QUALITY

by
DESIGN
By:
Ravi Ukawala
07BPH104
MYTH BUSTER
QbD: Myth Buster

QbD is an expensive
development tool !

QbD is a tool that makes

product development and
commercial scale
manufacturing simple!
It also saves money!

QbD: Myth and Fact

QUALITY BY DESIGN:
OVERVIEW
What is QbD…???

Quality

Suitability of either a drug substance or a drug product for its intended use

Quality by Design

Scientific, systematic, risk-based, holistic and proactive approach to product development

 Product and process performance characteristics are scientifically designed to meet

specific objectives.

 To achieve the objectives of QBD product and process characteristics important to

desired performance must be derived from a combination of prior knowledge and
experimental assessment during product development
QbD: Introduction

Traditional Vs QBD approach

Traditional
Quality byapproach
Testing QBD approach

• End product quality control • Quality management systems to

• Static quality control via raw material ensure product quality dynamically in
testing (drug substance, excipients), real time through online process
in process testing and fixed API monitoring and real time product
manufacturing process testing

Processes are narrowly defined Robust and well understood

through validation using a limited formulations and processes are
number of product lots developed

Quality cannot be TESTED into products

Quality can only be BUILT into products
QbD: Elements

Elements of QbD

1. Quality Target Product Profile (QTPP)

2. Critical Quality Attributes (CQA)

3. Critical Material Attributes: API & Excipients (CMA)

4. Critical Process Parameters (CPP)

5. Design Space

6. Quality Risk Management (QRM)

7. Control Strategy

8. Product Lifecycle Management & Continual Improvements

QbD: Pathway

Define QTPP

Define CQA
QbD Pathway for a Product

Define CMA

Link CMA &

CQA with
CPP

Achieve
Design
Space

Risk
Management

Control
Strategy
Quality Target Product profile (QTPP)

Target Product profile

 Strategic foundation for drug development

 TPP is primarily expressed in clinical terms

Planning with the end in mind

Quality Target Product profile

 Extension of TPP for product quality
 FDA defines QTPP as Product Attributes related to Quality, Safety and Efficacy.
 QTPP should only include patient relevant Product Performance elements.
 Quality characteristics that the drug product should possess to deliver the therapeutic
benefit promised in the label reproducibly
 QTPP should be defined early in development based on;
• Drug Substance property
• RLD characterization and RLD labeling information

How was the drug

What attributes product designed Identification of
should the drug
product possess? to have these QTTP
attributes?
QTPP Example

QTPP element Target Justification

Dosage form Tablet Pharmaceutical equivalence

requirement
Immediate release film
Dosage design coated tablet To meet the label claim
Pharmaceutical equivalence
Dosage strength X mg requirement

Route of Pharmaceutical equivalence

Oral
administration requirement
Description, Assay, Pharmaceutical equivalence
Drug product Uniformity, Impurities, requirement
attributes Dissolution, microbiological (Compendia, Literature and the
limits, water content, reference listed drug label claim)
residual solvents
90% confidence interval for
AUC and Cmax should fall Bioequivalence requirement to ensure
Pharmacokinetics
within bioequivalence limits rapid onset and efficacy
of 80-125%
Critical Quality Attributes (CQA)

 As per FDA, a CQA is a physical, chemical, biological, or microbiological property or

characteristic that should be within an appropriate limit, range, or distribution to
ensure the desired product quality.
 CQAs are generally associated with the drug substance, excipients, intermediates (in-
process materials) and drug product.
 CQAs are subset of QTPP and can be altered by change in Formulation &/or Process,
also from the prior knowledge.
 The identification of CQAs from QTPP is based on the severity of harm to a patient.
 List of potential CQAs can be modified based on product & process understanding
and knowledge.
 Potential CQAs prioritizing can be done using Quality Risk Management Tool like
Failure Mode Effect Analysis(FMEA).

Physical, chemical, biological, or microbiological property or characteristic that should be

within an appropriate limit, range, or distribution to ensure the desired product quality
Critical Quality Attributes (CQA)

Multidisciplinary

Quality Attribute Target Justification

Appearance Colour and shape should be
acceptable to the patient
Size Similar to reference product
Not directly linked to safety and efficacy. It
should be similar to reference product for
patient acceptability
For comparable ease of swallowing and
patient acceptability, set to be similar to
reference product

Quality

Quality Attribute Target Justification

Assay should be evaluated throughout the
Assay 90-110% of label claim development since variability of assay
affect safety and efficacy

Content Uniformity Should conform to USP <905> AV Evaluated throughout development as it

15 and RSD NMT 5% affects safety and efficacy
Affects safety and efficacy if the drug is
Water content As per stability data sensitive to moisture
Critical Quality Attributes (CQA)

Safety

Quality Attribute Target Justification

As per ICH guidelines or
Impurities characterization of Reference
product
Residual solvents As per USP <467>
Microbiological limits As per USP <61 and 62>
Degradation products may impact safety
and should be controlled since process and
formulation variables may impact
impurities. Limits are set as per ICH or
reference product
Affects safety but controlled during
manufacture of API
Impacts safety but process variables are
unlikely to affect this attribute

Efficacy

Quality Attribute Target Justification

Failure to meet the specification can impact
Dissolution NLT 80% dissolved in 30 minutes bioavailability. Formulation and process
variables may impact dissolution
Critical Process Parameter (CPP)

Process parameter whose realistic change can cause the product to fail to meet the QTPP

Example

Granulation Process QA after

granulation
Impeller speed Blend Uniformity
Granulation time Wet Granule PSD
Order of addition granulation Moisture
Binder addition rate BD/TD

A process parameter whose variability has an impact on a critical quality attribute and,
therefore, should be monitored or controlled to ensure the process produces the
desired quality
Critical Process Parameter (CPP)

Attribute of intermediates will go as in-process check;

 Dried granules- description, LOD

 Final blend- BD, TD
 Final blend- PSD
 Final blend- assay
 Core tablet- dissolution
 Core tablet- thickness, hardness
 Uniformity of dosage unit of core tablet
 Core tablet- assay, RS
Example: CPP risk analysis and control
Critical Material Attributes (CMA)

 Material Attributes that affects QTPP and CQAs will become CMA.
 CMA is of two types: 1. for API and 2. for Excipient

API CMA and Risk analysis: Example with Justification

CMA of API
CQA Process
Particle size Flow Moisture RS Solid state Solubility
impurity

Assay Low Low Low Low Low Low High

Uniformity High High Low Low Low Low Low

Dissolution High Low Low Low High High Low

Impurities Low Low Medium Medium Low Low High

CMA Failure mode Justification

Particle size Higher PSD Dissolution and Uniformity of drug product

and BA affected (Class II/IV)
Assay and impurity profile of drug product
Process impurity Less purity
may be affected
Risk Identification: Fish-Bone/Ishikawa Diagram

Cause-and-Effect Diagram
C oating C ompression Env ironment

S uspension
concentration F eeder speed
P an speed Temperature

S pray rate P recompression force

S olid concentration Relativ e humidity

of suspension C ompression force
E xhaust temperature

S creen used for Diluent P S D and LO D

siev ing
Blending speed D isintegrant
concentration
Blending time Lubricant concentration

M illing speed A PI PSD

Sizing and Blending Materials

CMA, CPP and CQA Impact
Quality Risk Management [Failure Mode Effect Analysis (FMEA)]
 Risk is combination of probability of Occurrence of Harm and Severity of that Harm.
 An effective QRM approach ensure the high quality of the drug product to the patient by providing a
proactive means to identify and control potential quality issues.
 QRM can be used at different stages of product development.

Overview of QRM Process

FMEA: A Tool for QRM

 FMEA relies on product and process

understanding.
 FMEA methodically breaks down the
analysis of complex processes into
manageable steps.
 It is a powerful tool for summarizing
the important modes of failure, factors
causing these failures and the likely
effects of these failures.
 USES:
 To prioritize risks and monitor the
effectiveness of risk control activities.
 Applied to equipment and facilities and
might be used to analyze a
manufacturing operation and its effect
on product or process.
FMEA Classical Practice

RPN = O x D x S
(Min: 1, Max: 1000)

 Top 10 should be picked up for immediate attention.

 Need to run multiple times during the development and continuous improvement program.
Design Space
 A design space is a multidimensional combination of input variables (e.g., material attributes), their
interactions and process parameters that have been demonstrated to provide assurance of quality.

 A design space may be constructed for a single unit operation, multiple unit operations, or for the entire
process. Though according to FDA guideline, defining design space is optional since the product and
process understanding can be established without a formal design space, nevertheless, such approach
can assist to better understanding and attain overall control of a system.

 From FDA perspective, regulatory submission in regards to design space should include the following
aspects:
 Description of design space, including critical and other relevant parameters.
 The interaction of various inputs variables and their relationship with the CQAs.
 Data supporting justification of design space, which can include but not limited to historic
knowledge base, conclusions from QRM and experimental studies.
 The relationship between the proposed design space and other unit operations or process steps.
 Justification that the control strategy ensures that the manufacturing process is maintained within
the boundaries defined by the design space.
Design of Experiments at a glance

Fundamentals before DoE to understand

• Variable, • Resolution,
• Factor, • Coding,
• Levels, • Blocking,
• Constraints, • Augmentation,
• Effect, • Response Surface,
• Interaction, • Randomization,
• Confounding or Aliasing, • Replication & Repetition

Decide before executing DoE:

• Goal/Objective of DoE
• Factors
• Range of factors to study
• Response
• Study design

Designs for different objectives;

• Screening: Fractional factorial, Full Factorial, Plackett-Burman

• Development/Optimization: Full factorial, Central composite, Box-Behnken designs
• Optimization of proportion in formulation: Mixture design
DoE: Example (Central Composite – Circumscribe Design)
Effect of Granulation process on Dissolution
CPP Unit -1 1
Impeller speed rpm 488 912
Kneading time sec 146 274
Response % Drug dissolved in 45 min

Selection of Model terms (Sequential)

Based on Lack of Fit and Model summary Statistics (PRESS), Quadratic model is chosen.
DoE: Example (Central Composite – Circumscribe Design)
Contour and Response Surface outcome

Response suface analysis reveals that with increase in impeller speed response, % drug
dissolved in 45 min tends to increase until attainment of constant levels, after which no
significant change in response was observed.

Similar was the effect with change in levels of kneading time.

DoE: Example (Central Composite – Circumscribe Design)
Optimization
Criteria:

The colored (yellow) area defines the

final optimal factor settings to
achieve the desired response of drug
dissolved in 45 min between 80-85%.

The response can be achieved at high

impeller speeds (beyond 650 rpm)
and kneading time beyond 180
seconds.
Control Strategy
 ICH Q10 defines a control strategy as “a planned set of controls derived from current
product and process understanding that assures process performance and product quality.”

 A control strategy ensures that the process is maintained within the boundaries described
by design space.

 Specifically, the control strategy may include:

1. Control of input material attributes (e.g., drug substance, excipients, primary
packaging materials)
2. Product specifications
3. Procedural controls
4. Facility controls, such as utilities, environmental systems and operating conditions
5. Controls for unit operations that have an impact on downstream processing or end-
product quality (e.g. the impact of drying on degradation (Critical for Abiraterone
acetate granules))
6. A monitoring program (e.g., full product testing at regular intervals) for verifying
multivariate prediction models (Multivariate Data Analysis) and Real Time monitoring
(PAT Tools).

 Depending on the risk associated with the CQA, multiple points of control should be
employed to monitor and control.
Control Strategy: Example (For RM and Process)
Continual Improvement
 QbD does not end with completion of development of the product and transfer to commercial
scale.

 Manufacturing experience should build upon the existing knowledge of product and process
understanding and enhance it.

 Manufacturing process at commercial scale can be optimized within design space which does not
require regulatory approval.

 There may be some occasions where operating within Design Space have some limitations in
production. This case should not be seen as a failure but accepted as successful acquisition of
knowledge and that should be utilized to strengthen the process as a part of Continual
Improvement.

 Utilization of PAT Tools may be a part of control strategy but full fledged utilization can be done
once process has been established and stabilized.
 In-process testing of CMAs and real time monitoring of Processes can be done more
efficiently using PAT Tools.
 Here, based on CMAs feedback loop can be set for Processes which may support more
flexible and robust manufacturing process.

 For processes, stability and capability analysis would be performed using statistical tools like Cp &
Cpk.
PAT Tools to work

Models can be established by MVD Analysis and feedback loop can be set for continuous monitoring and
control of the process.
REAL TIME RELEASE (RTR): MODERN WAY OF MANUFACTURING AND CONTROL
Any Questions?
References

 Guidance for Industry: Q8(R2) Pharmaceutical Development

 Guidance for Industry: Q9 Quality Risk Management
 Guidance for Industry: Q10 Pharmaceutical Quality System
 Guidance for Industry PAT: A Framework for Innovative Pharmaceutical Development,
Manufacturing, and Quality Assurance
 Quality by Design for ANDAs: An Example for Modified Release Dosage Forms
 Quality by Design for ANDAs: An Example for Immediate Release Dosage Forms
 GPhA presentations
 Draft QbR updated