INTRODUCTION
The Australian Therapeutic Goods Administration (TGA) has released the first final regional specification and validation criteria for eCTD format. Since late 2014, TGA was accepting eCTD submissions based on draft specification 0.9 in a pilot phase to assess the eCTD readiness of the agency and industry stakeholders and to collect comments from stakeholders during the ongoing consultation period. The pilot phase clearly demonstrated the feasibility of eCTD in Australia and triggered the finalization of the eCTD specification.

A bit surprisingly the first final version of the Australian eCTD was released as version 3.0 (and not 1.0 which could have been expected). Also the corresponding final eCTD validation criteria were released as version 3.0.Submissions using version 3.0 of the eCTD specification will be valid starting 1 June 2015. Submissions using version 0.9 of the eCTD specifications are valid until 31 December 2015.                    

Timelines:

• The TGA will accept eCTD submissions in accordance to the final version 3.0 from 1 June 2015 onwards
• The current pilot version 0.9 will still be accepted in parallel until 31 December 2015
• Any eCTD submitted starting 2016 will need to follow the version 3.0 of the specification

In parallel, the TGA is currently revising the NeeS format to align the corresponding validation criteria with the newly released final eCTD validation criteria. Furthermore additional guidance material for NeeS is being developed and will be released by TGA in the near future. The NeeS format will still be accepted by TGA but a revision of this policy is being considered.A time frame for transitioning from paper to NeeS/eCTD is not determined. TGA has yet to decide the transition period. Once a submission for a product is submitted in the eCTD format, all future submissions for that product must be in the eCTD format in order to take advantage of the lifecycle features of the eCTD standard.

When changing from paper or NeeS to eCTD, it is highly recommended but not mandatory to use a baseline as a start of an eCTD. A baseline submission is a compilation of the current status of the dossier, i.e. resubmission of currently valid documents that have already been provided to an agency but in another format. The baseline should normally be submitted as sequence 0000

It should be clearly stated in the cover letter of the 'baseline eCTD sequence' that

• Content of the previously submitted dossier has not been changed, only the format
• All the studies have previously been submitted to TGA and
• Any omissions do not render the submitted content misleading

The TGA will not convert new or existing submissions to eCTD format they will only accept validated eCTD submissions published by applicants. TGA is accepting electronic submissions in eCTD and NeeS format. TGA is still accepting regional specification V0.9 but starting from FY 2016 only V3.0 is acceptable. The TGA is planning for RPS (eCTD 4.0).Navigation through an electronic submission is greatly enhanced by the appropriate use of bookmarks and hypertext links. However, the overuse of hyperlinks may confuse rather than help assessors. The maximum size of an individual PDF files used for submission is 100MB. There is no maximum allowable size for the entire submission.

The TGA will encourage submission via DVD during the pilot and until they have a fully developed portal facility with capacity for upload. Each eCTD submission should have submission identifier issued by TGA. It is required in the ‘envelope’ information for each submission. Submissions will be referenced by this number and therefore subsequent sequences must include this identifier. To get an eSubmission Identifier, send an email to esubmissions@tga.gov.au (link sends e-mail) with the applicant's name, the Australian Approved Name, and description of the application (trade names, dose form, strength and route of administration).

The TGA expects sponsors and applicants to use validation tools to test their own eCTD applications before submitting them to the TGA. A copy of the validation report will need to be attached to the submission. Validation tools are available from software vendors or an example tool can be downloaded from the TGA’s website.TGA will adopt a set of technical validation criteria against which all eCTD and NeeS sequences can be checked. Two categories of validation rules apply: 'Pass/Fail' and 'Best Practice'.

The technical validation of an eCTD or NeeS formatted submission is a separate activity to the content validation of a submission and takes place irrespective of the type of the submission. Sequences which fail to meet one or more of the 'Pass/Fail' criteria will be returned to the applicant for correction and resubmission. TGA may accept sequences which fail to meet one or more of the 'Best Practice' criteria; however, the applicant should make every effort to address these areas before the eCTD is submitted to TGA.

Submissions which include STFs will be accepted but are not required. However, if STFs are included, they must pass validation. If an FDA submission containing STFs is modified by removing the STFs, the study files must be organized using node extensions.eCTD submissions will be preserved in the TGA's computer network file storage system according to the Australian Government electronic record keeping standards. Applicants should maintain archival copies of submissions according to their business rules. TGA recommends archiving all dossiers in the format the dossier was submitted to the

Thai eCTD Module 1 has been developed based on the EU eCTD Module 1 and ICH eCTD specifications v3.2.2 for Module 2 to Module 5. The EU structure is being used as a proven structure and to increase reusability from applications already submitted in the EU region. Thai FDA has released the TH eCTD (Thai eCTD) Module 1 Specifications draft version 0.92 and validation criteria, draft version 0.92.

eSubmission and Thailand
Thailand will become the first country to publish a national eCTD specification in ASEAN. Some of the positive aspects with the eSubmission include

• Countries with eCTD specification have increased access to medicines through ease of submitting (part of first or early wave of release)
• eSubmission also increases the ability to co-operate with agencies globally
• It promotes export as it equips local industries to compete internationally
• Offer a transparent review process thereby increasing the quality of review and also offer access to related information

Thailand’s Reason’s for Considering eCTD as Global Submission Strategy

• eCTD has worldwide acceptance
• Establish a single application format for all applications
• Timelines are met and is much more favorable than paper timelines
• Supports Lifecycle Management
• Harmonizing structure improves reviewing process
• There are minor differences between ACTD and eCTD

Thai eCTD Module:To Improve Reviewing Process

• Submissions are uploaded via electronic submission gateway (future) and can be available to reviewers within minutes
• Improves application review process
       - More efficient review
       - Changes and updates are easy for reviewers to identify and review
       - Bookmarks and Hyperlinks
       - Easy 24/7 access from any location
       - Everyone can access the document simultaneously
       - Document is more secure, no need to print desk copies, maintain duplicate electronic file

Pilot eCTD
Thai FDA is working in cohesion with several industry representatives to ascertain suitable eCTD pilot submissions (only e-submission will be accepted). The officials will conduct tests ahead of the adoption expected to be complete this year.
The following application types will be tested

• new chemical entity
• new biological
• new generic
• submissions prepared with different publishing tools

Pilot eCTD: Implementation Timeline

Thai eCTD implementation will have no impact to other or existing applications and variations

Filing Dossier in eCTD Format
Obtaining the eSubmission Identifier:

• Prior to filing the first regulatory transaction for an application in an electronic format, the applicant should submit a request to the THAI FDA online service to obtain an eSubmission identifier.
• The request will require the following information:
  - Licensee Number
  - Description of Application
  - Dosage Form
  - INN or Generic Name
  - Strength
  - WHO ATC Code
  - Sequence Type
  - Application form (CPP
• If the applicant wishes to provide single dossiers for the same active ingredient, dosage form and therapeutic group but has more than one strength, only one eSubmission identifier will be issued to cover all strengths.
• The eSubmission Identifier will be issued within 10 days of application. After receiving the identifier, the applicant must then make an appointment for submission within 30 days.

Validation Report

• An electronic copy of the validation report created should be submitted. A folder should be created in the application folder named after the eSubmission identifier with the naming convention of the sequence number followed by validation-report e.g. “0000-validation-report”

TH Regional Information

• The ICH Common Technical Document (CTD) specifies that Module 1 should contain region-specific administrative and product information.
• The content and numbering of Module 1 for Thailand is modeled after the EU Module 1 content as described in the 2008.
• Additional documents specifically required by Thailand not covered by the EU structure will be added to 1.A Additional Data.
• The following items listed in the Notice to Applicants may be included for an initial submission:

   - A cover letter
   - An application form(Form MA-1)
   - Product information documents
   - Information on the experts (optional)
   - Specific requirements for different types of applications (if required)
   - An environmental risk assessment
   - Information relating to pharmacovigilance  (optional)
   - Information relating to clinical trials (optional)
   - Information relating to paediatrics (optional)

Future Outlook
FDA is working alongside with other regulatory agencies to facilitate improvement processes for best practices.

• eSubmission gateway to be implemented to support application process through internet
• Improve bi-directional communication over electronic communication channel
• Only eSubmission will be received by 2017
• Prepare for next iteration of eCTD 4.0 (RPS)
• RPS (Regulated Product Submission) is able to support different types of application e.g. ACTD, Medical Devices, Veterinary
• Furthermore, it is very likely that the eCTD system will also be extended to medical device applications in the next several years.

• Provide strategic regulatory intelligence services for a Europe based, global $40+ Bn, pharmaceutical company
• Offer strategic support on global readability guideline for client’s product portfolio along with strategy implementation

STRATEGIC LABELING SERVICES FOR $20+ BN, BIO-PHARMA COMPANY

• Provide strategic labeling services for a US based, global $20+ Bn, bio-pharmaceutical company
• Develop and manage client’s labeling management services including (LPD’s, SPL)
• Leverage strong industry knowledge and expertise supporting further enhancement of global competitiveness and reduce operating cost for the multi-year project

• Over 60% Savings on Cost of Compliance
• Established and Streamlined Master Dossier Management Process

BUSINESS HIGHLIGHTS

• Successfully created and submitted electronic submissions
• Swift approvals from the Health Authorities

BUSINESS IMPERATIVES

• Client mainly focuses on disinfectants and antiseptics made from natural ingredients
• DIN is a computer-generated eight digit number assigned by Health Canada to a drug product prior to being marketed in Canada
• The DIN is unique and serves as a tool to help in the follow-up of products on the market, recall of products, inspections, and quality monitoring

CHALLENGES

The client wanted to urgently meet two-prong objectives:

• Client was completely unaware of electronic submissions and their requirements
• Client was looking for a reliable partner who can perform electronic submissions as per Module 1 DTD version 2.2

FREYR SOLUTIONS & SERVICES

• Developed and managed the project timelines
• Liaised with Canada Health Authority on behalf of client and responded to the queries
• Raw documents are received from the client and Freyr performed DLP (document level publishing)
• Preparation of the application form, Cover Letter and LCM tracking table
• Amendments for the initial submission were prepared, published and submitted to Health Canada via ESG gateway

CLIENT BENEFITS

• Freyr educated the client on migration from paper format to eCTD
• Successfully created and submitted electronic submissions on behalf of client to Health Canada
• Submitted the response submission with in a day reducing the time to get the approval
• Freyr continues to be a Lifecycle Submission partner and plays a long-term, strategic role

• Successfully completed 4 Clinical Study Reports (CSR)
• Zero defect & zero correction cycle, high quality delivery
• Fastest turnaround time of 30 days

BUSINESS HIGHLIGHTS

• Identification of gaps in formulation of composition
• Swift approvals from the Health Authorities
• Uninterrupted supply of product in the market

BUSINESS IMPERATIVES

• The client had priority requirement for preparing and submitting high quality variation submissions for ‘Type IA’ changes in Finland.
• The client required regulatory support to ensure the timely support for preparation and submission of CMC ‘Type IA’ variations.

CHALLENGES

• In collection of CMC documentation from the country representative as the product registered is very old and held ‘National’ license
• Additional multiple changes were identified during the review of source documents. These changes were previously unnoticed

FREYR SOLUTION & SERVICES

• A strategy on ‘Grouping’ for the additional identified changes was provided along with the ‘First time right’ draft variation package
• Data gathering
• Identification of Gaps between the current practices and documentation followed at the drug product manufacturing site
• Freyr scheduled the quick discussion with different stakeholders
• In case of short timelines, Freyr scheduled the quick discussion with the country representative in order to finalize the approach to file the variation package

CLIENT BENEFITS

• Identify the major gap in formulation composition
• The high quality ‘Type IA’ variations were provided to the client
• There was no rejection of the submission from the ‘Health Authorities’, which resulted in swift approvals
• Uninterrupted supply of product in market