This document summarizes a discussion forum on ICH Q7 & Q11 regarding DMFs, impurities, CTD, and challenges. It provides an outline of drug master files, types of DMFs, classes of impurities in APIs, elements of a control strategy, sections of the common technical document that contain established conditions, and challenges faced. The presentation focused on established conditions, control strategies, their relationship, and how established conditions are presented in CTD sections.

1. Discussion Forum on ICH Q7 & Q11
DMF, Impurity, CTD & Challenges
Dr. Obaid Ali
Deputy Director, DRAP
Member ISPE, PDA
23 April 2017 (Program A)
21 May 2017 (Program B)

2. DMF, Impurity, CTD &
Challenges

3. Drug Master File
An Outline

4. Drug Master File
It is a document containing confidential information related to:
Manufacturing of
drug substance
Specification and
test method
Stability and re-
test period

5. DMFs – FDA Position
DMFs are not to be submitted as
substitutes of IND, NDA or
Supplemental applications
No regulatory requirement that a DMF
be submitted
Provide confidential
information concerning
CMC
Reviewed only in
connection with drug
application
Information treated as
confidential

6. Types of DMFs
Type I
• Manufacturing
site, facilities,
operating
procedures and
personnel
Type II
• Drug
substance,
intermediate
material
used in the
preparation
of drug
product
Type III
• Packaging
materials
Type IV
• Excipient,
colorant,
flavour
Type V
• FDA-
accepted
reference
information
(clinical /
preclinical
data)

7. Impurities in API
An Outline

8. What is an Impurity and what it can be?
Impurities are unwanted
chemicals present in the
API or FPP arising from
normal manufacture.
They are not chemicals
accidently or
maliciously introduced.
Impurities have no
therapeutic value and
are potentially harmful.
Therefore they need to
be controlled.

9. Organic
Inorganic
Residual
solvents
Classes of Impurities

10. Organic Impurities
May arise during manufacturing process and storage
Starting materials
By products
Intermediates
Degradation products
Reagents, ligands and catalysts

11. May be from manufacturing process and are normally known and
identified:
In Organic Impurities
Reagents, ligands and catalysts
Heavy metals
Inorganic salts
other materials (e.g. filter aids, charcoal)

12. Limits to be based on pharmacopoeial standards or known
safety data
Toxicity generally known, therefore controls achievable
Organic or inorganic liquids used during the manufacturing
process
Residual Solvents

13. Changes in CTD
An Evolving Landscape of leading Regulatory Agency
Ref: US-FDA (May 22nd 2015)

14. Intent to facilitate
Harmonized
Application
Dossier
(Content and
Format)
Synchronized
R&D Strategy
Synchronized
NDA
Submission
NDA Review
Cooperation
Synchronized
Approval and
Marketing

15. Common Technical Document
Module 1
Module 3 Module 4 Module 5
2.1
2.2
2.3
2.4 2.5
2.6 2.7
1.0
Quality
3.0
Nonclinical
Study Reports
4.0
Clinical
Study Reports
5.0
1.0 Regional Administrative Information
1.1 ToC of Module 1 or overall ToC,
including Module 1
2.1 ToC of the CTD (Mod 2,3,4,5)
2.2 Introduction
2.3 Quality Overall Summary
2.4 Nonclinical Overview
2.5 Clinical Overview
2.7 Clinical Summary
2.6 Nonclinical Summary
Module 2
Source: ICH Implementation Coordination Group

16. Established Conditions
Control Strategy
Elements of Control Strategy
Relationship of Control Strategy & Established
Conditions
Sections of CTD Typically containing “Established
Conditions”
Presentation Focus

17. Established Condition (EC)

18. Established
Conditions
Product
Description
Mfg Process
Description
Facilities
and
Equipment
Elements of
associated
Control
Strategy
Changes to
the
established
conditions
MUST be
reported to
the
Regulatory
Authority
EC

19. Control Strategy (CS)

20. Current product
understanding
Current process
understanding
Planned set
of controls
Control Strategy
(Set of Controls)
Assures
Process performance &
Product quality
CS

21. What is Process Performance???
Ability of the process to RELIABLY
produce a quality product

22. Elements of Control Strategy
(ECS)

23. Drug substance Excipients
In-process
materials
Drug product
materials
Facility &
Equipment
Operating
Conditions
In-process controls
Finished product
specifications
Associated
methods &
Frequency of
monitoring
Associated
methods &
Frequency of
sampling
Associated
methods &
Frequency of
testing
Associated
methods &
Frequency of
control
Etc.
Parameters and attributes related toECS

24. ECS that can be considered part of EC
DS/DP (including in-process materials) manufacturing & testing
facilities
Source of and specifications for starting materials for biological
products
Process, including in-process tests and sequence of operations,
equipment, and process parameters and their ranges
Cont’d

25. Specifications including the tests, analytical procedures and
acceptance criteria, including specifications for the DS, other
components, in-process materials and the DP
Container closure system, components and specifications
Maintenance strategy for chemometric and/or multivariate models
(e.g. for models that have a high impact on product quality
ECS that can be considered part of EC

26. Control
Strategy
Control
Strategy
Elements
reported in an
application
Established
conditions
Relationship
of CS & EC

27. Elements of Control Strategy NOT generally considered
“Established Conditions”
Batch
Records
Development
Data
Characterization
Data
Validation
Data
Batch
Analysis
Data

28. Sections of CTD Typically containing “Established Conditions”

29. CTD Section Section Title Contains Established
Condition
3.2.S DRUG SUBSTANCE
3.2.S.1 General Information
3.2.S.1.1 Nomenclature √
3.2.S.1.2 Structure √
Example of Established Condition (not an all-inclusive list):
Established name or proper name (for biologics)
For a New Chemical Entity: structure of the drug substance, including stereo-
chemistry, molecular formula, molecular mass
For Biotech Products: Schematic amino acid sequence indicating glycosylation sites
or other post-translational modifications and relative molecular mass

30. CTD Section Section Title Contains
Established
Condition
3.2.S DRUG SUBSTANCE
3.2.S.1 General Information
3.2.S.1.3 General Properties NOT CHANGED

31. CTD Section Section Title Contains EC
3.2.S. DRUG SUBSTANCE
3.2.S.2 Manufacture
3.2.S.2.1
3.2.S.2.2
Manufacturer(s)
Description of Manufacturing Process
and Process Controls
√
√
Example of Established Condition (not an all-inclusive list):
Name, address, manufacturing steps and/ or type of testing, and responsibility
Sequential procedure narrative, including certain information in the control strategy
that assures process performance and drug substance quality, such as: identification
of steps, process controls & parameters (with ranges), equipment & operating
conditions (including target settings) , input materials, and intermediates.

32. CTD Section Section Title Contains EC
3.2.S. DRUG SUBSTANCE
3.2.S.2 Manufacture
3.2.S.2.3 Control of Materials √
Example of Established Condition (not an all-inclusive list):
Material specifications (tests, analytical procedures and acceptance criteria)
For Biologicals: Source of materials (e.g. cell and seed source, raw materials) and
specification of materials ((e.g., tests, analytical procedures and acceptance criteria

33. CTD Section Section Title Contains EC
3.2.S. DRUG SUBSTANCE
3.2.S.2 Manufacture
3.2.S.2.4 Controls of Critical Steps and
Intermediates
√
Example of Established Condition (not an all-inclusive list):
Critical process steps: Tests and acceptance criteria that are part of the overall control
strategy (including microbial control strategy)
Intermediates (e.g., isolated intermediates): Specifications (tests, analytical procedures
and acceptance criteria) and hold times

34. CTD Section Section Title Contains EC
3.2.S. DRUG SUBSTANCE
3.2.S.2
3.2.S.2.5
3.2.S.2.6
3.2.S.3
3.2. S.3.1
3.2. S.3.2
Manufacture
Process Validation and/or Evaluation
Manufacturing Process Development
Characterization
Elucidation of Structure and other
Characteristics
Impurities
NOT CHANGED

35. CTD Section Section Title Contains EC
3.2.S. DRUG SUBSTANCE
3.2.S.4 Control of Drug Substance
3.2.S.2.4.1
3.2.S.2.4.2
Specifications
Analytical Procedures
√
√
Example of Established Condition (not an all-inclusive list):
Drug substance specifications (tests, analytical procedures and acceptance criteria)
Parameters and criteria for analytical procedures for drug substance specifications that
are part of the overall control strategy

36. CTD Section Section Title Contains EC
3.2.S. DRUG SUBSTANCE
3.2.S.4
3.2.S.4.3
3.2.S.4.4
3.2.S.4.5
Control of Drug Substance
Validation of Analytical Procedures
Batch Analyses
Justification of Specification
NOT CHANGED

37. CTD Section Section Title Contains EC
3.2.S. DRUG SUBSTANCE
3.2.S.5
3.2.S.6
Reference Standards or Materials
Container Closure System
√
√
Example of Established Condition (not an all-inclusive list):
Qualification protocols for new and existing reference standards or materials
Selected container closure system and controls

38. CTD Section Section Title Contains EC
3.2.S. DRUG SUBSTANCE
3.2.S.7
3.2.S.7.1
3.2.S.7.3
Stability
Stability Summary and Conclusions
Stability Data
NOT CHANGED

39. CTD Section Section Title Contains EC
3.2.S. DRUG SUBSTANCE
3.2.S.7 Sability √
Example of Established Condition (not an all-inclusive list):
Tests, analytical procedures and acceptance criteria; storage conditions; shelf life; post-
approval testing protocol; and commitment(s)

40. Challenges
Just think … & keep thinking to turn into opportunity