The document discusses the International Council for Harmonization (ICH) and its goal of improving efficiency in drug development and registration. It provides an overview of the ICH's phases and agreement to continue harmonization efforts. The rest of the document focuses on Quality by Design (QbD), including defining the pharmaceutical development process, quality systems, quality risk management, and moving from empirical to systematic and knowledge-driven approaches. It provides details on the contents and topics that should be included in pharmaceutical development submissions to regulatory agencies.

2. BACKGROUND
•ICH established in 1990 as joint industry/
regulatory project to improve through
harmonization the efficiency of the process for
developing and registering new medicinal
products
•The Fourth International Conference on
Harmonization (ICH 4), Brussels, 1997 marks
the completion of the first phase
•It was agreed that the second phase of
harmonization continue to ensure the future
activities of ICH

4. Pharmaceutical Quality System
The Regulatory
Quality System
Quality by Design
(Pharmaceutical
Development)
Quality Risk
Management
Quality
Systems
Existing GMP’s
Quality
Systems
(Q10)
For companies with :
1. Good design and
control strategies
2. Good Risk
Management strategies
3. Good Quality Systems
Quality Risk
Management
(Q9)
Quality
by Design
(Q8)
Reduced regulatory
burden:
• Reduction of
submissions on
changes/variations
• Inspection of quality
systems

6. Q8– an opportunity for change
Traditional Future
Empirical
Data Driven
Retrospective
“Test to document
quality”
Acceptance criteria
based on limited batch
data
Variability not understood
and avoided
Q8
Systematic
Knowledge driven
Prospective
Science and Risk based
Acceptance criteria
based on patient needs
Variability explored and
understood (Design
Space)

8. TABLE CONTENTS
1. Introduction
1.1 Objective
2. Pharmaceutical Development
2.1 Components of Drug Product
2.1.1 Drug Substance
2.1.2 Excipients
2.2 Drug Product
2.2.1Formulation Development
2.2.2 Overages
2.2.3 Physiochemical and Biological Properties
2.3 Manufacturing Process Development
2.4 Container Closure System
2.5 Microbial Attributes
2.6 Compatibility

9. The Pharmaceutical Development
section provides an opportunity to
present the knowledge gained
through the application of scientific
approaches and quality risk
management to the development of
a product and its manufacturing
process.
I
N
T
R
O
D
U
C
T
I
O
N

10. OBJECTIVE
This guideline describes the suggested contents
for the 3.2.P.2 (Pharmaceutical Development)
section of a regulatory submission in the ICH
M4 Common Technical Document (CTD)
format.

11. P
H
A
R
M
A
C
E
U
T
I
C
A
L
DEVELOPMENT
The aim of pharmaceutical
development is to design a quality
product and its manufacturing process
to consistently deliver the intended
performance of the product.
The information and knowledge
gained from pharmaceutical
development studies and
manufacturing experience provide
scientific understanding to support the
establishment of the design space,
specifications, and manufacturing
controls.

12. COMPONENTS
OF
DRUG PODUCT
2.1.1
DRUGSUBSTANCES
2.1.2
EXCIPIENTS

13. DRUG SUBSTANCES
“The physicochemical and biological properties of the
drug substance that can influence the performance of the
drug product and its manufacturability.”
Examples of physicochemical and biological properties
that
might need to be examined include
•Solubility,
•Water content,
•Particle size,
•Crystal properties,
•Biological activity,
•Permeability.

14. EXCIPIENTS
The excipients chosen, their concentration, and the
characteristics that can influence the drug product
performance or manufacturability should be discussed
relative to the respective function of each excipients.
The compatibility of the drug substance with excipients
should be evaluated. For products that contain more than
one drug substance, the compatibility of the drug
substances with each other should also be evaluated.

15. DRUG PODUCT
2.2.1
FORMULATION
DEVELOPMENT
2.2.2
OVERAGES
2.2.3
PHYSIOCHEMICAL
& BIOLOGICAL
PROPERTIES

16. FORMULATION DEVELOPMENT
A summary should be provided describing the development
of the formulation, including identification of those attributes
that are critical to the quality of the drug product and also
highlight the evolution of the formulation design from initial
concept up to the final design.
Information from comparative in vitro studies (e.g.,
dissolution) or comparative in vivo studies (e.g., BE) that links
clinical formulations to the proposed commercial formulation.
A successful correlation can assist in the selection of
appropriate dissolution acceptance criteria, and can potentially
reduce the need for further bioequivalence studies following
changes to the product or its manufacturing process.

17. OVERAGES
Overages in the manufacture of the drug product, whether
they appear in the final formulated product or not, should
be justified considering the safety and efficacy
of the product.
Information should be provided on the
1) Amount of overage,
2) Reason for the overage (e.g., to compensate for
expected and documented manufacturing losses),
3) Justification for the amount of overage.

18. PHYSIOCHEMICAL & BIOLOGICAL
PROPERTIES
The physicochemical and biological properties relevant
to the safety, performance or manufacturability of the drug
product should be identified and discussed.
This includes the physiological implications of drug
substance and formulation attributes.

19. M
A
N
U
F
A
C
T
U
R
I
N
G
PROCESS
DEVELOPMENT
Important consideration to critical
formulation attributes, together with the
available manufacturing process options,
in order to address the selection of the
manufacturing process and confirm the
appropriateness of the components.
Appropriateness of the equipment used
for the intended products should be
discussed.
The manufacturing process
development programme or process
improvement programme should identify
any critical process parameters that
should be monitored or controlled (e.g.,
granulation end point) to ensure that the
product is of the desired quality.

20. C
O
N
T
A
I
N
E
R
CLOSURE
SYSTEM
The choice for selection of the
container closure system for the
commercial product should be
discussed.
The choice of materials for primary
packaging and secondary packaging
should be justified.
A possible interaction between
product and container or label should
be considered.

21. M
I
C
R
O
B
I
O
L
O
G
I
C
A
L
ATTRIBUTES
The selection and effectiveness of
preservative systems in products
containing antimicrobial preservative or
the antimicrobial effectiveness of products
that are inherently antimicrobial.
 For sterile products, the integrity of the
container closure system as it relates to
preventing microbial contamination.
The lowest specified concentration of
antimicrobial preservative should be
justified in terms of efficacy and safety,
such that the minimum concentration of
preservative that gives the required level
of efficacy throughout the intended shelf
life of the product is used.

22. C
O
M
P
A
T
I
B
I
L
I
T
Y
The compatibility of the drug product
with reconstitution diluents (e.g.,
precipitation, stability) should be
addressed to provide appropriate and
supportive information for
the labeling.

23. DEVELOPMENT PARADIGM –
Target
Product
Profile
Product/
Process
Dev.
Product/
Process
Design
Space
Control
Strategy
Define
product
intended
use &
quality
targets (wrt
efficacy &
safety)
Incorporate
prior
knowledge,
Risk
Assessment,
DoE and PAT
to create New
Scientific
Knowledge,
Through hypothesis
testing, create
scientific
understanding of
product and process.
Identify ’critical to
quality attributes’ and
establish multi-variate
”Design Space” that
assures Quality
Define control
strategy based
on Quality Risk
Mgmt & Design
Space leading
to control of
quality relevant
to safety and
efficacy.
QUALITY BY DESIGN

24. 1. TARGET
PRODUCT
PROFILE
2. CRITICAL
QUALITY
ATTRIBUTES
3. LINK
MAs AND PPs
TO CQAS
4. ESTABLISH
DESIGN
SPACE
5. ESTABLISH
CONTROL
STRATEGY
6. PRODUCT
LIFECYCLE
MNGMNT

25. “It is relative amount of drug from an administered
dosage form which enters the systemic circulation and
rate at which the drug appears in the systemic
circulation. The extent and rate at which its active
moiety is delivered from pharmaceutical form and
becomes available in the systemic circulation.”

26. May have a drug with very low bioavailability . Dosage form
or drug may not dissolve readily . Drug may not be readily
pass across biological membranes (i.e. be absorbed) . Drug
may be extensively metabolized during absorption process
(first-pass, gut wall, liver) . Important component of overall
variability i.e. Variable bioavailability may produce variable
exposure.

27. “Pharmaceutical Equivalents contain the same amount
of the same active substance in the same dosage form
meet the same or comparable standards intended to be
administered by the same route Pharmaceutical
equivalence by itself does not necessarily imply
therapeutic equivalence.”

28. “Two products are bioequivalent if they are pharmaceutically
equivalent bioavailabilities (both rate and extent) after
administration in the same molar dose are similar to such a
degree that their effects can be expected to be essentially the
same.”
“Therapeutic equivalence Two products are therapeutically
equivalent if pharmaceutically equivalent their effects, with
respect to both efficacy and safety, will be essentially the same
as derived from appropriate studies bioequivalence studies
pharmacodynamic studies clinical studies in vitro studies”