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Quality by Designs
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
4. IntroductionIntroduction
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
4
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
7
8. Background and Merits ofBackground 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 DrugKnowledge 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. kineticKnowledge on Biopharmaceutics & P. kinetic
factorsfactors
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 MyriadKnowledge 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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21. PRE STAGE - QbDPRE 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
22
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
23
25. COMPOSITION RLDCOMPOSITION 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 QbDStage 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 attributes Assay, 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 , Odor Acceptable No
Residual solvents Conform 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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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
38
40. Scale-up and ProductionScale-up and Production
Pilot production
Process parameters
Product Parameters
Evaluation
Scale – up and production
40
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
44. QbD – Coating Process ParameterQbD – Coating Process Parameter
Film Coating System Film Coating
Wight gain % 4
Pan Charge (Kg) 6.7
Inlet air volume (m3
/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 44
45. QbD in bioequivalent testingQbD in bioequivalent testing
Optimizing drug products
Cmax
Tmax
AUC
Onset time
Duration of action
MEC
MSC
Therapeutic window
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47. SummarySummary
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 47
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 48
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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