It’s honor to get invited as a speaker and to address “Pharma Formulation and Regulatory Symposium” organized by Merck Malaysia on 6th Sept, 2018 at Pullman Bangsar, Kuala Lumpur, Malaysia. The topic I presented was “Generic Product Development and Technology Transfer: At a Glance”. Scientists and industry experts from 31 Malaysia Pharma companies and Universities attended this symposium. The presentation covered challenges and remedies come across from product development to approval from regulatory agencies. Pleasured to share desk with Dr. Torsten Schadendorf, Marketing Manager Merck Germany, Dr. Gudrun Birk, Head of Controlled Release, Merck Germany and Professor Tin Wui Wong, Universiti Teknologi MARA, Malaysia.

1. Generic Product Development and
Technology Transfer : At a Glance
Girish Sonar, M. Pharm, PhD
Novugen Pharma (Malaysia) Sdn. Bhd.
Shah Alam, Selangor, Malaysia
Email: girish.sonar@novugen.com
Pharma Formulation & Regulatory Symposium
Sept 06, 2018, Kuala Lumpur, Malaysia

2. Generic Product Development and Technology Transfer : At a Glance
Generic product life cycle
2

3. Generic Product Development and Technology Transfer : At a Glance3
Challenges & Remedies
# Challenges Remedies
1. Difficult-to-develop product Reverse Engineering /Deformulation,
QbD approach
2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API
3. Reproducibility results CCP study
4. Early stability confidence Short term stability indicative study,
Pack characterization
5. Bio study Thorough literature search
Right study design
6. Scale-up Scale-up factor implementation,
QbD approach
7. Regulatory agency’s queries Understand requirement and start practicing

4. Generic Product Development and Technology Transfer : At a Glance4
Challenges & Remedies
# Challenges Remedies
1. Difficult-to-develop product Reverse Engineering /Deformulation,
QbD approach
2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API
3. Reproducibility results CCP study
4. Early stability confidence Short term stability indicative study,
Pack characterization
5. Bio study Thorough literature search
Right study design
6. Scale-up Scale-up factor implementation,
QbD approach
7. Regulatory agency’s queries Understand requirement and start practicing

5. Generic Product Development and Technology Transfer : At a Glance
Scope of reverse engineering:
o API particle size determination from reference product
o Pellet layer thickness determination
o Polymorph identification
o Quantitative estimation of excipients
o Polymer grade & ratio determination
5
Reverse Engineering

6. Generic Product Development and Technology Transfer : At a Glance6
API particle size determination from FP
SiO2 Particles
API used in in-house productAPI particle size from reference product tablets
Confidential

7. Generic Product Development and Technology Transfer : At a Glance7
Pellets layer thickness determination
-100
100
300
500
0 10 20 30 40 50
Size(µm)
Size count
Layer 1 (µm)
Layer 2 (µm)
Layer 3 (µm)
Sphere size (µm)
Parameter Layer-1 Layer-2 Layer-3 Sphere size
Average size (µm) 49 22 88 292
Min size(µm) 32 15 78 240
Max size(µm) 62 29 95 374
Confidential

8. Generic Product Development and Technology Transfer : At a Glance8
Polymorph identification
Confidential

9. Generic Product Development and Technology Transfer : At a Glance9
Quantitative estimation of excipients
Category Excipient How to determine?
Diluents
Lactose Innovator disclose quantity in SmPC/PAR
MCC Water insoluble matter, Chemical method
Mannitol Chemical method
Dicalcium phosphate Calcium content by flame photometry
Binder
HMPC Chromatographic method
HPC Chromatographic method
PVP Chemical method
Copovidone Chemical method
Disintegrant
Sodium starch glycollate Sodium content by flame photometry
Croscarmellose sodium Sodium content by flame photometry
Wetting agent
Sodium lauryl sulphate UV spectroscopy
Polysorbate 80 Chemical method
Confidential

10. Generic Product Development and Technology Transfer : At a Glance10
What is QbD?
o Systematic and proactive approach to pharmaceutical development
o Begins with predefined objectives
o Emphasizes product and process understanding and process control
o Based on sound science and quality risk management

11. Generic Product Development and Technology Transfer : At a Glance11
Why QbD?
o Ensure higher level of assurance of product quality for patient
• Improved product and process design & understanding
• Monitoring, tracking, trending of product & process
o More efficient regulatory oversight
o Encouraged continuous manufacturing process improvements
o Real-time quality control and reduced end-product release testing
o Fewer lost batches
o Fewer manufacturing deviations, saving costly investigative hours
o Reduced out-of-specification results, reducing rework
o Reduce post approval changes/Variations

12. Generic Product Development and Technology Transfer : At a Glance12
QbD Program
QTPP CQA Risk
Mitigation
Design Space
Quality Risk ManagementControl Strategy
INITIAL Risk Assessment
Drug Substance
Formulation variables
Process
Packing
UPDATED Risk Assessment
Drug Substance
Formulation variables
Process
Packing

13. Generic Product Development and Technology Transfer : At a Glance13
QbD examples
December 2011
April 2012

14. Generic Product Development and Technology Transfer : At a Glance14
QbD Software
QbD-Expert™ Software

15. Generic Product Development and Technology Transfer : At a Glance15
Systematic QbD flow in product development

16. Generic Product Development and Technology Transfer : At a Glance16
Challenges & Remedies
# Challenges Remedies
1. Difficult-to-develop product Reverse Engineering /Deformulation,
QbD approach
2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API
3. Reproducibility results CCP study
4. Early stability confidence Short term stability indicative study,
Pack characterization
5. Bio study Thorough literature search
Right study design
6. Scale-up Scale-up factor implementation,
QbD approach
7. Regulatory agency’s queries Understand requirement and start practicing

17. Generic Product Development and Technology Transfer : At a Glance
Category : Overactive bladder
Dosage form : Extended-release tablets
BCS : III
Dissolution media (QC) : USP I/900mL pH 6.8 Phosphate buffer/100 rpm
Tmax : 3 - 4 hrs
17
Case study

18. Generic Product Development and Technology Transfer : At a Glance18
Multimedia dissolution of Product ‘X’
USP I/900 mL pH 6.8 Phosphate buffer/ 100 rpm
Time
Reference
Product
Test
Product 1
Test
Product 2
Mean (%)
1 h 8 8 10
3 h 32 29 31
5 h 59 52 53
7 h 83 75 80
8.5 h 94 89 88
10 h 97 101 99
12 h 97 102 101
F2 - 64 70
USP I/900 mL pH 4.5 Acetate buffer/ 100 rpm
Time
Reference
Product
Test
Product 1
Test
Product 2
Mean (%)
1 h 14 15 16
3 h 41 42 44
5 h 70 69 67
7 h 92 94 93
8.5 h 99 99 100
10 h 100 101 101
12 h 100 102 100
F2 - 89 83
USP I/900 mL 0.1 N HCl/ 100 rpm
Time
Reference
Product
Test
Product 1
Test
Product 2
Mean (%)
1 h 22 22 20
3 h 59 55 54
5 h 88 85 84
7 h 101 99 98
8.5 h 102 101 100
10 h 100 100 101
12 h 99 100 101
F2 - 82 75
Confidential

19. Generic Product Development and Technology Transfer : At a Glance19
Bio results
0.0
5.0
10.0
15.0
20.0
25.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Concentration(ng/mL)
Time (h)
Mean Plasma Concentration Vs Time Profile
Mean Plasma Concentration Test_(T1)
Mean Plasma Concentration Reference_(T2)
Mean Plasma Concentration Reference_(R)
Study design : 3-way crossover,
Fasted
N = 18

20. Generic Product Development and Technology Transfer : At a Glance20
Human GIT & biorelevant dissolution medias
Physiology of the GI tract of healthy humans in FASTED state pH-gradient preprandial
Segment of GI tract Transit time (h) pH Biorelevant media pH
Stomach 1-2 1.5-1.9 FaSSGIF 1.6
Duodenum
3.6
6.5 FaSSIF-V2 6.5
Jejunum 6.8 Half-FaSSIF 7.0
Ileum 7.2 FaSSIF-sans 7.5
Colon 7-20 6.5 SCoF 5.8
Physiology of the GI tract of healthy humans in FED state pH gradient postprandial
Segment of GI tract Transit time (h) pH Biorelevant media pH
Stomach 1.4-4.0 3-7 FeSSGF 5.0
Duodenum
3.8
5.1-5.4 FeSSIF-V2 5.8
Jejunum 5.2-6.0 Half-FeSSIF 6.5
Ileum 7.5 FeSSIF-sans 7.5
Colon - 5.0 SCoF 5.8

21. Generic Product Development and Technology Transfer : At a Glance21
Dissolution in Bio-relevant media
Time
Reference
Product
Test
Product 1
Test
Product 2
USP I/ 900 mL FaSSGF (pH 1.6)/ 75 rpm/2 h
1 h 17 26 15
2 h 30 43 28
USP I/ 900 mL FaSSIF (pH 6.5)/ 75 rpm/12 h
3 h 47 60 44
4 h 58 71 53
5 h 69 81 64
6 h 77 91 75
7 h 86 100 88
8 h 97 101 101
10 h 100 100 99
12 h 103 102 100
The closer the dissolution test conditions to the physiology,
the better the chances of predicting in vivo performance.
Confidential

22. Generic Product Development and Technology Transfer : At a Glance22
Challenges & Remedies
# Challenges Remedies
1. Difficult-to-develop product Reverse Engineering /Deformulation,
QbD approach
2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API
3. Reproducibility results CPP study
4. Early stability confidence Short term stability indicative study,
Pack characterization
5. Bio study Thorough literature search
Right study design
6. Scale-up Scale-up factor implementation,
QbD approach
7. Regulatory agency’s queries Understand requirement and start practicing

23. Generic Product Development and Technology Transfer : At a Glance23
CPP study (1)
Process variables involve in WET GRANULATION based manufacturing process
Steps Granulation Drying Sizing and Milling
Blending and
Lubrication
CPP
HS Granulation
o Impeller speed
o Chopper speed
o Binder addition time
o Granulation time
o Wet milling
Fluid Bed Granulation
o Spray rate
o atomization air
pressure
o Air flow
o Product temperature
o Granulation time
o Product
temperature
o Air flow
o LOD
o Type of screens
(Plain/Grater)
o Screen size
o Mill speed
o Blending time
o Lubrication time
o Blender type

24. Generic Product Development and Technology Transfer : At a Glance24
CPP study (2)
Process variables involve in ROLLER COMPACTION based manufacturing process
Steps Granulation Sizing
CPP
1. Type of roller
2. Compaction force
3. Roller gap
4. Roller speed
5. Feed speed
1. Type of screens (Plain/Grater)
2. Screen size
3. Mill speed

25. Generic Product Development and Technology Transfer : At a Glance25
CPP study (3)
Process variables involve in MUPS TABLETS manufacturing process
Steps Pellets coating Compression
CPP
o Air flow rate
o Spray rate
o Atomization air pressure
o Product temperature
o Dew point
o Curing temperature and time
o Pre-compression force
o Main compression force
o Feeder speed
o Turret speed
o Feed frame design
o Tooling design

26. Generic Product Development and Technology Transfer : At a Glance26
Challenges & Remedies
# Challenges Remedies
1. Difficult-to-develop product Reverse Engineering /Deformulation,
QbD approach
2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API
3. Reproducibility results CCP study
4. Early stability confidence Short term stability indicative study,
Pack characterization
5. Bio study Thorough literature search
Right study design
6. Scale-up Scale-up factor implementation,
QbD approach
7. Regulatory agency’s queries Understand requirement and start practicing

27. Generic Product Development and Technology Transfer : At a Glance27
Case
40°C/75% RH –
6 months
RS test failure
1 FD of FP
Oxidation
sensitive API
Use oxygen
scavenger
2
Open
exposure at
75% RH – 1W
Moisture
sensitive API
Protective
pack

28. Generic Product Development and Technology Transfer : At a Glance28
Challenges & Remedies
# Challenges Remedies
1. Difficult-to-develop product Reverse Engineering /Deformulation,
QbD approach
2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API
3. Reproducibility results CCP study
4. Early stability confidence Short term stability indicative study,
Pack characterization
5. Bio study Thorough literature search
Right study design
6. Scale-up Scale-up factor implementation,
QbD approach
7. Regulatory agency’s queries Understand requirement and start practicing

29. Generic Product Development and Technology Transfer : At a Glance29
Case Study
Reference Product : Amlodipine / Valsartan 10 mg/160 mg (Exforge®)
Strengths : 10 mg/ 160 mg, 5 mg/160 mg, 5 mg/80 mg
Linearity : Amlodipine and valsartan exhibit linear
pharmacokinetics
Tmax : Valsartan : 3 hrs, Amlodipine : 6-8 hrs
Absolute bioavailability : Valsartan : 23%, Amlodipine : 64 to 80%
Elimination half-life : Valsartan : 6 hrs, Amlodipine : 30 to 50 hrs
Confidential

30. Generic Product Development and Technology Transfer : At a Glance30
Generic 1 / Winthrop Pharma UK (Zentiva)
Reference Product : Amlodipine / Valsartan 10 mg/160 mg (Exforge®)
Analyst : Valsartan
Reference : Public assessment report, MHRA, UK/H/5856-7/001-3/DC
Confidential
Confidential

31. Generic Product Development and Technology Transfer : At a Glance31
Generic 2/ Apotex Europe B.V.
Reference Product : Amlodipine / Valsartan 10 mg/160 mg, (Exforge®)
Analyst : Valsartan
Reference : Public assessment report, NL/H/3447/001-003/DC, 13 January 2017
Confidential
Confidential

32. Generic Product Development and Technology Transfer : At a Glance32
Generic 3/ Mylan
Reference Product : Amlodipine / Valsartan 10 mg/160 mg, (Exforge®)
Analyst : Valsartan
Reference : Assessment report, EMA/CHMP/182030/2016, 28 January 2016
Confidential
Confidential

33. Generic Product Development and Technology Transfer : At a Glance33
Generic 4/ Genericon Pharma
Reference Product : Amlodipine / Valsartan 10 mg/160 mg, (Exforge®)
Analyst : Valsartan
Reference : Public assessment report, SE/H/1573/01-03/DC, LAKEMEDELSVERKET Medical Products Agency
Confidential
Confidential

34. Generic Product Development and Technology Transfer : At a Glance34
Challenges & Remedies
# Challenges Remedies
1. Difficult-to-develop product Reverse Engineering /Deformulation,
QbD approach
2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API
3. Reproducibility results CCP study
4. Early stability confidence Short term stability indicative study,
Pack characterization
5. Bio study Thorough literature search
Right study design
6. Scale-up Scale-up factor implementation,
QbD approach
7. Regulatory agency’s queries Understand requirement and start practicing

35. Generic Product Development and Technology Transfer : At a Glance35
Regulatory agencies expectations

36. Generic Product Development and Technology Transfer : At a Glance
Explanation
Development
batches
• Formula
optimization
• Process
optimization
(partial)
Scale-up
batches
• Process
optimization
(Scale
dependent
process)
Bio batches
• No
optimization
Commercial
batches
• No
optimization

37. Generic Product Development and Technology Transfer : At a Glance37
Process Optimization
Process optimization planned based on knowledge of –
1. Scale dependent equipment/Process parameter
2. Scale independent equipment/Process parameter
If R&D scale and commercial scale equipment 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.

38. Generic Product Development and Technology Transfer : At a Glance38
Process optimization – Study plan (1)
# Equipment Scalable process parameters Recommended Remark
1 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
2 HSG Impeller speed, Chopper
speed, Granulation time
Tip velocity : Low speed = 3.0-3.5m/sec,
High Speed = 6.0-7.0m/sec at the R&D scale and
commercial scale
Scale
independent
3 FBP
(Top Spray
granulation)
Spray rate, atomization air
pressure, air flow volume,
dew point
Calculate the scale up factor based on vendor’s
recommendation and apply for critical process
parameters
Scale
independent
4 Multimill Milling screen opening, mill speed
and direction
Screen size/impeller direction/ mill speed should
be same
Scale
independent
5 Co-mill screen opening, mill speed
and direction
Screen size/impeller direction/ mill speed should
be same. Apply scale factor as per vendor’s
recommendation
Scale
independent

39. Generic Product Development and Technology Transfer : At a Glance39
Process optimization – Study plan (2)
# Equipment Scalable process parameters Recommended Remark
6 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
7 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
8 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
9 Coating Spray rate, atomization air
pressure, product temp, gun
to bed distance, pan rpm
Optimize the process parameters wrt
coating machine at manufacturing site
Scale dependent

40. Generic Product Development and Technology Transfer : At a Glance40
Risk Management Tools
1. Basic risk management facilitation methods
(flowcharts, check sheets etc.)
2. Failure Mode Effects Analysis (FMEA)
3. Failure Mode, Effects and Criticality Analysis (FMECA)
4. Fault Tree Analysis (FTA)
5. Hazard Analysis and Critical Control Points (HACCP)
6. Hazard Operability Analysis (HAZOP)
7. Preliminary Hazard Analysis (PHA)
8. Risk ranking and filtering
9. Supporting statistical tools

41. Generic Product Development and Technology Transfer : At a Glance41
Basic Risk Management Facilitation Methods
1. Flowcharts;
2. Check Sheets;
3. Process Mapping; Cause and Effect Diagrams (Ishikawa diagram or fish bone diagram)

42. Generic Product Development and Technology Transfer : At a Glance42
Challenges & Remedies
# Challenges Remedies
1. Difficult-to-develop product Reverse Engineering /Deformulation,
QbD approach
2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API
3. Reproducibility results CCP study
4. Early stability confidence Short term stability indicative study,
Pack characterization
5. Bio study Thorough literature search
Right study design
6. Scale-up Scale-up factor implementation,
QbD approach
7. Regulatory agency’s queries Understand requirement and start practicing

43. Generic Product Development and Technology Transfer : At a Glance43
Frequently asked queries
Elemental
impurities
data
Discriminato
ry power of
dissolution
media
1. Implement QbD approach during product
development and technology transfer
2. Understand regulatory agencies interest
3. Extrapolated regulatory agencies expectation
to pipeline products
4. Implement requirements covered in new/
revised guideline
and so on …

44. Generic Product Development and Technology Transfer : At a Glance44
Conclusion
# Challenges Remedies
1. Difficult-to-develop product Reverse Engineering /Deformulation,
QbD approach
2. Bio predictive dissolution condition Study PK and Physicochemical parameters of API
3. Reproducibility results CCP study
4. Early stability confidence Short term stability indicative study,
Pack characterization
5. Bio study Thorough literature search
Right study design
6. Scale-up Scale-up factor implementation,
QbD approach
7. Regulatory agency’s queries Understand requirement and start practicing

45. Generic Product Development and Technology Transfer : At a Glance
Girish Sonar, M. Pharm, PhD
Manager – Generic formulation R&D
Novugen Pharma (Malaysia) Sdn. Bhd.
Shah Alam, Selangor, Malaysia.
Email : girish.sonar@novugen.com
Skype : girish.sonar1
LinkedIn : https://www.linkedin.com/in/girishsonar/
Questions?