PILOT PLANT SCALE UP FOR LIQUID ORALS

PILOT PLANT SCALE UP FOR LIQUID ORALS

• Simple solutions are the easiest to scale up but requires tanks of adequate size and mixing capability

• The equipment can have heating/ cooling capabilities for rapid dissolution of ingredients

• Filtration equipment are required for removal of unwanted particles

• The material used in the construction of equipment is important

• Should be non-reactive and facilitate easy cleaning

• Fabricated stainless steel is most suitable as it is non-reactive (expect for some acidic substances)

• This can be overcome by Passivation (pre-treating the stainless steel with acetic acid or nitric acid solution to remove the surface alkalinity)

• Passivation has to carried out periodic intervals

• If the batch involves preparations containing alkaline substances, then passivation needs to be repeated before the next batch

Mixing vessels

SCALE UP CONSIDERATIONS- Solutions

1. Tank size (diameter)

2. Impeller type and number

3. Impeller diameter

4. Rotational speed of the impeller

5. Mixing capability of impeller

6. Clearance between Impeller Blades and wall of the mixing tank

7. Height of the filled volume in the tank

8. Filtration equipment (should not remove active or adjuvant ingredients)

9. Transfer system

Pilot Plant design for Suspensions

• Suspensions require more attention during scale up because of additional processing needs

• The addition and dispersion of suspending agents require a vibrating feed system

• A powder eductor   can facilitate the addition of a material that tends to clump during the process or that is difficult to disperse

• Or they can be made into a slurry with a portion of the vehicle before addition

Powder eductor

•  If the suspending agents are difficult to disperse, then it can be  made  into  a  slurry  with  a  portion  of  the  vehicle  and completely dispersed using a high shear mixer

• Helps in rapid and complete hydration of the suspending agent when added to a larger portion of the vehicle

• The time and temperature required to hydrate suspending agents is critical.

• If the hydration process is incomplete before the other ingredients are added, the quality of the suspension is adversely affected

High Shear Mixer

For uniform dispersion of active ingredients; prevent wetting difficulties and eliminate formation of dry agglomerates

1. Prepare a slurry with a wetting agent using a high shear mixer

2. Pre-treat the hard to wet material by blending it in a high shear powder blender with the liquid ingredients and a surfactant

• The type of mixers, pumps, mills and horse power of the motors should be carefully selected based on the scale up performance

• The equipment should be selected according to size of the batch and maximum viscosity of the product during the manufacturing process

E.g Size of mixer is important

• Undersized mixers- inadequate distribution or excessive production time

E.g Speed of mixing

• Mixing at high speed- incorporation of excessive amount of air into the entrapped air is difficult to remove and if left behind – can affect the physical and chemical stability of the product and the reproducibility of the filling operation

• The entrapped air can be removed using a vacuum unit called Versator

Versator

• The finished suspension needs to be filtered in order to remove any unwanted particulate matter

• The mesh size of the filter should be such that it removes only unwanted foreign particulates and not the active ingredient (since suspension has particulate matter)

• Filters with screens of 150 mesh having aperture size of 100 microns can be used to remove unwanted suspended materials that are below the easily visible range without retaining the suspended active ingredients

Filter Press

SCALE UP CONSIDERATIONS- Suspensions

1. Addition and dispersion of suspending agents

2. Hydration/Wetting of suspending agent

3. Time and temperature required for hydration of suspending agent

4. Mixing speeds (High speed leads to air entrapment)

5. Selection of the equipment according to batch size

6. Versator (to avoid air entrapment)

7. Mesh size (the one which is chosen must be capable of removing the unwanted foreign particulates but should not filter out any of the active ingredients)

Pilot Plant design for Emulsions

• Manufacturing of liquid emulsion products entails specialized procedures and scale up into production equipment involves extensive process development and validation

• The globule size of the internal phase affects the physical properties of the emulsion- appearance, viscosity and physical stability

Homogenizer

SCALE UP CONSIDERATIONS-Emulsions

1. Temperature

2. Mixing equipment

3. Homogenizing equipment

4. In process or final product filters

5. Screens, pumps and filling equipment

6. Phase volumes, viscosities and densities

Use of high shear mixers à causes à Air entrapment

Use of high shear mixers à Prevented by à Use of vessels that operate under controlled vacuum

Filtration in the final stage à causes à Affects quality of the emulsion

Filtration in the final stage à Prevented by à Filtration of oil and water phases separately before emulsification

Filling equipment

Liquid orals filling, sealing and labeling

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