| Q: When will
the CTD format and content be required for marketing applications? |
| A: As of July 2003 the CTD guideline
(ICH M4) is required for all marketing and post-marketing applications
in Europe, Japan, and Canada. Canadian INDs must also be in CTD format.
Although FDA is not currently requiring the CTD format, it is highly
recommended, and it will be required for electronic submissions
to CDER in 1/08. |
| Q: How do
I find the applicable guidelines for my CTD Quality submission? |
| A: See Links for US,
European, ICH, and Canadian web sites that provide current guidelines
for marketing and investigational applications. CTD Quality Consulting
can provide you with a comprehensive assessment of regulatory requirements
for your submission, as a consulting service (see "Mapping"
process under SMART process below). |
| Q:
What are the new requirements in the CTD Quality sections? |
A: The following sections are
new, compared to the NDA, BLA, and MAA:
- 3.2.S.2.4 Controls of Critical Steps and Intermediates
- 3.2.S.2.6 Manufacturing Process Development
- 3.2.P.4 Control of Excipients: methods validation and
- human/animal origin subsections
- 3.2.A.2 Adventitious Agents Safety Evaluation
- 3.2.A.3 Novel Excipients
The following sections are new to the NDA/BLA, although they have
been required by the MAA in Europe:
- 3.2.S.3, 3.2.P.5.5 Impurities
- 3.2.S.5, 3.2.P.5.6 Justification of Specifications
- 3.2.P.2 Pharmaceutical Development
For more information on CTD Quality requirements, see Dr. Foster’s
presentation at the 12/03 DIA conference on CTD/eCTD entitled “Converting
your CMC Submissions to the CTD Format”, or
to send us and email enquiry |
| Q: What are the regional differences? |
A: “Regional” refers
to requirements unique to certain regions, such as U.S., Canada,
Europe, and Japan. Dr. Foster lists regional differences into 4
categories:
- Module 1: Forms, Labeling, DMF Letters, Environmental
Assessment
- 3.2.R Regional Information
a) Executed Batch Record (U.S., in English)
b) Method Validation Package (U.S., EDQM*)
c) Comparability Protocols (U.S.)
d) Process Validation Scheme (EU)
e) Medical Device (EU)
- Reviewer-Specified Information
- Market-Specific Information (e.g. specs)
*EDQM = European Directorate for the Quality of Medicines (Method
validation package required to be submitted post-approval in Europe)
There are also some differences in level of detail required for
Europe vs. U.S. in certain sections, such as process validation
and facilities. There are creative ways to prepare your CTD in a
modular fashion to satisfy regional requirements;
to contact CTD Quality Consulting for more information.
|
| Q: At
what stage of development should we be using the CTD format in regulatory
submissions? |
| A: The Quality
section of the CTD is a living document that you have to live
with
for the lifetime of your product! Post-marketing applications are
inevitable, and careful planning can prevent costly delays in
approvals.
It is highly recommended that the CTD format and content be adopted
early in development, in IND submissions, DMFs, and pre-submission
meeting packages. The marketing application is essentially built
throughout phases 1, 2, and 3 of clinical development. To enhance
efficiency
of the process over time, make sure to consider requirements for
document management and electronic submissions. Create CMC documents
throughout
development with the marketing application in mind! See the article: “Advantages
and Preparation of Submission-Ready Documents” for a
more detailed discussion. |
| Q: Is the eCTD
required? What are the advantages of submitting an eCTD? |
A: The eCTD is currently not
required, although CDER electronic submissions must be eCTD by
1/08. See: See RAPS presentation: “Advantages of Preparing Submissions Electronically”.
In
addition to time and cost savings in preparing one core submission
for all
regions,
another
major
benefit
to
converting
to eCTD is lifecycle management. Planning ahead is key to success
and rapid approvals, so it is recommended to start your CTD
in Phase
1. The CTD facilitates global preparation and notification/approval
of manufacturing changes, and a good eCTD system makes efficient
use
of the document management system to facilitate sharing of databases
and preparation of GMP and submission documents . Your CMC
submission
is a living document that you have to live with for the lifetime
of your product, and the eCTD is one good solution for lifecycle
management. See the RAPS
presentation on "Advantages of eSubmissions" for
a more detailed discussion. |
| Q:
Can you provide any tips on how to prepare the CTD Quality submissions? |
A: Dr.
Foster recommends the SMART process for preparing
CTD Quality submissions:
(Download
PDF to see the complete article in the January 04 Issue of the
NESACS.org: "Nucleus".)
What is SMART?
Summaries
Mapping
Authors
Reviewers
Training
Summaries: Provide high level summaries to all sections
of the CTD Quality submission. These should contain key messages,
resolution of issues, and reference to any agreements with regulatory
agencies. The summary sections could be the basis of the Quality Overall
Summary in Module II of the CTD. Summaries should be drafted first,
not last, to identify key messages for the Map.
Mapping: Prepare a guidance document, a "Map",
that follows the CTD format, highlighting guidance requirements,
key content and messages, issues to be addressed, references to
previous submissions and agency agreements, and standards/templates
for fonts, references, tables, and figures. Obtain Management approval
of the Map and associated timeline to avoid any submission delays
from internal disagreements of content and format.
Authors: Choose authors wisely for each section
of the submission. Consider technical and regulatory background,
previous experience with submissions, writing and team skills, and
Departmental support of each author's role and time commitment.
Choose an overall Author/editor for the entire CTD Quality submission
to make sure the submission is seamless and has consistent terminology.
Reviewers: Choose reviewers wisely, and choose
the right number. Consider technical and regulatory experience,
negotiation skills, commitment to timelines, and buy-in of review
tools (such as electronic review.) Three review cycles are recommended:
1) functional review (within the technical department for each section),
2) first draft of completed submission, 3) final draft of completed
submission. Authors and regulatory coordinator should work together
to Resolve comments from reviewers; use a review meeting, if necessary,
with an agenda based on critical topics from the review and with
approvers in attendance.
Training: Provide the appropriate level of training
to authors, reviewers, and upper management on regulatory requirements
and the submission process. Emphasize the importance of a quality
Quality submission, to avoid approval delays. Promote Team building.
Provide the bigger picture and plan for the future!
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