1. QbD in PLCM Presented By: Mr. Girish Sonar,
Group Leader – R&D (Formulation),
Ipca Laboratories Ltd.,
Plot No. Plot 48, Kandivali (West), Mumbai, India.
Date :

2. Disclaimer
Any views or opinions expressed herein are solely those of the author and do not necessarily represent those of any company. This presentation is solely for educational purposes and provides only general expectations of regulatory agencies. For a complete requirements detail, please consult the relevant regulatory agency.

3. Content Introduction to QbD Misconception about QbD
Product Life Cycle – Flow diagram
Product Development Strategy
Initial batches
QbD Strategy I, II and III
Conclusion

4. Introduction to QbD
Systematic 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
Ref: ICH Q8

5. Benefits of QbD (1)
Ensure higher level of assurance of product quality for
patient
Improved product and process design & understanding
Monitoring, tracking, trending of product & process.
More efficient regulatory oversight
Rapid introduction of state-of-the art science and
technology
Encouraged continuous manufacturing process
improvements

6. Benefits of QbD (2)
Real-time quality control and reduced end-product release
testing
Fewer lost batches
Fewer manufacturing deviations, saving costly investigative
hours
Reduced out-of-specification results, reducing rework
Reduce post approval changes/Variations

7. Introduction to QbD
Misconception about QbD
Product Life Cycle – Flow diagram
Product Development Strategy
Initial batches
QbD Strategy I, II and III
Conclusion

8. Misconception about QbD (1)
DoE
Statistical technique used
in interpreting sets of experiments aimed at making sound decisions
DoE may be part of QbD
DoE is implemented using
statistical software program
QbD
Systemic development with predetermine objective for quality product
QbD contains DoE
No software used to
establish QbD
Conclusion : QbD and DoE are two different terminologies

9. Misconception about QbD (2)
Specifications
Includes all of the CQAs
Specification is a list of
- tests,
- references to analytical procedures
- acceptance criteria
Establishes the set of criteria to which DP should conform to be considered acceptable for its intended use
QTPP
Desired target for developmental work
Components of QTPP may or may not be in specification
Not in spec – Dosage form, strength
In spec – Assay, impurities
Does not include acceptance criteria
Conclusion : Defining a QTPP does not mean setting all acceptance criteria or the product specifications before development work begins

10. Misconception about QbD (3)
QbD based PDR is document mandatory for
regulatory submission and to make it for the sake to
fulfill the submission criteria
QbD is the USFDA requirement only
DoE is mandatory for QbD as mentioned in published
IR/MR product example

11. Introduction to QbD
Misconception about QbD
Product Life Cycle – Flow diagram
Product Development Strategy
Initial batches
QbD Strategy I, II and III
Conclusion

12. QbD Scheme PLCM – Flow Diagram Drug Substance Formulation Variables
Updated Risk Assessment
Initial Risk Assessment
Risk Mitigation
QTPP
CQA
Process
Packing
Design Space
Control Strategy
Quality Risk Management
PLCM –
Flow Diagram

13. Introduction to QbD
Misconception about QbD
Product Life Cycle – Flow diagram
Product Development Strategy
Initial batches
QbD Strategy I, II and III
Conclusion

14. Product Development Strategy

15. Introduction to QbD
Misconception about QbD
Product Life Cycle – Flow diagram
Product Development Strategy
Initial batches
QbD Strategy I, II and III
Conclusion

16. Initial Development Batches

17. Introduction to QbD
Misconception about QbD
Product Life Cycle – Flow diagram
Product Development Strategy
Initial batches
QbD Strategy I, II and III
Conclusion

18. QbD Stage I Strategy
Case Study

19. Development Batches

20. Formula Optimization

21. Process Optimization

22. Process Optimization

23. Process Optimization
Process optimization planned based on knowledge of –
Scale dependent equipment/Process parameter
Scale independent equipment/Process parameter
If R&D scale and commercial scale equipments have same mechanism, same geometry and scalable based on scientific basis, then process optimization batches can be perform in R&D scale equipment. If not, then process optimization batches will be performed in commercial scale equipment.

24. Process Optimization – Wurster
Scale  independent

25. Process Optimization - Wurster
Steps
Formulation Variables
Process Variables
PELLETS AND MUPS
Drug Loading/ Barrier Coating/ Functional Coating/ Over Coating
NPS – Composition, Size, Shape, Density and Porosity
Polymer qty
Plasticizer qty
Antitacking anent/wetting agent Qty
Pellets Coating
Air flow rate
Spray rate
Atomization air pressure
Product temperature
Dew point
Curing temperature and time
MUPS Compression
Pre-compression force
Main compression force
Feeder speed
Turret speed
Feed frame design
Tooling design

26. Process Optimization - Granulation
Steps
Formulation Variables
Process Variables
WET GRANULATION
 Granulation
Binder Qty
Water/Solvent Qty
Diluent/Superdisintegrant/
Polymer/ Wetting agent Qty …..
RMG Granulation
Impeller speed
Chopper speed
Binder addition time
Granulation time
Wet milling
Fluid Bed Granulation
Spray rate
atomization air pressure
Air flow
Product temperature
Drying
LOD

27. Process Optimization - Granulation
Steps
Formulation Variables
Process Variables
WET GRANULATION
Sizing and Milling
Type of mill (Multimill/Co-mill)
Type of screens (Plain/Grater)
Screen size
Mill speed
Blending and Lubrication
Superdisintegrant/Polymer Qty
Glidant/Antiadhering agent/Lubricant qty
Blending time
Lubrication time
Blender type

28. Process Optimization - Granulation
Steps
Formulation Variables
Process Variables
ROLLER COMPACTION
 Granulation
Dry Binder Qty
Diluent/Superdisintegrant/Polymer/ Wetting agent Qty
Type of roller
Compaction force
Roller gap
Roller speed
Feed speed
Sizing and Milling
Type of mill (Multimill/Co-mill)
Type of screens (Plain/Grater)
Screen size
Mill speed

29. Process Optimization – Study Plan (1)
Equipment
Scalable process parameters
Recommended
Remark
Wurster (Bottom spray)
Spray rate, atomization air pressure, air flow volume, dew point
ADP area is considered to calculate the scale up factor and apply to all critical process parameter except dew point and product temp
Scale independent
RMG
Impeller speed , Chopper speed, Granulation time
Tip velocity : Low speed = m/Sec,
High Speed = m/Sec at the R&D scale and commercial scale
FBP (Top Spray granulation)
Calculate the scale up factor based on vendor’s recommendation and apply for critical process parameters
Multimill Milling
screen opening, mill speed and direction
Screen size/impeller direction/ mill speed should be same
Co- mill
Screen size/impeller direction/ mill speed should be same. Apply scale factor as per vendor’s recommendation

30. Process Optimization – Study Plan (2)
Equipment
Scalable process parameters
Recommended
Remark
Blender
No of revolutions, Blender geometry
Blending : 300 ± 10 revolutions,
Lubrication: 50 ± 5 revolutions.
Calculate the blender rpm and time based on Froude no calculation.
Scale independent
Roller Compaction
Roller speed, roller gap, compaction force, milling parameters
Scaling up factor varies from mechanism of roller compaction and follow vendor’s guideline for scale-up
Scale independent most of the time
Compression machine
Turret speed, feeder speed, pre-compression force, main compression force, dwell time
Optimize the process parameters wrt compression machine at manufacturing site
Scale dependent
Coating
Spray rate, atomization air pressure, product temp, gun to bed distance, pan rpm
Optimize the process parameters wrt coating machine at manufacturing site

31. QbD Stage II Strategy

32. QbD Stage II Strategy
QbD II strategy = Updated risk assessment with justification based on development batches results

33. Quality Risk Management

34. Quality Risk Management
Ref: ICH Q9

35. Risk Management Tools
Basic risk management facilitation methods (flowcharts, check sheets etc.)
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
Ref: ICH Q9

36. Basic Risk Management Facilitation Method
Flowcharts;
Check Sheets;
Process Mapping; Cause and Effect Diagrams
(also called an Ishikawa diagram or fish bone diagram)

37. FMEA – Case Study (1) Risk Assessment Risk Reduction Source
Failure mode
Effect
Severity
Cause
Occurrence
Current Controls
Delectability
RPN
Action Plan
Document reference
Remark
Granulation
Dry mixing speed slow
May not meet the specifications for Blend uniformity, content uniformity and Drug release 7
Mixing speed of agitator not within acceptable range (50±5RPM) 4
Instruction for standard mixing speed and time given in the BMR
112
Four eye principle, Documentation for the same in BMR with signature. 1
BMR Instructions in granulation section.
Risk reduced.
Dry mixing Time
Mixing time less than or more than 5min
Time of Binder addition
Not meet the physical parameters of the Blend and Blend uniformity 10
Binder added less than 1min or more than 2min
Instruction for standard binder addition time given in the BMR
280 28
RPN : Risk Priority Number

38. FMEA – Case Study (2) Risk Assessment Risk Reduction Source
Failure mode
Effect
Severity
Cause
Occurrence
Current Controls
Delectability
RPN
Action Plan
Document reference
Remark
Granulation
Speed of agitator
Not meet the physical parameters of the Blend and Blend uniformity 7
Speed of agitator not maintain slow (50±5RPM) 4
Instruction for standard binder addition time given in the BMR.
112
Four eye principle, Documentation for the same in BMR with signature. 1
BMR Instructions in granulation section.
Risk reduced.
Use of Chopper (not to be use) 10
Chopper started.
Instruction for not using Chopper is given in BMR.
280 16
Max
Average
Min
180 28 11 04

39. QbD Stage III Strategy

40. QbD Stage III Strategy QbD III Strategy = Control Strategy
Control strategy should be discussed with manufacturing
person before finalize for the best results
All critical attributes control should be mentioned clearly
in control strategy and mentioned the name of reporting
documents

41. Post submission Phase
Easy to perform based on QbD based Dossier contains evaluated critical attributes

42. Introduction to QbD
Misconception about QbD
Product Life Cycle – Flow diagram
Product Development Strategy
Initial batches
QbD Strategy I, II and III
Conclusion

43. Conclusion QbD is the effective tool, should be implement from
the initial stage of the product development independent of
target market
Discuss QbD scheme with other groups and stake
holder to achieve aim of QbD and keep future projection to
avoid regulatory queries and post approval changes/Variation
DoE is not mandatory for QbD based submission
Try to cover maximum range of formulation and process
variables during optimization study to make fastest and
cost effective post approval changes/Variation

44. Girish Sonar Group Leader – R&D (Formulation) Ipca Laboratories Ltd.
Plot No. Plot 48, Kandivali Industrial Estate,
Kandivali (West), Mumbai , India.