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