eCTD Post Approval CMC

Aspects: FDA Perspective

Hasmukh B. Patel, Ph.D.
ONDQA, CDER, FDA
AAPS Workshop
Baltimore, Maryland
March 10-11, 2009

Presentation Outline

Product life cycle CMC changes

Post-Approval CMC submissions
CMC Submissions in eCTD
Points to consider
Summary

Product Life Cycle CMC

Changes

CMC Changes

Manufacturing and Control sites

Manufacturing Process
Specifications
Container/Closure system
Stability Protocol
Drug product formulation
Labeling
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Post-Approval CMC
Submissions

Types of Submissions

Supplemental application
Amendments
Annual report
Correspondence
Special report

Supplemental Applications
For a single change (e.g. manufacturing
site)
Multiple changes (e.g. manufacturing
site, manufacturing process, and inprocess controls)

Supplemental Applications
contd.
Paper and electronic
eCTD vs non-eCTD
eCTD: Individual files for different CTD
sections
Non-eCTD: One document may cover many
sections

CMC Submissions in eCTD

Life Cycle Attributes

Following are post-approval activities
related to the approved information in
the initial application:
Add new information
Amend information
Replace information
Delete information
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eCTD Submissions
In initial submission
Consider granularity Annex of the CTD
Organization document (i.e., number of files)
Consider sections likely to be supplemented
All operation attributes set to new

In subsequent submissions (amends & supps)

Use the same structure
Include only files that have changed
Use appropriate operation attribute
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eCTD Submissions contd.

Information submitted in the following
Modules
Module 1
Module 2
Module 3

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Module 1
Cover Letters
DMF (Letters of Authorization (LOAs)
In 1.4.1 from your suppliers
In 1.4.2 for who you authorize to reference
your DMF/IND/NDA
Not in P.3.1, S.2.1, or P.7

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Module 1 contd.
EA Categorical Exclusion
Some submissions contain justification
and rationale for change (which should
not be in this module)

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Module 2
Helpful for extensive changes (e.g.,
formulation change)
Not needed for trivial changes (e.g.,
secondary packaging site change)
Do not put all data in Module 2

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Example: CMC Supplement

Adding a New Manufacturer of
DP
The DP site change also involves:
Change in batch formula
Change in manufacturing process

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Example: CMC Supplement

Adding a New Manufacturer for
DP contd.
Initial submission has:
One file for manufacturer (3.2.P.3.1)
One file for batch formula (3.2.P.3.2)
One file for manufacturing process
description (3.2.P.3.3)

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Example: CMC Supplement

Adding a New Manufacturer for
DP contd.
Initial submission has:
One file for stability summary (3.2.P.8.1)
One file for stability protocol and postapproval stability commitment (3.2.P.8.2)
One file for stability data (3.2.P.8.3)
All have new operation attribute

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Example: CMC Supplement

Adding a New Manufacturer
for DP
Supplement #5, sequence #015 has:
One file for manufacturer (3.2.P.3.1) replace
One file for batch formula (3.2.P.3.2) new
One file for manufacturing process description
(3.2.P.3.3) new
One file for stability summary (3.2.P.8.1) new
One file for stability protocol and post-approval
stability commitment (3.2.P.8.2) new
One file for stability data (3.2.P.8.3) new
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Index.XML

eCTD DTD version 3.2

m3-quality
m3-2-body-of-data
m3-2-p-drug-product [manufacturer: AAA] [product name: YY] [dosage form:
intravenous]

m3-2-p-3-manufacture
m3-2-p-3-1-manufacturers
Manufacturer [replace]
m3-2-p-3-2-batch-formula
Batch Formula [new]
m3-2-p-3-3-description-of-manufacturing-process-and-process-controls
Description of Manufacturing Process and Process Controls [new]
m3-2-p-8-stability
m3-2-p-8-1-stability-summary-and-conclusion
Stability Summary and Conclusion [new]
m3-2-p-8-2-post-approval-stability-protocol-and-stability-commitment
Post Approval Stability Protocol and stability Commitment [new]
m3-2-p-8-3-stability-data
Stability Data [new]

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Example: CMC Supplement

Adding a New Test to DP Spec
and Updating DP Assay
method
Adding ID test
Change in specification
Addition of analytical procedure

Updating analytical procedure for DP assay

Amending the current analytical procedure
Validation of the updated analytical procedure
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Example: CMC Supplement

Adding a New Test to DP Spec
and Updating DP Assay
method

contd.
Initial submission has:
One file for Specification (3.2.P.5.1)
Several files for P.5.2 and P.5.3 (1 for each method)
All have new operation attribute

Supplement #1, sequence #005 has:

One file for Specification (3.2.P.5.1) new

One file for P.5.2 ID method new
One file for P.5.2 updated DP assay analytical procedure new
One file for P.5.3, validation of DP assay analytical procedure new

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Leaf Titles
eCTD DTD version 3.2
m3-quality
m3-2-body-of-data
m3-2-p-drug-product [manufacturer: ABC Inc] [product name:
XX] [dosage form: Cream]
m3-2-p-5-control-of-drug-product
m3-2-p-5-1-specifications
Specifications [new]
m3-2-p-5-2-analytical-procedures
SSS-00100: DP Assay [new]
MMM-00111: DP Identity [new]
m3-2-p-5-3-validation-of-analytical-procedures
Validation of Analytical Procedures [new]
TTT-00200: Method Validation for the Assay of DP [new]
MMM-00210: Validation of ID method [new]
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Points to Consider

Points to Consider
Cover letter
Purpose of submission
List all changes in the cover letter and
provide link to the body of data
Indicate which DMFs are involved
List related supplements and ARs
Do not include index for the submission,
navigation is via XML backbone

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Points to Consider contd.

Pre-Change and Post Change Comparisons
Critical for effective evaluation
Options include:
Word Track Changes
Highlighting of new information
Tabular comparisons
Submit both files
Pre-change file with New XML attribute if not
already in eCTD
Proposed changed file with Replace or Append
attribute
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Points to Consider contd.

Provide Table of Contents (TOC) in PDF and
link to tables, figures, data, references, and all
supportive information within file and
document, between documents, and where
possible to previously approved information
Manufacturing site(s): Identify which are
approved and which are proposed, use an
attribute for each site if more than one
Provide reference to approved information if
refered

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Points to Consider contd.

Do not spread out all materials data in
several documents
Dont have many small files with little
content
Provide link to the deleted/withdrawn
files

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eCTD DTD version 3.2

m3-2-s-2-1-manufacturer
3.2.S.2.1 Manufacturer [replace]
m3-2-s-2-2-description-of-manufacturing-process-and-process-controls
3.2.S.2.2.1 Description of the Manufacturing Process and Process
Controls - Process 2 [new]
3.2.S.2.2.2 Description of the Manufacturing Process and
Process Controls Process 3 [new]
3.2.S.2.2 Description of the Manufacturing Process and
Process Controls [delete]

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Points to Consider contd.

Global Submit document
In some submissions, the status of the file is
current even though the previously approved
files has been replaced
In the heading, no name of the drug along with
the NDA number to identify the drug
No way to identify the type of change proposed
in the CMC submission quickly

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Summary
Submit eCTD submissions as per the Guidance
for Industry M2 eCTD: Electronic Common
Technical Document Specification
Make information easily accessible through
appropriate links for navigation and
references
Clearly state what has changed and what is
approved
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Thank you!!