Pilot Plant Scale Up Techniques

Purpose Statement

At the end of the lecture the students should be able

to –
Understand scale up considerations for liquid
oral and seisolid formulations.
 CO and Competencies

Competencies
BP702T-1 : Outline the operational steps of pilot plant
scale up techniques

Course Outcome:
BP702 T-CO2 : Describe pilot plant setup and scale up
operations
 Learning Objective
Sr. Learning objectives Domain Level Criteri CO PO
No a
1 Understand Problems Cognitive Must All BP702 T- PO-1,
encountered during know CO2 PO-2
scaling up of liquid orals
PO-3,
2 Understand Scale up Cognitive Must All
Parameter to be know PO-4,
considered PO-6,
3 Describe the Factors to Cognitive Must All PO-7,
consider during scaling-up know PO-11
operation of suspensions
4 Describe the Factors to Cognitive Must All
consider during scaling-up know
operation of emulsions
5 Describe the pilot plant Cognitive Must all
scale up considerations know
for semi solids
 Liquid Orals
• Liquid dosage forms are dispersed systems or solutions.

• Equipments used:
o Mixer
o Homogenizer
o Filtration assembly
o Bottling assembly
• Simple solutions are the straight forward to scale up.
• Most significant factor to consider is the physical and chemical
stability of the ingredients and final product during processing.
 Problems encountered during scaling up of viscous/Non-
newtonian liquid orals:

• Viscous liquids generally show a tendency to undergo improper

mixing with conventional impellers.
• Non-newtonian liquids exhibit variability in the viscosity due to
the shear imparted by the impeller, this gradual change in
viscosity affects the mixing efficiency.
• Initial forces imparted to the viscous system during the mixing
process tend to dissipate quickly.
• Hence adequately designed mixing equipment are needed for
efficient mixing of highly viscous liquids.
 Scale up Parameter to be considered

Tank
• Material of the tank must not be additive to the product.
• Stainless steel is most non reactive. Stainless steel of different
grades –SS 308 and SS 316 are used. SS 316 is preferred.
• SS does react with some acidic pharmaceutical liquids, this
problem can be minimized by PASSIVATION.
• Passivation is pre-treating the SS with acetic acid or nitric acid
solution to remove the surface alkalinity of the SS.
• Interaction with metallic surfaces can be minimized by use of
glass or Teflon coating.
• Although they are highly inert materials, they have the
disadvantages of cracking and flaking with resultant product
contamination.
• Tank should have heating or cooling capabilities to effect rapid
dissolution of components of the system.
• Shape & size of the equipment must be selected according to
the batch size. In large scale - tanks with capacity-100 to
10000L are used.
• Height of the filled volume in the tank should be precisely
maintained.
• For most mixing applications, ideally the liquid level (fill
height) to tank diameter ratio should be 0.8.
• However, any ratio that is close to 1 is sufficient.
• A ratio that is too small does not allow proper axial mixing in
the tank. Anything less than a 0.6 ratio should be avoided.
• Adequate cleaning procedures must be developed.
• The effect of long processing times at suboptimal
temperatures should be considered on the physical or
chemical stability of ingredients as well as product.
 Mixing
Factors to be considered ;
• Impeller type - radial flow impeller for immiscible liquids &
axial flow impeller for homogenization process.
• Impeller diameter-size should be relevant to the production
size.
• Rotational speed of the impeller- low speed gives better
performance.
• Design of impellers – design of blades depends on the type
of flow and viscosity of the fluid, 3-7 impeller blades are used.
• Number of baffles-it affects the flow pattern & mixing.
• Air entrapment can be minimized by reducing the agitator
speed or by carrying out the mixing in a closed tank under
vacuum.
 Filtration

• In filtration, filtration pads used are made up of asbestos or

cellulose.
• Selection of type of filter depends upon
o Viscosity
o Volume
o Rate of filtration requirement
• It should not remove active or adjuvant ingredients
• During pilot run, the clarity of the filtrate should be checked
periodically to ensure the integrity of the filter pad and to
establish schedule for changing the filters.
• In lab scale- gravity & suction filters, but in large scale- vacuum
filters, the plate & frame filter press.
• Problems: Clogging of filter, tearing of the filter
 Transfer & filling

• Lab scale- funnel & measuring cylinder, but in Large scale-

Gravimetric filling (weight) and Volumetric filling (volume)
• Selection of filling equipment depends on
o viscosity
o surface tension of the liquid
o type of packaging.

• Problems- Non-uniform filling, foaming & dripping

 SUSPENSION
A pharmaceutical suspension is a coarse dispersion in which
internal phase (therapeutically active ingredient) is dispersed
uniformly throughout the external phase.

Ingredients used for manufacturing suspension

• API/ Insoluble particle
• Liquid vehicle
• Suspending agent
• Surfactant
• Viscosity enhancers
• Preservatives
• Flavouring agents
• Sweetening agents
• Colours
• Buffers
• Stabilizers
 Parameters to be considered:

1. Addition and dispersion of suspending agents

• Lab scale – sprinkling method & Production scale – vibrating feed

system

• Suspending agents are added to prevent/reduce settling of

suspended drug particles. Suspending agents must not be too
viscous to pour from container

• Dispersion produced by colloidal mill or an immersion

homogenizer.

• Quality of the final product (using colloidal mill) depends on the

following;
o Viscosity of the continuous phase
Colloid mill

Immersion
Homogenizer
2. Hydration/Wetting of suspending agent:
• Sometimes, heating is required for hydration of
suspending agent.
• Increase in temperature for hydration of suspending
agents may cause moisture loss, physical and chemical
instability.
• If heat is used, care must be taken during the cool-down of
the product to prevent settling.

3. Mixing speeds
• High speed leads to air entrapment, thus mixing speed
should be optimum to avoid air entrapment, and avoid
agglomeration.
• Maintain the same rpm throughout the process.
4. Air entrapment:

• Care must be taken to suspend the drug, without incorporation of

air.

• Air entrapment causes problems like;

o Difficult & time consuming to remove entrapped air
o Affects physical & chemical stability of product
o Variation in viscosity
o Problems in transfer and bottle filling
o Variation in amount of suspension filled in bottle.

• Hence Versator is used to remove entrapped air - it removes air, gas

and foam leaving a completely mixed and homogenized product.

• In Versator, the product is drawn into a vacuum evacuated chamber

through the feed assembly and is spread onto the centre of a
Versator
5. Mesh size of filter:

• Mesh size chosen must be capable of removing the

unwanted foreign particulates without filtering out
suspended particles.
• Most drugs have particle size less than 10 µ & none over 25
µ.
• Filtration screens with 150# shall be used (pore diameter
100 μm)

6. Transfer and filling

 EMULSION

Emulsion is the thermodynamically unstable system consisting of

at least two immiscible liquid phases, one of which is dispersed
as globules in other liquid phase, stabilized by the presence of
emulsifying agents.

Ingredients used for manufacturing suspension

• API/ Insoluble particle
• Liquid vehicles
• Emulsifying agent
• Antioxidants
• Buffering agents
• Preservatives
• Flavouring agents
• Sweetening agents
1. Mixing equipment

• It should be relevant to the production size batches.

• Emulsion is mixed using various impeller mounted on a

shaft.

• Degree of agitation is controlled by speed of impeller

rotation.

• But pattern of liquid flow & the resultant efficiency of mixing

are controlled by the type of impeller, its position in the
container, presence of baffles & shape of the container.
2. Homogenizing equipment:

• Homogenizer is used to produce fine droplets by compressing

the liquid &
passing it through the flat disc.

• Shearing stress applied is ranging from 500-5000 psi

• Size depends on the viscosity & the interfacial tension of a

system.

• Size reduction will define internal phase globule size, physical

properties of emulsion such as appearance, viscosity &
stability

• Lab scale – ultrasonic homogenizer, Large scale- High-Pressure

Homogenizer
3. In-process filters:

• Separate filtration of oil & water phase before emulsification

• The mesh size chosen must be capable of removing the
unwanted foreign particulates without getting clogged.

4. Phase volumes:
• In an emulsion the relative volume of water to oil is expressed
as phase volume ratio.
• Normally emulsion are prepared with a volume ratio of 50:50.
• The upper limit of 74% of oil (in case of o/w emulsion) can be
incorporated in an emulsion but this may lead to breaking of
emulsion, this value is referred as critical point.
• Critical point is defined as the concentration of internal phase
above which the emulsifying agent cannot produce a stable
emulsion of the desired type.
5. Pumps and filling equipment:
• Fill pump allow the product to remove from the machine at
the end of production.
• Automated equipment are available in the market for
pumping and filling operation.

6. Temperature
• Temperature should be optimum as required by particular
emulsion. It is critical to the quality of final product.
• Elevated temperature alters the partition characteristic of the
emulsifier & preservatives, which results in instability.

7. Phase viscosities
• It is of great importance for stability and pourability, as
viscosity increases, the settling velocity decreases.
8. Phase densities:
• By adjusting the density of the phases to the same value we
can increase the stability of emulsion.
• Oil phase density can be enhanced by adding brominated oil
when oil is an external phase.

9. Filling rate & volume:

• New batch should not be started until the previous batch is
completely filled & tanks are emptied.
• Filling rate should be optimized because increased rate may
cause incorporation of excessive air into the product
• Gravimetric method is commonly used for filling.
 PILOT PLANT SCALE UP CONSIDERATIONS FOR SEMI
SOLIDS

The following parameters are to be considered during the

scale up of semisolid products;

• Mixing speed.
• Mixing equipment (should be able to move semisolid mass
from outside walls to the centre and from bottom to top of
the kettle).
• Motors (should be able to drive mixing system at its most
viscous stage).
• Heating and cooling process.
• Homogenizer.
• Product transfer equipment.
• Addition of active ingredients.
• Shear produced during handling and transfer from
manufacturing to holding tank and to filling lines.
• Transfer pumps (should be able to easily must move
viscous material without applying excessive shear and
without entraping air).

Following parameters must be considered while

choosing the pump
• Pumping rate.
• Pumping pressure
• Product compatibility with the pump surface
• Product viscosity
 Summary:

• Problems encountered during scaling up of liquid

orals
• Scale up Parameter to be considered
• Factors to consider during scaling-up operation of
suspensions
• Factors to consider during scaling-up operation of
emulsions
• Pilot plant scale up considerations for semi solids
Reference:

• International Regulatory Affairs Updates, 2005. available at

[Link] 3. Douglas J Pisano and
David S. Mantus.
• Text book of FDA Regulatory Affairs A Guide for Prescription
Drugs, Medical Devices, and Biologics’ Second Edition.
• Regulatory Affairs brought by learning plus, inc. available
at http.//[Link]/[Link]
Questions

• Describe the factors considered for filtration, transfer and

filling operation in processing of liquid orals.
• Describe the factors considered for mixing operation of
liquid orals.
• Describe the factors for the tank selection for processing
of liquid orals.
• Enlist any four factors considered for the scaling-up of
liquid orals.
Thank
you.