Transcript PILOT PLANT SCALE UP TECHNIQUES Prof. Dr. Basavaraj K. Nanjwade M.

PILOT PLANT SCALE UP TECHNIQUES
Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D
Department of Pharmaceutics
KLE University College of Pharmacy
BELGAUM-590010, Karnataka, India
Cell No: 00919742431000
E-mail : [email protected]
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CONTENTS
Introduction
Objectives of the Pilot Plant
Importance of the Pilot Plant
Pilot plant design for tablets
Pilot plant scale-up techniques for capsules
Pilot plant scale-up techniques for Parenterals
References
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Introduction
What is Pilot plant :
“Defined as a part of the pharmaceutical industry where
a lab scale formula is transformed into a viable product
by the development of liable practical procedure for
manufacture.”
R&D
Production
Pilot Plant
Scale-up : “The art of designing of prototype using the
data obtained from the pilot plant model.”
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Objectives of Pilot Plant
“Find mistakes on small scale and make profit on
large scale.”
To produce physically and chemically stable
therapeutic dosage forms.
Review of the processing equipment.
Guidelines for productions and process control.
Evaluation and validation.
To identify the critical features of the process.
To provide master manufacturing formula.
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Importance of Pilot Plant
Examination of formulae.
Review of range of relevant processing equipments.
The specification of the raw materials.
Production rates.
The physical space required.
Appropriate records and reports to support GMP.
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Pilot Plant design for Tablets
The primary responsibility of the pilot plant staff is to
ensure that the newly formulated tablets developed by
product development personnel will prove to be
efficiently,
economically,
and
consistently
reproducible on a production scale.
The design and construction of the pharmaceutical
pilot plant for tablet development should incorporate
features necessary to facilitate maintenance and
cleanliness.
If possible, it should be located on the ground floor to
expedite the delivery and shipment of supplies.
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Pilot Plant design for Tablets
Extraneous and microbiological contamination must be guarded
against by incorporating the following features in the pilot plant
design:
1. Fluorescent lighting fixtures should be the ceiling flush type.
2. The various operating areas should have floor drains to simplify
3.
4.
5.
6.
cleaning.
The area should be air-conditioned and humidity controlled.
High -density concrete floors should be installed.
The walls in the processing and packaging areas should be
enamel cement finish on concrete.
Equipment in the pharmaceutical pilot plant should be similar to
that used by production division- manufacture of tablets.
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Pilot Plant design for Tablets
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Pilot Plant design for Tablets
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Material handling system
In the laboratory, materials are simply scooped or poured by
hand, but in intermediate- or large-scale operations,
handling of this materials often become necessary.
If a system is used to transfer materials for more than one
product steps 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 handling materials such as
vacuum loading systems, metering pumps, screw feed
system.
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Material handling system
Vacuum loading machine
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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 agglomerates.
For these reasons, screening and/or milling of the
ingredients usually makes the process more reliable
and reproducible.
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Dry Blending
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The equipment used for blending are:
V- blender
Double cone blender
Ribbon blender
Slant cone blender
Bin blender
Orbiting screw blenders vertical and horizontal high intensity
mixers.
SCALE UP CONSIDERATIONS
Time of blending .
Blender loading.
Size of blender.
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Dry Blending
V – cone blender
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Double cone blender
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Dry Blending
Ribbon blender
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Granulation
The most common reasons given to justify
granulating are:
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.
Traditionally, wet granulation has been carried out
using,
 Sigma blade mixer,
 Heavy-duty planetary mixer.
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Granulation
Sigma blade mixer
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Planetary mixer
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Granulation
Wet granulation
can also be
prepared using
tumble blenders
equipped with
high-speed
chopper blades.
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Granulation
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.
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Granulation
Binders:
Used in tablet formulations 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.
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Granulation
Some granulation, when prepared in production sized
equipment, 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.
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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 airflow, air temperature, and the
depth of the granulation on the trays.
If the granulation bed is too deep or too dense, the drying
process will be 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.
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Drying
Fluidized bed dryers are
an attractive alternative
to the 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 and
humidity.
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Reduction of Particle size
Compression factors that may be affected by the particle
size distribution are flowability, compressibility,
uniformity of tablet weight, content uniformity, tablet
hardness, and tablet color uniformity.
First step in this process is to determine the particle size
distribution of granulation using a series of “stacked”
sieves of decreasing mesh openings.
Particle size reduction of the dried granulation of
production size batches can be carried out by passing all
the material through an oscillating granulator, a hammer
mill, a mechanical sieving device, or in some cases, a
screening device.
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Reduction of Particle size
Oscillating type granulator
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Hammer mill
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Reduction of Particle size
As part of the scale-up of a milling or sieving
operation, the lubricants and glidants, which in the
laboratory are usually added directly to the final blend,
are usually added to the dried granulation during the
sizing operation.
This is done because some of these additives, especially
magnesium stearate, tend to agglomerate when added in
large quantities to the granulation in a blender.
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Blending
Type of blending equipment often differs from that
using in laboratory.
In any blending operation, both segregation and mixing
occur simultaneously are a function of particle size,
shape, hardness, and density, and of the dynamics of the
mixing action.
Particle abrasion is more likely to occur when highshear mixers with spiral screws or blades are used.
When a low dose active ingredient is to be blended it
may be sandwiched between two portions of directly
compressible excipients to avoid loss to the surface of
the blender.
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Reduction of Particle size
Equipments used for mixing
Sigma blade mixer.
Planetary mixer.
Twin shell blender.
High shear mixer
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Slugging (Dry Granulation)
A dry powder blend that cannot be directly compressed
because of poor flow or compression properties.
This is done on a tablet press designed for slugging, which
operates at pressures of about 15 tons, compared with a
normal tablet press, which operates at pressure of 4 tons or
less.
Slugs range in diameter from 1 inch, for the more easily
slugged material, to ¾ inch in diameter for materials that
are more difficult to compress and require more pressure
per unit area to yield satisfactory compacts.
If an excessive amount of fine powder is generated during
the milling operation the material must be screened & fines
recycled through the slugging operation.
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Dry Compaction
Granulation by dry compaction can also be achieved by
passing powders between two rollers that compact the material
at pressure of up to 10 tons per linear inch.
Materials of very low density require roller compaction to
achieve a bulk density sufficient to allow encapsulation or
compression.
One of the best examples of this process is the densification of
aluminum hydroxide.
Pilot plant personnel should determine whether the final drug
blend or the active ingredient could be more efficiently
processed in this manner than by conventional processing in
order to produce a granulation with the required tabletting or
encapsulation properties.
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Dry Compaction
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Compression
The ultimate test of a tablet formulation and granulation
process is whether the granulation can be compressed on
a high-speed tablet press.
During 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.
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Compression
When evaluating the compression characteristics of a
particular formulation, prolonged trial runs at press speeds
equal to that to be used in normal production should be tried.
Only then are potential problems such as sticking to the punch
surface, tablet hardness, capping, and weight variation
detected.
High-speed tablet compression depends on the ability of the
press to interact with granulation.
Following are the 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.
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Compression
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.
The smaller the tablet , the more difficult it is to get a
uniform fill a high press speeds.
For high-speed machines, induced die feed systems is
necessary.
These are available with a variety of feed paddles and
with variable speed capabilities.
So that optimum feed for every granulation can be
obtained.
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Compression
After the die cavities are filled ,the excess is removed by the feed
frame to the center of the die table.
Compression of the granulation usually occurs as a single event as
the heads of the punches pass over the lower and under the upper
pressure rollers.
This cause the punches to the penetrate the die to a preset depth,
compacting the granulation to the thickness of the gap set between
the punches.
The rapidity and die wall time in between this press event occurs is
determined by the speed at which the press is rotating and by the
size of compression rollers.
Larger the compressions roller, the more gradually compression
force is applied and released.
Slowing down the press speed or using larger compression rollers
can often reduce capping in a formulation.
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Compression
The final event is ejection of compressed tablets from
die cavity.
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 0.001 to 0.005 inch wider at
the upper portion than at the center in order to relieve
pressure during ejection.
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Compression
DIFFERENT PUNCHES &DIES
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Compression
HIGH SPEED ROTARY
MACHINE
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MULTI ROTARY MACHINE
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Compression
DOUBLE ROTARY
MACHINE
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UPPER PUNCH AND
LOWER PUNCH
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Compression
SINGLE ROTARY MACHINE
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Tablet Coating
Sugar coating is carried out in conventional coating pans,
has undergone many changes because of new
developments in coating technology and changes in safety
and environmental regulations.
The conventional sugar coating pan has given way to
perforated pans or fluidized-bed coating columns.
The development of new polymeric materials has resulted
in a change from aqueous sugar coating and more
recently, to aqueous film coating.
The tablets must be sufficiently hard to withstand the
tumbling to which they are subjected in either the coating
pan or the coating column.
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Compression
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.
This is because of increased pressure & abrasion to
which tablets are subjected when batch size is large &
different in temperature and humidity to which tablets
are exposed while coating and drying process.
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Pilot Plant scale-up techniques for Capsule
Capsules are solid dosage forms in which the drug
substance is enclosed in either a hard or soft soluble
container or shell of a suitable form of gelatin.
Steps in capsule production
1. Mixing of ingredient
2. Granulation and lubrication
3. Making of capsules
4. Filling of capsules
5. Uniformity testing
6. Packing and labeling
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Pilot Plant scale-up techniques for Capsule
The manufacturing process for capsulated products
often same to that tablets.
Both tablets & capsules are produced from
ingredients that may be either dry blended or wet
granulated to produce a dry powder or granule mix
with uniformly dispersed active ingredients.
To produce capsules on high speed equipment ,the
powder blend must have the uniform particle size
distribution, bulk density & compressibility required
to promote good flow properties & result in the
formation of compact of the right size and sufficient
cohesiveness to be filled in to capsule shells.
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Manufacture of Hard Gelatin Capsules
1. Shell composition :
Gelatin :
 Prepared by the hydrolysis of collagen.
 Gelatin in its chemical and physical properties,
depending upon the source of the collagen and
extraction.
 There are two basic types of gelatin:
Type – A and Type – B.
 The two types can be differentiated by their isoelectric
points (7.0 – 9.0 for type A and 4.8 – 5.0 for type B) and
by their viscosity and film forming characteristics.
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Manufacture of Hard Gelatin Capsules
 Combination of pork skin and bone gelatin are often used to
optimize shell characteristics.
 The physicochemical properties of gelatin of most interest to
shell manufactures are the bloom strength and viscosity.
Colorants :
 Various soluble synthetic dyes (“coal tar dyes”) and insoluble
pigments are used.
 Not only play a role in identifying the product, but also may
play a role in improving patient compliance.
E.g., white, analgesia; lavender, hallucinogenic effects; orange
or yellow, stimulants and antidepressants.
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Manufacture of Hard Gelatin Capsules
Opaquing agents :
 Titanium dioxide may be included to render the shell
opaque.
 Opaque capsules may be employed to provide
protection against light or to conceal the contents.
Preservatives :
 When preservatives are employed, parabens are often
selected.
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Manufacture of Hard Gelatin Capsules
2) Shell manufacture :
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Manufacture of Hard Gelatin Capsules
I.
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Dipping :
Pairs of the stainless steel pins are dipped into the dipping
solution to simultaneously form the caps and bodies.
 The pins are at ambient temperature; whereas the dipping
solution is maintained at a temperature of about 500C in a
heated, jacketed dipping pan.
 The length of time to cast the film has been reported to be
about 12 sec.
II. Rotation :
 After dipping, pins are elevated and rotated 2-1/2 times until
they are facing upward.
 This rotation helps to distribute the gelatin over the pins
uniformly and to avoid the formation of a bead at the capsule
ends.
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Manufacture of Hard Gelatin Capsules
III.Drying :
 The racks of gelatin coated pins then pass into a
series of four drying oven.
 Drying is mainly done by dehumidification.
 A temperature elevation of only a less degrees is
permissible to prevent film melting.
 Under drying will leave the films too sticky for
subsequent operation.
IV. Stripping :
 A series of bronze jaws strip the cap and body
portions of the capsules from the pins.
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Manufacture of Hard Gelatin Capsules
V. Trimming :
 The stripped cap and body portions are delivered to
collects in which they are firmly held.
 As the collects rotate, knives are brought against the
shells to trim them to the required length.
VI. Joining :
 The cap and body portions are aligned
concentrically in channels and the two portions are
slowly pushed together.
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Manufacture of Hard Gelatin Capsules
3) Sorting :
 The moisture content of the capsules as they are from the
machine will be in the range of 15 – 18% w/w.
 During sorting, the capsules passing on a lighted moving
conveyor are examined visually by inspectors.
 Defects are generally classified according to their nature and
potential to cause problems in use.
4) Printing :
 In general, capsules are printed before filling.
 Generally, printing is done on offset rotary presses having
throughput capabilities as high as three-quarter million
capsules per hour.
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Manufacture of Hard Gelatin Capsules
5) Sizes and shapes :
 For human use, empty gelatin capsules are manufactured in eight
sizes, ranging from 000 to 5.
 Capsule capacities in table:
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Size
Volume
Fill weight(g) at 0.8
g/cm3 powder density
000
1.37
1.096
00
0.95
0.760
0
0.68
0.544
1
0.50
0.400
2
0.37
0.296
3
0.30
0.240
4
0.21
0.168
5
0.15
0.104
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Manufacture of Hard Gelatin Capsules
 The largest size normally acceptable to patient is a No: 0.
 Three larger size are available for veterinary use: 10, 11, and
12 having capacities of about 30, 15, and 7.5 g, respectively.
 The standard shape of capsules is traditional, symmetrical
bullet shape.
 Some manufactures have employed distinctive shapes.
e.g. Lilly’s pulvule
tapers to a bluntly pointed end.
Smith Kline Beacham’s spansule capsules
taper at
both the cap and body ends.
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Manufacture of Hard Gelatin Capsules
6) Sealing :
 Capsules are sealed and somewhat reshaped in the
Etaseal process.
 This thermal welding process forms an indented ring
around the waist of the capsule where the cap
overlaps the body.
7) Storage :
 Finished capsules normally contain an equilibrium
moisture content of 13-16%.
 To maintain a relative humidity of 40-60% when
handling and storing capsules.
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Filling of hard gelatin capsules
Equipment used in capsule filling operations
involves one often of two types of filling
systems.
Zanasi or Martelli encapsulator:
Forms slugs in a dosatar which is a hollow
tube with a plunger to eject capsule plug.
Hofliger-Karg machine:
Formation of compacts in a die plate using
tamping pins to form a compact.
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ZANASI AUTOMATIC
CAPSULE FILLING MACHINE
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HOFLIGER KARG AUTOMATIC
CAPSULE FILLING MACHINE
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Filling of hard gelatin capsules
In this both system, the scale-up process
involve
bulk
density,
powder
flow,
compressibility, and lubricant distribution.
Overly lubricated granules are responsible for
delaying
capsule
disintegration
and
dissolution.
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OSAKA MODEL R-180 SEMI AUTOMATIC CAPSULE FILLING MACHINE
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Manufacture of Soft Gelatin Capsules
I. Composition of the shell:
 Similar to hard gelatin shells, the basic component
of soft gelatin shell is gelatin; however, the shell has
been plasticized.
 The ratio of dry plasticizer to dry gelatin determines
the “hardness” of the shell and can vary from 0.31.0 for very hard shell to 1.0-1.8 for very soft shell.
 Up to 5% sugar may be included to give a
“chewable” quality to the shell.
 The residual shell moisture content of finished
capsules will be in the range of 6-10%.
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Manufacture of Soft Gelatin Capsules
II. Formulation :
 Formulation for soft gelatin capsules involves
liquid, rather than powder technology.
 Materials are generally formulated to produce the
smallest possible capsule consistent with maximum
stability, therapeutic effectiveness and manufacture
efficiency.
 The liquids are limited to those that do not have an
adverse effect on gelatin walls.
 The pH of the liquid can be between 2.5 and 7.5.
 Emulsion can not be filled because water will be
released that will affect the shell.
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Manufacture of Soft Gelatin Capsules
The types of vehicles used in soft gelatin capsules fall in to
two main groups:
1. Water immiscible, volatile or more likely more volatile
liquids such as vegetable oils, mineral oils, medium-chain
triglycerides and acetylated glycerides.
2. Water miscible, nonvolatile liquids such as low molecular
weight PEG have come in to use more recently because
of their ability to mix with water readily and accelerate
dissolution of dissolved or suspended drugs.
 All liquids used for filling must flow by gravity at a
temperature of 350c or less.
 The sealing temperature of gelatin films is 37-400C.
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Manufacture of Soft Gelatin Capsules
III.Manufacture process :
A. Plate process :
The process involved
•
•
•
•
•
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Placing the upper half of a plasticized gelatin sheet over
a die plate containing numerous die pockets,
Application of vacuum to draw the sheet in to the die
pockets,
Filling the pockets with liquor or paste,
Folding the lower half of gelatin sheet back over the
filled pockets, and
Inserting the “ sandwich” under a die press where the
capsules are formed and cut out.
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Manufacture of Soft Gelatin Capsules
B. Rotary die press:
 In this process, the die cavities are machined in to
the outer surface of the two rollers.
 The die pockets on the left hand roller form the left
side of the capsule and the die pockets on the right
hand roller form the right side of the capsule.
 Two plasticized gelatin ribbons are continuously and
simultaneously fed with the liquid or paste fill
between the rollers of the rotary die mechanism.
 As the die rolls rotate, the convergence of the
matching die pockets seals and cuts out the filled
capsules.
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Manufacture of Soft Gelatin Capsules
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Manufacture of Soft Gelatin Capsules
C. Accogel process:
 In general, this is another rotary process involving
• A measuring roll,
• A die roll, and
• A sealing roll.
 As the measuring roll and die rolls rotate, the measured doses
are transferred to the gelatin-linked pockets of the die roll.
 The continued rotation of the filled die converges with the
rotating sealing roll where a second gelatin sheet is applied to
form the other half of the capsule.
 Pressure developed between the die roll and sealing roll seals
and cuts out the capsules.
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Manufacture of Soft Gelatin Capsules
4. Bubble method:
 The Globex Mark II capsulator produces truly
seamless, one-piece soft gelatin capsules by a
“bubble method”.
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Manufacture of Soft Gelatin Capsules
 A concentric tube dispenser simultaneously
discharges the molten gelatin from the outer annulus
and the liquid content from the tube.
 By means of a pulsating pump mechanism, the
liquids are discharged from the concentric tube
orifice into a chilled-oil column as droplets that
consists of a liquid medicament core within a molten
gelatin envelop.
 The droplets assume a spherical shape under surface
tension forces and the gelatin congeals on cooling.
 The finished capsules must be degreased and dried.
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Soft/Liquid-filled hard gelatin capsules
 Important reason: the standard for liquid filled capsules
was inability to prevent leakage from hard gelatin
capsules.
 As banding and of self-locking hard gelatin capsules,
together with the development of high-resting state
viscosity fills, has now made liquid/semisolid-filled
hard gelatin capsules.
 As with soft gelatin capsules, any materials filled into
hard capsules must not dissolve, alter or otherwise
adversely affect the integrity of the shell.
 Generally, the fill material must be pumpable.
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Soft/Liquid-filled hard gelatin capsules
 Three formulation strategies based on having a high resting
viscosity after filling have been described.
1. Thixotropic formulations,
2. Thermal-setting formulations,
3. Mixed thermal-Thixotropic systems.
 The more lipophilic contents, the slower the release rate.
 Thus, by selecting excipients with varying HLB balance,
varying release rate may be achieved.
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AUTO MATIC
CAPSULE
ARRANGEMNT
CAPSULE
POLISHING
MACHINE
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Scale-up for Parenterals
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Injectables
• The majority of the parenteral solutions are solutions
requiring a variety of tankage, piping and ancillary
euipment for liquid mixing, filteration, transfer and
related activities.
• The majority of the equipments are composed of 300
series austenitic stainless steel, with tantalum or glass
lined vessels employed for preparation of
formulations sensitive to iron and other metal ions.
• The vessels can be equipped with external jackets for
heating and/or cooling and various types of agitators,
depending upon the mixing requirements of the
individual formulation.
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Working area of a parenteral pilot plant
• Incoming goods are stored in special areas for Quarantine,
Released and Rejected status.
• A cold room is available for storage of temperature-sensitive
products. Entrance into the warehouse and production areas is
restricted to authorized personnel.
• Sampling and weighing of the raw material is performed in a
dedicated sampling area and a central weighing suite, respectively.
• The route for final products is separated from the incoming goods;
storage of final products is done in designated areas in the
warehouse while they are awaiting shipment.
• Several clothing and cleaning procedures in the controlled
transport zone and production area ensure full quality compliance.
• In addition, a technical area is located in between the production
zone and the area for formulation development.
• Here, the water for injection equipment is located, as well as the
technical installation of the lyophilizer.
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Lay-out of the pilot-plant
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Facility Design
To provide the control of microbial, pyrogen and
particles controls over the production environment are
essential.
 Warehousing:
All samples should be aseptically taken, which
mandates unidirectional airflow and full operator
gowning.
These measures reduce the potential for contamination
ingress into materials that are yet to receive any
processing at any site.
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Facility Design
 Preparation Area:
The materials utilized for the production of the sterile
products move toward the preparation area through a
series of progressively cleaner environments.
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Preparation Area
First the materials are passed through class 100,000 i.e. grade D
environment for presterilization.
Transfer of materials are carried out in air-locks
to avoid cross contamination
The preparation areas are supplied with HEPA filters.
There should be more than 20 air changes per hour
The preparation place is Class 100 area.
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Production area
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Production area
 Compounding area:
The manufacture of parenterals is carried out in class
10,000 (Grade C) controlled environments in which
class 100 unidirectional flow hoods are utilized to
provide greater environmental control during material
addition.
These areas are designed to minimize the microbial,
pyrogen, and particulate contamination to the
formulation prior to sterilization.
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Production area
 Aseptic filling rooms:
The filling of the formulations is performed in an Class 100
environment.
• Capping and Crimp sealing areas:
The air supply in the capping line should be of Class 100
• Corridors:
They serve to interconnect the various rooms. Fill rooms, air locks
and gowning rooms are assessed from the corridor.
• Aseptic storage rooms.
• Air-locks and pass-throughs:
Air locks serve as a transition points between one environment and
another.
They are fitted with the UltraViolet lights, spray systems, or other
devices that may be effectively utilized for decontamination of
materials.
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Formulation aspects
 Solvent:
The most widely used solvent used for parenteral
production is water for injection.
WFI is prepared by by distillation or reverse osmosis.
Sterile water for injection is used as a vehicle for
reconstitution of sterile solid products before
administration and is terminally sterilized by
autoclaving .
 Solubilizers:
They are used to enhance and maintain the aqueous
solubility of poorly water-soluble drugs.
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Formulation aspects
Solubilizing agents used in sterile products include:
1. co-solvents: glycerine, ethanol, sorbitol, etc.
2. Surface active agents: polysorbate 80, polysorbate 20,
lecithin.
3. Complexing agents: cyclodextrins etc
They act by reducing the dielectric constant properties
of the solvent system, thereby reducing the electrical,
conductance capabilities of the solvent and thus
increase the solubility.
 Antimicrobial preservative agents:
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Formulation aspects
 Buffers:
They are used to maintain the pH level of a solution in
the range that provides either maximum stability of
the drug against hydrolytic degradation or maximum
or optimal solubility of the drug in solution.
 Antioxidants:
Antioxidants function by reacting prefentially with
molecular oxygen and minimizing or terminating the
free the free radical auto-oxidation reaction.
Examples phenol (0.065-0.5%), m-cresol (0.16-0.3%)
etc.
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Instrumentation
• Mixer
• Homogenizer
• Filteration assembly
• Filling machinery
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Mixer/Homogenizer
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Filtration assembly
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Bottling/Filling machinery
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Sterilization and Depyrogenation
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Steam sterilization
Dry-heat sterilization and depyrogenation
Gas and vapour sterilization
Radiation sterilization
Sterilization by filteration
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Aseptic processing control and evaluation
• In-process Testing:
• End-product Testing:
• Process simulations:
Quality Assurance
• Particulate matter
• Pyrogen test
• Stability test
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Particulate matter detector
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Liquid orals
• The physical form of a drug product that is pourable
displays Newtonian or pseudoplastic flow behaviour
and conforms to it’s container at room temperature.
• Liquid dosage forms may be dispersed systems or
solutions.
• In dispersed systems there are two or more phases,
where one phase is distributed in another.
• A solution refers two or more substances mixed
homogeneously.
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Steps of liquid manufacturing process
• Planning of material requirements:
• Liquid preparation:
• Filling and Packing:
• Quality assurance:
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Critical aspects of liquid manufacturing
 Physical Plant:
• Heating, ventilation and air controlling system:
The effect of long processing times at suboptimal
temperatures should be considered in terms of
consequences on the physical or chemical stability of
ingredients as well as product.
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Formulation aspects of oral liquids
• Suspensions:
Purpose
Agent
Facilitating the connection
between API and vehicle
-wetting agents
Salt formation ingredients
Protecting the API
- Buffering-systems, polymers,
antioxidants
Maintaining the suspension
appearance
Colorings, suspending agent,
flocculating agent.
Masking the unpleasant
taste/smell
Sweeteners, flavorings
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Formulation aspects of oral liquids
• Emulsions:
Purpose
Agent
Particle Size
Solid particles, Droplet particles
Protecting the API
Buffering-systems, antioxidants,
polymers
Maintaining the appearance
Colorings, Emulsifying agents,
Penetration enhancers, gelling
agents
Sweetners, flavorings
Taste/smell masking
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Formulation aspects of oral liquids
• Solutions:
Protecting the API
Buffers, antioxidants,
preservatives
Maintaining the appearance
Colorings, stabilizers,
cosolvents, antimicrobial
preservatives
Taste/smell masking
Sweetners, flavorings.
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Layout of the pilot plant
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Equipments
• Mixer
• Homogenizer
• Filteration assembly
• Bottling assembly
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Filtration assembly
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General flow chart
Raw Materials
Measured and weighed
Mixing
Distilled water
Filling
Packing
Finished products storage
Quality Assurance
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Quality assurance
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•
•
•
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Dissolution of drugs in solution
Potency of drugs in suspension
Temperature uniformity in emulsions
Microbiological control
Product uniformity
Final volume
Stability
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References
• Lachman L. The Theory and practice of
industrial pharmacy. 3rd Edition. Varghese
publication house.
• www.google.com
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Thank You
Cell No: 00919742431000
E-mail : [email protected]
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