PHARMACEUTICAL POWDERS

CONTENTS:
1. Introduction to powders
2. Layout of manufacturing: Qualitative & Quantitative
3. Equipments as per GMP
Sieving
Milling
1. Ball mill
2. Fluid energy mill
3. Hammer mill
4. Roller mill
Mixing
Tumble blender:
Double cone blender
V-blender
Agitated batch mixer:
Ribbon mixer
Sigma blade mixer
Conta mixer
Octagonal mixer
Drying equipments
Filling
Packaging
4. SOPs (Standard Operating Procedure)
5. IPQC
6. Validation
7. Documentation
8. BMR (Batch Manufacturing Record)
9. BPR (Batch Packaging Record)
10. Cleaning card
11. Documents needed for re-calling of batch
12. Problems associated with Powder manufacturing
13. Hazards of Powder manufacturing
14. Processing of Powder
15. Recovery System of Powder
16. Innovations in Powder dosage form
17. List of Pharmaceutical powders available in market
18. Study questions
19. References

1. INTRODUCTION TO POWDER

Powder are homogeneous mixture of drug/drugs and excepient/excepients in a dry, fine
state of subdivision.

API + EXCIPIENT POWDER DOSAGE FORM
(BOTH ARE IN POWDERED FORM)
It includes all fillers, sweeteners, taste modifiers, adsorbents, coloring agents, flavoring
agents etc.
Powder used for external purpose are called as Dusting powders.

Characters of good powder:
Fine state of sub division
A perfectly homogeneous preparation
Small particle size, large surface area and high absorptive capacity are
important character for antacid, antidiarrhoeal and other medicaments
which are use for local treatment of skin and g. i. tract.
Advantages:
Each dose can contain a different amount of active drug.
Can be administered easily to infants and young children who cannot swallow tablets or
capsules.
Drug will have a rapid onset of action since disintegration is not required .
Can be applied to many body cavities such as ears, nose, tooth socket, throat.
Drugs tend to most stable as a solid. eg, Dry Antibiotic syrups. Half life of Antibiotics in
solid form is about 2-3 years but once it is formulated in liquid form it reduces to 1-2
weeks. So, dry syrups are better option for those types of drugs.
Can be made into many different dosage formulations (capsules, tablets, powders for
reconstitution, dusting powders, bulk powders, powders for inhalation, etc.).
Convenient for large dose.
Disadvantages:
Masking of unpleasant taste is a big problem.
Less convenient to carry as compared to tablets & capsules.
Less accuracy in dispensing potent drugs in powder dosage form.
We can not supply drugs in powder dosage form which are degraded in stomach.
Time consuming to prepare.

Powders as a primary requirement for pharmaceutical dosage
forms:
o Before thinking of production of any dosage form we must think about the powder which
serves as the precursor for most of the dosage forms. So, we must think about powders
required for preparation of these dosage forms because it affects the success of most of
the dosage forms.
o Now a day, Pharma people are diverting towards developing the dry powder syrups,
sterile powders for instant preparation of injectables solutions. It also tells the story about
the importance of the powders in pharmaceutical industry.
o Powders are primary requirement for:

Tablet
Capsule
Suspension
Dry syrup
Parentral
Aerosol

Standards of powders:
According to IP/BP powders can be graded into seven classes. Degree of fineness or
coarseness of a powder is differentiated & expressed by the size of the mesh of the
sieve through which the powder is able to pass.
Grade of powder Sieve through which all
particles must pass
Sieve through which
not more than
40% of particles
pass
Relative
Coarse 10 44 01
Moderately coarse 22 60 1/6
Moderately fine 44 85 1/24
Fine 85 120 1/90
Very fine
Micro fine

Super fine
120
90% pass through 350
mesh
90% pass through 10m
-
-

-
1/120
-

-

Classification of powders:








Bulk powder:-
o Bulk powders are non potent powders and can be dosed with acceptable accuracy and
safety using measuring devices like teaspoon, cup, or insufflators.
o Examples: - Antacids, dietary supplements, laxatives, and a few analgesics and some of
bulk powders used topically.

Divided powder:-
o Divided powders or charts are single doses of powdered medicinal individually wrapped.
o Wrapping material used:-Cellophane, metallic foils, or paper.
o It is a more accurate dosage form than bulk powders.

Dusting powder:-
o Dusting powders are fine medicinal (bulk) powders intended to be dusted on the skin.
o Sifter-top containers are required for dispensing them.
o Inert bases for dusting powders: - Bentonite, Kaolin, Kieselguhr, Magnesium carbonate,
Starch, and Talc.
o 100-200 mesh sieves are required for preparation of dusting powders.

Insufflations:-
o Insufflations are extremely fine powders to be introduced into body cavities.
o To administer insufflations, the powder is placed in the insufflators, and when the bulb
is squeezed, the air current carries the fine particles through the nozzle to the region for
which the medication is intended.
o All extemporaneously compounded insufflations must be passed through a 100 mesh
sieve.

Douche powder:-
o Definition:-They are used to prepare solutions that cleanse the vagina. Most douche
powders are used for their hygienic effects, but a few contain antibiotics.
o They are formulated in such a way that the pH ranges from 3.5 to 5 when the solution is
prepared. Feminine bulb syringes or fountain syringes are used for vaginal irrigation.
o Packaging:- Some commercial douche powders are available in metal foil packets, which
contain the proper amount of powder for a single douche.
o Douche powders should be packaged in glass jars with a wide mouth.
o Many douches are also available as prepared unit of use solutions in disposable
applicators.











PROCESS FLOW OF POWDER MANUFACTURING:






2. LAYOUT OF POWDER MANUFACTURING


special requirements for effervescent powders:-
Formulation of effervescent powders require more care of environmental factors like
humidity control and temperature control because of involvement of anhydrous materials
like citric acid, tartaric acid etc. Preservation of the active principles is important in this
case because they are sensitive to moisture.

special requirements for antibiotic dry syrups:-
Packaging area for antibiotic dry syrups must fulfill the requirements of sterile
manufacturing area as per GMP regulations. Aseptic environment must be maintained at
the filling point of vials to avoid contamination.







QUANTITATIVE LAYOUT FOR POWDER MANUFACTURING:
Suppose, BATCH SIZE is: 10,000 sachets each containing 10gms. Of powder.
Therefore, We need:
RAW MATERIAL:100kg.(inclusive of excepients)


MILLER CAPACITY: 100 kg.


MIXER CAPACITY : 50kg. per turn


PACKAGING MACHINE CAPACITY : 100-150 sachets/min.


3.EQUIPMENTS AS PER GMP:

The following equipments are recommended for the manufacture of powder: -
Milling equipments.
Sieving equipments
Mixer.
Drying Equipments
Filling equipments.
Packing equipments

3.1 Sieving equipments:
Sieving can be done by one of the following methods.
I. Agitation method by vibration, by oscillation e.g. VIBRO-SIFTER
II. Brushing methods
III. Centrifugal methods












INNOVATION IN SIEVE TECHNOLOGY

PHOTO ELECTRO FORMING (PEF) made sieves: No trapping during sieving or grading.
Because of no woven wires.
Apertures formed by LASER technology on the metallic plates.
Good strength and rigidity as compared to woven sieves.

SCREEN CLOTH

UNDER SIZE
DISCHARG
E

OVER SIZE
DISCHARGE



3.2 Milling equipments:


3.2.1 BALL MILL
Horizontal rotating hollow vessels with cylindrical shape.
Balls ,pebbles or rods are used as per requirement.

Hardinage mill:-
Cylinder has conical end towards discharge units.
The size of balls is different. The small balls are at the apex of
the cone and large balls are at the bottom.
CRITICAL SPEED : 76.6 / D
OPTIMUM SPEED : N = 57 40 log D
D= inside diameter of mill in ft.



3.2.2 FLUID ENERGY MILL
Material is conveyed at high velocity by air or steam.
Air /steam is passed through the nozzle at 100 to 150 psi.
Violent turbulent decrease particle size by
interparticular attrition and impact.
Size obtained is 1 to 20 micron.
Use for biological products.


3.2.3. HAMMER MILL


Types of mill Action Product size Used for Not used for
Cutter Cutting 20-80 mesh Fibrous, crude
animal and
vegetable
drugs
Friable material
Revolving Attrition and
impact
20-200 mesh Fine grinding of
abrasive
material
Soft material
Hammer Impact 4-325 mesh Almost all drugs Abrasive material
Roller Pressure 20-200 mesh Soft material Abrasive material
Attrition Attrition 20-200 mesh Soft and fibrous Abrasive material
Fluid-energy Attrition and
impact
1-30 m Moderately hard
and friable
material
Soft and sticky
material
A hammer mill is essentially a steel drum containing a vertical or horizontal rotating shaft
or drum on which hammers are mounted. The hammers are free to swing on the ends of the
cross, or fixed to the central rotor. The rotor is spun at a high speed inside the drum while material
is fed into a feed hopper. The material is impacted by the hammer bars and is thereby shredded
and expelled through screens in the drum of a selected size.
ROLLER MILL:
It consists of 2 rollers rotating in the opposite direction. Material flows from the
hopper above, in between the rollers & get milled. Rollers are run by motor.

Mixer (Blender)

Parameters to be consider while selecting mixer are,

Material consistency & P. size distribution through one mixing.
Acceptable limit of variations in final mixture.
Variations in batch size the mixer must handle.
Requirement of liquid addition for the mixture.
Requirement of shearing or de-lumping.
Space availability Floor space or Head room.


Blender Selection vs. Material Type

Non-cohesive blend (flows & mixes easily)
Bin Blender
Twin Shell
Other precision, rotational blender

Cohesive blend (lumpy, not free-flowing)
High Shear (e.g. Twin Shell w/ I-Bar, Colette, Lodige)

Ordered Mix (drug << excipient)
Tumbling mixers, cone mixer, high energy many types are allowable.

3.3.1. Tumble Blenders
Batch tumble blenders rotate, tumbling the material to achieve mixing. The blenders
are available in various geometries, affecting each unit's material movement, mixing
efficiency, and ease of between-batch cleaning.
Tumbling blenders are best suited to mixing dry powders and granules and can
include liquid addition components for coating and similar applications.
SCREEN

However, excessive moisture can cause the material to agglomerate and form lumps
that will impede mixing. To break up the lumps, the units can be equipped with
delumping components (such as internal baffles or agitators). From the outlet, the
batch can be discharged via an optional retractable sleeve into drums or other
containers for shipping.
A tumbling batch blender can be one of two basic types:
Double-cone blender.
V-shaped blender.

Double-cone blender (Rota-Cone)
The Rota-Cone Blender consists of two cone-shaped sections typically with 45-degree
slopes.
The cone sections are welded at their wide ends to a center band. The blender is
mounted between two trunnions that permit the unit to tumble end over end.
An opening in one cone's end can serve as both the inlet and outlet, or the inlet can be
in one cone's end with the outlet in the other.
Cleaning access is through the outlet. As with any tumble blender, the unit can be
equipped with a spray line for liquid addition and an agitator for delumping or
introduction of high shear if required (eg, for granulation).
The spray line with various nozzles designed for precise atomization at different
viscosities and the agitator each extend from one trunnion into the vessel. Each
function is controlled independently for maximum process control.
In operation, material is loaded to fill level of typically 50 to 60 percent of the
blender's capacity. The blender tumbles, and the material in the vessel spreads out. The
transition area at the band between the cones prevents the material from sliding along
the inner wall and instead causes the material to fold over itself. This provides gentle
mixing with only very slight shear.
At the 50 to 60 percent fill level, the blender typically achieves a mixture in 5 to 10
minutes with a 95 percent or better homogeneity. But at any fill level between 35 and
75 percent (or within the blender's center band), the blender will eventually obtain an
acceptable mixture. (For a batch mixer, the fill level determines the batch size.)
The blender is ideal for soft powders or granules that degrade by attrition. At a fill
level of 50 percent or higher, the agitator can typically delump agglomerated material
during mixing. The smooth transition area in the vessel also simplifies cleaning
because there are no areas to trap particles and cross-contaminate batches.
A variant of the standard double cone blender is the Off-Set Rota-Cone Blender -
utilizing the same basic geometry as the Rota-Cone but with the center-band slanted to
ensure that the material along the sides is shifted away from the vessel walls to effect a
"figure 8" type motion during tumbling that allows for a slightly higher fill level than
in the standard Rota-Cone design. All other features are the same as the standard Rota-
Cone.

3.3.1.2. V-shaped blender (Rota-Vee)

The Rota-Vee Blender is similar to a double-cone unit but consists of two large-
diameter pipe sections cut at a 60-degree angle and welded together to form a V.
Inlets are typically located in the top of both legs of the V; a bottom outlet is at the V
point where there is a transition from an elliptical to cylindrical (circular) discharge.
The unit is also mounted on trunnions to allow it to tumble and can be equipped with a
spray line for liquid addition and an agitator for delumping, each running through
trunnions into the vessel. Cleaning access is through both inlets.
In operation, material is loaded to a fill level of typically 50 to 60 percent of the
blender's capacity. The unit tumbles end over end like the double-cone blender, but the
mixing action is different because of the vessel shape. As the V-shaped blender
tumbles, the material continuously splits and recombines, with the mixing occurring as
the material free-falls randomly inside the vessel. Mixing is achieved in 5 to 15
minutes with a 95 percent or better homogeneity.
The free-falling action combined with increased frictional contact between the material
and the vessel's long, straight sides result in slightly less gentle mixing than a double-
cone unit. This can create slight shear, producing some particle size reduction through
attrition.
The blender is suited to most powders and is often used for pharmaceuticals, but the
mixing action's slight shear limits the blender's use for some very soft powders or
granules. Cleaning between batches takes longer in this blender than in the double-
cone unit.
3.3.2. Agitated Batch Mixers
Agitated batch mixers are available with various geometries, agitators, and agitation
patterns. Depending on the type, the mixers can handle materials ranging from dry
powders to non-flowing and gritty, viscous pastes. The mixers can be equipped with
components for liquid addition and delumping. The batch typically discharges from the
mixer outlet to a mechanical conveyor for transfer to bagging or packaging.
Some common types of agitating batch mixers are:
Ribbon mixers.
Sigma blade mixers.
Conta blander.
Octagonal mixer.

3.3.2.1. Ribbon mixer

The ribbon mixer typically has a U-shaped trough with a rotating single-shaft,
double-helix agitator and a large top cover. (A twin-trough unit with a double-shaft
agitator is also available - especially for the more difficult materials that tend to
"pack" during mixing.)
The agitator's shaft is mounted in the trough center and has welded spokes. Inner and
outer sets of ribbons (also called spirals) are welded to the spokes, conforming to the
trough shape.
The clearance between each ribbon's outer edge and the trough wall typically range
from 1/8 to 1/4 inch.
The inlet is located in the vessel's cover; and the discharge valve is typically located
in the trough's bottom center, but can also be at either end of the trough.
A spray bar for adding liquids can be mounted above the ribbons. To reduce chunky
feed or agglomerates that the ribbons can't break apart, the mixer walls can be fitted
with spinning high-speed choppers. The cover can be taken off for cleaning access.
In operation, material is filled to the top of the outer ribbon's rotation. The shaft
rotates at relatively low speed, and the moving ribbons push the material back and
forth, mixing it. With a center discharge, the inner ribbons move the material toward
the trough ends, and the outer ribbons push the material in the opposite direction
toward the center discharge valve.
Mixing is achieved in 15 to 20 minutes with a 90 to 95 percent or better homogeneity.
If so required, the high-speed choppers are operated intermittently to break down
agglomerates and reduce the overall mixing time.
The mixer can handle various materials ranging from powders to some slurries.
However, the mixer's pushing action can wedge particles between the ribbons and
trough wall, creating shear that can reduce a soft material's particle size. The unit is
also suitable to applications with limited headroom. Because of its intricate
configuration, the agitator requires extensive cleaning to prevent batch cross-
contamination; the agitator can remain in the mixer or be removed for cleaning.
A common variation of the ribbon mixer - the paddle mixer - has flat paddles rather
than ribbons. The mixer operates similarly but the paddles tend to last longer and are
suited to mixing abrasive materials. Large particles are also less likely to wedge
between the paddles and trough wall, which can prevent material degradation.
3.3.2.2. Sigma blade mixer
The sigma blade mixer consists of twin troughs, each fitted with a rotating agitator.
Each agitator is a heavy-duty Z-shaped blade.
The inlet is located in the mixer's top cover.
The mixer can be tilted to one side for discharge or can be equipped with a screw
discharge at the bottom between the troughs.
A spray bar can be mounted above the blades and cleaning access is through the top
cover.
In operation, material is loaded through the inlet to typically 40 to 65 percent of the
mixer's capacity. The blades can overlap and operate at the same speed or can run
tangentially at different speeds. In either case, the blades force material onto the sharp
edge between the troughs, producing very high shear and reducing any large particles.
The mixing action produces a mixture in 10 to 30 minutes with a 99 percent or better
homogeneity. The mixing action also produces a consistent particle size distribution
without requiring an additional delumping agitator.
The mixer handles pasty, sticky, and gritty slurries with viscosities up to 2,000,000
centipoises. Examples are rubber, carbide powders, silicones, caulking compounds
and other industrial applications. Sanitary designs are available for food and
pharmaceutical applications (chocolates, chewing gums and other pastes). When
equipped with a screw discharge, difficult materials can be more easily discharged.

3.3.2.3. Conta mixer
Mixing in the diagonal and eccentric planes.
Low shear blending action prevents excessive fines or change in particle shape.
Fast loading.
Complete discharge.
Short cycle time.
Low power requirement.
Double column is lifted at two ends and rotated. Therefore, blending occurs only in
diagonal plane not in eccentric plane.
3.3.2.4. Octagonal mixer
Designed to process large batch size
Baffles to break lumps.
Lesser power consumption.
Powder charging can be done by any of the 3 methods:-
Drum charging.
Lifting & positioning device.
Vacuum power conveying process.
Most ideal for lubrication of granules & homogenization of multiple batches into single
batch
Other applications
Most batch mixers can be modified to dry and cool materials as well as mix them.
The modifications include adding heat or cooling to the mixer vessel, operating
the vessel under a vacuum, or both.
3.4.DRYING EQUIPMENTS:
Fluidised bed dryer
Spray freeze dryer

3.5 Filling equipments:

Automatic dry powder syrup filling machine:


A micro dosing of antibiotic powder is now used for dry syrup powder filling
through a small intermediate funnel to avoid manual handling of bottles and
achieving speed without loosing conceptual high degree of accuracy for
uniform density free flowing dry syrups.


OPERATION
The dry syrup granules placed in the powder hopper is continuously agitated by a pair of agitators for
maintaining bulk density of powder, before it is drawn into the port of the powder wheel.
The powder wheel's port when subjected to the vaccum draws powder from the hopper and indexed
further, where the excess powder is doctored off.
The powder remains in the port due to the vacuum, till the indexed port of the powder wheel reaches
in the vertical position.
Bottles continuously received on the infeed side of the conveyor are positioned and held perfectly in
vertical position by separators, just below the funnel.
The timed dose of low pressure compressed air / inert gas empties powder from the port of powder
wheel into the funnel.
Further, the powder gets transferred from funnel to the bottle and the bottle after filling is
released by the bottle separators to move further on the exit side of the conveyor.


3.6 Packaging of powders:
The methods of packaging powders in bulk do not differ from those used for the
various substances already described, but they are sometimes presented in single dose
containers.
These may include sachets, filled automatically on suitable strip-packaging machines
using paper, aluminium foil, and plastic films or laminations of these, depending upon
the degree of protection required.
Much of this work is carried out by contract packers who specialize in this type of
packaging.
Powders containing drugs which are unstable in aqueous solution, along with flavouring,
are sometimes issued in screw capped bottles containing predetermined quantities. To
these, sufficient water is added by the pharmacist to produce a stated volume of a solution
or suspension, suitable for oral administration, and which will retain its potency for as
long as it takes for the patient to use it. The main feature of such containers is the
efficiency of the closures in preventing the ingress of water vapour.
Some biologics, which are administrated parenterally, but which are unstable in
solution, are issued as freeze-dried (lyophilized) powders in hermetically sealed
containers.
These may be ampoules or rubber capped bottles and their size will depend upon the
strength of the solution which is to be freeze-dried. It will also depend on any
tendency to froth when exposed to a high vacuum at a low temperature in a freeze-
drying machine, whereby the solvent is volatilized. Thus a 2 or 3 ml ampoule may be
used for an injection which, when reconstituted by the introduction of necessary
solvent, may have a volume of only 1 ml. If rubber capped bottles are used the closure
must be of a type which sits lightly on the necks of the bottles until all of the solvent
has evaporated, whereupon it can be pressed home to make a moisture vapour proof
seal.
Packaging of effervescent granules: The most important requirement of the
packaging of effervescent granules, again, is the exclusion of moisture, which will also
ensure the preservation of the active principles if they happen to be sensitive to moisture.
For consumer packs, glass bottles or plastics bottles or sachets of suitable film or
laminates may be used.
For bulk quantities, metal containers may also be used provided reaction between
them and their contents is prevented by means of suitable plastics linings if necessary.
Effer-Soda Sodium Bicarbonate is dried and partially desiccated to increase its stability, making it a
more stable form of sodium bicarbonate. It has been manufactured to include a desiccant skin of
sodium carbonate that surrounds the core of sodium bicarbonate. This desiccant skin makes up
8 to 12% of Effer-Sodas total mass. This sodium carbonate outer layer protects the sodium
bicarbonate core by absorbing moisture to form a hydrate salt (sodium sesquicarbonate), which is
stable up to 70 C. The temperature stability of the sodium sesquicarbonate moisture trap is the
key to the protection mechanism. Even when stored at elevated temperatures, this protection
prevents the hydrated moisture from causing the effervescent reaction to happen too early, such
as when the product is in the final packaging.
Sachet packing machine
Product Range:
Powders / Granules Spices, Soups, Yeast, Desserts, Detergents, Pharmaceutical and
Agricultural Powders / Granules, Tea, Tobacco, Pan Masala, Coffee.
Pack Size:
Width from 35 mm to 1 00 mm or 80 mm to 150 mm
Length from 50 mm to 120 mm or 90 mm to 240 mm
Capacity:
From 0.5 gms to 25 gms
From 25 gms to 100 gms
From 100 gms to 250 gms
(depending upon bulk density of the product).
Output:
From - 20 pack / min
Upto - 70 pack / min
The machine can be fitted with additional options i.e. Conveyor, Over printer, Product
Level Control Dust Extractor, Sachet Batching, Liquid Filler
General I nformation:
A vertical form, fill and seal machine for producing center sealed sachets handling all
types of free flowing powders/granules. The machine speed is infinitely controlled from
20-70 cycles/minute. Single reel film laminate stock reel feed. Max reel dia. 400 m/m on
76 m/m core I/Dia. Product dosing by cup filler. All part in contact with product are high
quality stainless steel. Sealing dies gear operated. With complete pressure and
temperature control on sachet seal area.
Specifications:
A robust machine with particular consideration for minimum maintenance and ease of
adjusting and giving high reliable output. All parts in contact with product, manufactured
in stainless steel. Accurate sealing die temperature control and fully controllable die
pressure. Cut off blade for separating sachet from film web housed in horizontal die for
maximum efficiency. Photo cell print registration. Comprehensive push. button control
panel with cycle counter. Front safety guard and access doors electrically interlocked.
Tool kit. and operators manual.
Optional Filling Systems:



4.SOPs:
SOP for Ball Mill:
Wear the usual safety measures such as safety glasses, Laboratory coat , Glove
and Foot wear which covers toes. No loose clothing, jewelry, or hair.
Keep a solvent spill kit near the Ball Mill
Keep the MSDS of the material and solvents to be used near the Ball Mill.
Before operating the machine make sure electric power connections are made
correctly and power cable is not damaged
Before inserting the sample jar, turn on the mill and check the sound , if it is so
noisy put some oil on the bearings.
Choose a jar based on the amount of material being grinded.
Take the material in the porcelain jar and add 1: 20 wt ratio porcelain balls , screw the
cap tightly.
Keep open sources of water/solvents away.
Mill in use notification. Turn off the mill


SOP (CLEANING PROCEDURE FOR PROCESSING DEPARTMENTS)
DAILY ( OR AS NEEDED)
1. Mop floor in the morning and end of day, or as needed, with an approved detergent.
2. Sanitize the floor at least once daily with an approved disinfectant. The mop used for
sanitizing should be placed in a pail of water and steam bubbled through for 15
minutes first.
3. Empty waste containers.
4. Wash countertops with a solvent such as isopropyl alcohol.
5. Inspect bulk drums and tanks top and exterior walls and wipe with a solvent.
6. All spills must be wiped up Immediatelly.
7. All waste should be deposited in the proper trash receptacles provided.
WEEKLY
1. Wash plastic entrance curtains with an approved detergent.
2. Sanitize sink with an approved disinfectant.

SOP FOR CLEANING OF MIXER
1. Clean the lid and vessel of the mixer with the jet of tap water.
2. The mixer is rinsed with hot tap water, to remove adhered lumps of powder, keeping
it in tilting position.
3. Pour approximately 100 liter water into the mixer. To it add 5o ml of Teepol and run
the mixer for 15 minutes. Then use nylon brush to remove any adhered material.
4. Ensure that no material is adhered to the corner and edges of the shaft.
5. Remove the water and rinse with fresh hot DM water and dry it by using clean muslin
cloth.
6. Collect the rinse of the final checking and send to QC department for checking of
contamination from previous batch.
7. Paste the specified clean label after getting approval from QC department.
8. Cover the mixer with lid, when in use.
9. Protect the mixer from atmosphere dust by using polythene bag.
10. Clean the mixer prior to use to manufacturing operation.

SOP FOR OPERATION OF DOUBLE CONE BLENDER
Note:
1. Use latex gloves elbow size during loading and unloading of materials.
2. Before loading of the materials, ensure that the inner and outer surface of the drum
blender is cleaned as per the standard cleaning procedure.
Loading position for blender
Adjust the angle of the powder with the help of a moving wheel to a required position for
convenience in loading of materials.
Loading of materials
1. Load the materials from the container into the blender as per the sequence specified in
the individual MFC and BMR.
2. After loading the materials, close the lid of the blender.
3. Put the safety pin on the lid and fit it properly within its groove. Lock the blender lid
by moving the wheel in clockwise direction.
Operations
1. Before starting the operation, ensure that the lid and the safety pin lock are properly
assembled.
Caution: Put the safety guard before commencement of the operation. Cover the area
below the blender with polybags.
2. Switch on the equipment and start the blending.
3. Blend the material as per the time specified in the individual MFC and BMR.
Note:
During blending operation attach an in-process label to the drum blender specifying the
name of the product, batch No., its status along with signature of production officer.
Unloading
1. Ensure that main switch of the equipment is put off.
2. Remove the polybags and the safety guard.
3. Adjust the position of the blender at the required angle for convenience in unloading
the materials.
4. Unlock the safety pin and remove the lid from the blender.
5. Unload the blended materials.
Clean the blender and dismantled parts as per standard cleaning procedure.
SOP (Maintenance procedure for mixers)
1. Grease all fittings.
2. Visually inspect the lugs on the base for wear and signs of cracking.
3. Start mixer and listen for any squeaks. Correct as necessary.
4. Record all operations in the attached log, for each mixer.
5. Report any problems to the maintenance Supervisor.

5. Testing of the POWDER (QC)
Fineness
Slide Control & Lighting : Compare with std when spread on a white paper background
OR Compare Sample with Standard by Skin tone
Dispersion of Color: It is checked by spreading it on white paper & examining it with
magnifying glass.
Pressure testing (Penetrometer)
Uniformity of mixing.

6. VALIDATION:
Validation of raw material
Depending on the susceptibility of the raw material on aging, either physical,
chemical, or microbiological stability should be assessed.
It is suggested that, it is appropriate to manufacture several lots of final products with
raw material at the low & high end of specification limit. This type of testing is useful
when it is known that the product may be sensitive to small changes in the
characteristics of the excipients or active ingredient.
Final step of raw-material validation should involve on site inspection of the supplier,
to review the vendor manufacturing operation & control.
Validation of Blending operation
Determination of optimal blend time.
Check if excessive blending will cause demixing or segregation of components.
The mixing process is validated by the verification of the homogeneity of mixed
powders, by taking samples at three different levels of the mixer (top, bottom &
middle).
Possible interaction between process & material
Characteristics of blend-
o Bulk density
o Particle size distribution
o Color uniformity
Test different sized loads in the blending apparatus e.g. 30 %, 50 %, 70 %, of working
volume
Powder flow from hopper observation can include rat hole & bridging etc.

Process Variables validated
1. Sizing Screen type, Screen size,
Feed rate
2. Blending Load size, RPM, Blending time,
Order of addition
3. Granulating Load size, Amount of granulating agent

Variable

Parameters
Blending time
Blender speed
Intensifier bar
Blend Content Uniformity
Assay
Particle size distribution
Powder flow
Densification/Aeration


The standards for blend uniformity is as follows:
Readily passing -RSD is less than 4%
Marginally passing-RSD is more than 4% but less than or equal to 6%.
The limit in both the cases is 90-110%.
The USP Standard is 85-115% and RSD is not more than 7.8%

Validation of final packed material
Checking integrity of foils
Checking integrity of sealing
Checking opening ease
Permeability of foils
7. DOCUMENTATION
AIM OF DOCUMENTATION
To define specifications for all materials.
To define methods of manufacture and control.
To ensure that all personnel connected with manufacture and control know what to do
and when to do.
To ensure that the personnel authorized to release a batch for sale or rejection have all
information that is necessary to take the decision.
To provide information during investigation if a batch is suspected to have defect.
DOCUMENTATION MUST ANSWER.
Who did the work?
When was the work done?
What was the work done?
Where was the work done?
How was the work done?
What conditions prevailed
during performance of the work?
What conclusions can be drawn
from the work?

MASTER FORMULA RECORD
Contents of MFR as per section 211.186 of the regulations are
Name and strength of the product along with dosage form.
The name & weight / measure.
A complete list of all the ingredients to be used indicating any special quality
characteristics.
An accurate statement of weight / measure.
Permissible limits beyond which investigation is required.
A description of containers, closures & packaging materials, equipments to be used.
Processing and packaging procedures.
In process controls to be exercised during processing & packaging.
Precautions to be taken during manufacturing& storage of semi finished product.

8. BATCH MANUFACTURING RECORD (BMR)

To be prepared as per 211.188 section of regulations.

1) NAME OF PRODUCT:-
2) GENERIC NAME:-
3) BATCH NO.:-
4) MFR REF.NO.:-
5) DATE OF MANUFACTURING:
6) BATCH SIZE:-
Name of
ingredient
.
Code no. Quantity
taken /
pack
Quantity
taken/
batch
Answer of these questions give us
complete idea about the dosage
form starting from its Raw
materials to the final pack
including the persons involved in
it directly or indirectly.



7) NAME OF EQUIPMENT USED:-
8) ENVIRONMENTAL SPECIFICATIONS :-
TEMP.:- HUMIDITY:-
9) PRACTICAL YIELD:-
10) THEORETICAL YIELD:-
11) IPQC & VALIDATION RECORD:-
i) PRODUCT STABILITY TEST:-
ii) ASSAY OF ACTIVE INGREDIENT:-
12) DATE OF STARTING:-
13) DATE OF COMPLETION:-
14) DATE OF EXPIRY:-











ATTACHMENTS FOR BMR
MIXING RECORDS:-
1) NAME OF EQUIPMENT USED:-
DATE TIME DURATION OF MIXING


SIGN OF OPERATOR
2) RESULT OF UNIFORMITY OF MIXTURE:-
(ATTACH ANALYTICAL REPORTS)


SIGN OF HEAD OF QC DEPT.


ATTACHMENTS FOR BMR
DRYING RECORDS:-

1) EQUIPMENT USED:-
CHECKED BY
PRODUCTION
MANAGER

CHECKED BY
HEAD OF QC DEPT
Date Time Drying temp. Duration



If tray dryer has used, use this chart
Time Temperature


Moisture content of powder:-
Actual yield of powder:-
Theoretical yield of powder:-
Whether within permissible limit (Yes/No):-



SIGN OF OPERATOR





9. BATCH PACKAGING RECORD (BPR)
To Be Prepared As Per Section 211.130 &211.125(F) Of Regulations
1) PACKAGING DESCRIPTION:-
2) PRECODING OF LABELS AND PRINTED PACKAGING MATERIALS
EXAMINED AND VARIFIED BY:-
(Attach specimen)
3) NO. OF PRECODED:-
4) LABELS RECEIVED:-
5) PRINTED PACKAGING MATERIAL RECEIVED:-

Date Start
tim
e
Close
tim
e
Name of person responsible for
Packaging

Other
operations
packaging

Checking
Packed
containers
Counting &
filling in
boxes

6) TOTAL QUANTITY PACKED:-
7) DATE OF COMPLETION:-
8) QUANTITY COLLECTED AS SAMPLES BY QC DEPARTMENT:-


RECONCILIATION OF LABELLING & PRINTED PACKAGING MATERIALS

Labels Foil Cartons
Requisitioned/Received

Used

Returned

Destroyed

Destroyed on (date)

Destroyed by


SIGN OF
PACKAGING INCHARGE




10. CLEANING CARD

1) NAME OF THE EQUIPMENT:-
2) LAST PRODUCT HANDLED:-
3) BATCH NO.:-
4) CLEAN AND READY FOR PRODUCT.:-
5) CLEANED BY:-
6) DATE:-


SIGN OF CLEANER SIGN OF SUPERVISOR


11. Document Needed For Recalling Batch
We must preserve our records more than one year from the date of expiry of the batch
so that if any problem occurs, it can be manipulated.
A separate Register is provided which must include all the names and address of
customers who buy the products in earlier times.

12.PROBLEMS ASSOCIATED WITH POWDER MANUFACTURING:

Segregation: Particles having lesser density segregate from particles having
higher density. Solution : having narrow particle size distribution of the blend.
Cross contamination
Dusting
Development of surface energetics on the constituent particles
e.g. Resistivity of a powder mixture which contained lactose and glucose was
found to follow a linear relationship with the concentration.
Triboelectrification of pharmaceutical powders may cause problems during
processing and manufacture due to adhesion/cohesion effects


13.HAZARDS OF POWDER MANUFACTURING:
Dust explosions are more insidious, and potentially more
dangerous.
Milling & mixing processes of highly potent API can cause health hazards in
workers. So, project engineers are often faced with the requirement to place the
entire feeding and milling operation in an isolator or glove box.
In designing such milling systems, it is imperative that the feeding device used be
completely accessible and dismantled through the use of gloves in glove ports.


14.Powder Processing:
Air/solids cyclone technology provides an effective and very efficient
solution for the separation and collection of powders in dust
extraction applications. Based around established cyclone principles for air and
solids separation, the design put much emphasis on an easy-clean hygienic
construction with an option of a full safe-change facility for the powder collection
receptacle. A further benefit of the filter-less design meant that filter cleaning by
compressed air is no longer necessary, further simplifying the system and improving
the integrity of the design.
15.Powder Recovery System:
The benefits of the Uni-Dust Powder Recovery System are of great significance to any
powder processing application requiring the highest levels of containment and efficiency.
As waste material is retained within the confines of the process room it ensures that
centralised dust collectors are able to operate in a clean condition for longer than average,
thus saving money by reducing the number of filter changes.


16.INNOVATIONS IN POWDER DOSAGE FORM:
Novel powder formulations for controlled delivery of poorly soluble anticancer drug:
Biodegradable poly (lactic-co-glycolic acid) (PLGA), D--tocopheryl polyethylene glycol
1000 succinate (TPGS) and/or polyethylene glycol (PEG) were combined as
pharmaceutical excipient to fabricate microparticles containing sparingly soluble drug
paclitaxel by spray-drying technique with successful achievement.
LIPOSOMAL drug dry powder formulation have promising features for pulmonary
drug administration.
Timolol maleate powder Occular dry powder topical formulation
Nasal dry powder delivering system- These are of 2 types: Active- Based on the
principle of air pressure driven mechanism & Passive- Based on the act of
sniffing.
17. LIST OF PHARMACEUTICAL POWDERS AVAILABLE IN MARKET

Sr.no
.
Trade name Type of dosage
form
Drug/api Company name
1 Hepamerz Granules(3gm/sac
het)
L-ornithine-L-aspartate Win-medicare.
2 Adrovit-Z Zinc dry powder
suspension
Zinc sulphate(monohydrate) Adlay formulations
3 cuclav Dry syrup. Amoxycillin200mg.,clavulanic acid28.5mg. Curex labs.
4. Comtrix-O Dry sypup Cefixime 50 mg+20 mn LB spores/5ml. Comed chemicals.
5. C-PROT granules Protein,vitamins,carbohydrates,minerals.

Corona labs.
6. C-LYTE powder Ors salt Corona labs.
7. SPORLAC
PLUS
SINGLE DOSE
SACHETS
Lactobacillus
sporogenus,L.acidophillus,L.rhamnosus,bi
fidobacterium longum.
Uni sankyo.




References
1. The Theory & practice of Industrial Pharmacy By Lachman and Lieberman.
2. Encyclopedia of pharmaceutical technology , volume 12,Page no-389
3. Pharmaceutical dosage forms.(VOL-3) by Kenneth E. Avis and H.A. Lieberman.2
nd

edition.
4. www.fda.gov.
5. www.saanessar.com
6. www.crystalautomation.com
7. www.wintechpharmachem.com
8. www.spectroscopymag.com
9. www.cadmach.com
10. www.cipmach.com
11. www.pharma-machines.com.
12. Pharmaceutical process validation by Loftus and Nash.
13. Guidance for Industry: Powder Blends and Finished Dosage Units Stratified In-
Process
Dosage Unit Sampling and Assessment.oct2003
14. Ref:J.Pharm.Sci.,Vol-95,Feb2006
15. Remington pharmaceutical science,21
st
edition,2005.


Study questions
1. Define & classify powder dosage forms
2. Explain departmental lay out of powder manufacturing.
3. Explain in detail sachet packing machine.
4. Explain documentation and its need in pharmaceutical industry.
5. Discuss the list of equipments, manufacturing steps, in process testing parameters, finished
goods testing and stability testing in final packaged goods for powders or tablets or
capsules (hard or soft). (JULY 20 04)
6. Explain about BMR & BPR
7. Explain about packaging of powders & effervescent granular powders