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

Existing Existing GMPGMP’’ss

Quality by Design

(Pharmaceutical Development)

Quality Risk

Management

The Regulatory

Quality System

Pharmaceutical Quality System

Quality

Systems

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

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)

Q8– an opportunity for change

TABLE CONTENTS1. 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

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.

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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.

OBJECTIVE

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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.

COMPONENTS

OF

DRUG PODUCT

2.1.1

DRUGSUBSTANCES

2.1.2

EXCIPIENTS

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.

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.

DRUG PODUCT

2.2.1

FORMULATION

DEVELOPMENT

2.2.2

OVERAGES

2.2.3

PHYSIOCHEMICAL

& BIOLOGICAL

PROPERTIES

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.

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.

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.

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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.

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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.

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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.

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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.

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.

DEVELOPMENT PARADIGM –QUALITY BY DESIGN

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

“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.”

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.

“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.”

“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”