Ectd Guidance

8/16/2019 Ectd Guidance

1/37

eCTD Post Approval CMCAspects: FDA Perspective

Hasmukh B. Patel, Ph.D.

ONDQA, CDER, FDA

AAPS Workshop

Baltimore, MarylandMarch 10-11, 2009


2/37

2

Presentation Outline

• Product life cycle CMC changes

• Post-Approval CMC submissions

• CMC Submissions in eCTD

• Points to consider

• Summary


3/37

Product Life Cycle CMC

Changes


4/37

4

CMC Changes

• Manufacturing and Control sites

• Manufacturing Process

•

Specifications• Container/Closure system

• Stability Protocol

• Drug product formulation

• Labeling


5/37

Post-Approval CMC

Submissions


6/37

6

Types of Submissions

• Supplemental application

• Amendments• Annual report

• Correspondence

•Special report


7/37

7

Supplemental Applications

• For a single change (e.g. manufacturing

site)

• Multiple changes (e.g. manufacturing

site, manufacturing process, and in-

process controls)


8/37

8

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


9/37

CMC Submissions in eCTD


10/37

10

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


11/37

11

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


12/37

12

eCTD Submissions – contd.

• Information submitted in the following

Modules – Module 1

– Module 2

– Module 3


13/37

13

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


14/37

14

Module 1 – contd.

• EA Categorical Exclusion

• Some submissions contain justification

and rationale for change (which shouldnot be in this module)


15/37

15

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


16/37

16

Example: CMC Supplement

Adding a New Manufacturer ofDP

• The DP site change also involves:

– Change in batch formula

– Change in manufacturing process


17/37

17


Adding a New Manufacturer forDP – 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 processdescription” (3.2.P.3.3)


18/37

18


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 post-approval stability commitment” (3.2.P.8.2)

– One file for “stability data” (3.2.P.8.3)

–

All have “new” operation attribute


19/37

19


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-approvalstability commitment (3.2.P.8.2) “new”

– One file for stability data (3.2.P.8.3) “new”


20/37

20

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]

http://cdsesub1/evsprod/NDA021821/0075/m3/32-body-data/32p-drug-prod/patheon-tygacil-intravenous-5ml-50mg/32p3-manuf/batch-formula-lactose.pdf


21/37

21


22/37

22


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



23/37

23


Adding a New Test to DP Spec

and Updating DP Assaymethod – 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”


24/37

24

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]


25/37

25


26/37

Points to Consider


27/37

27

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


28/37

28

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 notalready in eCTD

– Proposed changed file with “Replace” or “Append”

attribute


29/37

29


•Provide Table of Contents (TOC) in PDF andlink to tables, figures, data, references, and allsupportive information within file anddocument, between documents, and where

possible to previously approved information• Manufacturing site(s): Identify which are

approved and which are proposed, use anattribute for each site if more than one

• Provide reference to approved information ifrefered


30/37

30


• Do not spread out all materials data inseveral documents

• Don’t have many small files with little

content• Provide link to the deleted/withdrawn

files


31/37

31

eCTD DTD version 3.2

m3-2-s-2-1-manufacturer3.2.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]


32/37

32


33/37

33


• Global Submit document

– In some submissions, the status of the file is

“current” even though the previously approvedfiles 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 proposedin the CMC submission quickly


34/37

34


35/37

35


36/37

36

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


37/37

Thank you!!

Documents

Ectd Guidance