The document discusses Quality by Design (QbD) principles for pharmaceutical product development. It defines key QbD concepts like quality target product profile, critical quality attributes, critical material attributes, critical process parameters, risk assessment, design space, and control strategy. It provides examples of applying these concepts for developing different dosage forms like tablets, capsules, solutions, and creams. The document aims to guide systematic development of pharmaceutical products using a QbD approach with a focus on understanding and controlling critical factors influencing quality.
FDA’s emphasis on quality by design began with the recognition that increased testing does not improve product quality (this has long been recognized in other industries).In order for quality to increase, it must be built into the product. To do this requires understanding how formulation and manufacturing process variables influence product quality.Quality by Design (QbD) is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.
This presentation - Part II in the series- deals with the concepts of Quality Target Product Profile and Critical Quality attributes.This presentation was compiled from material freely available from FDA , ICH , EMEA and other free resources on the world wide web
FDA’s emphasis on quality by design began with the recognition that increased testing does not improve product quality (this has long been recognized in other industries).In order for quality to increase, it must be built into the product. To do this requires understanding how formulation and manufacturing process variables influence product quality.Quality by Design (QbD) is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.
This presentation - Part III in the series- deals with the concepts of critical material attributes, critical process parameters , their linage to the the critical Quality attributes of the Product and Quality Risk Management and its pivotal role in the QbD process.Concepts of control strategy are also discussed briefly.
This presentation was compiled from material freely available from FDA , ICH , EMEA and other free resources on the world wide web.
FDA’s emphasis on quality by design began with the recognition that increased testing does not improve product quality (this has long been recognized in other industries).In order for quality to increase, it must be built into the product. To do this requires understanding how formulation and manufacturing process variables influence product quality.Quality by Design (QbD) is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.
This presentation - Part II in the series- deals with the concepts of Quality Target Product Profile and Critical Quality attributes.This presentation was compiled from material freely available from FDA , ICH , EMEA and other free resources on the world wide web
FDA’s emphasis on quality by design began with the recognition that increased testing does not improve product quality (this has long been recognized in other industries).In order for quality to increase, it must be built into the product. To do this requires understanding how formulation and manufacturing process variables influence product quality.Quality by Design (QbD) is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.
This presentation - Part III in the series- deals with the concepts of critical material attributes, critical process parameters , their linage to the the critical Quality attributes of the Product and Quality Risk Management and its pivotal role in the QbD process.Concepts of control strategy are also discussed briefly.
This presentation was compiled from material freely available from FDA , ICH , EMEA and other free resources on the world wide web.
Pharmaceutical Quality by Design (QBD) is a concept introduced by the International Conference on Harmonization (ICH) Q8 guideline, as a systematic approach to development that begins with predetermined objectives and emphasizes the understanding of production and processes and process control, based on sound science and quality risk management.
The basic concept of QBD is “The Quality cannot be tested into the product, but it should be built into it.”
Introduction, Regulatory requirements for validation, Role of FDA, Code of Federal regulation, Validation life cycle, Significance of validation, Types of validation, Process valiadation, Phases of process validation, Process capability design, Process Qualification, Validation maintainance phase
Types of Process validation, Examples
FDA’s emphasis on quality by design began with the recognition that increased testing does not improve product quality (this has long been recognized in other industries).In order for quality to increase, it must be built into the product. To do this requires understanding how formulation and manufacturing process variables influence product quality.Quality by Design (QbD) is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.
This presentation - Part V in the series- deals with the concepts of Control strategy and PAT. This presentation was compiled from material freely available from FDA , ICH , EMEA and other free resources on the world wide web.
Pharmaceutical Quality by Design (QBD) is a concept introduced by the International Conference on Harmonization (ICH) Q8 guideline, as a systematic approach to development that begins with predetermined objectives and emphasizes the understanding of production and processes and process control, based on sound science and quality risk management.
The basic concept of QBD is “The Quality cannot be tested into the product, but it should be built into it.”
Introduction, Regulatory requirements for validation, Role of FDA, Code of Federal regulation, Validation life cycle, Significance of validation, Types of validation, Process valiadation, Phases of process validation, Process capability design, Process Qualification, Validation maintainance phase
Types of Process validation, Examples
FDA’s emphasis on quality by design began with the recognition that increased testing does not improve product quality (this has long been recognized in other industries).In order for quality to increase, it must be built into the product. To do this requires understanding how formulation and manufacturing process variables influence product quality.Quality by Design (QbD) is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.
This presentation - Part V in the series- deals with the concepts of Control strategy and PAT. This presentation was compiled from material freely available from FDA , ICH , EMEA and other free resources on the world wide web.
DEFINITION,PRINCIPLE, OBJECTIVES, ELEMENTS AND TOOLS OF QUALITY BY DESIGN (Qb...Durgadevi Ganesan
Quality by Design is a concept first outlined by Joseph M. Juran in various publications. He supposed that quality could be planned. The concept of QBD was mention in ICH Q8 guidelines, which states that, “To identify quality can not be tested in products, i.e. Quality should be built in to product by design.”
What is Quality by Design (QbD)?
Quality by Design (QbD) is a strategic approach employed in various industries, including pharmaceuticals, manufacturing, and product development, to ensure the consistent delivery of high-quality products.
Why QbD?
Principle of QbD
Objectives of QbD
ELEMENTS OF PHARMACEUTICAL QUALITY BY DESIGN:
- Quality Target Product Profile
- Critical Quality Attributes
- Product Design and Understanding
- Process Design and Understanding
- Process Design and Understanding
- Design space
- Control Strategy
- Continual Improvement
DESIGN TOOLS
- Prior Knowledge
- Risk Assessment
- Mechanistic Model, Design of Experiments, and Data Analysis
- Process Analytical Technology
Qbd is a technique of planing a safeguard for the formulation from the process of starting material to the final product , its main aim is to built the quality in the product not to testing.
The successful development of a biosimilar presents unique challenges compared to that of an innovator biologic. In particular, one must prove the biosimilar candidate's structural and functional differences do not have a meaningful impact on the clinical safety and efficacy profile already established for the innovator. Comprehensive and rigorous analytical testing to assess biosimilarity is thus the foundation upon which the successful development of a biosimilar begins.
The successful development of a biosimilar presents unique challenges compared to that of an innovator biologic. In particular, one must prove the biosimilar candidate's structural and functional differences do not have a meaningful impact on the clinical safety and efficacy profile already established for the innovator. Comprehensive and rigorous analytical testing to assess biosimilarity is thus the foundation upon which the successful development of a biosimilar begins.
Pharmaceutical industry is constantly looking for ways to ensure and enhance product safety, quality and efficacy. However, drug recalls,
manufacturing failure cost, scale up issues and regulatory burden in recent past suggest otherwise. In traditional quality by testing (QbT) approach, the product quality and performance are predominantly ensured by end product testing, with limited understanding of the process and critical process parameters. Regulatory bodies are therefore focusing on implementing quality by design (QbD), a science based approach that improves
process understanding by reducing process variation and the enabling process-control strategies. In this regards, pharmaceutical industry is currently undergoing a significant transformation to streamline their R&D process, provide greater manufacturing flexibility and control, and to reduce regulatory burden. However, there is limited understanding and major concerns regarding the implementation of QbD principles in the
pharmaceutical arena. The objective of this review article is therefore to provide a comprehensive understanding on various aspects of QbD, along with addressing the concerns related to its implementation.
A Review on Quality by Design and its Approachesijtsrd
The Pharmaceutical Quality By Design QBD is a systematic approach to the development that starts with the predetermined objectives and is based on the process of understanding process processes and process control, sound science and quality risk management. Quality Design QBD has been created to increase the assured of providing safe, effective medicines to customers and promised to make significant improvements in product quality performance. Supriya Khatal | Ashok Bhosale | Tejaswini Kande | Pallavi Dhekale | Punam Bramhadandi | Pratima Pokale "A Review on Quality by Design and its Approaches" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-3 | Issue-6 , October 2019, URL: https://www.ijtsrd.com/papers/ijtsrd29248.pdf Paper URL: https://www.ijtsrd.com/pharmacy/medicinal-chemistry/29248/a-review-on-quality-by-design-and-its-approaches/supriya-khatal
In this slide contains Quality-by-Design in Pharmaceutical Development.
Presented by: T. MOUSAMI BHAVASAR (Department of pharmaceutics). RIPER, anantapur
FDA’s emphasis on quality by design began with the recognition that increased testing does not improve product quality (this has long been recognized in other industries).In order for quality to increase, it must be built into the product. To do this requires understanding how formulation and manufacturing process variables influence product quality.Quality by Design (QbD) is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management. A presentation compiled from material freely available on the WEB to introduce the concepts of QbD for beginners.
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The dimensions of healthcare quality refer to various attributes or aspects that define the standard of healthcare services. These dimensions are used to evaluate, measure, and improve the quality of care provided to patients. A comprehensive understanding of these dimensions ensures that healthcare systems can address various aspects of patient care effectively and holistically. Dimensions of Healthcare Quality and Performance of care include the following; Appropriateness, Availability, Competence, Continuity, Effectiveness, Efficiency, Efficacy, Prevention, Respect and Care, Safety as well as Timeliness.
Stem Cell Solutions: Dr. David Greene's Path to Non-Surgical Cardiac CareDr. David Greene Arizona
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ICH Guidelines for Pharmacovigilance.pdfNEHA GUPTA
The "ICH Guidelines for Pharmacovigilance" PDF provides a comprehensive overview of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines related to pharmacovigilance. These guidelines aim to ensure that drugs are safe and effective for patients by monitoring and assessing adverse effects, ensuring proper reporting systems, and improving risk management practices. The document is essential for professionals in the pharmaceutical industry, regulatory authorities, and healthcare providers, offering detailed procedures and standards for pharmacovigilance activities to enhance drug safety and protect public health.
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QbD for Product Development of Solid Semisolid and Liquid Dosage Forms
1. Dr. Basavaraj K. Nanjwade
Principal Scientist
Trroy Life Sciences Pvt Ltd
C-14, New Town Yelhanka
Bangalore-560064, Karnataka, India
1Krupanidhi College of Pharmacy, Bangalore-560035
QbD for Product Development of Solid,
Semisolid and Liquid Dosage Forms
12/10/2019
2. Content
• Components of the Drug Product
• Drug Product
• Manufacturing Process Development
• Container Closure System
• Microbiological Attributes
• Compatibility
• Quality Target Product Profile
• Critical Quality Attributes
• Risk Assessment: Linking Material Attributes and Process Parameters
to Drug Products CQAs
• Design Space
• Control Strategy
• Product Lifecycle management and Continual Improvement
• Submission of Pharmaceutical Development and Related Information
in Common Technical Document (CTD) Format (3)
2Krupanidhi College of Pharmacy, Bangalore-56003512/10/2019
3. Dosage Forms
Sl.
No
Dosage Sl.
No
Dosage
01 Capsules 09 Ointments
02 Cream 10 Oral Liquids
03 Ear Drops 11 Oral powders
04 Eye Drops 12 Parenteral preparations
05 Eye Ointment 13 Pessaries
06 Gels 14 Suppositories
07 Inhalation preparations 15 Tablets
08 Insulin Preparation 16
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4. Quality by Design
A Systematic approach
• To development
• That begins with predefined objectives
• Emphasizes product and process understanding
• Process control
• Based on sound sciences and quality risk
management
4Krupanidhi College of Pharmacy, Bangalore-56003512/10/2019
5. Quality by Design
• Pharmaceutical quality refers to product free of
contamination and reproducibly delivers the therapeutic
benefit promised in the label to the consumer.
• The Quality of the pharmaceutical product can be
evaluated by in vivo or in vitro performance tests.
• Quality by design assures in vitro product performance
and In vitro product performance provides assurance of
in vivo product performance.
5Krupanidhi College of Pharmacy, Bangalore-56003512/10/2019
7. QbD Tools
• Design of experiments (DoE)
• Risk assessment
• Process analytical technology (PAT)
7Krupanidhi College of Pharmacy, Bangalore-56003512/10/2019
8. 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 and responses
to evaluate all the potential factors simultaneously,
systematically and speedily.
• With complete understanding of the process to assist in
better product development and subsequent process scale-up
with pretending the finished product quality and
performance.
8Krupanidhi College of Pharmacy, Bangalore-56003512/10/2019
9. Risk assessment
• Basic Risk Management Facilitation Methods
• Failure Mode Effects Analysis (FMEA)
• Failure Mode, Effects and Criticality Analysis (FMECA)
• Fault Tree Analysis (FTA)
• Hazard Analysis and Critical Control Points (HACCP)
• Hazard Operability Analysis (HAZOP)
• Preliminary Hazard Analysis (PHA)
• Risk Ranking and Filtering
• Supporting Statistical Tools
9Krupanidhi College of Pharmacy, Bangalore-56003512/10/2019
10. Process analytical technology (PAT)
• Multivariate tools for design, data acquisition
and analysis
• Process analyzers
• Process control tools
• Continuous improvement and knowledge
management tools
10Krupanidhi College of Pharmacy, Bangalore-56003512/10/2019
11. Quality by End Product Testing
11Krupanidhi College of Pharmacy, Bangalore-56003512/10/2019
13. Traditional approach & Enhanced QbD approach
Aspects Non-QbD QbD
Pharmaceutical
Development
Empirical, Random,
Focus on optimization
Systematic, Multivariate
experiments, Focus on control
strategy and robustness
Manufacturing
Process
Fixed Adjustable within design space,
managed by company’s quality
systems
Process Control Some in-process testing PAT utilized, Process operations
tracked and trended
Product Specification Primary means of quality
control, based on batch
data
Part of the overall quality control
strategy, based on desired product
performance
Control Strategy By testing and inspection Risk-based control strategy , real-
time release possible
13Krupanidhi College of Pharmacy, Bangalore-56003512/10/2019
14. Components of the Drug Product
• Drug Substance: The physicochemical and biological
properties of the drug substance that can influence the
performance of the drug product and its
manufacturability, or were specifically designed into
the drug substance (e.g., solid state properties), should
be identified and discussed.
• Excipients: The excipients chosen, their concentration,
and the characteristics that can influence the drug
product performance (e.g., stability, bioavailability) or
manufacturability should be discussed relative to the
respective function of each excipient.
14Krupanidhi College of Pharmacy, Bangalore-56003512/10/2019
15. Drug Product
• Formulation Development: Any excipient
ranges included in the batch formula
• Overages: Amount of drug substance listed in
the batch formula.
• Physicochemical and Biological Properties:
Selection of dissolution vs. disintegration
testing
15Krupanidhi College of Pharmacy, Bangalore-56003512/10/2019
16. Manufacturing Process Development
• The manufacturing processes used to produce
batches for pivotal clinical trials (safety,
efficacy, bioavailability, bioequivalence) or
primary stability studies.
• Process robustness can be useful in risk
assessment and risk reduction
16Krupanidhi College of Pharmacy, Bangalore-56003512/10/2019
17. Container Closure System
• The choice and rationale for selection of the container
closure system for the commercial product (described
in 3.2.P.7) should be discussed.
• The choice of materials for primary packaging should
be justified.
• Justification for secondary packaging materials
should be included, when relevant.
17Krupanidhi College of Pharmacy, Bangalore-56003512/10/2019
18. Microbiological Attributes
• The selection and effectiveness of preservative
systems in products containing antimicrobial
preservative
• For sterile products, the integrity of the container
closure system as it relates to preventing
microbial contamination
• Antimicrobial preservative effectiveness should
be demonstrated during development.
18Krupanidhi College of Pharmacy, Bangalore-56003512/10/2019
19. Compatibility
• The compatibility of the drug product with
reconstitution diluents (e.g., precipitation,
stability) should be addressed to provide
appropriate and supportive information for the
labeling.
• This information should cover the recommended
in-use shelf life, at the recommended storage
temperature and at the likely extremes of
concentration.
19Krupanidhi College of Pharmacy, Bangalore-56003512/10/2019
20. Target of QbD
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Quality Target product Profile (QTPP)
-Therapeutic Equivalence for Generic Drug Product
-Pharmaceutical Equivalence (same dosage form, route of administration, strength and same quality)
-Bio-Equivalence (same pharmacokinetics in terms of Cmax, AUC to reference product)
Critical Quality Attributes (CQAs)
-Quality: Assay, Uniformity of Dosage units
-Safety: Impurities (Related substances), Residual Solvents, Microbiological limits
-Efficacy: Dissolution & Absorption &
-Multidisciplinary: Patient Acceptance & Compliance
Quality Risk Assessment of CMAs & CPPs with CQAs
-Risk Identification by Ishikawa Fishbone
-Risk Analysis by Relative Risk Based Matrix Analysis
-Risk Evaluation by Failure Mode Effective Analysis (FMEA)
Designing of Experiments (DoE) & Design Space
For Screening & Optimization of CMAs &CPPs with respect to CQAs by superimposing contour plot to generate
Overlay Plot (Proven acceptable Ranges & Edges of failure) based upon desired ranges of Responses
Process Analytical Technology (PAT)
For continuous automatic IN LINE analyzing & Feed Back controlling critical processing through timely
measurements of CMA & CPAs by INLINE Analyzers with auto sensors with the ultimate goal of consistently
ensuring finished product quality with respect to desired CQAs
Implementation of Control Strategy
For Controls of CMAs, CPPs within Specifications by Real Time Release Testing, Online Monitoring System, Inline
PAT Analyzers based upon previous results on development, Scale Up. Exhibit/Validation batches.
21. Quality Target Product Profile
(QTPP) of Tablet
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Therapeutic
Equivalence of
generic Drug
Product
Pharmaceutical
Equivalence
Bio-Equivalence
Of Generic Tablets With Patient Compliance
22. Pharmaceutical Equivalence
Similar Dosage form Tablet
Dosage Design IR
Route of Administration Oral
Dosage strength X mg
Drug product Quality Assay, Uniformity, Impurity, Dissolution,
Microbiological limits, water content,
residual solvent with acceptable limits of
specification.
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23. Bio-Equivalence
Similar Drug Product
Performance Matching
Pharmacokinetics Matching
Rate of Absorption AUCo-t, AUCo-∞
Extent of absorption Cmax 90% CI of these PK Parameters should fall
within bioequivalence limits of 80-125 with reference
product.
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24. Patient compliance
Primary Packaging HDPE container: PP closure to achieve desired
stability and target shelf life
Ease of storage & Distribution Should be stable against hydrolysis, oxidation, photo
degradation and microbial growth
Patient Acceptance Should passess acceptable taste (in case of
soluble/dispersible effervescent tablet)
Patient Compliance Can be easily administered similar with reference
product labelling
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25. Quality Target Product Profile
(QTPP) of Tablet
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26. Critical Quality Attribute (CQA) of
Tablets
Physical Attributes Color, Size, Shape, Score configuration should acceptable to the patient mostly
similar to reference product to ensure Patient Compliance
Identification Positive for Drug Substance but controlled at drug substance release stage itself
Assay Should be between 90.0 to 110% of labeled claim to ensure safety and efficacy
Weight/Content Should conform to USP<905>; Uniformity of dosage form units: 90.0-110.0% of
labeled claim with AV: NMT 15.0; RSD: NMT 5.0% to ensure patient safety and
product efficacy.
Water Content Should be as per in house specification according to stability data to ensure patient
safety.
Impurities Should be within limits as per ICH Q3A and Q3B OR Reference product
characterization to ensure patient safety.
Dissolution NLT 80% (Q) of labeled amount of drug should be dissolved within 30 mins. In pH 6.8
buffer, 900 ml, Apparatus I 100 rpm to ensure desired bioavailability and Efficacy.
Residual Solvents Should conform to USP<467> option 1 RS controlled at Drug Substance and Incipient
Release stage itself
Microbiological Limits Should conform to USP <61 & 62> But controlled and Drug Substance and Exicipient
Release stage itself.
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27. Critical Material Attribute
(CMA) of Tablets
• Independent formulation variable i.e.
Physicochemical properties of active (drug
substance) & inactive ingredients (excipients)
affecting CQAs of semi-finished and/or
finished drug products.
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28. Critical Process Parameter (CPP)
of Tablets
• Independent process parameter
• Most likely to affect the CQAs of an
intermediate or finished drug product and
therefore should be monitored or controlled.
• To ensure the process produces the desired
quality product.
Note: 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
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29. Quality Target Product Profile
(QTPP) for Cream
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30. Critical Quality Attribute (CQA)
for Cream
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31. Quality Target Product Profile (QTPP)
• A prospective summary of
• The quality characteristics of a drug product
• That Ideally will be achieved to ensure the
desired quality,
• Taking into account Safety and Efficacy of the
drug product.
Krupanidhi College of Pharmacy, Bangalore-560035 3112/10/2019
32. QTPP of Solution
QTPP Element Target Justification
Dosage Form Solution Same dosage form
Dosage Design IR Formulation Label claims
Route of Administration Oral/External
Dosage Strength
Drug Product Quality Attributes
Appearance
Assay
Content Uniformity
Impurities
pH of system
Microbial limits
Antimicrobial content
Antioxidant content
Extractable
Viscosity/Specification
Primary and Secondary Packaging
Pharmaco-Kinetics
Ease of Storage and Distribution
Stability and Self Life
Patient Acceptance and Patient Compliance
32Krupanidhi College of Pharmacy, Bangalore-56003512/10/2019
33. Critical Quality Attribute (CQA)
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.
Krupanidhi College of Pharmacy, Bangalore-560035 3312/10/2019
34. CQA of Solution
Quality Attributes of Drug Product Target In this a
CQA?
Physical Appearances Colour, Odor & taste etc Yes
Identification Monograph Yes
Rheological properties (viscosity/specific
gravity
As Per Pharmacopoeia Yes
Assay 90.0 to 110.0% Yes
Weight variation/Content Uniformity Labelled claim (NMT 15.0%) Yes
Antimicrobial Preservative content As per Pharmacopoeia Yes
Antioxidant preservative content As per specification Yes
pH of System As per Pharmacopoeia Yes
Impurities/Degradation Product As per ICH Q3A & Q3B Yes
Microbiological Limits Conforms to USP, BP, IP Yes
Extractable Conforms to USP, BP, IP Yes
Dissolution As per specification Yes
34Krupanidhi College of Pharmacy, Bangalore-56003512/10/2019
35. Risk Assessment: Linking Material Attributes
and Process Parameters to Drug Products CQAs
• Risk assessment tools can be used to identify
and rank parameters (e.g., process, equipment,
input materials) with potential to have an
impact on product quality, based on prior
knowledge and initial experimental data.
35Krupanidhi College of Pharmacy, Bangalore-56003512/10/2019
37. Critical Material Attribute (CMA)
• Independent formulation variables i.e.
Physicochemical properties of active (drug
substance) & inactive ingredients (excipients)
• Affecting CQAs of semi-finished and/or
finished drug product.
Krupanidhi College of Pharmacy, Bangalore-560035 3712/10/2019
38. Critical Process Parameter (CPP)
• Independent process parameter
• Most likely to affect the CQAs of an
intermediate or finished drug product and
therefore should be monitored or controlled.
• To ensure the process produces the desired
quality product.
Krupanidhi College of Pharmacy, Bangalore-560035 3812/10/2019
39. Critical Material Attribute (CMAs)
Physico-Chemical
Properties
Critical Material Attribute
(CMAs)
Failure Mode Effect
Analysis (FMEA)
(Critical Event)
Physical Properties
Solid State Form Different Polymorph/form
Particle Size Distribution
(PSD)
High PSD
Moisture content High water content
Residual solvents High residual solvent
Chemical Properties
Solubility Different salt/Form
Volatility High
Process Impurities Less Purity
Chemical Stability Poor
Biological Properties Microbial Content High
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40. Critical Material Attribute (CMAs)
Excipient (Inactive Ingredient) Critical Material Attribute Failure Mode (Critical Event)
Vehicles/Solvents Quantity of Vehicle/Solvent Less than optimum
More than optimum
Hydrocolloid (Suspending agent as
a structured vehicle)
Source of Hydrocolloid Natural
Concentration of Hydrocolloid
Less than optimum
More than optimum
Surfactants (As
Solubilizing/agents)
Ionic Nature of surfactant Cationic/Anionic in nature
Concentration of Surfactant
Less than optimum
More than optimum
Buffering Agent
pH of the Buffer
Within Neutral Range
Within Acidic/Basic Range
Anti-Microbial Concentration of Anti-Microbial Less than optimum
Anti-Oxidant Concentration of Anti-oxidant Less than optimum
Sweetener/Flavouring agent Concentration of sweetener/Flavour Not Optimum
Coloring agent Concentration of Coloring Agent Not Optimum
Krupanidhi College of Pharmacy, Bangalore-560035 4012/10/2019
41. Critical Process Parameters (CPP)
Krupanidhi College of Pharmacy, Bangalore-560035 41
Unit Operations Critical Process Parameters (CPPs) Failure Mode (Critical Event)
Vehicle/Solvent Preparation Storage & Distribution
Rate of Addition Higher than Optimum
Filtration Rate
Heating Rate (Temp Time) Lower than Optimum
Higher than Optimum
Mixing Rate (Speed Time)
With Co-Solvents
Lower than Optimum
Solubilization of solid (API+Presevative) by
surfactants
Order of addition Incorrect
Impeller Design & Position Improper
Mixing Rate (Speed Time) Lower than Optimum
Heating Rate (Temp Time) Higher than Optimum
Supporting by structured Vehicles Order of Addition Incorrect
Rate of Addition Higher than Optimum
Mixing Rate (Speed Time) Lower than Optimum
Organoleptic addition with mixing Order of Addition Incorrect
Mixing Rate (Speed Time) Lower than Optimum
Heating Rate (Temp Time) Higher than Optimum
pH Adjustment with Buffer & Final Volume make
up with vehicle & final mixing
Rate of Addition Higher than Optimum
Impeller Design & Position Improper
Mixing Rate (Speed Time) Lower than Optimum
Heating Rate (Temp Time) Lower than Optimum
Higher than Optimum
Ultrafiltration in Colloidal mill
Type & Principle of Filter Improper
Filter Screen size Incorrect
Rate of Filtration Higher than Optimum
Filling, Capping & Sealling with nitrogen purging
Filling rate (Speed Time) Not Optimum
Higher than Optimum
Nitrogen purging rate Lower than Optimum
Capping & sealing rate Lower than Optimum
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42. 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 and responses to
evaluate all the potential factors simultaneously, systematically
and speedily;
• With complete understanding of the process to assist in better
product development and subsequent process scale-up with
pretending the finished product quality and performance.
Krupanidhi College of Pharmacy, Bangalore-560035 4212/10/2019
43. Design Space
The Multidimensional Combination and
Interaction of
• Critical Material Attributes and
• Critical Process Parameters that have been
demonstrated to provide assurance of quality.
Krupanidhi College of Pharmacy, Bangalore-560035 4312/10/2019
44. Design Space
1. Selection of Variables
2. Describing a Design Space in a Submission
3. Unit Operation Design Space(s)
4. Relationship of Design Space to Scale and
Equipment
5. Design Space Versus Proven Acceptable
Ranges
6. Design Space and Edge of Failure
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45. Design Space
45Krupanidhi College of Pharmacy, Bangalore-560035
Temperature
Pressure
Large square shows the ranges tested in the DOE
Red area shows points of failure
Green area shows points of success.
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46. 1. Selection of Variables
• A description should be provided in the application of
the process parameters and material attributes
considered for the design space, those that were
included, and their effect on product quality.
• The rationale for inclusion in the design space should
be presented.
• In some cases, it is helpful to provide also the
rationale as to why some parameters were excluded.
• Knowledge gained from studies should be described
in the submission.
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47. 2. Describing a Design Space in a
Submission
• A design space can be described in terms of ranges of
material attributes and process parameters, or through
more complex mathematical relationships.
• It is possible to describe a design space as a time
dependent function (e.g., temperature and pressure
cycle of a lyophilisation cycle), or as a combination of
variables such as components of a multivariate model.
• Scaling factors can also be included if the design space
is intended to span multiple operational scales.
• Analysis of historical data can contribute to the
establishment of a design space.
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48. 3. Unit Operation Design Space(s)
• The applicant can choose to establish
independent design spaces for one or more unit
operations, or to establish a single design
space that spans multiple operations.
• While a separate design space for each unit
operation is often simpler to develop, a design
space that spans the entire process can provide
more operational flexibility.
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49. 4. Relationship of Design Space to
Scale and Equipment
• When describing a design space, the applicant should consider
the type of operational flexibility desired.
• A design space can be developed at any scale.
• The applicant should justify the relevance of a design space
developed at small or pilot scale to the proposed production
scale manufacturing process and discuss the potential risks in
the scale-up operation.
• If the applicant proposes the design space to be applicable to
multiple operational scales, the design space should be
described in terms of relevant scale-independent parameters.
• Dimensionless numbers and/or models for scaling can be
included as part of the design space description.
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50. 5. Design Space Versus Proven
Acceptable Ranges
• A combination of proven acceptable ranges
does not constitute a design space.
• However, proven acceptable ranges based on
univariate experimentation can provide useful
knowledge about the process.
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51. 6. Design Space and Edge of Failure
• It can be helpful to determine the edge of failure for
process parameters or material attributes, beyond
which the relevant quality attributes cannot be met.
• However, determining the edge of failure or
demonstrating failure modes are not essential parts of
establishing a design space.
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52. Design Space for drying
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53. Process Analytical Technology (PAT)
A System for-
• Designing,
• Analysing &
• 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.
Krupanidhi College of Pharmacy, Bangalore-560035 5312/10/2019
54. Control Strategy
• A planned set of controls for CMAs and 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
Krupanidhi College of Pharmacy, Bangalore-560035 5412/10/2019
55. Control Strategy for CMA
Factors CMA’s Purpose of Control
Active Pharmaceutical Ingredient (API) CMA
Polymorphic Form 2 values To ensure batch to batch consistency in Dissolution
Excipient CMA
Vehicle Grade To ensure consistence compatibility, purity & Micro. Stab.
Surfactant Type (Tween 80) To ensure batch to batch consistency in solubility, pour
ability, Physical Stability & Compatibility
Concentration (%w/w)
Hydrocolloids Source (CMA)
Concentration (%w/w)
Sweetener Concentration (%w/w) To ensure batch to batch consistent Patient Acceptance &
Compliance
Flavor Concentration (%w/w)
Color Concentration (%w/w)
Anti-Microbial Concentration (%w/w) To ensure batch to batch consistency Chemical &
Microbiological stability
Anti-Oxidant Concentration (%w/w)
Buffer Concentration (%w/w)
Krupanidhi College of Pharmacy, Bangalore-560035 5512/10/2019
56. Control Strategy for CPP
Factors (s) CPPs Purpose of Control
Vehicle/Solvent Preparation with
Sweetener, Flavor, Color
Heating Temperature To ensure consistance
compatibility, acceptability, purity
& Micro. Stability
Mixing Time
Controlled Solubilization by
surfactant & hydrocolloids
Heating Temperature To ensure batch to batch consiste
cy in Solubility, Pour ability,
Physical Stability & Compatibility
Mixing Time
pH Adjustment with Buffer &
Final Volume make up with
vehicle & final Mixing
Heating Temperature To ensure batch to batch
consistency Chemical &
Microbiological stability
Mixing Time
Ultrafiltration Particulate Matter Screen
Size
To ensure batch to batch purity to
warrant Safety
Microbial Filter Screen Size
Filling, Capping & Sealing Temperature To ensure Chemical Stability
Vacuum Pressure with
Nitrogen Purging
Krupanidhi College of Pharmacy, Bangalore-560035 5612/10/2019
57. Product Lifecycle Management and
Continual Improvement
• Throughout the product lifecycle, companies have
opportunities to evaluate innovative approaches to
improve product quality
• Process performance can be monitored to ensure that it is
working as anticipated to deliver product quality
attributes as predicted by the design space.
• Expansion, reduction, or redefinition of the design space
could be desired upon gaining additional process
knowledge.
• Change of design space is subject to regional
requirements.
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58. Continual Improvement
Risk Review and Risk Communication
Lifecycle
Management
Formulation
R&D
Analytical
R&D
Regulatory
Affairs
Manufacturing
Plant
Quality
Assurance
Quality
Control
Krupanidhi College of Pharmacy, Bangalore-560035 5812/10/2019
59. SUBMISSION OF PHARMACEUTICAL
DEVELOPMENT (3)
• Quality Risk Management and Product and Process
Development
• Design Space
• Control Strategy
• Drug Substance Related Information
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60. Quality Risk Management and Product
and Process Development (3.1)
• Quality risk management can be used at different stages
during product and process development and
manufacturing implementation.
• The assessments used to guide and justify development
decisions can be included in the relevant sections of P.2.
• For example, risk analyses and functional relationships
linking material attributes and process parameters to
product CQAs can be included in P.2.1, P.2.2, and P.2.3.
• Risk analyses linking the design of the manufacturing
process to product quality can be included in P.2.3.
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61. Design Space (3.2)
• As an element of the proposed manufacturing process, the design space(s)
can be described in the section of the application that includes the
description of the manufacturing process and process controls (P.3.3).
• If appropriate, additional information can be provided in the section of the
application that addresses the controls of critical steps and intermediates
(P.3.4).
• The product and manufacturing process development sections of the
application (P.2.1, P.2.2, and P.2.3) are appropriate places to summarize and
describe product and process development studies that provide the basis for
the design space(s).
• The relationship of the design space(s) to the overall control strategy can be
discussed in the section of the application that includes the justification of
the drug product specification (P.5.6).
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62. Control Strategy (3.3)
• The section of the application that includes the
justification of the drug product specification
(P.5.6) is a good place to summarize the overall
drug product control strategy.
• However, detailed information about input
material controls and process controls should still
be provided in the appropriate CTD format
sections (e.g., drug substance section (S), control
of excipients (P.4), description of manufacturing
process and process controls (P.3.3), controls of
critical steps and intermediates (P.3.4)).
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63. Drug Substance Related Information (3.4)
• If drug substance CQAs have the potential to affect
the CQAs or manufacturing process of the drug
product, some discussion of drug substance CQAs
can be appropriate in the pharmaceutical development
section of the application (e.g., P.2.1).
Krupanidhi College of Pharmacy, Bangalore-560035 6312/10/2019
64. Benefits of QbD
• Better understanding of the process.
• Less batch failure.
• More efficient and effective control of change.
• Return on investment / cost savings.
• An enhance QbD approach to pharmaceutical
development provides opportunities for more flexible
regulatory approaches.
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65. Benefits of QbD
• Consistent product quality
• Reduced risk of recalls
• Real-time release
• Cost Reduction
• Reduced inventories
• Less waste
• Higher yields
• Increased process understanding resulting in more efficient production
processes
• Faster process development, upscaling and tech transfer
• Regulatory flexibility, relief and easier regulatory approach
• Improved clinical outcome quality
• Easy Technology Transfer
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66. Manufacturing changes within the approved design space
• Reduction of post-approval submissions.
• Better innovation due to the ability to improve processes without
resubmission to the FDA when remaining in the Design Space.
• More efficient technology transfer to manufacturing.
• Greater regulator confidence of robust products.
• Risk-based approach and identification.
• Innovative process validation approaches.
• Less intense regulatory oversight and less post-approval
submissions.
• For the consumer, greater drug consistency.
• More drug availability and less recall.
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67. Manufacturing changes within the approved design space
• Improved yields, lower cost, less investigations, reduced testing, etc.
• Time to market reductions: from 12 to 6 years realized by amongst
others.
• First time right: lean assets management.
• Continuous improvement over the total product life cycle (i.e.
controlled, patient guided variability).
• Absence of design freeze (no variation issues).
• Less validation burden.
• Real time controls (less batch controls).
• Realistic risk perceptions.
• Contributes substantially to realize the better, cheaper and safer
mandate.
Krupanidhi College of Pharmacy, Bangalore-560035 6712/10/2019
68. QbD activities within FDA
• In FDA’s Office of New Drug Quality Assessment
(ONDQA), a new risk-based pharmaceutical quality
assessment system (PQAS) was established based on the
application of product and process understanding.
• Implementation of a Question-based Review (QbR)
Process has occurred in CDER’s Office of Generic Drugs.
• Implementation of QbD for a Biologic License
Application (BLA) is progressing.
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69. International Conference on
Harmonization (ICH)
• Pharmaceutical Development Q8 (R2)
• Quality Risk Management Q9
• Pharmaceutical Quality System Q10 (Science-
based and risk- based approaches)
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70. International Conference on
Harmonization (ICH)
• The difference between QbD for NDA and
ANDA products is most apparent at the first
step of the process.
• For an NDA, the target product profile is under
development while for the ANDA product the
target product profile is well established by the
labelling and clinical studies conducted to
support the approval of the reference product.
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71. RPN = Probability* Severity* Detectability
Probability Severity Detectability
Probability of Risk occurrence
can reduced by systematic
series of experiments through
Designing of Experiments
(DoE)
Severity of Risks
could not be reduced
Detectability of Risk can
increased by implementation of
automatic inline
Process Analytic Technology
(PAT)
Which generated safe and
optimized ranges of CMAs &
CPPs with respect to desired
CQAs par overlaid Design
Space, Where all the desired in
process & finished product
CQAs are met simultaneously
Which ensured timely
measurement of critical quality
and performance attributes of
raw and in-process materials or
parameters to control the
quality of finished product.
Krupanidhi College of Pharmacy, Bangalore-560035 71
RPN (Risk Priority Number) more than 30 seek critical attention for DoE for possible failure
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72. Total Risk Priority Number (RPN)
Probability Severity Delectability Score
Very Unlikely Minor Always Detected 01
Occasional Moderate Regular Detected 02
Repeated Major Likely Detected 03
Regular Extreme Normally not Detected 04
Krupanidhi College of Pharmacy, Bangalore-560035 72
Risk Priority Number (RPN) more than 30 seek critical attention for DoE for possible failure
12/10/2019
73. 73Krupanidhi College of Pharmacy, Bangalore-560035
THANK YOU
12/10/2019
E-mail: nanjwadebk@gmail.com