Quality by Design in Product Development

Quality by
Design (QbD) in Product Development

v  Systematic,
holistic and proactive approach to pharmaceutical development.

v  Begins
with predefined objectives

v  Emphasizes
product and process understanding and process control

v  Based
on sound science and quality risk management

Ref.: ICH Q8 (R2)

Generic industry business model: Regulator’s perspective

v  File
first, learn later

v  Major
amendments during review process

                          
–   Exhibit batch stability
failure, formulation revision

v  Longer
time for generic product approval

v  Approved
product may not be marketed

v  Post
approval changes – prior approval supplements

How QbD will help improve? 

v  Ensure
higher level of assurance of product quality for patient

Ø  Improved
product and process design & understanding

Ø  Monitoring,
tracking & trending of product & process.

v  More
efficient regulatory oversight

v  Efficiency
and cost saving for industry

Ø  Increase
efficiency of manufacturing process

Ø  Minimize
/ eliminate potential compliance actions

Overview of QbD

Quality Target Product
Profile à Product Design and Understanding à Process Design and Understanding à Control Strategy à Continuous Improvement

v  Quality
Target Product Profile (QTPP)

v  Define
Critical Quality Attributes (CQAs)

v  Perform
risk assessment

v  Link
raw material attributes and process parameters to CQAs

v  Design
and implement a control strategy

v  Manage
product lifecycle, including continuous improvement

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

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

QTPP components for IR tablet – Example

Specific requirements in QTPP

v  Scored
tablets

Ø  Weight
variation between two halves

Ø  Dissolution
of half tablet

v  Orally
Disintegrating tablets

Ø  Hardness

Ø  Disintegration
time

Ø  Container
closure

v  Extended
Release products

Ø  Alcohol
induced dose dumping

Critical Quality Attributes – CQAs

v  CQAs
are a subset of the QTPP

v  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

v  CQAs
are monitored throughout the DP development.

v  CQAs
ensure that DP remains within safe and effective levels.

QTPP and CQAs

                                               â

QTPP and Specifications

QTPP

•       Desired
target for developmental work

•       Components
of QTPP may or may not be in specification

–         
Not in spec – Dosage form, strength

–         
In spec – Assay, impurities

•       Does
not include acceptance criteria

Specifications

•       Includes
all of the CQAs

•       Specification
is a list of

–         
tests,

–         
references to analytical procedures

–         
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.

QbD Tools – Risk Assessment

Why risk assessment in product development?

v  To
identify relative risk levels at the beginning of product development

v  To
prioritize limited development resources

v  To
document the decision making process throughout development

v  To
assess the needs of additional studies for scale up and technology transfer

v  To
identify appropriate specifications, critical process parameters and
manufacturing controls

v  To
decrease variability of critical quality attributes

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

Various formal methodologies available for risk assessment

v  Failure
Mode Effects Analysis & Failure Mode Effects & Criticality Analysis

v  Hazard
& Operability Analysis

v  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!

Quality by Design for ANDAs:

An Example for Immediate-Release Dosage Forms

v  Generic
product development for Acetriptan Tablets, 20 mg.

v  Acetriptan
is a BCS Class II compound displaying poor aqueous solubility (less than 0.015
mg/mL) across the physiological pH range.

v  It
exists in three different polymorphic forms which may affect dissolution.

v  Polymorph
III is the most stable polymorph.

v  Drug
product is prepared with roller compaction process.

Risk assessment for formulation components

Risk assessment of DP manufacturing process

Justification for assigned risks

CMAs, CPPs and CQAs

What factors affect drug product CQAs?

v  Properties
of Input Materials- Identify Critical Material Attributes (CMAs)

v  Properties
of in-process materials- CQAs of one step become  CMAs for a downstream unit operation

v  Manufacturing
process parameters- Identify Critical Process Parameters (CPPs)

Critical Material Attributes (CMAs)

Risk Assessment of the drug substance attributes

Solid state form and particle size of DS are CMAs

CPPs

•       Risk
assessment of manufacturing process

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

Process Step: Compression

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.

Control Strategy Implementation Options

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.

Process Analytical Technology (PAT)

Ø  Timely
measurements during processing

v  Critical
quality and performance attributes

v  Raw
and in-process materials

Ø  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

PAT in Tablet manufacturing

PAT Examples

Spectral Probe NIR Analyzer installed on viewing window of
Glatt FBD without any dryer modification.

Real-time Blend
Uniformity by using TruProcess™ Analyzer

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

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