Submission-Ready Documents

Imagine what it would be like to be nearing a marketing application in appreciation that most of the reports for the filing were nearly complete, having been preparing “submission-ready” throughout development. Sounds unreal? With some planning and training, this could be a reality for your products, at any stage of development. Preparation of submission-ready documents during preclinical and clinical development reduces preparation and review time, makes more efficient use of resources, and expedites and achieves shorter sustainable submission cycles, thereby reducing cost and stress to the organization.

Documents may be written in early development in an expandable/modular format that allows for submitting in the IND and then amending, modifying and replacement throughout development. As the product moves through the development stages, gaps are filled with new data and findings, to meet marketing application demands. Regional differences, e.g. differences between what is required for Europe and the U.S., may be addressed using a modular format, allowing different subsections for different regions. Information that does not need to be submitted to regulatory agencies, but must be kept on file for GMP documentation, can be placed in appendices. The report can be quickly customized prior to submission with the relevant information.

Challenges in CMC Documentation
Preparation of Chemistry, Manufacturing, and Controls (CMC) documentation for regulatory submissions faces unique challenges not usually found in nonclinical and clinical documentation. Regulatory guidance is readily available for clinical study reports, for example, but format/content guidance is not as complete for all types of CMC documents. Preparation of CMC documentation is done by multiple departments, e.g. Research and Development, Manufacturing, Validation, Quality Control, Stability, etc. within the company as well as contract manufacturing and testing labs. Unless authors are trained up front with agreed-upon templates, inconsistency of content and format between reports can create problems for the regulatory reviewer. Knowing this potential issue well, Regulatory Affairs often asks departments to rewrite reports for the submission.

CTD Quality Consulting has been working with clients in the IND stages to prepare reports in submission-ready format to avoid inefficiencies and delays in finalizing submission reports for the NDA or other marketing application. The following lists examples of reports for which training can be provided to prepare submission-ready documents:

o Characterization
o Formulation Development
o Manufacturing Development
o Method Validation
o Justification of Specifications
o Process Validation
o Stability
o Stress Studies
o Container-Closure Evaluation

Benefits of the CTD Format
The Common Technical Document (CTD) developed by the International Conference on Harmonization (ICH) is required in Europe, Japan, and Canada and “highly recommended” by FDA for marketing applications. The CTD format is required in Europe (according to IMPD guidance) and Canada for investigational applications; it is also accepted by FDA for investigational new drug applications (IND). The CTD format and content is also, of course, required for eCTD submissions. The eCTD format is required for electronic submissions in the U.S.

The advent of the CTD not only allows for global harmonization of marketing applications but also provides standards to prepare submission-ready documents in the IND phases. This standardization also benefits project management and information management and facilitates drug development planning and life cycle management. Each section of the CTD can be treated as a technical report that can be written early in development and updated as needed until it is finalized for the submission.

Preparing the CTD from IND to NDA
Module 3 of the CTD, the “Quality” or CMC section of the CTD, can be expanded from the IND to the NDA according to requirements for each phase of development. The following table illustrates key differences between the IND and NDA for Quality:


IND: Quality Overall Summary not required (except in Canada or for eCTD)
>NDA: Quality Overall Summary required (Module 2)
IND: Detailed manufacturing flow chart is sufficient for phase 1
>NDA: Complete manufacturing description, flow chart, manufacturing development history
IND: Viral safety evaluation required; other process validation not required
>NDA: Process validation summaries required for critical steps
IND: Assessment of critical method parameters
>NDA: Complete method validation reports
IND: Brief description of container closure
>NDA: Complete container closure evaluation
IND: Stability data support the duration of the clinical study
>NDA: Stability data support the proposed marketing shelf life, per ICH
IND: A.1 Facilities/Equipment not required
>NDA: A.1 Facilities/Equipment, A.2 Adventitious Agents for biologics
IND: The focus is on safety
>NDA: Complete details of CMC required

Writing Submission-Ready Documents
SRDs should be planned and written throughout development with four levels of reports in mind:

1) Reports that are submitted in full, with raw data and appendices, e.g. method validation report.
2) Summary reports without appendices, e.g. process development report.
3) High level summaries suitable for the Quality Overall Summary
4) Reports that are kept on file and not submitted

All reports required to meet GMP must of course be kept on file (level 4) even if they do not need to be submitted. For a level 1 report, the entire report would be submitted. For a level 2 report, the full report would be written with a body of the report that is in a summary format, such as a section of Module 3. The body of the report would include a summary of the protocol, key data tables and figures, summaries of methods, and conclusions. Raw data and other appendices could be removed prior to the submission. It is recommended that all reports have an up-front executive summary (level 3) that introduces key findings, resolution of issues, and recommendations. The content of these summaries would be integrated into the Quality Overall Summary in Module 2.

Reports written early in development may be written in submission-ready format and amended or updated throughout the course of development. One example of this is the method validation report, where methods are often refined or changed completely throughout development.

SRDs should be written in a modular format that has subsections for different regions, such as differing specifications in Europe and the U.S.. Just prior to submission, the subsections not relevant to that region are removed for the final report, with appropriate version control.

To make your reviewers’ job as easy as possible, it is highly recommended to keep consistency between reports of the same type in the submission, e.g. stability reports or method validation reports. Training of authors should also include consistency of terminology in all submission documents.

Electronic submission tools afford us some creative options in linking submissions to databases using XML. Ideally, the submission writer should not have write access to GMP data (such as release and stability data). Data tables within reports could be automatically populated from Quality-controlled databases using customized templates, with generation of graphs and statistical analysis

Regulatory Project Management
Planning a submission is a major project that requires skill, experience, and teamwork (see FAQ on the SMART Process at www.ctdquality.com). Using the CTD format to prepare submission-ready documents can greatly facilitate regulatory project management, by mapping data and reports to the CTD from the start. Project management software can be set up with sub-projects organized according to CTD subsections to track action items for each phase of development. This makes it easy to track and perform gap analysis.

CTD Quality Consulting wishes you the best in your submission preparation, and we would be happy to assist you with effective and efficient preparation of CMC submissions.

Do a piece at a time to have peace in time.
- Dr. Michelle Herrera Foster, CTD Quality Consulting