CTD Dossier Preparation

K. Srikantha Reddy
Sr.Manager-Regulatory Affairs

Medreich Limited
Srikanth.k@medreich.com

CTD Dossier Preparation

CTD (Common Technical Document) contains 5 modules
Module 1 Module 2 Module 3 Module 4 Module 5

DMF
Drug Master File (DMF) is a submission to the Food and Drug Administration (FDA) that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging and storing of one or more human packaging, drugs. The information contained in the DMF may be used to support following,
Investigational New Drug Application (IND), (IND) New Drug Application (NDA), Abbreviated New Drug Application (ANDA), Export Application.

ANDA:
An Abbreviated New Drug Application (ANDA) is an application for a U.S. generic drug approval l for f an existing i ti li licensed d medication di ti or approved drug. The ANDA contains data which when submitted to FDA's Center For drug Evaluation and Research (CDER), Office of Generic Drugs, provides for the review and ultimate approval p pp of a generic drug product. Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low cost alternative to the American public.

Module 1

(e.g. EU)

Module-1: Administrative Information and Prescribing Information 1 0 Cover Letter 1.0 1.1 Comprehensive Table of Content 1.2 Application Form 1 3 Product 1.3 P d tI Information f ti 1.3.1 SPCs, Labelling and Packaging 1.3.2 Mock-Up 1.3.3 Specimen 1.3.4 Consultation with target patient group 1 3 5 SPC 1.3.5 SPCs s already approved in the Member states 1.3.6 Braille

Module - 1
1.4 1.5 1.6 1.7 1.8 1.9 Information about the Experts Specific p Requirements q types of applications for different

Environmental Risk Assessment g to Orphan p Market Information relating Exclusivity Information relating to Pharmacovigilance Information relating to Clinical Trials

1.10 Information relating to Pediatrics 1.11 Response to Queries 1.12 Additional Data

Module - 2
Module - 2: CTD Summary
2.1 2 1 2.2 Table T bl of fC Content t t (Comprehensive) (C h i ) Introduction (general introduction to the pharmaceutical, including its pharmacology class, mode d of f action, ti and d proposed d clinical li i l use) ) Quality Overall Summary Non-clinical Overview Clinical Overview Non-clinical Written and Tabulated Summaries y Clinical summary

2.3 2.4 2.5 2.6 2.7

Module - 2
2.4 Non-clinical Overview General e a Aspects spects 2.4.1 Ge 2.4.2 Content and Structural Form at 2.5 Clinical Overview 2.5.1 Product Developm ent of Content Rationale 2.5.2 Overview of Biopharm aceutics 2 5 3 Overview of Clinical Pharm 2.5.3 acology 2.5.4 Overview of Efficacy 2.5.5 Overview of Safety 2.5.6 Benefits and Risks Conclusions 2.5.7 Literature References

Module - 2
2.6 Non-clinical Written and Tabulated Summaries 2.6.1 Pharmacology 2 6 2 Pharmacokinetics 2.6.2 Ph ki ti 2.6.3 Toxicology 2 7 Clinical summary 2.7 2.7.1 Biopharmaceutic Studies and Associated Analytical Methods 2.7.2 Clinical Pharmacology Studies 2.7.3 Clinical Efficacy 2 7 4 Clinical 2.7.4 Cli i l S Safety f t 2.7.5 Literature References 2 7 6 Synopses of Individual Studies 2.7.6

Module - 3
Module 3: Quality Q y 3.1 Table of Contents 3.2 Body y of Data 3.2.S Drug Substance 3.2.S.1 General Information 3.2.S.1.1 Nomenclature 3.2.S.1.2 Structure 3 2 S 1 3 General Properties 3.2.S.1.3

Module - 3
3.2.S.2 Manufacture 3.2.S.2.1 Manufacturer Details 3.2.S.2.2 Description of Manufacturing Process and Process Controls 3 2 S 2 3 Control of Materials 3.2.S.2.3 3.2.S.2.4 Controls of Critical Steps and Intermediates 3 2 S 2 5 Process 3.2.S.2.5 P Validation V lid ti and d /or / Evaluation E l ti 3.2.S.2.6 Manufacturing Process Development 3.2.S.3 Characterisation 3.2.S.3.1 Elucidation of structure and other Characteristics 3.2.S.3.2 3 3 Impurities pu

Module - 3
3.2.S.4 Control of Drug Substance 3.2.S.4.1 Specification of Drug Substance 3.2.S.4.2 Analytical Procedures 3.2.S.4.3 Validation of Analytical Procedures 3.2.S.4.4 Batch Analyses 3.2.S.4.5 Justification of Specification 3 2 S 5 Reference Standards or Materials 3.2.S.5 3.2.S.6 Container Closure System 3.2.S.7 Stability 3.2.S.7.1 Stability Summary and Conclusions 3.2.S.7.2 Post-approval Stability Protocol and Stability Commitment 3.2.S.7.3 Stability Data

Module - 3
3.2.P Drug Product 3.2.P.1 Description and Composition of the Drug Product 3 2 P 2 Pharmaceutical 3.2.P.2 Ph ti l D Development l t 3.2.P.2.1 Components of Drug Product 3 2 P 2 2 Drug Product 3.2.P.2.2 3.2.P.2.3 Manufacturing Process Development p 3.2.P.2.4 Container Closure System 3.2.P.2.5 Microbiological Attributes 3.2.P.2.6 Compatibility

Module - 3
3 2 P 3 Manufacture 3.2.P.3 M f t 3.2.P.3.1 Manufacturer 3 2 P 3 2 Batch Formula 3.2.P.3.2 3.2.P.3.3 Description of Manufacturing Process and Process Controls 3.2.P.3.4 Controls of Critical Steps and Intermediates 3 2 P 3 5 Process Validation and /or Evaluation 3.2.P.3.5

Module - 3
3 2 P 4 Control of Excipients 3.2.P.4 3.2.P.4.1 Specifications 3 2 P 4 2 Analytical Procedures 3.2.P.4.2 3.2.P.4.3 Validation of Analytical Procedures 3.2.P.4.4 Justification of Specifications 3 2 P 4 5 Excipients of Human or Animal 3.2.P.4.5 Origin 3.2.P.4.6 Novel Excipients

Module - 3
32P5 C 3.2.P.5 Control t l of fD Drug Product P d t 3.2.P.5.1 Specification of Drug Product 3 2 P 5 2 Analytical Procedures 3.2.P.5.2 3.2.P.5.3 Validation of Analytical Procedures 3.2.P.5.4 Batch Analyses 3.2.P.5.5 Characterisation of Impurities p 3.2.P.5.6 Justification of Specification 3.2.P.6 Reference Standards or Materials 3.2.P.7 Container Closure System

Module - 3
3.2.P.8 Stability 3.2.P.8.1 Stability Summary and C l i Conclusions 3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment 3 2 P 8 3 Stability Data 3.2.P.8.3

Module - 3
3.2.A Appendices 3.2.A.1 Facilities and Equipment 3.2.A.2 Adventitious Agents Safety Evaluation 3 2 A 3 Novel Excipients 3.2.A.3 3.2.R Regional Information/ Requirements 3.2.R.1 Process Validation and or Evaluation 3.2.R.2 Medical Device 3.2.R.3 Restricted part of DMF 3 2 R 4 Medicinal 3.2.R.4 M di i l products d t containing t i i or using i i in the manufacturing process materials of animal and / or human origin. 3.3 List of Literature References

Module - 4
Module - 4: Non-clinical Study y Reports p
4.1 Table of contents 4.2 Study Reports 4 2 1 Pharmacology 4.2.1 4.2.1 Primary Pharmacodynamic 4.2.2 Secondary Pharmacodynamic 4 2 3 Safety 4.2.3 S f t pharmacology h l 4.2.4 Pharmacodynamic drug interactions

Module - 4
4.2.2 Pharmacokinetics 4.2.2.1 Analytical Methods and validation Reports 4 2 2 2 Absorption 4.2.2.2 4.2.2.3 Distribution 4.2.2.4 Metabolism 4.2.2.5 Excretion 4.2.2.6 Pharmacokinetic Drug Interactions 4.2.2.7 Other Pharmacokinetic studies

Module - 4
4.2.3 Toxicology 4 2 3 1 Single-dose toxicity 4.2.3.1 4.2.3.2 Repeat-dose toxicity 4.2.3.3 Genotoxicity y 4.2.3.4 Carcinogenicity 4.2.3.5 Reproductive and developmental t i it toxicity 4.2.3.6 Local tolerance 4 2 3 7 Other toxicity studies 4.2.3.7 4.3 Literature References

Module - 5
M d l - 5: Module 5 Clinical Cli i l Study St d Reports R t
5.1 5.2 5.3 Table of Contents Tabular Listings of All Clinical Studies Clinical Study Reports 5.3.1.1 Bioavailability (BA) study Reports 5.3.1.2 Comparative BA and Bioequivalence study reports 5.3.1.3 In-vitro In-vivo Correlation study reports 5.3.1.4 Reports of Bioanalytical and Analytical methods 5 3 2 1 Plasma Protein Binding Study 5.3.2.1 Reports 5.3.2.2 Reports of Hepatic metabolism and Drug Interaction Studies 5.3.2.3 Reports of Studies Using human Biomaterials

Module - 5
5331 H 5.3.3.1 Healthy lth S Subject bj t PK and d Initial I iti l Tolerability study reports 5.3.3.2 Patient PK and Initial Tolerability y study reports. 5.3.3.3 Intrinsic Factor PK study reports 5 3 3 4 Extrinsic 5.3.3.4 E t i i F Factor t PK study t d reports t 5.3.3.5 Population PK study reports 5 3 4 1 Healthy subject PD and PK/PD 5.3.4.1 study reports 5.3.4.2 Patient PD and PK/PD study reports 5.3.5.1 Study reports of controlled clinical studies

Module - 5
5.3.5.2 Study reports of Uncontrolled clinical studies 5.3.5.3 Reports of Analyses of data from more than one study 5.3.5.4 Other clinical study reports 5.3.6 Reports of Post-Marketing E Experience i 5.3.7 Case report forms and Individual patient listings 5.4 List of Key Literature References

eCTD
(Version 3.2.2)

06.05.2011

K. Srikantha Reddy Medreich Limited

Sr. ManagerManager-Regulatory Affairs

Srikanth.k@medreich.com

eCTD
eCTD electronic Common Technical Document The eCTD is the electronic equivalent to the CTD. CTD Regulatory Perspective The eCTD is defined as an interface for industry to agency transfer of regulatory information while at the same time taking g into consideration the facilitation of the creation, review, lifecycle management and archival of the electronic submission submission. Common structure for Modules 2 through 5 Agency specific requirements for Modules 1

eCTD
Technical Perspective Structured set of common folders structure containing PDFs and SAS files (Statistical Analysis Software) on a CD/DVD (Can also be submitted through Agency web portals) The eCTD backbone is an XML file (Extensible M k L Markup Language) ) representing ti the th structure t t of f the th submission, it includes links to files and other metadata such as check sum information. The schema for the XML is very rigid. PDF hyperlinks

eCTD
Granularity of files submitted is small (there are no longer issues of creating large volumes of PDFs). Increased potential for reusing the same submission content across agency submissions. The standard, and many of the modules have been agreed upon by the main worldwide agencies. Once a submission is sent in eCTD format all future submissions for the application should be in eCTD format. Opportunity O t it to t use Part P t 11 Compliant C li t Electronic El t i Signatures. Use only file formats specified in the guidance

eCTD Benefits
Easy to distribute and review More efficient use of resources, less cost and stress to the organization Highly organized electronic table of contents Searchable Self-validating Integrated document and life-cycle management Cross submission integration Living document New, replace, append & delete

How it is different to Paper/Document CTD Overall Table of contents provided in XML (Extensible Markup Language) Utility files to enable technical conformance and viewing i i Submission Folders, XML and Utility Files are created automatically t ti ll if an eCTD CTD builder b ild is i used. d Generally high level of granularity in documents Structure is more precise Lifecycle Management of the submission is easier.

eCTD Implementation - FDA

Jan 1, 2008, eCTD became CDERs standard for electronic submission. FDA has made it mandatory for all ELECTRONIC submissions b i i to be b in i eCTD format f since i 2007-08. However, paper copies are still accepted. Suitable waivers will have to be taken before hand. The number of ANDA submissions to FDA has increased from 72 in the year 2006 to 1550 in 2009

eCTD Implementation - EU ( p (http://esubmission.emea.europa.eu/) p )

Requirements on Electronic submissions (Nees (Non-eCTD electronic submission, Version 2.0 March-2010) and eCTD) and paper documentation for New Application within MRP, DCP or National procedure Refer CMDh/085/2008/Rev7 October 2010) From F 1 1st t July J l 2010, 2010 th the EU M1 v1.4 1 4 must tb be used df for all ll eCTD submissions for all European procedures,

eCTD Implementation - MHRA

http://www.mhra.gov.uk/Pharmaceuticalindustry/Marketingauthoris htt // h k/Ph ti li d t /M k ti th i ations/index.htm

The preferred format for new marketing authorization (MA) applications li i i is the h electronic l i C Common T Technical h i l Dossier D i (eCTD) ( CTD) eCTD applications must be created according to the current specifications: eCTD specification v 3.2.2 MHRA will accept applications in PDF-only format (Note that all PDF
files included in an eCTD (irrespective of the module) should be v1.4, except where there is an agency-specific requirement for a later version (e.g. for an application form)).

The Summary of Product Characteristics (SmPC) will need to be prepared using the Word template. Use the MHRA Adobe Application form which is available via the MHRA Portal. This will produce an XML file that MHRA can upload directly into their database. database

Regulatory Contact information

eCTD Modules
When making an electronic submission, each document should be p provided as a separate p file. The documents, whether for a marketing application, an investigational application, or a related submission, should be organized based on the five modules in the CTD: Module d l 1 includes i l d administrative d i i i information i f i and d prescribing information, Mod le 2 incl Module includes des CTD summary s mmar documents, doc ments Module 3 includes information on quality, Module 4 includes the nonclinical study reports, and Module 5 includes the clinical study reports.

eCTD Template

eCTD Screen Shot

eCTD Screen Shot of Module 2

eCTD Screen Shot of Module 3

eCTD Screen Shot of Module 4

eCTD Screen Shot of Module 5

eCTD Screen Shot of Module 5

eCTD Screen Shot of Module 5

eCTD Management Software

eCTDXPress Image Solutions http://www imagesolutions com imagesolutions.com MasterControl Submissions Gateway - Master Control http://www.mastercontrol.com Control, http://www mastercontrol com Liquents EZsubs software solution, http://www.liquent.com/ p q Data Farm, http://www.datafarminc.com/ Take solution : www.PharmaReady.com www PharmaReady com Lorenz Life Sciences : www.lorenz.cc

Thank You
SRIKANTH.K