Quality by Designs

CURRENT SCENARIO IN FORMULATION DEVELOPMENT IN PHARMA INDUSTRY

1. Rahul Krishnan.P.RRahul Krishnan.P.R
M.Pharm, 11nd SemesterM.Pharm, 11nd Semester
Grace College of PharmacyGrace College of Pharmacy
Palakkad, KeralaPalakkad, Kerala
CURRENT SCENARIO IN
FORMULATION
DEVELOPMENT IN PHARMA
INDUSTRY
1

2. QbD in Pharma Development QbD in Pharma Development
2

3. Main Menu Main Menu
Introduction
Quality based Designs (QbD)
Stages of QbD
Summary
Conclusion
References

3

4. Introduction Introduction
A systematic approach to development that
begins with pre-defined objectives for
Product, process understanding and control
based on sound science and quality risk
management.
The umbrella over that is QbD
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5. Introduction Cont..dIntroduction Cont..d
Pharma Products regulation
Enhance quality / Patient compliance
Quality by Testing
Quality by design (QbD)
Principles of QbD
QbD Oriented formulation development
Benefit of QbD of Formulation 5

6. Introduction Con…tIntroduction Con…t
Newer formulation / Existed formulation
Rationale for the formulation
Expected out come
Cost effective
Improved Bioavailability
Improved shelf life
Improved quality of the formulation
Better patient compliance
6

7. Comparison of QbD Vs QbTComparison of QbD Vs QbT
Quality by chance
Current status on manufacturing
Relies on end product testing
Attain the quality is never guaranteed
Quality control test outweigh the design
Time, efforts and time consuming
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8. Background and Merits of Background and Merits of
(QbD) (QbD)
JM Juran -American engineer and quality analyst
Scientific approach-design the product and process
Quality of the drug product is accomplished
End product testing is validation only
Complement well with FDA, ICH –Q8,Q9, Q10
Wider operating ranges
8

9. Goals of QbDGoals of QbD
Design robust products – meet patient needs
Understand the impacts on formulation
Avoid raw material lot selectin
Indentify the risk factors
Continuously moniter
Update
9

10. Importance of QBDImportance of QBD
High level assured product quality
Cost savings
Reduce project rejects
Opportunity for continuous improvement
Ease of US FDA approvals
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11. QbD - RequirementsQbD - Requirements
Knowledge on Formulation
Knowledge on Excipients
Knowledge on Drugs
Knowledge on Biopharmaceutics and PK
Knowledge on Processing
Experience on the Formulation Development
Knowledge on Statistical Optimization
Knowledge on Process Validation
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12. Knowledge on FormulationKnowledge on Formulation
Types of dosageform
Formulation design of dosageform
Manufacturing method
Stability of dosageform
Character of dosageform
Quality Control parameters
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13. Knowledge on ExcipientsKnowledge on Excipients
Property of the inactive ingredients
Functions of inactive ingredients
Polymers Characters
Range, Specification of excipients
Stability / storage condition
Raw material analysis method
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14. Knowledge on Drug Knowledge on Drug
Indication, Category
Mechanism of action
Dose
Frequency of administration
Route(s) of administration
Adverse effects
Schedule
Risk factors
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15. Knowledge on Biopharmaceutics & P. kinetic Knowledge on Biopharmaceutics & P. kinetic
factors factors
Physical and Chemical property of drugs
M.Wt, Pka, particle Size
BCS Classification
Crystalline / amorphous
Hydrate / anhydrate, Wetability
Partition coefficient, Solubilization
Polymorphism, Permeability
Salt form
Cmax, tmax, AUC, Ka, Ke, T1/2 Vd, Cl
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16. Knowledge on ProcessKnowledge on Process
Manufacturing Methods
Critical manufacturing parameters
Temperature and Relative humidity
Operation of knowledge on Machinery and
instruments
Sterilization methods
Quality assurance and quality control
parameters
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17. Knowledge on Process Cont…dKnowledge on Process Cont…d
Film Coating System
Weight gain, Pan Speed
Solid content, Spray rate
Inlet air volume, Pan Charge
No of guns, Atomizing pattern and Air
pressure
Tablet bed temperature
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18. Knowledge on Sources of Myriad Knowledge on Sources of Myriad
API variability
Excipients variability
Process variability
Packaging variability
Others & Interaction
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19. Stages in QbDStages in QbD
Pre-Stage for QbD
1. Set the formulation objectives
2. Priority- Input variables for optimization
3. Design guided experimentation& Analysis
4. Validation of QbD methodology
5. Scale – up and production
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20. PRE STAGE QBDPRE STAGE QBD
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21. PRE STAGE - QbD PRE STAGE - QbD
Analysis of RLP
Clinical Analysis RLP
Pharmacokinetics of RLP
Drug Release
Physiochemical Character of RLP Formulation
Composition of RLP
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22. Character of RLD ProductsCharacter of RLD Products
Batch No, Expiry date
Strength (Label), Average weight (mg)
Length (mm) , Width (mm)
Thickness (mm), Volume
Hardness (kP) , Disintegration time
Dissolution
SEM
Assay, % w/w of labeled amount
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23. QbD- dissolution testQbD- dissolution test
Nature of dissolution test method
Temperature of test medium, Apparatus,
speed/ flow rate, volume, sampling probe and
procedures need to be monitored periodically
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24. Possible differences Possible differences
Two pharmaceutical products
Reference ( Possible Differences ) Test
Is Dissolution Equivalent –Yes The 2 product are
equivalent
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25. COMPOSITION RLD COMPOSITION RLD
ER Coated beads
40 mg
Function Unit (mg) Unit (%)
X Drug
7 2.8
Povidone Binder
2 -4 0.8- 1.6
EC Coating Polymer
3 -5 1.2 -2
PEG Plasticizer
0.2 -0.8 0.08 -0.3
Sugar Sphere Substrate
18 -28 16
I R Granules
-210mg

Drug Drug
3 1.2
MCC Filler
100-140 40-56
Lactose Filler
40-70 16-28
SSG Disintegrants
10-20 4-8
Mg Stearate Lubricants
1.5-3.5 0.6-1.4
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26. STAGE 1 QbDSTAGE 1 QbD
Set The Formulation ObjectivesSet The Formulation Objectives
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27. Set the Formulation objectivesSet the Formulation objectives
Begin with end in mind
Patient centric approach
Prior knowledge on drug/excipients/process
Experience on production batches
Quality of target product profile
Critical quality attributes (CQA)
Limit, Ranges, Distribution, Specifications
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28. Stage 1: Target Objectives for QbD Stage 1: Target Objectives for QbD
Quality target
product profile
Target
Doasgeform Extended Release
Administration Oral
Pharmacokinetics Cmax, tmax, AUC , Ka, Ke, F(rel),
F, BE, PE, CE
Stability 2 year
Formulation attributesAssay, Drug release, Release
kinetics, INIVC
Container, closure ,
Label
Ensure tablet integrity, shelf life
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29. Stage 1:Target Objectives for QbD -CQAStage 1:Target Objectives for QbD -CQA
QADP Target CQA
Appearance , OdorAcceptable No
Residual solventsConform to USP yes
Water content Less than 2% yes
Friability Less than 1% yes
Assay (label) 100 % yes
Microbial limit USP limit yes
Drug release Similar to RLD yes
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30. STAGE 2 QbDSTAGE 2 QbD
Prioritizing Input Variables for Prioritizing Input Variables for
Optimization Optimization
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31. Priority input variables for optimizationPriority input variables for optimization
Input / dependent variables identification
Materials attributes ( X1)
Process parameters (X2)
Critical Material attributes
Critical Process parameters
Preliminary Trials for factorial design

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32. Preliminary trial for factorial design Preliminary trial for factorial design
Ingredients
(mg)
F1 F2 F3 F4
Drug 7 07 7 7
Povidone 2 2.5 3.0 3.0
EC 3 3.5 4.0 4.5
PEG 0.2 0.4 0.6 0.8
Sugar Spheres 18 22 24 26
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33. STAGE 3 - QbDSTAGE 3 - QbD
Design Guided Experimentation and
Analysis
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34. Design Experiment MethodsDesign Experiment Methods
Response surface methodology
Full factorial
Fractional Factorial
Central composite
Box Behnken
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35. Design Experiment - ModelDesign Experiment - Model
Parameter Low Medium High
X -1 (MCC) -1 0 +1
X2 (Compression
Force)
-1 0 +1
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36. 33
22
Factorial Design – A modelFactorial Design – A model
CODE
X1 X2
F1 -1 -1
F2 -1 0
F3 -1 +1
F4 0 -1
F5 0 0
F6 0 +1
F7 +1 -1
F8 +1 0
F9 +1 +1
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37. STAGE 4STAGE 4
Modelization and ValidationModelization and Validation
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38. 4. Validation of QbD Methodology4. Validation of QbD Methodology
Modelization - apt Mathematical
model
2D, 3 D Response Variables
Identification of Optimum Batches
Formulation of optimized batch
Validation of optimized formulation
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39. STAGE 4STAGE 4

Scale up and Production
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40. Scale-up and ProductionScale-up and Production
Pilot production
Process parameters
Product Parameters
Evaluation
Scale – up and production
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41. Tablet Coating - QbDTablet Coating - QbD
Reason for the moisture Coating
Key Consideration for moisture control
Process and environment control
Packaging control
Excipients selection
Use of moisture barrier coating
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42. QbD – Film CoatingQbD – Film Coating
Core Tablets
Coating Formulation
Process
42
CQA

43. Core parametersCore parameters
Hardness
Friability – less than 0.5% after 300 rpm
Shape – normal concave
Size
Design – withstand mechanical stress, adhesion
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44. QbD – Coating Process ParameterQbD – Coating Process Parameter
Film Coating System Film Coating
Wight gain % 4
Pan Charge (Kg) 6.7
Inlet air volume (m
3
/h) 229
Tablet Bed Temperature
Spray rate(g/min) 50
Solid Content (%) 20
No of guns 1
Air pressure (bar) 2.5
Total Coating time (minutes) 46
Pan Speed (rpm) 14
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45. QbD in bioequivalent testing QbD in bioequivalent testing
Optimizing drug products
Cmax
Tmax
AUC
Onset time
Duration of action
MEC
MSC
Therapeutic window
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46. Additional QbDAdditional QbD
Bioequivalence Testing
Biological and Herbals
Stability Testing
Analytical method development
Dissolution testinng
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47. Summary Summary
QbD Coupled with Quality Risk
Management
Systematic approach product development
Understanding of Process and process
control
Quality cannot be tested
Design the product and process to meet
required quality
Regulatory flexibility, Big data
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48. ConclusionConclusion
QbD application complex
Critical material attributes is key issue
Federal agency look – patient centric
quality
Submissions based on QbD more scientific
approach
Quality cannot be tested into products, built
QbD
Win – Win situation
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49. QbDQbD
Prior Knowledge
Regulatory risk Mitigation
Security of supply
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50. REFERENCESREFERENCES
1. www.usfda.org
2. Conference n Harmonization (ICH) Q8(R2)
Pharmaceutical Development 2009.
3. Larence Yu. Process quality by design:
Product and process development
understanding and control: Pharmaceutical
Research. 25(4), 2008
50

51. References Cont..dReferences Cont..d
4.Lionberger R. Quality by design concept for
ANDA. The AAPS Journal. 2008.10(2)268-275
5.Shanthanu D. Pharma times 2014, 46(8) 13- 17.
6. Bhupinder Singh. QbD Holistic Pharma
Excellence and Regulatory Complinace. Pharma
Times 2014, 46(8)26-33.
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52. 52
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