1. Presented By: Vipul Patel
Quality By Design
Presented By: Vipul Patel

2. Syllabus
QbD and PAT: Elements of QbD, QbD tools, significance of QbD Design of experiments –Methods and applications of optimization techniques to assure quality in product, critical quality attributes, critical process, Process analytical technology (PAT) in Pharmaceutical manufacturing. Goal of PAT, Benefits of PAT, PAT tools, Process Analyzer, Application of PAT in chemical and pharmaceutical industry.

3. HISTORY
In 2007 FDA received an 5000 supplements, it was actually a striking raise in the number of manufacturing supplements to applications of New Drug Applications (NDAs), Biological License Applications (BLAs) and Abbreviated New Drug Applications (ANDA’s). FDA recognized that there is an increase in lapse of NDA or ANDA submissions by the firms, large number of a supplemental application for every manufacturing change were received. In both original applications and supplements the data mainly focused was on chemistry. And the least attention was given on other important aspects of the manufacturing, such as engineering, product development. Eventually, the FDA acknowledged that more and more controls were required for drug manufacturing processes for efficient drug product and no doubt for better regulatory decision making. It resulted in more stringent regulatory upbringing. To solve this issue in 2002, the FDA implemented changes through the Pharmaceutical cGMP (good manufacturing practice) for the 21st Century.

4. Facilities and equipment
What is QbD?
Integrated, systematic and scientific approach to design, development and delivery of performance attributes that ensure consistent delivery of specific quality, safety and efficacy objectives.
People
Product
Facilities and equipment
Process
Ref.: ICH Q8 (R2)

5. DEFINITION
Systematic, holistic and proactive approach to pharmaceutical development.
Begins with predefined objectives
Emphasizes product and process understanding and process control
Based on sound science and quality risk management

6. Quality by Design (QbD) is a concept first outlined by well-known quality expert Joseph M. Juran who believed that quality could be planned, and that most quality crises and problems relate to the way in which quality was planned in the first place.
Proactive & risk based approach for predictable & predefined quality
Planning quality into the process.
A leading indicator for better controls & to handle quality crises and problems early in the cycle.
Quality by Design means –designing and developing formulations and manufacturing processes to ensure a predefined quality

7. Benefits of QBD Eliminate batch failures
Minimize deviations and costly investigations
Avoid regulatory compliance problems
Organizational learning is an investment in the future
QbD is good Science
Better development decisions
Empowerment of technical staff
Efficient, agile, flexible system
Increase manufacturing efficiency, reduce costs and project rejections and waste
Build scientific knowledge base for all products
Ensure consistent information
Incorporate risk management

8. Enhances scientific foundation for review.
Improves information in regulatory submissions.
Ensures decisions made on science and not on empirical information.
Provides for better coordination across review, compliance and inspection.

9. Interpretations of Quality
Meeting Specifications
Features
Perception
Easy Maintenance
Fitness for use
Cost
Time
Satisfaction
QUALITY
Safety
Standards compliance
Regulations
Experience
Look & Feel
Aesthetics
Performance
Quality by Design (QbD), FICCI, 19th Jan 2012

10. Target Quality Profiling- A Perspective
Market
Regulations
Corporate Social Responsibility
Customer
Research
HRM)
Installation &
Service
Business insights
Engineering
Manufacturability
Suppliers
Purchasing
Competitor(s)

11. Overview of QbD Quality Target Product Profile Ref.: ICH Q8 (R2)
Product Design and Understanding
Process Design and Understanding
Control Strategy
Continuous Improvement
Ref.: ICH Q8 (R2)

12. Elements of QbD Elements of QbD
Different elements of pharmaceutical development
include,
Defining an objective
Determination of critical quality attributes (CQA)
Risk assessment
Development of experimental design
Designing and implementing control strategy
Continuous improvement

14. Defining an objective (QTPP)
Elements of QbD
Defining an objective (QTPP)
Quality target profile (QTP) forms the basis of QbD, which is in relation to the predefined objective criteria mentioned in the definition of QbD.
Considerations for the Quality Target Product Profile could include:
Intended use in clinical setting, route of administration, dosage form, delivery Systems.
Dosage strength(s), Container closure system.
Therapeutic moiety release or delivery and attributes affecting, Pharmacokinetic characteristics (e.g., dissolution, aerodynamic performance).
Drug product quality criteria like sterility, purity, stability and drug release as appropriate for dosage form the intended for marketing

15. Elements of QbD
QbD requires a Target Product Profile; it may be called as Quality Target Product Profile (QTPP) which defines the expectations in final product. In case of analytical method development it is called as analytical target profile (ATP), it is also called as Target Product Profile (TPP).
The TPP will help to identify critical quality attributes such as potency, purity, bioavailability or Pharmacokinetic profile, shelf-life, and sensory properties.

16. Model Quality Target Product Profile (QTPP)

17. Model Quality Target Product Profile (QTPP)

18. Prepare Quality Target Product Profile for following Dosage form
Immediate Release tablet, Control Release tablet, Hard Gelatine capsule, Cream, Insitu gelling System

19. Determination of critical quality attributes (CQA)
Elements of QbD
Determination of critical quality attributes (CQA)
According to ICH Q8 R2 ‘‘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’’.
QAs are generally linked with the drug substance, excipients, intermediates (in process materials) and drug product.
For example CQAs of solid oral dosage forms are typically those aspects affecting product purity, strength, drug release and stability whereas for Parenterals they are Sterility and clarity.
The CQAs can additionally include properties like particle size distribution, bulk density that affect drug product. Mostly CQAs are derived from the Quality Target Product Profile and/or prior knowledge is used to guide the product and process development and Subsequently CQAs are accessed for risk management.

20. Elements of QbD
Dissolution test is crucial for a controlled release drug product and on other hand dissolution test for an immediate release drug product which belongs to the high aqueous solubility and high permeability i.e. BCS class I drug will not prove as critical attribute for quality control viewpoint.

21. Basic Terminology: (CQA Can be independent or dependent) In scientific language those attributes are called as variables..
Independent variables
Conc. Of Polymer, Agitation Speed
Binder (%), Granulation time
Dependent variables
Friability, hardness
Pharmacological activity

22. Independent variable:
Significant variable
More important..
Go on changing level..
E.g. Polymer Conc,
Granulation time
Insignificant variable
Not that much importance
you can keep it at constant level also..
E.g. Effect of lubricant on floating tablet
Independent variable may positive or negative result on
to the dependent variable

23. Dependent variable Also Known as Response variable.
Its output of our experiment.
Not limit for dependent variable.
This variable depends on independent variable.
Keep as many as you wish.
e.g. Angle of repose, Disintegration time,
Friability, Hardness.

24. QTPP and CQAs QTPP components CQAs Assay (Efficacy)
Dosage Form
Route of administration
Strength
Pharmacokinetics
Stability
Appearance
Identity
Assay
Impurities
Residual Solvents/Monomers
Adhesion Test(Peel Test, Peel from Liner Test , Probe Tack)
Cohesion Test(Shear)
Drug Release
CQAs
Assay (Efficacy)
Adhesion (Efficacy)
Impurities (safety)
Residual Monomer(Safety)
Stability (Efficacy)

25. What factors affect drug product CQAs?
Properties of Input Materials - Identify Critical Material Attributes (CMAs)
Properties of in-process materials - CQAs of one step become CMAs for a downstream unit operation
Manufacturing process parameters - Identify Critical Process Parameters (CPPs)
Input Materials
CMA1
Output Materials
Product
CQAs
CPP1
Unit Operation 1
Unit Operation 2
CMA2
CPP2

26. Critical Material Attributes (CMA)

27. Critical Process Parameters (CPP) Critical process parameters
Unit operations
Critical process parameters
Mixing
Mixing speed
Mixing time
Product temperature
Addition rate
Coating drying and lamination
Zone temperature
Blower speed
Residence time
Lamination pressure
Web tension
Slitting
Machine speed
Slit roll width
Printing and die cutting
Patch dimension

28. Activity
Prepare list of all possible quality attributed for following pharmaceutical unit operation: (i) Drying, Mixing, (ii) Size reduction, Wet granulation, (iii) Compression, Pan coating

29. Risk assessment Elements of QbD
It is commonly understood that risk is defined as the combination of the probability of occurrence of harm and the severity of that harm. Risk assessment helps to increase quality of method or process. Also it is determinant for effect of input variable on method or processes. From risk assessment one can recognize critical attributes that are going to affect final quality of product. A risk assessment is helpful for effective communication between FDA and industry, research/development and manufacturing and among multiple manufacturing sites within company. There may be risk and uncertainty in validation of bioanalytical method though the guidelines for validation are given by various regulatory bodies there may be a variation in interpretation of those guidelines and hence in experimental method designing which leads to unfit method development for intended purpose.

30. Principles of quality risk management are: Scientific knowledge based evaluation of the risk to quality which eventually links to the protection of the patient.
Adequate effort should be taken; formality and documentation of the quality risk management process should be done with the level of risk involved. Risk management is joint responsibility of quality unit, business development, engineering, regulatory affairs, production operations, sales and marketing, legal, statistics and clinical department

31. QbD Tools - Risk Assessment
Risk Identification
“What might go wrong?”
A systematic use of information to identify hazards
historical data
theoretical analysis
informed opinions
concerns of stakeholders

32. Risk Analysis QbD Tools - Risk Assessment
“What is the likelihood it will go wrong?”
The estimation of the risk associated with the identified hazards.
A qualitative or quantitative process of linking the likelihood of occurrence and severity of harm
Consider detectability if applicable (used in some tools)

33. Risk Evaluation QbD Tools - Risk Assessment “What is the risk?”
Compare the identified and analyzed risk against given risk criteria
Consider the strength of evidence for all three of the fundamental questions
What might go wrong?
What is the likelihood (probability) it will go wrong?
What are the consequences (severity)?

34. Risk Control: Risk Reduction
QbD Tools - Risk Assessment
Risk Control: Risk Reduction
“Decision-making activity”
Is the risk above an acceptable level?
What can be done to reduce or eliminate risks?
Are new risks introduced as a result of the identified risks being controlled?
Focus actions on severity and/or probability of harm; don’t forget detectability

35. Risk Control: Risk Acceptance
QbD Tools - Risk Assessment
Risk Control: Risk Acceptance
Discuss the appropriate balance between benefits, risks, and resources
Focus on the patients’ interests and good science/data
Risk acceptance is not
Inappropriately interpreting data and information
Hiding risks from management / competent authorities

36. QbD Tools - Risk Assessment
Risk Communication
Bi-directional sharing of information about risk and risk management between the decision makers and others
Communicate at any stage of the QRM process
Communicate and document the output/result of the QRM process appropriately
Use existing channels as specified in regulations, guidance and SOP’s

37. Risk review QbD Tools - Risk Assessment
Review the output / results of the QRM process
Take into account new knowledge and experience
Utilize for planned or unplanned events
Implement a mechanism to review or monitor events
Reconsideration of risk acceptance decisions as appropriate

38. QbD Tools - Risk Assessment Risk Ranking and Filtering
Steps in Risk Ranking & Filtering
Potential Risks are identified
The probability is estimated (Qualitative/Quantitative)
The severity of the harm is estimated (Qualitative/Quantitative)
Each individual risk is assigned a specific score, based on the Probability & Severity. Based on this score the overall score is determined for each identified potential risk.
Risks are ranked and filtered, using criteria specific to the circumstances.

39. Risk Ranking and Filtering
QbD Tools - Risk Assessment
Risk Ranking and Filtering
Risk Ranking/Score
> 6
High
3-4
Medium
1-2
Low
Probability 3 6 9 2 4 1
Severity
Low
Broadly acceptable risk. No further investigation is needed.
Medium
Risk is accepted. Further investigation may be needed in order to reduce the risk.
High
Risk is unacceptable. Further investigation is needed to reduce the risk.

40. What happening With Trial And Error Method
Traditional Trend
Randomized fashion of research
Required More number of trials..,
Take more time
Cant predict the extension… i.e. cant say what happen if such change are made within that particular system.

41. Activity
Derived Possible number of experimentation for following formulation optimization .
e.g. In process of Extrusion Spheronization,
Three attributes…
Binder (%) (1 % to 20 %)
Granulation time (Min) (1 min to 500 min)
Spheronization speed (RPM) (5 RPM to 1000 RPM)

42. Is there Any alternative??
Optimization
Designing experiments to yield the most information from the fewest runs
Reduce the number of trial to minimum but in
logical manner
Carry out research in systematic way
Identify the characteristic you want in your product

43. Development of experimental design
Elements of QbD
Development of experimental design
Experimental design is the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Design space is proposed by the applicant and is subject to regulatory assessment and approval of ICH Q8 (R2).

44. Various technique for optimization.,
Factorial design
Fractional Factorial design
Simplex lattice design
Plackett-burman design
Central composite design
Constrained mixture design
Box Behnken design

45. FACTORIAL DESIGN
Basic Terminology: In scientific language those attributes are called as variables..
Independent variables
Conc. Of Polymer, Agitation Speed
Binder (%), Granulation time
Dependent variables
Friability, hardness
Pharmacological activity

46. Independent variable:
Significant variable
More important..
Go on changing level..
E.g. Polymer Conc,
Granulation time
Insignificant variable
Not that much importance
you can keep it at constant level also..
E.g. Effect of lubricant on floating tablet
Independent variable may positive or negative result on
to the dependent variable

47. Dependent variable Also Known as Response variable.
Its output of our experiment.
Not limit for dependent variable.
This variable depends on independent variable.
Keep as many as you wish.
e.g. Angle of repose, Disintegration time,
Friability, Hardness.

48. LEVEL What is level?? Level of factor are the values or designations
assigned to the factors.
In General Factor and Level are keep below 3.
No of trial depend upon...
No of independent variable
No of level
So choosing the independent variable and no of level that is the crucial step in optimization.

49. Example of level in actual value and in a form of coded value:
Coding of level
Example of level in actual value and in a form of coded value:
Variable
Level
Actual value
Coded value
Temp
2 level
30 ° & 50 ° c
-1 & +1
3 level
30°, 40° & 50 °c
-1, 0, & +1
4 level
30°, 40° , 50 ° and 60 ° c
-2,-1 & +1, +2

50. Polynomial Equation Y = β0 constant + β1X1 + β2X2 + β3X3 main effects
+ β11X12 + β22X22 + β33X curvature
+ β12X1X2 + β13X1X3 + β23X2X3 interaction
+ ε error

51. Contour Plot Contour plot is formed by:
Horizontal axis: Independent variable 1
Vertical axis: Independent variable 2
Lines: iso-response values

53. Designing and implementing control strategy
Elements of QbD
Designing and implementing control strategy
Control strategy is required to ensure that material and process are within the expected lower and upper limits. Parameter and material are routinely controlled during production in order to assure reproducibility. The control space should be within the design space. Generally scale up is trial and error basis. During scale up processes parameters may differ but attributes which affect quality remain the same hence control strategy is required. QbD gives trace on reproducibility and robustness. Process capability index expresses reproducibility of process.

54. Continuous Improvement throughout product life cycle
Elements of QbD
Continuous Improvement throughout product life cycle
Product quality can be improved throughout the product life cycle; companies have opportunities to opt inventive approaches to improve quality. Process performance can be monitored to make sure consistency in quality. Additional experience and knowledge is gained during routine manufacture which contributes to method/process development. Periodic maintenance can be done within a company’s own internal quality system; but design space should be unchanged. The QbD approach avails the continuous improvement throughout products’ life cycle this is distinguishing point from the conventional method which is much frozen process.

55. Problems in adoption of QbD
PAT and QbD require collection of data, to act on that, and capitalize indicators and parameters but when a company does not own the equipment, it is often difficult to implement.
Internal unwillingness in company
Lack of belief in a business case. It is assumed that QbD would require more time to file generic products or that the amount of clinical trials necessary to implement QbD for drug substance production
Lack of technology to implement.
Alignment with third parties. It is difficult to manage a multipart supply chain that includes both suppliers and contract manufacturers.
Inconsistent treatment of QbD across FDA. It is believed that FDA may not review filings in a consistent manner.
Lack of concrete guidance for industry. Companies wanted clarification from FDA on matters such as acceptable methods, criteria to select critical quality attributes, standards by which to judge adequacy of controls, and criteria for analytical method substitution.
Presented regulatory benefits does not inspire to follow QbD
Misalignment of international regulatory bodies.

56. Quality by Design Tools :
Design of experiments (DoE)
Risk assessment
Process analytical technology (PAT)
Design of Experiments (DOE) :
Design of Experiments (DOE) Structured, organized method for determining the relationship between factors affecting a process and the response of that process. DOE Methodology (1) Choose experimental design (e.g., full factorial, d-optimal) (2) Conduct randomized experiments (3) Analyze data (4) Create multidimensional surface model.

57. Risk assessment :
As discussed earlier

58. Process Analytical Technology(PAT)
Process Analytical Technology(PAT) A system for designing, analyzing, and 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. The term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner.

59. Example: Current Tablet Production
Raw Material : Dispensing, Blending Compression
Identification Tests (Chemical Only)
Test Product Quality for Release (Active Only)
End- Product Focused Testing to Document Quality Process at Risk

60. PAT Tablet Production :
Compression Functional Tests (Chemical and Physical)
Validate Process Control
Control Blending (Particle Size & Disintegrant Distribution)
Process Focused
Mitigate the Process Risk
Predictive Models

61. QbD Tools - Process Analytical Technology (PAT)
Off-line
Analysis performed in laboratory
Day
At-line
Analysis performed on factory floor
Minutes
On-line
Automated sampling and analysis
seconds
In-line
No sampling- in process instrument
< 1 second
Time delay
Frequency of sampling

62. PAT in Tablet manufacturing
Stage
Technique
Measurement
Dispensing
NIR / Raman
Identification of raw materials
Wet Granulation
NIR
Moisture distribution
Drying
Moisture content
Blending
Blend Uniformity
Compression
Strain gauges
Compression force
Content Uniformity

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

64. Real-time Blend Uniformity by using TruProcess™ Analyzer
PAT Examples
Real-time Blend Uniformity by using TruProcess™ Analyzer

65. QbD: Required or Optional?
Quality target product profile (QTPP) including critical quality attributes (CQAs) of the drug product and including Product design and understanding
Product design and understanding
Critical material attributes (CMAs) of the drug substance and excipients
Process design and understanding
Critical process parameters (CPPs)
Control strategy, including justification
Optional
Design Space
Process Analytical Technology