The document discusses considerations for scaling up a pilot plant process. It outlines key roles in the pilot plant including ensuring safety, overseeing operations, training personnel, and managing quality systems. It also describes responsibilities for optimizing processes, evaluating scale up, and maintaining equipment and facilities. The document then covers specific scale up checkpoints for solid dosage forms, including material handling, blending, granulation, particle size reduction, tableting, and coating operations. Process parameters that need attention during scale up like equipment size, processing times, and material throughput are indicated.

1. PILOT PLANT SCALE UP STUDIES
PREPARED BY :
Vaishnavi Gohri

2. ROLE OF MANAGER
● Ensure a safe work environment for all pilot plant operations and
compliance with all health and safety policies and procedures.
● Provide technical leadership and operational oversight of Pilot
Plant facility.
● Partner with Process Development to optimize and implement
new processes and technology at the pilot scale.
● Train engineers and associates in the functional tasks necessary
to successfully perform their duties.
● Schedule activities of pilot plant personnel and ensure the tasks
are completed in a timely manner.
● Provide personnel career development, coaching, and feedback
including performance management discussions with each direct
report.
● Train and oversee compliance with Quality Assurance policies
and procedures that relate to the Pilot Plant.
● Write and review standard operating procedures, batch records,
process deviations reports, CAPAs, and change control requests.
● Manage raw material receipt and release system.
● Manage plant supplies and raw materials inventory.

3. ● Ensure that batch records and other Quality documents are faithfully and timely
executed, reviewed, and retained as permanent records.
● Maintain pilot plant in a functional and calibrated state.
● Develop and monitor metrics to track operational performance.
● Develop goals and set priorities to meet safety, business and quality needs of
customer on-time and in-full.
● Lead initiatives for the continuous improvement of safety, quality, and operations.
● Partner with and be accountable to Commercial Operations, Process Development,
and Quality Assurance.

4. ROLE OF PLANT ENGINEER
Plant engineers oversee the electrical mechanical systems of a
manufacturing plant, from installation to troubleshooting. They
are called upon to improve the plant's efficiency, upgrade to new
technologies, repair equipment, increase production, and reduce
manufacturing issues .
● Try to process on a model of proposed plant before committing
large sum of money on a production unit.
● Examination of the formula to determine its ability to withstand
batch scale & process modification.
● Evaluation & Validation for process and equipment.
● To identify the critical features of the process.
● Guidelines for production & process controls.
● To provide master manufacturing formula with instructions for
manufacturing procedure.
● To avoid the scale up problems.

5. Pilot plant scale up Design
The primary responsibility of
the pilot plant staffs is to
ensure that the newly
formulated tablets developed
by product development
personnel will prove to be
efficiently, economically &
consistently reproducible on a
production scale .

6. Pilot plant scale-up checkpoints for solids:
•Material handling system : In large-scale production, proper handling of materials is
necessary.
•Dry Blending- Granulated powders must be well blended to ensure proper distribution
of drug.
•Binders
•Granulation
•Size reduction & Lubricating
• Drying
•Compression
•Tablet Coating

7. Material handling system
● If a system is used to transfer materials for more than one product, steps must be taken to
prevent cross contamination.
● Deliver the accurate amount of the ingredient to the destination.
● The type of system selected depends on the characteristics of the materials.
● Vacuum loading systems, metering pumps, screw feed system.

8. Dry Blending
● Powders to be used for encapsulation or to be granulated must be well
blended to ensure good drug distribution.
● Inadequate blending could result in the batch being either
high or low in potency.
● Ensure that all the ingredients are free of lumps and agglomerates.
● Screening and/or milling of the ingredients prior to blending
● usually makes the process more reliable and reproducible.

9. The equipment used for blending are:
V- blender Double cone blender Ribbon blender

10. The equipment used for blending are:
Slant cone blender Orbiting screw blender Bin blender

11. SCALE UP CONSIDERATIONS :
1. Time of blending
2. Blender loading
3. Size of blender

12. Binders
● Help to make powders more compressible and to produce
tablets that are more resistant to breakage during handling.
● In some instances the binding agent imparts viscosity to the
granulating solution so that transfer of fluid becomes
difficult.
● This problem can be overcome by adding some or all
binding agents in the dry powder prior to granulation.

13. ● Some granulations take on a dough-like consistency and
may have to be subdivided to a more granular and porous
mass to facilitate drying.
● This can be accomplished by passing the wet mass through
an oscillating type granulator with a suitably large screen or
a hammer mill with either a suitably large screen or no
screen at all.

15. GRANULATION

16. Scale up consideration for Granulation
1. To impart good flow properties to the material.
2. To increase the apparent density of the powders.
3. To change the particle size distribution.
4. Uniform dispersion of active ingredient.

17. METHODS OF GRANULATION
1. Wet method : Which utilizes some form of liquid to bind with primary
particles, Sigma blade mixer is used for heavy planetary mixing purpose.
Typical solvents include water, ethanol and isopropanol and methylene
chloride either alone or in combination.
2. Dry method : which do granulation minimizes the technical risks.mostly
Roller compaction mill or shear mill is used
Traditionally for wet Granulation Tumble blenders equipped with high speed
chopper blader.

18. Sigma blade mixer

19. Planetary mixer Tumble blender

20. REDUCTION OF PARTICLE SIZE
● Compression factor may affected by size distribution are flowability,
compressibility, uniformity of tablet weight, content uniformity, tablet
hardness & colour uniformity.
● Firstly determine the particle size distribution of granulation using series of
stacked sieves of decreasing mesh opening.
● Size reduction of dried granulation of production size batches can be
carried out by passing all the materials through an oscillating granulator, a
hammer mill ,a mechanical sieving device or in some case screening
device used.
● As part of the scale up of milling or seiving operation, the lubricants &
glidants,which in lab usually added directly to final blend are added to
dried granulation during the sizing operation.
● This is done becoz some of these additives especially magnesium
stearate ,tend to agglomerate when added in large quantities to the
granulation in a blender.

21. ROLLER (Ball) MILL

22. FLUIDIZED ENERGY MILL

23. Lubrication :
● Lubricants reduce the friction between the tablet and the die metal
surface, which reduces the ejection force and helps to ensure that the
tablet is cleanly ejected and without cracking or breakage.
Talc Silica gel

24. ● Minerals such as talc
or silica, and fats.
● e.g. vegetable
stearin, magnesium
stearate or stearic
acid are the most
frequently used
lubricants in tablets

25. Drying
Drying is the process of removing the presence of solvents (i.e. water or other liquids) in a formulation with
the presence of heat. The final product of this unit operation is a dry solid mass or powders.
METHODS :
● MICROWAVE RADIATION :
Microwave radiation in the wavelength range 10 mm to 1 m has been found to be an efficient heating and
drying method, as such, these dryers are used in the pharmaceutical industry.
Advantages of microwave drying includes:
1. Rapid drying at fairly low temperature
2. Highly efficient equipment
3. GMP compliant design

26. ● SPRAY DRYING :
Spray drying is the most useful method for drying
solutions and suspensions as it disperses the
liquid to a spray of small droplets.
This operation uses a spray dryer which atomizes
the liquid into smaller droplets, thus creating a
large surface area for heat and mass transfer.
These are sprayed into a stream of hot air, so that
each droplet dries to an individual solid particle.
Thus particle formation and drying occurs.

27. ● FREEZE DRYING :
Freeze drying is a process used to dry extremely heat-sensitive materials as it allows
drying without the excessive damage to substances such as: proteins, blood products, and
even microorganisms (with a small significant viability).

28. SCALE UP CONSIDERATION FACTORS :
● Air flow, air temperature & depth of the granulation on the trays.
● If the depth of granulation bed is too deep or too dense, the drying process will be
inefficient & if soluble dyes are involved, migration of the dye to the surface of the
granules may occur.
● Drying time at specified temperature & airflow rates must be established for each
product & for each particular oven load .
● FLUIDIZED bed dryers are alternative to circulating hot air ovens.
● The important factor considered as part of scale up FLUIDIZED bed dryer are
optimum loads ,rate of airflow ,Inlet air temperature & humidity.

29. COMPRESSION :
The tablet press performs the following functions:
1. Filling of empty die cavity with granulation.
2. Precompression of granulation (optional).
3. Compression of granules.
4. Ejection of the tablet from the die cavity and take-off
of compressed tablet.
Potential problems :
1 Sticking to the punch surface
2 Tablet hardness
3 weight variation
parameters to be considered while choosing speed of press :
1. Granulation feed rate.
2. Delivery system should not change the particle size distribution.
3. System should not cause segregation of coarse and fine particles, nor it should induce static charges.

30. Start-up & Operation:
● Before starting the machine carefully inspect the
punches and dies that their edges should be sharp
without kink, cracks or deformation and they are
properly mounted.
● Before mounting the dies and punches ensure that
the machine is free by rotating manually and also
ensure that the rotation is correct.
● Inspect that the granulate material is dry and the water
context present is within limits.
● Pour the material into the feed hopper, turn the turret
by handle wheel manually and regulate the file and
pressure until the desired weight and hardness of the
tablets is obtained.
● Start the motor and engage the clutch to proceed with
operation.
● During the operation regularly inspect the quality of the
tablets produced. If any fault is found necessary
adjustment should be made.

31. Filling-
● The die feed system must be able to fill the die cavities adequately
in the short period of time that the die is passing under the feed frame.
● For high-speed machines, induced die feed systems is necessary.
So that optimum feed for every granulation can be obtained.
● Smaller the tablet, the more difficult it is to get a uniform fill a
high press speeds.
● Slowing down the press speed or using larger compression rollers
can often reduce capping in a formulation Compression.
Compaction & Ejection -
● During compression, the granulation is compacted to form tablet, bonds
within compressible material must be formed which results in sticking.
● High level of lubricant or over blending can result in a soft tablet, decrease
in wettability of the powder and an extension of the dissolution time.
● Binding to die walls can also be overcome by designing the die to be wider
at the upper portion than at the center.

32. COATING :
● The conventional sugar coating pan has given way to
perforated pans or fluidized-bed coating columns.
● The tablets must be sufficiently hard to withstand the
tumbling to which they are subjected in either the
coating pan or the coating column.
● Some tablet core materials are naturally hydrophobic,
and in these cases, film coating with an aqueous system
may require special formulation of the tablet core
and/or the coating solution.
● A film coating solution may have been found to work
well with a particular tablet in small lab coating pan
but may be totally unacceptable on a production scale.

33. PAN COATING FILM COATING