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

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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)

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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

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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

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Overview of QbD
Quality Target
Product Profile

Product Design
and
Understanding

Process Design
and
Understanding

Control
Strategy

Continuous
Improvement

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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

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Quality Target Product ProfileQTPP

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
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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
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QTPP components for IR tablet Example

Dosage Form
Route of administration
Strength
Weight
Pharmacokinetics
Appearance
Identity
Assay
Impurities
Content uniformity
Friability
Dissolution
Residual solvents
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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
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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.

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QTPP and CQAs

QTPP components
Dosage Form
Route of administration
Strength
Weight

CQAs

Pharmacokinetics

Assay (efficacy)

Appearance
Identity
Assay
Impurities

Impurities (safety)
C.U. (efficacy)
Dissolution (efficacy)

Content uniformity
Friability
Dissolution
Residual solvents

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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,
- references to analytical
procedures
- acceptance criteria

be in specification
- Not in spec Dosage form, strength
- In spec Assay, impurities
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.
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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
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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
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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!

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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.

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Risk assessment
Risk assessment for formulation components

Formulation Variables
Drug Product CQA

Drug Substance
PSD

MCC/Lactose
Ratio

CCS
Level

Talc Level

Magnesium
Stearate Level

Assay

MEDIUM

MEDIUM

LOW

LOW

LOW

Content Uniformity

HIGH

HIGH

LOW

LOW

LOW

Dissolution

HIGH

MEDIUM

HIGH

LOW

HIGH

Degradation
Products

LOW

LOW

LOW

LOW

MEDIUM

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Risk assessment
Risk assessment of DP manufacturing process
Process Steps
Drug Product
CQAs

Pre-RC*
Blending and
Lubrication

Roller
Compaction

Milling

Final Blending
and
Lubrication

Compression

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

* RC: Roller compaction

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Justification for assigned risks

Process
Steps

Drug
Product
CQAs

Assigned
Risk

Justification
Suboptimal pre-roller compaction blending and lubrication

Assay

Pre-Roller
Compaction

MEDIUM

The PSD and cohesiveness of the drug substance

Content
Uniformity

HIGH

Lubrication

adversely impact its flowability. If not blended properly

with excipients, it may affect CU.

Blending
and

may cause variable flowability of the blend affecting Assay.

Blending process variables may impact the distribution of

Dissolution

MEDIUM

CCS in the blend which could impact disintegration of the

granules and ultimately, dissolution of the tablets.
Blending

Degradation
Products

LOW

process

variables

are

unrelated

to

the

degradation products of Generic Acetriptan Tablets, 20

mg.

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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)
CPPs2

CPPs1

CMAs1
Input
Materials

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Unit
Operation 1

CMAs2
Output
Materials

Unit
Operation 2

CQAs

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Product

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Critical Material Attributes (CMAs)

Risk Assessment of the drug substance attributes
Drug Substance Attributes
Drug Product
CQAs

Solid
State
Form

Hygroscopicity

Particle
Size

Residual
Solvents

Process
Impurities

Chemical
Stability

Physical
Attributes (size
and splitability)

LOW

LOW

LOW

LOW

LOW

LOW

Assay

LOW

LOW

LOW

LOW

LOW

LOW

Content
Uniformity

LOW

LOW

LOW

LOW

LOW

LOW

Drug Release

HIGH

LOW

HIGH

LOW

LOW

LOW

Solid state form and particle size of DS are CMAs

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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*
Blending and
Lubrication

Roller
Compaction

Milling

Final
Blending and
Lubrication

Compression

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

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CPPs
Process Step: Compression
CPPs

Main
compression
force

Press speed
(dwell time)

DP CQAs

Risk
Assessment

Content
Uniformity

LOW

Dissolution

HIGH

Content
Uniformity

Justification and Strategy

CU is dominated by BU and flowability and is
unrelated to main compression force.
Suboptimal compression force may affect tablet
hardness and friability and, ultimately, dissolution.
A faster than optimal press speed may cause

HIGH

inconsistent die filling and weight variability which

may then impact CU and dissolution. For efficiency,
the press speed will be set as fast as practically

Dissolution

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HIGH

possible without adversely impacting tablet quality.

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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.
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Control Strategy

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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

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

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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

NIR

Content Uniformity

Compression

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PAT Examples

Spectral Probe NIR Analyzer installed on viewing window of Glatt FBD

without any dryer modification.

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PAT Examples

Real-time Blend Uniformity by using TruProcess Analyzer

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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
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QbD

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QbD

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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

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