QbD Concept and

CMA: A step
Ahead
Hemgir Gosavi Ph D.
Manager, Global Formulation Application
Lab, Mumbai, India

TIPA Seminar, BKK, Thailand

26th August 2021

1 QbD and CMA : A step ahead TFDA BKK 2021

 Agenda

Introduction QbD A Concept

1. Introduction

2
2. Design

1 1. Examples

4 Case studies
3
CMA
1. CQA
2. CMA
3. Approach/Application

Opinions expressed in this presentation are those of speaker and do not necessarily reflect the views and policies of the Merck
2 QbD and CMA : A step ahead TFDA BKK 2021
 A Ultimate Goal is to
develop with .. …
API &
Excipient

Regulatory
Equipment
Bodies

Patient

People in Mfg
operation Process

Quality
Parameter
& Testing
….A Quality product

3 QbD and CMA : A step ahead TFDA BKK 2021

 Body of tablet: Composition

•A component use to • Ingredient having

pack the drug therapeutic use/
product pharmacological
• Ex: Blister pack, activity
Sachet, HDPE
bottle,
Packing
Active
material

MFG Core
Process Excipients

•Manufacturing is •Functional or
important part for to nonfunctional
achieve desired quality ingredients used in drug
of product product Ex: filler,
binder, glidant etc

4 QbD and CMA : A step ahead TFDA BKK 2021

World Wonders!
What we should learn from them!

Pyramid of Christ the Uniqueness is a key in these

Gizza Redeemer 07 wonders

Important to know

1. Purpose/objective
Great wall of Chichen
china 2. Raw material used
3. Equipment used
Taj Mahal 4. Process adopted
Petra 5. Technical skill of people
6. Science behind
7. Design!
Colosseum

5 QbD and CMA : A step ahead TFDA BKK 2021

What it says Exactly!

“Pharmaceutical QbD is a systematic, scientific risk based and proactive

approach to pharmaceutical development that begins with the predefined
objectives and emphases product and processes understanding and process
control.”

Principle QbD Concepts:

▪ Risk and knowledge based decisions
▪ Systematic approaches for process
Development
▪ Continuous Improvement
▪ This leads to “capable” processes
 Journey of Guideline
• ICH Q8
Finalized • ICH Q10
• Critical Path
• ICH Q9 • ICH Q11
Initiative finalized • Biowai
Finalized finalized • Elemen
• 21st Century • ICH Q8 (R1 • QbR
• OGD QbR • Q&A Q8, tal ver BCS
Initiative and R2) revisi
Final report
Announced
finalized Q9, Q10 Impurit class I
• Quality on
• PAT • OGD QbR • QbD Mock ies and III
System
Guidance
Guidance announced Example
Finalized

2004 2005 2006 2008 2009 2011 2012 2013 2014 2015 2016 2018

• Process
Validation
• ONDQA Guidance • Quality
Finalized • QbD for
CMC Pilot attributes
Program • EMA-FDA Generic
QbD Pilot
Process
Drugs
Program validation
• QbD Mock
Examples

Other guidances (Year): ODT (’08), ANDA-Impurities (’09), Residual solvents (’09), Size of beads in
7
DP labeled for sprinkle (’12), Tablet scoring, Size and shape and other physical attributes of generic
QbD and CMA : A step ahead TFDA BKK 2021
tablets and capsules (’15),
 Why QBD is in need to Pharma?

▪ Increased product Recalls and Customer complaints

▪ Keeping less time on learning how best to make the drug product.
▪ Not investing enough resources to develop Quality products.
▪ Heavy competition for to be the first generic player

8 QbD and CMA : A step ahead TFDA BKK 2021

Traditional vs Enhanced QbD approach

Traditional QbD
▪ Empirical and Univariate ▪ Systematic & Multivariate
experimental development experimental development
▪ Focus on reproducibility ▪ Manufacturing process
▪ Offline analysis adjustable within the design space
▪ Quality assured by testing ▪ Focus on control strategy and
robustness of the product
▪ Quality built in by design
What is Quality by Design?

Quality by design (QbD) is:

QbD isn’t:
▪ a Quality System for managing a product’s ▪ New
lifecycle ▪ Design of Experiment

▪ a regulatory expectation toward quality product (DoE)

▪ Design Space
▪ Intended to increase process and product

understanding and thereby decrease patient risk

▪ a multifunctional exercise

10 QbD and CMA : A step ahead TFDA BKK 2021

 Elements of QbD

1 Quality Target Product Profile

Critical Material Attributes and

2
Critical Quality Attributes

3 Critical Process Parameters

4 Control Strategy

11 QbD and CMA : A step ahead TFDA BKK 2021

 Quality Target Product Profile and Critical Quality Attributes

Quality Target Product profile

(QTPP): A quality characteristics
product which we desired.

Critical Quality Attributes (CQA): 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.

12 QbD and CMA : A step ahead TFDA BKK 2021

Quality Target Product Profile (QTPP)

Quality Attribute Target Rationale

Active ingredient Same as Reference Product Pharmaceutical equivalence
Dosage form Same as Reference Product Pharmaceutical equivalence
Strengths Same as Reference Product Pharmaceutical equivalence
Pharmaceutical equivalence &
Description/shape/size Same as Reference Product
patient acceptability
Pharmaceutical equivalence &
Color Same as Reference Product
patient acceptability
Hardness Proven acceptable range Since it impacts dissolution
Friability NMT 1.0% Formulation affects friability
Assay 90 – 110% Label claim
As per ICH / Pharmacopoeial
Degradation products Known, unknown and Total
standards
Consistent for Immediate To produce the desired
Dissolution
release therapeutic effects
Pre-define the Objectives: QTPP Vs CQAs
QTPP CQA
Clinical Or Patient centric /s either a QTPP Or helps to achieve QTPP
Use? Purity?
Strength? Stability?
Example of CQA which is a QTPP

Relates to Drug Product

Route of
Sterility? Eg., Dissolution Profile
administration?
Forms part of Whats in first House of
Quality/QFD
Dissolution? Container Closure Example of CQA which is not a QTPP
System?
Relates to Drug Substance, Excipients &
Intermediates
Relates to Drug Product
Eg., PSD to achieve dissolution profile

Essentially forms part of ‘Whats’ in House of Forms part of Hows in first House of
Quality/QFD Quality/QFD

All QTPPs are CQAs but all CQAs are not QTPPs
14 QbD and CMA : A step ahead TFDA BKK 2021
Build Product and Process Understanding:
Cause and Effect Analysis by 6M’s
Man Measurement Material

Human
errors In-appropriate Excipient Grade
In process analytical
and method API PSD
testing
Critical impurities
The Drug Product
does not meet
pre-defined safety,
efficacy and
API shipping quality
and storage Formulation Equipment
conditions composition design
Operational
Choice of principle
packaging
process Occupancy
Miscellaneous Method Machine
 Quality Attributes of Product flow

CMA: Critical Material Attributes

CPPs: Critical Process Parameters
CQAs: Critical Quality Attributes

16 QbD and CMA : A step ahead TFDA BKK 2021

 Drivers of Product Quality: Define CQA & CPP

API
Critical Material
Attributes
Critical Process
Parameters
Excipient Process

17 CQA CPP and QbD : Concept to Understanding , TFDA, BKK, 2019

 Build Product and Process Understanding:
Identification of QbD Elements
CMA+CPPs=CQA

CMAs CPPs CQAs

Particle size
Identification of critical Dissolution
Organic impurities
steps in MFG process
Water content Related Substances
Viscosity Mixing Speed
Metal impurities Mixing time Drug content
stability Rate of addition
Design of equipment Bio equivalence
Polymorph
PSD
Process and
degradants
Solubility
 Quality Target Product Profile (QTTP): A case of OSD

Controlled by
API

Controlled by
API/Excipient/
process

Multiple
factors of
API/Excipient/
process

19 QbD and CMA : A step ahead TFDA BKK 2021

http://qbdworks.com/qbd-case-study-ace-tablets-qtpp-cqa-cpp-cma/
20 QbD and CMA : A step ahead TFDA BKK 2021
21 QbD and CMA : A step ahead TFDA BKK 2021
 How is a quality attribute deemed critical?

Continual Improvement

Potential
No
impact to
Quality
the safety, Non-critical
attribute
efficacy
quality?
revisit

Low Risk

Yes Critical

@ A severity scale is used to assess Severity@

relative magnitude of impact. A change
in criticality only occurs with change in Critical
severity and not probability of
High Risk
occurrence

22 QbD and CMA : A step ahead TFDA BKK 2021

 Effect of API and Excipient on Quality Attribute of Product: An Example

23 CQA CPP and QbD : Concept to Understanding , TFDA, BKK, 2019

 Active Substance: Critical Material Attributed
Material attributes
▪ pH stability
API source/status ▪ pH solubility
▪ Particle characterization
▪ Powder characterization, etc
API Characterization
Evaluation of Vendor CoA
Literature
Stage 1- CMA identification
w.r.t. product characteristics
Edge of failure studies

Study of identified attributes in OFAT/DoE

formulation or as such
Literature
Stage 2- Risk Updation

Control strategy
OFAT=one factor at time
API Specification
DoE: Design of Experiment
24 CQA CPP and QbD : Concept to Understanding , TFDA, BKK, 2019
 Effect of API and Excipient on Quality Attribute of Product: An Example

25 CQA CPP and QbD : Concept to Understanding , TFDA, BKK, 2019

 Excipient: Critical Material Attributed

Excipient Identification Rationale for grade selection

Excipient characterization Excipient compatibility

Critical Material Attributes

Stage 1- CMA identification
w.r.t. product characteristics

EoF/OFAT/DoE
Study of identified
attributes in formulation
or as such Formula & Process
interaction study

Stage 2- Risk Updation

Specification
finalization/
Control strategy

26 CQA CPP and QbD : Concept to Understanding , TFDA, BKK, 2019

Example of CMA : Parteck SI® (Sorbitol)

pH
Critical material attributes
may vary from product to
product thus need to identify it
according to CQA’s of such
product

Reducing sugars

Water content
PSD

27 QbD and CMA : A step ahead TFDA BKK 2021

Oseltamivir formulation : Powder for Reconstitution
Process challenges & Solutions

Powder Blending Lubrication Bottle filling

Flow properties of the

Content uniformity Blend
Diluent High adsorption capacity Spray dried diluent
API Stability
Formulation stability
Excipients with low impurity
Addition of preservatives

28
Oseltamivir Powder for Reconstitution
Content uniformity/Blend uniformity

Impact of different particle Size & Surface area

Large particle size

Fine particle size Medium particle size
• Lower surface area
• High surface area • Balance of stability and
Segregation of
Increase the contact powder flow, and uniform
particles fail to
of glucose in sorbitol distribution API &
achieve blend
with API Preservative
uniformity of API and
• Results formation of preservative.
adduct impurity.

Diluent with optimum (PSD), flow properties & surface area are key parameters to
ensure blend uniformity of API and Preservative

29 Covid19 treatment and Merck Products

Tamiflu® :Oseltamivir Powder for Reconstitution
Stability
As per the literature and FDA submission by innovator

https://www.ema.europa.eu/en/documents/scientific-discussion/tamiflu-epar-scientific-discussion_en.pdf

There are two main degradation products generally observed

1. Ro 68-7010 is reaction product of oseltamivir API and reducing sugar (glucose)
impurity of sorbitol
2. Degradant product of Ro 68-7010.

The product specification contains at release: limits for impurities- a) specified, unspecified
0.3%, b) total impurities 1.0%

The sorbitol with minimum glucose content as impurity is primary choice.

Developer should select ‘right’ sorbitol and fix the glucose content at release of
material for MFG
Reducing sugar content in diluent is critical Material Attribute and its
important to have it controlled under lower limits
30 Covid19 treatment and Merck Products
Merck’s QbD strategy:
Identify test parameters and performance parameters

Our unique spray-drying process results in

particles which are:
• Very loosely packed
• Randomly orientated
• Interwoven, filamentary crystals
Benefits:
• Excellent direct compression properties
• High dilution and adsorption capacity
• Structured surface area
SEM of Parteck® SI excipient: 50 x (left) and 2500 x (right)
• Low amount of reducing sugars, <0.05%
• Good flowability: angle of repose
• Emprove® documentation and regulatory support

Low amount of reducing sugars and high adsorption capacity make Parteck® SI to
preferred choice for Oseltamavir drug formulation.
31 Supporting Drug Manufactureres Fighting the Covid-19 Pandemic - April 2020
Parteck® SI: High Adsorption Capacity
Ensures uniform mixing of active with sorbitol

drug content after sieving [%]

7,5

Parteck® SI 400

cryst. sorbitol
5

2,5

0
0 20 40 60 80 100

pressure of air jet sieve [mm/H2O]

Strong bonds with active lowers probability of demixing & ensures

reliable content uniformity of the API

32 Supporting Drug Manufactureres Fighting the Covid-19 Pandemic - April 2020

Parteck SI at glance
Parteck® SI (Sorbitol): Right choice of Sorbitol !

33 Covid19 treatment and Merck Products

 CMA: Particle Size Distribution in Product Quality
Excipient – Calcium carbonate CQA criteria : “Right” Calcium Carbonate
precipitated102069 for desired Drug dissolution profile &
Stability of API
Molecule: Atorvastatin calcium
CQA identification (practical approach) :-
Role of excipient:
Evaluation of three different venoder/lot of
1. Stabilize product material with variable Particle size to test
2. Dissolution enhancer effect on dissolution and stability
PSD
As
Thus to establish the PSD data.
CQA
Vendor 1

Vendor 2

Vendor 3

34
CQA: The PSD of Calcium carbonate
should be below 5 micron

CQA CPP and QbD : Concept to Understanding , TFDA, BKK, 2019

Impact of CQA on in vitro dissolution and stability

Comparison Between difference strengths 100

% drug release
80
100

60
80
40
% Drug dissolution

60 20

10 mg 0
40 0 20 40 60
20 mg Time (min)
40 mg Total impurities
20
80 mg
0.8
0.73
0 0.7 0.57 0.62
0 5 10 15 20 25 30 0.6
Time (min) 0.5
0.4
0.3
0.2
0.1
0
Vendor
Merck 1 Vendor
Competitor 2
1 vendor
Competitor32

Initial 40C/75%RH/1W
35 CQA CPP and QbD : Concept to Understanding , TFDA, BKK, 2019
 CMA 3 :PSD/surface area of Diluent (mannitol)
in Direct compression

1 Unique Particle size

2Stable polymorph & Shape 32 Low Reducing Sugar

 DC Mannitol  High Surface area  3 times lower limit

 High compactibility  Useful in blend unformity  Stabilizes Amino product
 Excellent flow  Improves DT & Dissolution  Prevents browning of
 High dilution potential tabletses Dissolution
 Less hygroscopic

36 CQA CPP and QbD : Concept to Understanding , TFDA, BKK, 2019

 Mannitol: Shape and surface area
A unique structure Mannitol Polymorph & BET
surface area
SEM of Spray dried Beta mannitol
Product Polymorph appr. BET (m²/g)

Parteck® M 100 beta 3

Parteck® M 200 beta 3

Competitor A alpha 0,6

Competitor A alpha 0,5

Competitor A beta 0,5

Competitor A beta 0,4

Competitor A beta 0,3

Competitor B alpha 0,5

Competitor B beta 0,3

Competitor B beta 0,5

Competitor B beta 0,4

37 CQA CPP and QbD : Concept to Understanding , TFDA, BKK, 2019

 Mannitol in Direct compression

5
rel. humidity
4,5
1= 7.2
55% 76% 1
x x2 x3
2= 9.3
4
3= 12.5
Water content [%]

3,5 68% 86%

2,5

1,5

0,5

0
Parteck® M 200 Parteck® M 300 DC-Lactose DC-Sucrose DC-Dextrose
(anhydrous)

Less water uptake will be beneficial for direct compression

38 CQA CPP and QbD : Concept to Understanding , TFDA, BKK, 2019

 CQA: Particle size & particle shape in manufacturing scale up

39 CQA CPP and QbD : Concept to Understanding , TFDA, BKK, 2019

40 CQA CPP and QbD : Concept to Understanding , TFDA, BKK, 2019
 Parteck® M: Tablet Hardness at different Machine speed

@10KN

41 CQA CPP and QbD : Concept to Understanding , TFDA, BKK, 2019

 Parteck® M: Effect of Overlubrication on Tablet Hardness

42 CQA CPP and QbD : Concept to Understanding , TFDA, BKK, 2019

Critical Process Parameters

▪ Parameters monitored before or in process that influences the appearance, impurity and
yield of the final product significantly.

▪ A parameter is considered to be critical when a slight change in that parameter causes

the product to fail, to meet the QTPP.

▪ Thus the first step in classifying the parameters is to define the range of interest which is
called as Potential Operating Space.

▪ It is the region between the maximum and minimum value of the interest to the operator
for each process parameter.

43 QbD and CMA : A step ahead TFDA BKK 2021

 Integration of QbD in Product Development
Product introduction

Prototype development

Pilot bio

Formulation and process ▪ Excipient attribute understanding

development ▪ Risk based Formula understanding
Analytical method

▪ Risk based Process development

validation

▪ Scale up on scientific principles

Scale up batch ▪ More understanding on scale
dependent/independent parameters
▪ Interim data review

Exhibit Batches ▪ Linkage of process development

with commercial manufacturing
▪ Risk based control strategy is laid
down for API, excipients and
Process
Dossier Filing ▪ Risk based compilation in
development report

44 CQA CPP and QbD : Concept to Understanding , TFDA, BKK, 2019

Control Strategy:
Design of Robust Process
Robustness is defined as the ability of a process to demonstrate acceptable
quality and performance and tolerate variability in inputs at the same time.

45 QbD and CMA : A step ahead TFDA BKK 2021

Disclaimer!
Always be there with regulatory!

1. Opinions expressed in this presentation are those of speaker and do not necessarily reflect
the views and policies of the Merck
2. For better understanding of content refer the ICH/FDA guidelines or Industry guidance
document.
3. The Examples are used for the illustration of content only and not for sharing with anyone
for its use for commercial or any other purposes.

46 QbD and CMA : A step ahead TFDA BKK 2021