Quality management

1. Name of Student- Ms. Vinayshri S. Salunkhe.
Name of Guide- Dr. H.S.Mahajan (H.O.D)Pharmaceutics
Roll No – MPH-14
Department- Pharmaceutics
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Quality by Design in Pharmaceutical
Product Development

2. Contents-
- Background
- Introduction
- QbT versus QbD Approach
- Elements of Quality by Design
- Tools of Quality by Design
- Challenges in Implementing QbD
- Conclusion
- References
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3. • In past few decades, The conventional development process uses an empirical approach that requires
continuous end product testing and inspection to determine quality(7).
• That lack of automation, Pharmaceutical products are facing high degree of variability in their quality,
• In order to overcome these roadblocks,
• In year 2002, the U.S.FDA published a concept paper on current good manufacturing practice for 21st
century(6).
• This document expressed suggestions that companies should build safety, quality and efficacy into their
new pharmaceutical products as early as possible(6).
• Based on principles of six sigma, the QbD concept was first developed by Joseph M Juran.
Background-
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4. Definition-
QUALITY BY DESIGN
“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.”(2)
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Reasons for QbD-
 Recalls and Customer complaints
 Manufacturers fail to spend enough time learning how
best to make the drug product.
 Industries may not be investing enough resources to make
high quality and safe products.
 Stampede by manufacturers to be the first generic player
There are 2 QbD’s in industry -
1. Formulation QbD –
When we say CMA
2. Process QbD –
When we say CPP

5. QbT versus QbD Approach
The main aim of QbD is to switch from the traditionally used QbT approach which typically involves raw
material testing, drug substance or drug product manufacturing process, in-process material testing, and end
product testing. to improving the understanding of processes and products to improve product quality, process
efficiency, and regulatory flexibility.
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Quality target product profile
Critical quality attributes
Risk assessment linking material attributes and process
parameter to CQAs
Design space
Control strategy
Life cycle management and continuous improvement
Elements of QbD(1)-

7. Quality Target Product Profile (QTPP) -
 “A Perspective summery of quality characteristics of drug product that ideally will be achieved to ensured the
desired quality, taking into account safety and efficacy of the drug product is realized(1) .
 Should includes only patient related product performance
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What forms basis QTPP
-Reference/Innovator product
-Research publication
-Product already developed/published
When to defined QTPP
-At the beginning
-Revised based on knowledge gained
About QTPP
-Set of elements that defines DP
-Target/goals set in advance
-Guide to DP development

8. QTPP Elements Target Justification
Dosage form Tablet
(Same as Reference Product )
Pharmaceutical equivalence.
Dosage design Immediate release tablet
Without score or coating
Immediate release design needed to meet label
claims
Routes of administration Oral
(Same route of administration)
Pharmaceutical equivalence
Dosage strength X
(Same strength )
Pharmaceutical equivalence
Pharmacokinetics Immediate release Bioequivalence requirements
Dosage product quality
attributes
Assay
(must meet the same)
Pharmaceutical equivalence
Content uniformity,
Dissolution ,
Disintegration
Compendial or other applicable (quality )
standards
Container closure system Container closure system qualified as
suitable for this drug product
To achieve target shelf life and to ensure tablet
integrity during shipping
Case study- Table 3:QTPP : Quality Target Product Profile for IR tablet dosage form of drug X.
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9. Critical Quality Attribute (CQA)(6) -
 “A Physical ,chemical, biological or microbiological property or characteristics that should be
within an appropriate limit ,range, or distribution to ensure the desired product quality.”
 CQA’s are subset of QTPP – Potential to altered by change in formulation or process variables.
 Should be within an appropriate limit, range or distribution to ensure the desired product
quality (ICH Q8).
Critical Process Parameters-
• Physical, chemical, biological or
microbiological Properties - output material
including finished drug product.
• Critical when it has a high impact
on a critical quality attributes.
Critical material attributes (CMA)-
• Physical, chemical, biological or
microbiological properties - input material.
• Critical when a practical change in attribute
can significantly impact the quality of the
output material.
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10. Quality Attributes of Drug
product
Target Is this CQA Justification
Assay 100% w/w of label claim Yes Assay variability will affects safety and
efficacy.
Process variables may affect assay
Content uniformity (CU) Conforms to USP<905>
Uniformity of Dosage Units
Yes Variability will affect safety & efficacy
Both affects formulation and process
Dissolution NLT 80% at 30 min Yes Impact bioavailability
Both affects formulation and process
Disintegration NLT 15 min Yes Indicates tablet going into solution and
Indicate In vivo performance
Case study- Table 5 : Justification of CQA of Generic IR tablet dosage form of drug X.
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11. Risk assessment (1,2):
Linking Material Attributes and Process Parameters to Drug Product CQAs.
 Risk assessment consists of the identification of hazards and the analysis and evaluation of
risks associated with exposure to those hazards(2) .
 That can aid in identifying which material attributes and process parameters potentially have an
effect on product CQAs.
 Facilitate and improve science-based decision making with respect to risk.
It involves (2) –
-Risk identification
-Risk analysis
-Risk evaluation (1)
 Risk related to individual CMAs &/or CPPs will be identified, analyzed qualitatively & then
evaluated quantitatively in order to reduce the probability of risk through optimization by DoE
&/or inline detection by PAT(4).
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12. Process
steps
Drug product COQ’s Initial Risk Justification
Milling Content uniformity (CU) High If generates excessive fine
Bulk density & flowability of blend impacted which
may impact CU
Dissolution Medium Large amount of fine may impact tablet hardness
and dissolution
Compressio
n
Content uniformity (CU) High Compression Process variable causes weight
variability and causes tablet to fall out of
specifications
Dissolution High Over lubrication may causes slow dissolution
Table 6- Justification of Initial risk assessment of Manufacturing process of generic IR tablet of drug X.
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13. a) Risk Identification (1,2) -
• Fig -Cause and effect diagrams (also called an Ishikawa diagram or fish bone diagram)(1)
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A cross-functional team of experts could work together to develop an Ishikawa (fishbone) diagram that identifies potential
variables which can have an impact on the desired quality attribute.

14. b)Risk Analysis(4) -
-Risk is expressed quantitatively and qualitatively as ‘high’, ‘medium’ and ‘low’.
Qualitative Risk based Matrix Analysis of Active Pharmaceutical Ingredient’s (API) Attributes
FP CQAs
S
olid s
tate
/Polymorph
Particle
s
ize
Flow
Properties
Mois
ture
content
Res
idual
S
olvent
S
olubility
Proces
s
Impurity
Chemical
S
tability
Phys
ical High Low Low Low Low Low Low Low
As
s
ay Low Low Low Low Low Low High High
Impurit ies Low Medium Low Medium Medium Low High High
Particle S
ize Low High Low Low Low Low Low Low
Flow Property High High High Low Low Low Low Low
Weight
Variation
Low High High Low Low Low Low Low
Uniformity Low High High Low Low Low Low Low
Thicknes
s Low Low Low Low Low Low Low Low
Hardnes
s Low Low Low Low Low Low Low Low
Friability Low Medium Low Low Low Low Low Low
Dis
integrat ion Low Low Low Low Low Low Low Low
Dis
s
olution High* High* Low Low Low High* Low Low
Water Content Low Low Low High Low Low Low Low
Microbial
Content
Low Low Low High Low Low Low Low
Low Broadly acceptable risk. No further investigation is needed
Medium Risk is acceptable. Further investigation/justification may be needed in order to reduce the risk.
High Risk is unacceptable. Further investigation is needed to reduce the risk.
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c) Risk evaluation(4) -
It compares the identified and analyzed risk against given risk criteria.
For effective risk evaluation robustness of data is important.

15. Tools of QbD-
Design Space –
-The material attributes and process parameters that assures quality.
-The Multidimensional Combination & Interaction of input variables :
Ex: Critical Material Attributes and critical Process Parameters that have been
demonstrated to provide assurance of quality (1,4) .
Design of Experiments (DoE) –
A Systematic Series of Experiments :
-In which purposeful changes are made to input factors to identify causes for significant changes in the output
responses.
-Determining the relationship between factors & responses to evaluate all the potential factors simultaneously,
systematically and speedily (1,4).
Process Analytical Technology (PAT) -
A System for-
-Designing , Analyzing & Controlling Manufacturing through Timely Measurements (i.e., during processing) of
Critical Quality and Performance attributes of raw and in-process materials and processes with the goal of
ensuring final product quality.
 Through PAT, Online Feedback Controlling System for each & individual CMAs &/or CPPs will be developed.
through designing of controls by analysis at line/ on line/ in line analyzer system (1,4) .
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16. Control Strategy(1,3) -
A planned set of controls for CMAs & CPPs derived from current product and process understanding:
• During Lab Scale Developmental Stage
• Scaled Up Exhibit-Submission Stage that ensures process performance and product quality
• During Commercial Stage (1,3).
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Factors
Attributes /
Parameters
Proposed strategy
for commercial Purpose of control
Drug X
D90 10-30µm To ensure the in vitro
dissolution, in vivo
performance & Batch to
batch consistency .
D40 6-24µm
D10 3.6-14.4µm
Mmagnesium
stearate
Specific surface area 5.8-10.4m2/g To ensure sufficient
lubrication &to reduce
risk of retarded
disintegration and
dissolution.
Table 6- Control strategy for generic IR tablet of drug X.

17. Formulation R&D
Analytical R&D
Regulatory Affairs
Manufacturing Plant
Quality Control
Quality Assurance
Product Lifecycle Management(1,4) -
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For Continual Trend Analysis in Process Control Charts that assures the process remains in a state of control (the validated state)
during commercial manufacture (4).
For Excellent Product
Lifecycle Management
Throughout the product lifecycle, the manufacturing process performance will be monitored to ensure that -
It is working as anticipated to deliver the product with desired quality attributes. Process stability and process capability will be
evaluated. If any unexpected process variability is detected, appropriate actions will be taken to correct, anticipate, and prevent
future problems so that the process remains in control (4).
During Routine Commercial Manufacturing Continual Risk Review & Risk Communication between Stockholders of:

18. Challenges to implementing QbD FDA perspective(5):-
• Implementation Challenges:
– Putting new concepts/ approaches into practice.
– Diversification of products.
– Different regulatory processes (NDA, ANDA, BLA).
– Expectations for QbD based submission while addressing traditional requirements
(dual processes).
– Integration of review and inspection(5).
• Broad spectrum of approaches to develop manufacturing, and quality operations across
industry(5).
• Implementing while harmonizing(5).
• Heavy workload and limited resources(5).
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19. With respect to CQAs, Risk associated
with each CMAs & CPPs were extensively
analyzed out by FMEA, which decided
“which risk should get first priority?”
based upon Severity * Probability *
Detectability of individual risk.
Severity of Risks could not be reduced.
Probability of Risk occurrence was reduced by
systematic series of experiments through
IVIVC, DoE & Stability Studies; while
Detectability of Risk was increased by online/
inline/ at line PAT tools.
A planned set of controls for CMAs
& CPPs were derived from Lab Scale
Developmental batch & Scaled Up Exhibit
batches, which were verified by Process
Performance indices (Pp, Ppk).
From the targets defined in QTPP,
required in-process & finished product
specifications were determined in the
form of in process
& finished product CQAs.
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Conclusion

20. 1. ICH. Q8(R2): pharmaceutical development. 2009.
2. ICH. Q9: quality risk management. 2005.
3. ICH. Q10: pharmaceutical quality system. 2008.
4. Chaudhari,S.,2016. Quality by Design (QbD) Model for “Tablet’s” © by Dr.Shivang Chaudhary from
QbD-ExpertTM . International Journal of Pharmaceutics October 22, 2016,9-100.
5. Embracing Quality by Design (QbD) in pharmaceutical industry – Pharma mirror Magazine.
(2021).Retrived 17 April 2021, from http://www.pharmamirror.com/pharmaceutical-articles/embracing-
quality-by-design-qbd-in-pharmaceutical-industry/
6. Izat N, Yerlikaya F, Capan Y. A glance on the history of pharmaceutical quality by design. OA Drug
Design & Delivery 2014 Jan 18;2(1):1.
7. Shashank jain (2014). Quality by design (qbd): a comprehensive understanding of implementation and
challenges in pharmaceuticals development, International Journal of Pharmacy and Pharmaceutical
Sciences,6(1), 29-35.
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Bibliography-

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THANK YOU