scale-up of tablet manufacturing - · pdf filescale-up of tablet manufacturing jari pajander,...

Scale-up of Tablet Manufacturing

Jari Pajander, PhD Senior Research Scientist

Mobile Course on QbD and PAT

February 3rd 2015 University of Eastern Finland, Kuopio, Finland

3rd Feb 2015 Scale-up of Tablet Manufacturing

Outline

1. Background

2. Introduction to Scale-up

3. Typical Manufacturing Scheme

4. Mixing

5. Tableting

6. Conclusions

Scale-up of Tablet Manufacturing 3rd Feb 2015

• A world leader since 1923 • in diabetes care

• in insulin

• in injection devices

• Also leading positions in: • Haemostasis Management

• Growth Hormone Therapy

• Hormone Replacement Therapy (HRT)

Novo Nordisk at a Glance

Novo Nordisk R&D competencies

Background - Clinical Trials

Preclinical testing

• Testing in non-human subjects • In vitro and in vivo

• Efficacy

• Toxicity

• Pharmacokinetic parameters


Preclinical Phase 0 Phase I Phase II Phase III Phase IV

Global Research Chemistry, Manufacturing and Control (CMC)

Research Development Commercialisation

Background – Preclinical

• Early development aiming for proof of concept

• Lead Active Pharmaceutical Ingredient (API)

• Efficacy in vitro and in vivo

• Pharmacokinetic parameters

• Formulation

• New formulation concepts for the lead compound

• How to deliver the API to the site of action


Background – Preclinical in Practice

• Very small batches of API • Varying typically from 100 mg to 300 mg

• Formulations

• No considerations for scale up properties due to proof of concept principle • Often slow and unpractical formulations

• Mixing by hand • Poorly flowing powder blends • Complicated dosage forms, e.g. triple layer tablets and multiple coatings

• Actual tablet batches can vary between 15 to 200 tablets


Clinical trials

• Confirmation of safety and efficacy

• Therapeutic dose

• Phase I to III n of subjects = 10 - 10 000

• Increased demands for tablet manufacturing

• Final goal is the tablet production for the market


Preclinical Phase 0 Phase I Phase II Phase III Phase IV

Global Research Chemistry, Manufacturing and Control (CMC)

Research Development Commercialisation

Main Challenge of Scale-up

• Find the balance between how to increase production and maintain the properties of the solid dosage form

• The simpler the tablet design – the more probable is the robust scale up

• Problems can arise from sophisticated dosage forms


Scaling-up

• From regulatory point of view an increase by a factor of 10 times during each step is allowed

• If original batch was 100 tablets, then the next step could be 1 000 tablets

• Remember

• No changes are acceptable in the equipment design and operating principles, if they change the drug product

• Similar as possible but not necessarily the same formulation and manufacturing procedures

• In the case of changes bioequivalence studies might be required


Increase by Factor of 5 – an Example

• Batches are small in early development

• Coating is done for 30 tablets by mini coater

• Batch size increase by factor of 5 results in batch size of 150 tablets

• How to ensure that the coating is also increased by factor of 5?

• What about the next increase by factor of 10 yielding 1 500 tablets?


x 5 = or

When not to Scale-up?

• Properties of the dosage form are changed • If the product is not similar after the large scale

production, then there is something wrong with the scale-up

• If one of the process steps does not work on the small scale • The process step is already problematic the chances are

that it will not work on the large scale either

• If one process step is not upscalable • API production, etc.


Work Flow of Tablet Manufacturing

• Particle size reduction

• Particle size enlargement

• Granulation


Particle design

Mixing Tableting Coating

• Powders with powders

• Powders with granules

• Granules with granules

• Compaction

• Matrix tablets, double and triple layer tablets

• Flat faced, double convex, oblong tablets

• Non-functional coating

• Functional coating

• Multiple coatings

Problematic Areas of the Process Steps

• Polymorphism

• Degradation

• Loss of material


Particle design

Mixing Tableting Coating

• Powder transfer

• Powder handling

• Powder blend uniformity

• Granule disintegration

• Powder flowability

• Segregation

• Type of machine

• Compression profile

• Uneven or insufficient coating

• Sticking

• Too weak tablets

• Sedimentation of coating liquid

Mixing

Small scale

• Small amounts are handled • Varying from 60 mg to 200 g

• Powder transfer • By spatula or spoon

• Mixing • Geometric series

• By hand using mortar and pestle

• Small scale turbula mixing

Large scale

• Varying amounts of powder • From 10 to 500 000 g

• Powder transfer • Manual lifting

• Automatic handling

• Intermediate bulk container

• Stainless steel containers

• Drums

• Mixing • Planetary mixers

• Diffusion mixers

• Any SUPAC listed mixers


Powder transfer

• Small scale the amounts are typically very small

• Small risks for powder transfer

• Special care due to hygroscopicity

• In large scale the amounts of excipients can be up to 500 kg

• Great care has to be used in powder transfer

• API production is challenging and API thus expensive

• The whole batch of API is never transferred at once


Mixing

• Most often tumbling blenders are used in large scale • V-blender • Double-cone • BIN-blender

• Tumbling blenders are used due to • Large capacities • Low shear stresses • Ease of cleaning

• Variables during the mixing • Rotation speed • Time of mixing or number of revolutions • Filling rate


http://http://www.servo-lift.com A.W. Alexander and F.J. Muzzio in Pharmaceucical Process Scale-Up, ed. M. Levin, Informa Health Care, 2005

Mixing

• Froude number has been used in order to predict the scale-up of tumbling blenders

• Froude number up can be estimated by equation

• Ω = rotation rate (rpm)

• R = the vessel radius

• g = the acceleration of gravity


Fr =W2R

g

http://www.pms-group.net A.W. Alexander and F.J. Muzzio in Pharmaceucical Process Scale-Up, ed. M. Levin, Informa Health Care, 2005

http://www.pms-group.net/




Mixing

• Mixing setup for small scale • Rotation rate = 15 rpm (= 225 revolutions)

• Time = 15 min

• Aim is to scale up the volume of mixing for 5 times, what is the blending time? • Linear increase of the mixer’s radius is 51/3 = 71 %

• If R (vessel radius) is increased by 71 %, in order to keep Fr the same, Ω must be reduced with a factor 1.711/2 resulting 11.5 rpm

• In order to achieve the same amount of revolutions, the mixing time has to be increased to 19.5 min

• However, the mixing rpm is decreased


Fr =W2R

g

http://www.pms-group.net A.W. Alexander and F.J. Muzzio in Pharmaceucical Process Scale-Up, ed. M. Levin, Informa Health Care, 2005

Mixing – effect of rpm

• Decreased rpm affects to the powder surface velocity

• Slower powder surface velocity results less efficient mixing • Important especially in the case

of highly cohesive material

• If the mixing time is increased according to the Froude number, it might be not be long enough due to the less efficient mixing


T.A. Willemsz et al. AAPS Pharm Sci Tech 14, 2013:183-188

Uncertainties associated with scale-up of mixing

• Mixers with a similar geometry can be scaled up!

• In small scale, mixing is done by hand or turbula mixer

• In order to scale up, experiments has to be started from the scratch


≠ ≠

http://www.wab.ch/en/mischer/turbula.html http://http://www.servo-lift.com


• Filling rate influences to the mixing

• The higher the filling rate, the slower the particle velocity and less efficient mixing process


Brone et al. AIChe Journal 44, 1998:271-278 T.A. Willemsz et al. AAPS Pharm Sci Tech 14, 2013:183-188


• Filling rate is not directly scalable • The more powder is introduced, the less is the relative volume of

particles in the cascading layer compared with the bulk

• If volume of powder is increased by 5 times • Increase in the radius is 71 %

• If R = 10 cm, then A1 = 100 cm2 and A2 = (17.1 cm)2 = 292.41 cm2

• Increase in the mixing area is 292 % (≠ 500 %)

• Despite the increase in the mixing area, the depth of cascading layer is more or less the same

• Thus the relative volume of particles in the cascading layer compared to bulk is not the same



• Small scale mixing is affected by the cohesiveness

• Gravitational forces overcome the effect cohesiveness

• Setup for the small scale does not apply in the large scale due to the different gravitational forces


B. Chaudhuri et al. Powder Tech 165, 2006:105-114 A.W. Alexander and F.J. Muzzio in Pharmaceucical Process Scale-Up, ed. M. Levin, Informa Health Care, 2005

Conclusion - Mixing

• Froude number can be used to estimate the scale-up

• Even if the Froude number is kept as close as possible, one needs to pay attention to

• Mixer geometry

• Mixing rate

• Filling rate of the mixer

• In practice, scale up of mixing is done by trial and error


Tableting

Small scale

• Batch sizes from 15 to 300 tablets

• Powder is weighed by hand and poured into a die

• Batches of 100 tablets, a funnel can be used

• Single press tableting machine

• Rotary machine having only one pair of die and punches

Large scale

• Batch sizes from 50 to millions of tablets

• Rotary machine

• Increased production speed

• Powder can be force fed into the die


Tablet press

• To increase batch size and output of process, tablet instrument is changed from a single press into a rotary press


http://www.korsch.com

• 15 – 200 tbl/ min • One pair of punches • Fixed die • One sided

compaction • Hopper moves

• Up to 10 000 tbl/ min • 6 – 60 pair of

punches • Dies are attached to

a moving table • Double sided

compaction • Hopper fixed

Tableting – changes due to the tablet press

• The change from single press to rotary press affects to

• Powder feed rate

• Compression profile (one sided, double sided, pre-compression, profile shape)

• Compression time (dwell time)

• Tablet ejection speed and force

• Faster tableting sets more requirements for the powder properties

• Flowability

• Segregation

• Flowability and segregation both contribute to the quality of the end product, i.e. tablet


Tableting - Flowability

• Flowability is usually not an issue in small scale production

• Surprises can occur during scale-up

• Powder behavior can be divided in the following flow patterns


Mixed flow

Funnel flow

Mass flow

Arching

D. Schulze, Powder and Bulk Solids – Behavior, Characterization, Storage and Flow, Springer, Berlin, 2008

Tableting - Flowability

• Problems in powder flow • Arching

• Rat hole formation (funnel flow)

• Erratic flow is the summation of these two patterns

• Can be a severe problem in large scale • Higher pressure due to increased powder amount induces arching

• Outlet large enough to prevent the arch formation – not always possible

• Hopper walls are steep and smooth allowing the flow

• If funnel flow takes place during production, situation can be handled by cutting part of the process off


Tableting – Segregation

• Segregation takes place due to forces applied to the powder bed • Gravity • Vibration • Air flow

• Particle properties affecting the segregation include

• Particle size • Particle density • Particle shape • Surface area • Surface energy • Crystal form • Moisture content • Electrostatic properties


Paracetamol form I Paracetamol form II

Scale bar 100 µm Scale bar 10 µm

G. Nichols and C.S. Frampton, J Pharm Sci, 87, 1998:684-693

Tableting – Segregation

• Segregation can be divided in three categories

• Sifting – small particles fall in the gaps between coarser particles

• Air entrainment (fluidization) – finer/lighter particles concentrate above larger/denser particles

• Particle entrainment (dusting) – finer/lighter particles remain suspended in the air


D. Schulze, Powder and Bulk Solids – Behavior, Characterization, Storage and Flow, Springer, Berlin, 2008

Segregation


Paracetamol form I Paracetamol form II

Scale bar 100 µm Scale bar 10 µm

G. Nichols and C.S. Frampton, J Pharm Sci, 87, 1998:684-693

• Change in the supplier might change

• Polymorphic form

• Particle size

• Particle shape

• Density

How to Prevent Segregation?

• Particle properties

• Particle size distribution

• It is easier to achieve a perfect or random mix, when the particle size distributions of the components are similar

• Granulation

• Granulation binds components of different particle size distributions readily together

• Granule size distribution can be controlled

• Ordered mix

• Adhesion between two particles is at its best, when they have different surface energies and very different particle size

• Small particle tend to stick on the surface of the bigger one


Barra et al. Pharm Res 15, 1998,1727-1736 D. Schulze, Powder and Bulk Solids – Behavior, Characterization, Storage and Flow, Springer, Berlin, 2008

How to Prevent Segregation?

• Handling and equipment properties

• Minimize transfer steps

• By avoiding to introducing unnecessary force to powder blend segregation tendency can be diminished

• Prevent dust formation

• Regulate drop height, use bags to move powder and use slow fill rate

• Aim for mass flow in the hopper

• Smooth and steep hopper walls


Tableting scale-up prediction

Approaches to predict scale-up

• Fix the compaction parameters

• Compression force

• Tablet thickness

• Compaction simulator

• Study the effect of the changes in compaction profiles

Changes in the process

• Compaction profile

• One-sided vs. double-sided

• Dwell time

• Ejection time


Tableting Scale-up Prediction


• Compaction force • Tablet thickness can be regulated by

compaction force

• Tablet density and porosity are dependent of the compaction force and tablet thickness

V. Busignies et al. Eur J Pharm Biopharm 64, 2006:38-50



• Compaction force and tablet thickness

• Tooling has to be identical in order to predict the scale-up

• X-ray computed microtomography of microcrystalline cellulose tablets

I.C. Sinka et al. Int J Pharm 271, 2004:215-224



• Compaction force and tablet thickness • Compaction profiles (shape and

speed) might be different in single and rotary presses

• Effect of compaction profile on tablet properties • Thickness of the lactose tablets for the

double-sided compaction was doubled

• Double-sided compaction produced tablets with lower tensile strength but lower porosity

A. Munoz-Ruiz et al. J Pharm Sci 86, 1997:481-486



• Compaction force and tablet thickness

• Compaction profiles (shape and speed) might be different in single and rotary presses

• Instruments may have a difference in compaction speed or dwell time

• Effect of dwell time to porosity

• Microcrystalline cellulose

• Dicalcium phosphate

• Pre-gelatinized

• Longer dwell time – lower porosity

C.K. Tye et al. J Pharm Sci 94, 2005:465-472



• Ejection time

• Faster ejection speed results lower ejection force and consequently less friction

• Usually it is not a problem in large scale

Patel et al. AAPS Pharm Sci Tech 8, 2007:E1-8



• Ejection time and speed

• Friction during small scale manufacturing can be overcome by lubricant

• Lubricant concentration

• If lubricant is needed only in the small scale formulation, should it be included in the final formulation?

E. Doelker and D. Massuelle Eur J Pharm Biopharm 58, 2004:427-444


• Compaction simulator can be used to study changes in compaction profiles

• Complete control over the compaction profiles • One-sided vs. double sided compaction

• Compaction force

• Dwell time

• Simulator does not take powder filling properties into account

• Powder flowability

• Segregation


M. Paakkunainen et al. Chemometr Intell Lab 97, 2009:82-90

Conclusions


• Single press machine or rotary press with one pair of punches and dies are used in the small scale production

• The change from small scale to large scale affects to • Powder properties, e.g. segregation and flowability

• Compaction profile

• Processing speed

• Scale-up can be predicted by • Compression force

• Tablet thickness

Take home message


• Scale up is not a straight forward process

x 10 ≠

https://whyevolutionistrue.wordpress.com/2013/04/06/caturday-felids-cats-and-boxes/ http://www.thepetcollective.tv/why-do-cats-love-boxes/

Acknowledgements

• CMC

• Thomas Vilhelmsen

• Global Research

• Niels Christian Felumb

• Birgitte Nissen


Thank you!


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