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Gero Hooff
Merck KGaA
Concept for early Drug Product Development
StreamlinedEarly DP Development
Formulation Development
Formulation concept for early Development
Reality
Outline
DP Development considerationsTarget Product Profile (TPP)
API & TPPPhys-chem Drug Load
Stability
Solubility
PSD
Flow
Morphology, etc……
low and high Drug Load
formulations
Type of formulation
=
increasing evelopment
efforts
The Suspect
The Development guy
short timelines
strategy changes
uncertain dose ranges
changing DS characteristics
API and/or budget limitations
…etc
„Yeah right, just be quick and supply and
sufficient quantities and in the right
quality“
FormulationDevelopment
fit for purpose
fit for demand
fit for commercial
Fast Track Medication
Interim Drug Product
Intended Final Formulation
PhI
PhII
PhIII
Development
efforts
High Shear
Core granulation Technologiesin Development space
SinglePot
Dry Granulation
/ Roller Compaction
Wet Granulation/ Fluid Bed
past
present
futureTwin Srew
Roller compaction@ Merck Darmstadt
Commercial
past future
Development and Pilot plant dry
granulation
Feeding
Compaction
Sieving
Agitator, feed and tamp auger to deliver consistent material flow
Roller compactionThe Process
The Why No liquid/water addition, continuous & well scalable process, formation of intermediate in single operational step
The How
Two compaction rolls (different surfaces available) to deliver compressed intermediate (ribbon)
Gap and force control to deliver consistent intermediate quality
Oscillating rotor and sieve (different types available, resp.) to deliver granules for inner phase
Development
PAT
PSD &
granule
hardness
Tableting
Compression
modeling/analysis
Granulationrelated instrumentation in development
DP DevelopmentGetting to work……..quickly
The Suspect
ONE Mitigation Drug Load Limits, focused technologies and selected excipients
The Development guy
The Instrumentation
10
DP DevelopmentStreamlining formulation development
ONE fits all
Simple work
Novel approach
…BUT
Simple compositions (number of excipients)
with limited Drug Load (15-20%)
Specifically selected excipients (characterization, manufacturability, robustness, pre-screening,
qualification status)
Focus on key process parameters
Early understanding of formulation in combination with applied technology (QbD)
11
Platform formulations
filler evaluation
work hardening effect of MCC
dry binder
Disintegrants
External phase
Model API: caffeine
Tabletting → EK0
Compactability, compressibility, bondability
Disintegration
Systematic selection leading to a single final formulation followed by proof of concept on larger scale (@ Merck)
Pre-tests for MCC concentration and fillers
API effect (various compounds)
Large(r) scale evaluation
Flowability testing
Transfer Styl’One to EK0/IMA/Fette102i
API: caffeine + 3 internal compounds
Specified large-scale trials (IMA; Fette)
Compactability, compressibility, bondability
Disintegration
Evaluation of various excipients providing different rollercompaction prototypes for PhI/II
Collaboration with…
Merck
Definition of MiPa instrument set-up and parameters
[%]
Caffeine 21,25
Di-CAFOS D160 73,75
Kollidon VA64 fine 2,5
Kollidon CL-F 2,5
Pocketed rotor Star rotor
Use of «coarse granules»
(10 kg)
Roller compactionKey observations for development concept
Feeding
Compaction
Sieving
vs
Aerosil addition typically redundant with Gerteis feedingEarlier Development
candidate with 50% Drug
Load (poorly flowable API)
transfer to MiPa
Formulation screening with standard
excipients and 15-20% Drug LoadCompaction pressures below 3 kN and above 10-
12 kN not preferred
Less fines while allowing
high throughput with star
rotor (w/ square wired
sieve)
Feeding
Compaction
Sieving
• Batch size: ~0.5 – 35 kg
• Compaction rolls: smooth/smooth (or knurled)
• Gap: 3 mm (Prio 2)
• Roll speed: 3 rpm (Prio 3)
• Compaction force: 4 – 8 kN/cm (Prio 1)
• Rotor: Star
• Speed: 80/80 (CW/CCW)
• Rotation angel: 480/360 (CW/CCW)
• Sieve: 1.00 - 1.25 mm (squared)
• Granulator–sieve distance: ≤ mesh size
Roller compactionDefinition of standard parameters for initial DP development
Gerteis MiniPactor
Subsequent tableting on single punch press
or rotary press (selected prototypes)
14
Plattformformulation developmentAPI Selection
15
API
Caffeine anhydrous
fine powder
Filler Filler Lubricant*
Magnesium
stearate
15.0% 85.0% GranuLac® 200 0.5%
15.0% 85.0% Avicel® PH-102 0.5%
15.0% 85.0% Pearlitol® 50 C 0.5%
15.0% 85.0% DI-CAFOSA 60 0.5%
15.0% 85.0% galenIQ™ 801 0.5%
15.0% 85.0% Avicel® PH-105 0.5%
Plattformformulation developmentExcipients Selection
*added for tabletting, not present during roll compaction
Exemplified for filler selection
- Friability of granules
- Compactibility (Tensile strength vs Compression pressure; next slide)
- Compressibility (Ejected solid fraction vs Compression pressure)
- Bondability (Tensile strength vs Ejected solid fraction)
- Disintegration
Investigation by means of
…by courtesy of
85% DI-CAFOS A 60
4 kN/cm 8 kN/cm
85% galenIQ® 801
4 kN/cm 8 kN/cm
85% GranuLac® 200
4 kN/cm 8 kN/cm
85% Pearlitol® 50 C
4 kN/cm 8 kN/cm
85% Avicel® PH-105
4 kN/cm 8 kN/cm
85% Avicel® PH-102
4 kN/cm 8 kN/cm
0.0
2.0
4.0
6.0
0 50 100 150
Compression pressure (upper punch) [MPa]
200
Te
nsile
str
en
gth
[N/m
m²]
12 kN/cm 16 kN/cm
0.0
2.0
4.0
6.0
0 50 100 150
Compression pressure (upper punch) [MPa]
200
Te
nsile
str
en
gth
[N/m
m²]
12 kN/cm 16 kN/cm
0.0
2.0
4.0
6.0
0 50 100 150
Compression pressure (upper punch) [MPa]
200
Te
nsile
str
en
gth
[N/m
m²]
12 kN/cm 16 kN/cm
0.0
2.0
4.0
6.0
0 50 100 150
Compression pressure (upper punch) [MPa]
200
Te
nsile
str
en
gth
[N/m
m²]
12 kN/cm 16 kN/cm
0.0
2.0
4.0
6.0
0 50 100 150
Compression pressure (upper punch) [MPa]
200
Te
nsile
str
en
gth
[N/m
m²]
12 kN/cm 16 kN/cm
0.0
2.0
4.0
6.0
0 50 100 150
Compression pressure (upper punch) [MPa]
200
Te
nsile
str
en
gth
[N/m
m²]
12 kN/cm 16 kN/cm
16
• DI-CAFOS A 60 is too low in the resulting tensile strength
• GranuLac® 200 and galenIQ®
801 provide best results• galenIQ® shows some work
hardening, but overall harder tablets
• Avicel® PH-102 and PH-105show distinct work hardeningeffects
Filler Selectioncompactibility
…by courtesy of
17
Excipients [%]
API 15
Granulac 200 69.5
Kollidon CL-M 5
Kollidon VA 64 fine 5
Kollidon CL-SF 5
Mg-Stearat 0.5
Excipients [%]
API 15
Granulac 200 28
MCC Type 101 56
Mg-Stearat 1
• CL-M provides some disintegration power
• Disintegration is much quicker for CL-M than for VA 64 fine
• External phase: 5% VA 64 fine and CL-SF provide high tablet strength and good disintegration → 2.5% provides faster disintegration times
PlattformformulationsFurther experiments and Exemplified prototypes
- MCC titration (work hardening)
- Dry binder
- Disintegrants
- External phase
- API Impact
- Scale-up
- Flowability
Further Investigations
- Selected APIs show moderate impact on Granule properties
- 0.5% Mg-Stearat in inner phase for less friction on rolls if necessary
- Disintegrant if necessary in external phase, API-dependent
- Good (flexible) selection of compositions to deal with different APIs (compatibility)
Observations Examples
18
Plattformformulationsflowability of formulations on rotary tablet press
ParameterCaffeine +
Ludipress®*
Caffeine in
Formulation 1
Cpd A
in formulation 1
Caffeine
in formulation 2
Cpd A
In formulation 2
Tableting speed
*1000/ h30 90 30 30 60 90 30 60 90 30 60
Srel
Compression force2-4 2-4 3-5 3-4 3-4 3-4 4-6 4-6 4-6 4-6 6-8
Tablet weight [mg]1000.6 ±
0.7%
993 ±
0.6%1026.8 ± 1.1%
1007.1
± 0.6%
998.4 ±
0.8%
972.7 ±
2.2%
999.7 ±
1.0%
941.9 ±
1.6%
932.5 ±
1.1%
1014.1 ±
0.9%
1002.8 ±
0.9%
Hardness [N]147 ±
4.0%
140 ±
4.6%143 ± 16.6%
205 ±
5.2%
182 ±
4.5%
143 ±
17.8%
148 ±
9.3%
139 ±
17.6%
128 ±
18.4%129 ± 7.4%
121 ±
10.6%
Fette 102i: DC RC
*Lactose, Kollidon® 30 and Kollidon® CL
• DoE for Dry Granulation
• Concept screening ongoing for Fluid Bed and Twin Screw granulation
• Selected formulations currently applied for two pipeline projects
• Project A: 1 % Drug Load
• Project B: different Roller Compactor → modification of instrument settings necessary
Plattformformulations
Acknowledgements
Thankyou
Thorsten Cech
Rainer Dobrawa
Florian Bang
Thorsten Agnese
Monika Haberecht
Verena Geiselhart
Merck
Magdalena Münster
& PharmTech Team
Carsten Schmidt
Matthias Fischbach
Corinna Schoch