Scale up for capsule

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SCALE UP AND TECHNOLOGY TRANSFER
PCE-MIP 202 T
Topic: PILOT PLANT SCALE UP FOR CAPSULES
UNDER THE GUIDANCE OF:
Dr. Mahalaxmi Rathnanand
Associate Professor
Dept. Of Pharmaceutics
MCOPS, MAHE
SUBMITTED BY:
Seema Kamath
190617004
MPharm (Semester-2)
Industrial pharmacy

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CAPSULES : It is a solid unit dosage form in which the drug is enclosed with
either hard or soft soluble shell generally made of gelatin intended to be
swallowed whole.
STAGES OF CAPSULE PRODUCTION:
1. Material Handling
2. Mixing of ingredients
3. Granulation
4. Drying
5. Lubrication
6. Making of capsules
7. Filling of capsules
8. Finishing
Unit operations: -
1. MATERIAL HANDLING SYSTEM: In laboratory the materials are simple
scooped or poured by the hands, but in intermediate or large scale
operations, handling of these materials often becomes necessary. If a
system is used to transfer materials for more than one product, care
must be taken to prevent cross contamination. Any material handling
system must deliver the accurate amount of the ingredient to the
destination. The type of system selected also depends on the
characteristics of the materials. More sophisticated methods of
material handling materials such as vacuum loading systems, metering
pumps, and screw feeds systems are used.
2. DRY BLENDING: Powders to be used for encapsulation or to be
granulated must be well blended to ensure good drug distribution.
Inadequate blending at this stage could result in discrete portion of
the batch being either high or low in potency. Steps should also be
taken to ensure that all the ingredients are free of lumps and

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agglomerates. For these reasons screening/mixing of ingredients
usually makes the process more reliable and reproducible.
The equipment’s used for blending are: -
 V blender
 Double cone blender
 Ribbon blender
 Slant cone blender
 Bin blender
 Orbiting screw blenders vertical and horizontal high intensity mixer
Scale up consideration in dry blending
a. Variations of the blender geometry between scales acceptable:
Mixing action is determined by the mechanics of the mixer and can
only be changed by converting from one to another or by modifying
the blender through addition of baffles or plates.
b. The order of addition of components to the blender: A low-dose
active ingredient may be sandwiched between two portions of
directly compressible excipient in the blender to improve
dispersion and/or avoid loss to the surface of the blender.
c. The blender load (load level or fill level): The amount of material
volume to the total mixer volume affects the efficiency of the
blender. Each blender has an optimum working volume and a
normal working range. Overloading a blender retards the free flow
of the granulation and reduces the efficiency of the blender.
Conversely, if the load is too small, the powders slide rather than
roll in a blender and proper mixing does not occur, or time of mixing
increases.
d. Rate of rotation (rpm) or mixing rate: Mixing speed differs for
different type of mixers example- blade rotation speed of planetary
type mixer, and mixer tumbling or rotational speed for a twin shell,
cone type, or similar type of mixer.

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e. Time of Mixing: the mixing time can be decreased if available data
show the materials to be consistently and uniformly mixed in less
time than originally directed. Alternatively, the time may need to
be increased if the mixing time is shown to produce material with
borderline uniformity. Mixing time also affects the compressibility
of the finished blend. Excessive mixing time may fracture fragile
excipient and ruin their compressibility.
In Process Quality Control test: Content uniformity test.
3. GRANULATION: The most common reasons given to justify
granulation are: -
a) To impart good flow properties to the material
b) To increase the apparent density of the powder
c) To change the particle size distribution
d) Uniform dispersion of active ingredients
Traditionally, wet granulation has been carried out using, Sigma blade
mixer, and Heavy-duty planetary mixer.
Wet granulation can also be prepared using tumble blenders equipped
with high- speed chopper blades.
More recently, the use of multifunctional “processors” that are
capable of performing all functions required to prepare a finished
granulation, such as dry blending, wet granulation, drying, sizing and
lubrication in a continuous process in a single equipment.
Scale-up considerations for Fluidized Bed Granulations:
i. Process Inlet Air Temperature
ii. Atomization Air Pressure
iii. Air Volume
iv. Liquid Spray Rate
v. Nozzle Position and Number of Spray Heads
vi. Product and Exhaust Air Temperature

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vii. Filter Porosity
viii. Cleaning Frequency
ix. Bowl Capacity.
IPQC Test: hardness of granules, flow properties, moisture content.
4.DRYING:
 The most common conventional method of drying a granulation
continues to be the circulating hot air oven, which is heated by either
steam or electricity.
 The important factor to consider as part of scale-up of an oven drying
operation are:
i. airflow
ii. air temperature
iii. depth of the granulation on the trays.
 If the granulation bed is too deep or too dense, the drying process willbe
inefficient, and if soluble dyes are involved, migration of the dye to the
surface of the granules.
 Drying times at specified temperatures and airflow rates must be
established for each product, and for each particular oven load.
 The importantfactor to consideras partof scale up of fluidized bed drying
operation include:
i. Optimum load
ii. Air flow rate
iii. Inlet air temperature
iv. Humidity of incoming air
 Fluidized bed dryeris an attractivealternative to thecirculating hot air ovens.
Their main advantage. Their main advantage is reduction in drying time.
Fluidized bed drying times are usually less than 1 hour.
 First, optimum loads must be established then, rate of airflow and inlet air
temperature as well as the humidity of the incoming air mustbe established,
sincetheseall affectthe dryingtime. Iftheair is drawnfromoutsidethe plant
without being conditioned, the large-scale seasonal variation in terms of
temperature and humidity that may exist can alter the drying process.
IPQC TEST: moisture content

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5.LUBRICATION
Lubricants are added to enhance the powder flow by reducing the
inter particle friction.
Equipments used are:
 Octagonal blender
 Ribbon blender
Factors affecting Lubrication:
 Amount of lubricant added
 Grade of lubricant used
 Compatibility with other ingredients
 Mixing time.
IPQC Test for Lubrication:
• Angle of Repose:
The angle between the surface of the pile and the horizontal
surface.
𝜃 = 𝑇𝑎𝑛−1
ℎ
𝑟
 At a higher angle of repose- powder may not have sufficient
mobility to distribute.
 At lower angle of repose powder has sufficient mobility to
maintain uniform bed.
• Carr’s Compressibility Index & Hausner Ratio:
Both are determined by measuring bulk volume and the tapped
volume of a powder.

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6.Capsule-filling:
In contrast, there are several types of capsule-filling equipment, each
with its own operations. The fill material is treated in different ways in
each case, and hence the challenges of fitting instrumentation also
differ.
i. Dosing Disc Machine:
• Contains dosing disc which has got a number of holes similar to that
of die cavity of tablet press.
• Below the dosing disc there is a sealing pate that closes the holes.
• Above the dosing disc a constant level of powder is maintained.
• Five sets of pistons compress the powder into cavities to form plugs.
i.e. each powder plug is compressed five times per cycle
• Any excess powder is scrapped off and plugs are ejected into capsule
body by transfer piston.
ii. Dosator machine :
• This machine contains a cylindrical tube filled with a movable piston
known as dosator.
• The end of the tube is open and the height of the piston is adjusted
depending upon the amount of the powder to be filled.
• The tube is brought down into the powder bed
• The powder enters the open end and slightly gets compressed
against the piston
• Then the pressure is applied to the piston pushing the powder bed
forming a powder plug due to compression
• The dosator holding the powder plugs is then withdrawn from the
powder hopper and moved over empty capsule body
• Finally the piston is pushed downwards to eject plug into the capsule
body.

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Filling Scale Up Techniques
In the production of capsules, the powder blend (simple/granulated) is
converted into plugs, either by single stroke or multi stroke. Plugs are soft
and having breaking strength less than 1N, but retains sufficient mechanical
integrity until it is delivered into the capsules. The scale up of capsule filling
operation considers the operating principles and designing principles. The
machinery produces plugs by compression and ejects into the capsule body.
A few factors are relevant.
 Plug height to diameter ratio >1
 Compression force range: 50-200N
 Piston or tamping pin compression speed range: about 100-500m/sec
According to SUPAC IR
Level 1 change: batch sizes 10 times of the pilot batch
Level 2 change: batch size is beyond 10times of pilot
Level 2 changes could significantly impact the formulation quality and
performance. Supplement of changes effected is to filed to USFDA. If the in
vivo equivalence data remains same, then the changes are accepted. The
CGMP procedures are followed and full description of the change is
documented and reported to FDA.
Processing conditions
During pilot plant scale up, the following factors are considered for gelatin
capsules. These conditions are applicable to both the systems, dosator
machine and dosing disc machine.
 Mixing load, mixing speed, mixing time: As per CGMP,
blending/mixing is an important process, which ensures the drug
content uniformity in capsules. Material load, mixing speed and
mixing time are critical parameters and the blend uniformity is tested.

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 Moisture content: it is a critical factor for granules to become
compact as well as to maintain physical stability (sticking and picking)
and chemical stability (degradation).
 Plug formation: the tamping pressure on the pins affects the
dissolution rate. Hence minimum tamping pressure is required in case
of dosing disc machine. In case of dosator machine the stable powder
arch is needed to prevent loss of material ejection and quantitative
transfer of powder into the capsule shell.
Scale up considerations:
 Multiple tamp principle (in dosing disc machine) is more efficient than
the single stroke dosator machine (without vacuum densification). A
dosator machine requires a high degree of compatibility, because the
open of the dosator is exposed, while lifting the dosator. Higher
weight variation is reported.
 Free flowing powders often do not form plugs well enough to be
transferred by the dosator. In this case, dosing disc machine is
preferred.
 The dosing disc machine requires about half of the amount of
magnesium stearate for plug formation and ejectibility. In this
machine, shearing of lubricant (mg stearate) is high. During tampering
step, the formulation is coated excessively with the lubricant.
 In dosing disc machines high shearing of lubricant (Mg stearate) is
achieved due to multiple tamping. Accordingly dissolution may be
slow.
7. FINISHING: Finished capsules from the filling equipment’s require some
sort of dusting /polishing operation before the remaining operations of the
inspection, bottling, and labeling are completed. Dusting and polishing
operations vary according to the type of filling equipment used, the type of
powder used for filling and the individual desires for the finished
appearance of the completed capsules. The following are the methods most

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commonly used, based on the desired output, formulation, required final
appearance, etc.
 Pan polishing: - Because of its unique design the Acceta Cota pan
may be used to dust and polish the capsules. A polyurethane or
cheese cloth liner is placed in the pan, and the liner is used to trap
the removed dust as well as to impart the gloss to the capsules.
 Cloth dusting: - In this method, the bulk filled capsules are rubbed
with a cloth that, may or may not be impregnated with an inert oil.
This procedure is a hand operated, but one that can handle
reasonable volumes, and that results in a positive method for
removal of resistant materials. In addition, it imparts an improved
gloss to the capsules.
 Brushing: - In this procedure, capsules are fed under the rotating
soft brushes, which serves as to remove the dust from the capsule
shell. This operation must be accompanied by the application of the
vacuum for dust removal. Some materials are extremely difficult to
remove by brushing, even to the point of impregnating the brushes
and causing scratches or deformation of the capsules.
Equipments for sorting of the capsules and polishing are as follows:
i. Rotosort
ii. Erweka KEA
iii. PM 60
Scale up considerations for finishing:
 In cloth dusting- number of capsules to be rubbed with a
cloth.
 In polishing- type and quality of polishing agent, pan
rotation speed.
 In brushing- types of brush, brush rotation speed, extent of
vacuum required.
IPQC test- Appearance, disintegration, dissolution, microbial test.

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LAYOUT OF CAPSULE MANUFACTURING PLANT
 It refers to the allocation of space and the arrangement of machines and
necessary services needed in a production process within a factory building in
other to perform the various unit operations involved in the manufacturing
process of dosage forms.
 A proper layout increased productivity and helps in proper utilization of man,
money, material and machines.
 Process areas require high quality finishes maintaining CGMP standards.
Traditionally pharmaceuticalmanufacturingfacilities havebeen designed on the
basis of single rooms or cubicles for each stage of the manufacturing process.
Environmental Conditions:
 The storage of filled capsules is closely controlled and monitored
 Humidity has a significant effect on moisture content
 The processing room is controlled within 45 to 55 % RH

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REFERENCES
 The Theory & Practice of Industrial Pharmacy by Leon Lachman,
Herbert A. Lieberman, Joseph L. kenig, 3rd edition, published by
Varghese Publishing house.
 CVS Subrahmanyam and J Thimmasetty, “Industrial Pharmacy
Selected Topics” 1st edition
 Nash, R. A. Process validation for solid dosage forms. Pharm Tech June
(1979).
 Larry L. Augsburger, Stephen W. Hoag; Pharmaceutical Dosage Forms
Capsules, CRS Press.
 B.Venkateswara Reddy, A.Deepthi, P.Ujwala. CAPSULE PRODUCTION
– INDUSTRIAL VIEW. Journal of Global Trends in Pharmaceutical
Sciences Vol.3, Issue 4, pp -887-909, October–December 2012