD Assistant.,a free

esy to use.This is the only offering to create the regional XMI files in addition to the ICH.The

liquents free Ectdliquent,Inc.,the global leader in regulatory field provides e CTD Assistant.,a

free esy to use.This is the only offering to create the regional XMI files in addition to the

ICH.The liquents free Ectdliquent,Inc.,the global leader in regulatory field provides e CTD

Assistant.,a free esy to use.This is the only offering to create the regional XMI files in

addition to the ICH.The liquents free e CTD Assistant 1.0 supports all currently available e

CTD specifications and can provide direct integration with both documentum and Microsoft

windows file system simultaneously ,which means non technical publishers can immediate

become productive because they do not have to make changes to exciting content.Such free

software which creates only XML back bone for the dossiers must be approved by WHO,a

global harmonization organization,to make uniformity and applicability internationaslly by

avoiding discomfort.

CONCLUSION

eCTD can be considered as an envelope enabling the industry to communicate and exchange

information in an easier and simpler manner. eCTD applications may be treated as dynamic

applications that can support dossier life cycle management. Since there have been new

developments in the electronic submissions arena across the world, specifically in the ICH

regions ,several initiatives ,some independent and some directly related to the e-submission

have been implemented or are at the point of being finalized for implementation. In the

for submission to CDER. In Japan, it is optional due to the language problem and in Canada.

The e CTD software for regulatory submissions is a powerful, feature-packed

document/knowledge management solution that does virtually everything from store to

organize, to share, to manage the TD documents quickly, efficiently, reliably and above all

securely. E CTD software solution helps pharmaceutical companies to create, update, store,

and publish the complete set of dossier documents and manage, compile, review, r egister and

archive eCTD submission to regulatory agencies like US FDA and UK MHRA. e CTD leads

to the Regulated Product Submission. The regulated product submission standard developed

by the Health Level Seven organisation will be a key element in the FDA bioinformatics

vision for a fully automated and inter-operable infrastructure for managing the exchange of

regulatory product information. Sponsors can utilize experience gained with e CTD

submission to prepare for FDA adoption of the RPS standard. As RPS, will be implemented,

those who have adopted e CTD will likely be at a strong advantage, having already developed

their electronic workflows and electronic submission preparation competencies.

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