Presented at length on 23 April and 21 May 2017 at ICCBS, HEJ and Getz Pharma Auditorium, Karachi in a Discussion Forum of about 800 practicing university qualified professionals of various pharmaceutical manufacturing industries
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)
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)
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.
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)
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
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
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)