Regulatory Compliance for

Global Pharma Market

Quality by Design (QbD) in Product

Development

Dr. Nitin Dharmadhikari

Sun Pharma Advanced Research Company Ltd.,
Mumbai

18th Dec 12 This document is the property of SPARCL 1

 What is QbD?

Systematic, holistic and proactive approach to

pharmaceutical development.
Begins with predefined objectives

Emphasizes product and process understanding and

process control
Based on sound science and quality risk management
Ref.: ICH Q8 (R2)

18th Dec 12 This document is the property of SPARCL 2

 Why QbD?

Generic industry business model: Regulators perspective

File first, learn later
Major amendments during review process
- Exhibit batch stability failure, formulation revision
Longer time for generic product approval
Approved product may not be marketed
Post approval changes prior approval supplements

18th Dec 12 This document is the property of SPARCL 3

 How QbD will help improve?

Ensure higher level of assurance of product quality for

patient
Improved product and process design &
understanding
Monitoring, tracking & trending of product & process.
More efficient regulatory oversight
Efficiency and cost saving for industry
Increase efficiency of manufacturing process
Minimize / eliminate potential compliance actions

18th Dec 12 This document is the property of SPARCL 4

 Overview of QbD

Product Design
Quality Target
and
Product Profile
Understanding

Process Design
Control
and
Strategy
Understanding

Continuous
Improvement

18th Dec 12 This document is the property of SPARCL 5

 Elements of QbD

Quality Target Product Profile (QTPP)

Define Critical Quality Attributes (CQAs)
Perform risk assessment
Link raw material attributes and process parameters to
CQAs
Design and implement a control strategy
Manage product lifecycle, including continuous
improvement

18th Dec 12 This document is the property of SPARCL 6

 Quality Target Product Profile-
QTPP
What is QTPP?
A set of elements that defines the drug product
The target or goal set in advance
A guide to Drug Product development
What forms the basis for QTPP?
The RLD and its label
Applicable regulatory guidelines
When to define QTPP?
At the start of development
Knowledge gained in development may change some
elements

18th Dec 12 This document is the property of SPARCL 7

 Components of QTPP

Components related to safety, efficacy, identity, purity and

potency

Critical and non-critical components, e.g.

Critical: Assay, content uniformity
Non-critical: Appearance

Fixed and variable components

Fixed elements must be present
e.g. Dosage form, strength
Variable elements may have a range of acceptable values
e.g. Tablet weight, assay
18th Dec 12 This document is the property of SPARCL 8
 QTPP components for IR tablet -
Example
Dosage Form
Route of administration
Strength
Weight
Pharmacokinetics
Appearance
Identity
Assay
Impurities
Content uniformity
Friability
Dissolution
Residual solvents

18th Dec 12 This document is the property of SPARCL 9

 Specific requirements in QTPP

Scored tablets
Weight variation between two halves
Dissolution of half tablet

Orally Disintegrating tablets

Hardness
Disintegration time
Container closure

Extended Release products

Alcohol induced dose dumping

18th Dec 12 This document is the property of SPARCL 10

 Critical Quality Attributes CQAs

CQAs are a subset of the QTPP

Include critical parameters that are likely to change
based upon variations in raw materials and processes
-Identity test for dosage form Not a CQA
-Assay, Content uniformity CQAs
CQAs are monitored throughout the DP development.
CQAs ensure that DP remains within safe and
effective levels.

18th Dec 12 This document is the property of SPARCL 11

 QTPP and CQAs

QTPP components
Dosage Form
Route of administration
Strength
Weight CQAs
Pharmacokinetics
Assay (efficacy)
Appearance
Impurities (safety)
Identity
C.U. (efficacy)
Assay
Dissolution (efficacy)
Impurities
Content uniformity
Friability
Dissolution
Residual solvents

18th Dec 12 This document is the property of SPARCL 12

 QTPP and Specifications

QTPP Specifications

Desired target for developmental work Includes all of the CQAs

Components of QTPP may or may not Specification is a list of

- tests,
be in specification - references to analytical
- Not in spec Dosage form, strength procedures
- In spec Assay, impurities - acceptance criteria
Does not include acceptance criteria
Establishes the set of criteria to
which DP should conform to be
considered acceptable for its
intended use

Defining a QTPP does not mean setting all acceptance criteria

or the product specifications before development work begins.

18th Dec 12 This document is the property of SPARCL 13

 QbD Tools Risk Assessment
Why risk assessment in product development?
To identify relative risk levels at the beginning of product
development
To prioritize limited development resources
To document the decision making process throughout
development
To assess the needs of additional studies for scale up and
technology transfer
To identify appropriate specifications, critical process parameters
and manufacturing controls
To decrease variability of critical quality attributes

18th Dec 12 This document is the property of SPARCL 14

 Risk Assessment

Risk assessment for

Formulation starting material properties, levels of
components
Manufacturing process

Steps for risk assessment

List out all components / processes
Prepare the process flow chart
Identify all potential failure modes for each item with
risk query (what might go wrong?)
Risk analysis
Risk evaluation

18th Dec 12 This document is the property of SPARCL 15

 Risk Assessment
Various formal methodologies available for risk assessment

Failure Mode Effects Analysis & Failure Mode Effects & Criticality Analysis

Hazard & Operability Analysis

Supporting statistical tools

It is neither always appropriate nor always necessary to use a formal risk

management process.. The use of informal risk assessment processes can
also be considered acceptable. ICH Q9

A risk-based justification based on experience and data is always

necessary!

18th Dec 12 This document is the property of SPARCL 16

 Risk Assessment

Quality by Design for ANDAs:

An Example for Immediate-Release Dosage Forms

Generic product development for Acetriptan Tablets, 20 mg.

Acetriptan is a BCS Class II compound displaying poor
aqueous solubility (less than 0.015 mg/mL) across the
physiological pH range.
It exists in three different polymorphic forms which may affect
dissolution.
Polymorph III is the most stable polymorph.
Drug product is prepared with roller compaction process.

18th Dec 12 This document is the property of SPARCL 17

 Risk assessment
Risk assessment for formulation components

Formulation Variables
Drug Product CQA Drug Substance MCC/Lactose CCS Magnesium
Talc Level
PSD Ratio Level Stearate Level

Assay MEDIUM MEDIUM LOW LOW LOW

Content Uniformity HIGH HIGH LOW LOW LOW

Dissolution HIGH MEDIUM HIGH LOW HIGH

Degradation
LOW LOW LOW LOW MEDIUM
Products

18th Dec 12 This document is the property of SPARCL 18

 Risk assessment

Risk assessment of DP manufacturing process

Process Steps
Drug Product
Pre-RC* Final Blending
CQAs Roller
Blending and Milling and Compression
Compaction
Lubrication Lubrication

Assay MEDIUM LOW MEDIUM LOW MEDIUM

Content
HIGH HIGH HIGH LOW HIGH
Uniformity

Dissolution MEDIUM HIGH MEDIUM HIGH HIGH

Degradation
LOW LOW LOW LOW LOW
Products

* RC: Roller compaction

18th Dec 12 This document is the property of SPARCL 19

 Justification for assigned risks

Drug
Process Assigned
Product Justification
Steps Risk
CQAs
Suboptimal pre-roller compaction blending and lubrication
Assay MEDIUM may cause variable flowability of the blend affecting Assay.

The PSD and cohesiveness of the drug substance

Pre-Roller Content
HIGH adversely impact its flowability. If not blended properly
Compaction Uniformity
with excipients, it may affect CU.
Blending
Blending process variables may impact the distribution of
and
Dissolution MEDIUM CCS in the blend which could impact disintegration of the
Lubrication
granules and ultimately, dissolution of the tablets.
Blending process variables are unrelated to the
Degradation
LOW degradation products of Generic Acetriptan Tablets, 20
Products
mg.

18th Dec 12 This document is the property of SPARCL 20

 CMAs, CPPs and CQAs
What factors affect drug product CQAs?
Properties of Input Materials- Identify Critical Material Attributes
(CMAs)
Properties of in-process materials- CQAs of one step become
CMAs for a downstream unit operation
Manufacturing process parameters- Identify Critical Process
Parameters (CPPs)

CPPs1 CPPs2

CMAs1 CMAs2 CQAs

Unit Unit
Operation 1 Operation 2
Product
Input Output
Materials Materials

18th Dec 12 This document is the property of SPARCL 21

 Critical Material Attributes (CMAs)

Risk Assessment of the drug substance attributes

Drug Substance Attributes

Drug Product Solid
CQAs Particle Residual Process Chemical
State Hygroscopicity
Size Solvents Impurities Stability
Form
Physical
Attributes (size LOW LOW LOW LOW LOW LOW
and splitability)
Assay LOW LOW LOW LOW LOW LOW

Content LOW LOW LOW LOW LOW LOW

Uniformity
Drug Release HIGH LOW HIGH LOW LOW LOW

Solid state form and particle size of DS are CMAs

18th Dec 12 This document is the property of SPARCL 22

 CPPs
Risk assessment of manufacturing process

Identify high risk steps (unit operation) that affect the CQAs of DP.

Process Steps

Drug Product CQAs Pre-RC* Final

Roller
Blending and Milling Blending and Compression
Compaction
Lubrication Lubrication

Assay MEDIUM LOW MEDIUM LOW MEDIUM

Content Uniformity HIGH HIGH HIGH LOW HIGH

Dissolution MEDIUM HIGH MEDIUM HIGH HIGH

Degradation Products LOW LOW LOW LOW LOW

18th Dec 12 This document is the property of SPARCL 23

 CPPs
Process Step: Compression

Risk
CPPs DP CQAs Justification and Strategy
Assessment

Content CU is dominated by BU and flowability and is

LOW
Main Uniformity unrelated to main compression force.
compression
force Suboptimal compression force may affect tablet
Dissolution HIGH
hardness and friability and, ultimately, dissolution.

A faster than optimal press speed may cause

Content
HIGH inconsistent die filling and weight variability which
Uniformity
Press speed
may then impact CU and dissolution. For efficiency,
(dwell time)
the press speed will be set as fast as practically
Dissolution HIGH possible without adversely impacting tablet quality.

18th Dec 12 This document is the property of SPARCL 24

 Control Strategy

A planned set of controls, derived from current product and process

understanding that ensures process performance and product
quality..
ICH Q8 (R2) & Q10

Control Strategy includes following elements (but not

limited to):
Input material attributes (e.g. drug substance, excipients,
container closure)
Equipment operating conditions (process parameters)
In-process controls
Finished product specifications
Controls for each unit operations
Methods and frequency of monitoring and control.

18th Dec 12 This document is the property of SPARCL 25

 Control Strategy

18th Dec 12 This document is the property of SPARCL 26

 Control Strategy
Control Strategy Implementation Options

Enhanced Approach
Level 1
Real-time automatic
control + Flexible process
parameters

Level 2
Reduced end product testing +
Flexibility for critical material
attributes and critical process
parameters within design space

Level 3
End product testing + tightly
constrained material attributes and
process parameters
Traditional Approach

18th Dec 12 This document is the property of SPARCL 27

 QbD Tools DoE
Design of experiments (DoE)
Useful for screening of variables with significant impact on DP CQAs

Classical approach uses OFAT (One Factor At A Time)

Limited number of experiments gives limited information.

DoE helps study effects of interaction of multiple factors at a time

Used in optimization studies, enables creation of design space

Design space is proposed by the applicant and subject to regulatory

assessment and approval.
Design space developed at lab or pilot scale can be proposed for
commercial scale, but needs to be verified at production scale for
scale dependant parameters.

18th Dec 12 This document is the property of SPARCL 28

 Process Analytical Technology
(PAT)

Timely measurements during processing

Critical quality and performance attributes
Raw and in-process materials
At-line, on-line or in-line measurements
Founded on Process Understanding

Opportunities for improvement

More reliable and consistent processes (& product)
Less failures, less reworks, less recalls
Flexibility w.r.t. scale and equipment
Better / faster Quality Systems
Process Enhancement Opportunities

18th Dec 12 This document is the property of SPARCL 29

 PAT in Tablet manufacturing

Stage Technique Measurement

Dispensing NIR / Raman Identification of raw materials

Wet Granulation NIR Moisture distribution

Drying NIR Moisture content

Blending NIR Blend Uniformity

Strain gauges Compression force

Compression
NIR Content Uniformity

18th Dec 12 This document is the property of SPARCL 30

 PAT Examples

Spectral Probe NIR Analyzer installed on viewing window of Glatt FBD

without any dryer modification.

18th Dec 12 This document is the property of SPARCL 31

 PAT Examples

Real-time Blend Uniformity by using TruProcess Analyzer

18th Dec 12 This document is the property of SPARCL 32

 QbD: Required or Optional?
Required
Quality target product profile (QTPP) including critical quality
attributes (CQAs) of the drug product and including Product design
and understanding
Product design and understanding
Critical material attributes (CMAs) of the drug substance
and excipients
Process design and understanding
Critical process parameters (CPPs)
Control strategy, including justification

Optional
Design Space
Process Analytical Technology

18th Dec 12 This document is the property of SPARCL 33

 QbD

18th Dec 12 This document is the property of SPARCL 34

 QbD

18th Dec 12 This document is the property of SPARCL 35

 References for QbD

1. Guidance for Industry: Q8(R2) Pharmaceutical Development

2. Guidance for Industry: Q9 Quality Risk Management

3. Guidance for Industry: Q10 Pharmaceutical Quality System

4. Guidance for Industry PAT: A Framework for Innovative Pharmaceutical

Development, Manufacturing, and Quality Assurance

5. Quality by Design for ANDAs: An Example for Modified Release Dosage

Forms

6. Quality by Design for ANDAs: An Example for Immediate Release Dosage

Forms

7. GPhA presentations

8. Draft QbR updated

18th Dec 12 This document is the property of SPARCL 36