Chapter.

4
MANUFACTURING
Introduction
 ECONOMIC CONSIDERATION
• Hospital pharmacy department in hospital should have in-house production unit. Hence
the department must establish manufacturing unit in the hospital.
• To establish manufacturing in the hospital some economic factors should be considered
such as,
1. Production: it is that process by which value is created or increased indicated by output
of the process.
2. Consumption: it is that process by which production outputs are used to satisfy needs.
3. Cost: it is the measure of resource consumption.
4. Land : this factor of production consists of space upon which physical structure in built.
5. Labour : human resources or services provided in order to create value or utility in
terms of wages.
6. Capital : this factor consist of equipment's, machineries, apparatus and other goods to
convert natural resources on services.
7. Profit : it the excess revenue over cost, usually for specified period of time.
 Economic Order Quantity ( EOQ)
• It is useful to consider while deciding the total cost of production.
• For calculation cost per unit following data will be required,
1. name of the product
2. total production per unit.
3. direct cost like labour, equipments, labelling and packing of material and testing
expenses.
4. indirect cost like maintenance of building , machinery, furniture, repairing, house
keeping, electricity etc.
• Total cost= prime cost + production cost+ office cost
Total cost
Cost/ unit = ---------------------
No. of unit.
Conti..
• Sometimes EOQ can be applied to make decision for deciding the total cost of
production
• EOQ is one of the known model for inventory control.
• The purpose of EOQ is to answer two important decision.
A) when should an item will be recorded?
B) what quantity should be recorded?
• Thus the model can be used to determine how much inventory needs to be caused to
meet the demand,
• The formula for calculating EOQ is,

EOQ = 2 CS
ID
• Where, C = Consumption over a period of time
S = setup / purchase cost
I = Inventory carrying charge as a expressed as a percentage
D = Direct production cost / unit
 Economic Factors affecting make or buy decision

• Quality : If better quality of any drug can be obtained by manufacturing in

hospitals, than those purchased from outside , then that product / drug can be
prepared in the manufacturing unit of the hospital , but at the same time it should
not be costlier.

• Quantity : The drugs which are frequently required in hospitals for everyday use,
in large quantities , can be manufactured in the hospital itself. But items required
in small quantities, can be purchased from outside sources.

• Cost : Compare the cost of items / drug purchased from outside and the cost of in
house production.
 Estimation of Demand (EOD)
• Methods for Estimation of Demand

1. Judgmental method: On the basis of judgment, experience of clinical and pharmacy

staff, the demand of product can be decided. this is called as judgmental method.

2. Past history : The past consumption pattern of hospital is extended to future for
deciding the demand for the product.

3. casual method : It depends upon the several factors like number of admissions in
causality or emergency wards and in infectious diseases wards and number of surgeries
performed. Regression analysis is done to calculate the demand for a product.
 Manufacturing in
Hospital

Non – sterile
Sterile Manufacture Manufacture
E.g. SVP, LVP, TPN, eye drops and
e.g, tablets, capsules, ointments
hemodialysis solutions
liquid orals etc.
 Sterile Manufacture
• Sterile products are dosage forms of therapeutic agents that are free of viable
microorganisms.
• It includes, Parenteral, Ophthalmic and Irrigating preparations.
Parenterals
Definition : Parenterals are liquid injectable preparations, which are sterile , non –
pyrogenic and isotonic with blood plasma and are administered directly in to blood stream
rather than taken via the oral route.
 Characteristics/ Requirements of Parenteral Dosage Forms
• It must be sterile.

• It must be free from pyrogenic (endotoxin) contamination and viable microorganisms.

• Injectable solutions must be free from visible particulate matter. This includes reconstituted sterile
powders.

• It must be isotonic with blood plasma.

• Its specific gravity must be similar to blood plasma.

• It must be non toxic, non irritant to the body.

• It must be stable, and free from physical and chemical contamination.

• It must be free from dust and dirt particles.

• It must be chemically inert in nature.

Classification / Types

A) Small Volume Parenteral (SVP)

B) Large Volume Parenteral ( LVP)

 Requirements and Equipments for manufacturing of sterile products
• Storage equipments for ampoules, vials, bottles, and closures
• Washing and drying equipments
• Dust proof storage cabinets
• Water stills
• Mixing and preparation tanks
• Mixing equipments
• Filtering equipments
• Hot air oven
• Cold storage
• Autoclave
• Storage for distilled water
• Sintered glass funnel
• Filter press
• Equipments for evaluation and quality control
• Labeling and packaging unit
• Seitz filter
• An inspection table
Requirements and Equipments for Aseptic Filling and Sealing Room

• Benches for filling and sealing

• Bacteriological filters

• Filling and Sealing unit

• Laminar air flow bench with HEPA filters

• UV rays tubes

• Air blowers with fresh air

 Facilities for Manufacturing of Sterile Products
• Sterile manufacturing must contain best construction material and design
• The ceiling, walls and floors should be constructed of materials, which is easily
cleanable.
• The ceiling and walls should contain ceramic epoxy finish, applied by spraying and
painting to form a continuous smooth seal coating on the walls and ceiling.
• Movable metal partitions are sometimes used to provide rearrangements of equipments.
• Glass is the best material to be used for partitioning and also useful for supervision.
• Electric wiring or other piping should not present in the area as this can leads for
collection of dirt on it.
• Furniture inside area must be made of stainless steel, instead of wood.
• The materials and equipments which can not be sterilized easily should be kept in the
aseptic area.
• Electrical gas, water, air connections should be accessible and properly maintained.
• It should contain laminar air flow bench, with HEPA filters.
 Restrictions imposed to carry out effective process in the Aseptic area
1. Environmental Control: For proper control, high standards of cleanliness must be
maintained in the area. To achieve this, proper facilities must be provided. Time to time
fumigation and disinfection should be done.
2. Traffic Control:
• The area should be carefully designed to minimize the traffic particularly in and out of
aseptic area.
• Airlock system is used for control over the movements.
• Pass through openings and double ended sterilizers are provided to permit controlled
passage of materials from non- aseptic to aseptic area.
• The persons who have to enter the aseptic area , have to remove their usual cloths and wear
sterile gowns hats, shoes, face masks, and gloves.
• They should enter only after washing their hands. Once they enter the aseptic area , they
should not be permitted to move in and out, before finishing the procedure.
• Access for the common people is restricted.
• Disinfection and cleaning: All equipments are cleaned at the end of operations. After
cleaning, all surfaces should be disinfected. Irradiation can be done from UV lamps.
Conti…

3. Air Control :

• Air must be circulated at frequent intervals.

• Recycled air must be filtered to remove gross particulate matter. A spun glass, cloth or shredded
polyethylene filter may be used for primary cleaning.

• For removing microorganisms , high efficiency particulate air (HEPA ) filters are used.

• Blowers should be installed for air ventilation.

• Class 100 clean room : It is defined as a room in which the particle count in the air is not more
than 100 per cubic foot of 0.5 micron . It the new air control system . For such purposes, Laminar
air flow bench is used.
 Laminar Air Flow(LAF) Bench
• It contains unidirectional flow of air, which sweeps away dust, dirt, insects, microorganisms
and only fresh air is created over the work bench.

• It contains HEPA filters. Filtered air is blown on entire work bench.

• The air velocity should be 100 + 20 ft./min.

• It provides positive pressure.

• Uv lamp is also provided on work bench.

• Positive pressure air flow: It should be used to prevent contaminated air from flowing in to
the clean room. In order to achieve this, the air pressure inside the clean room should be
greater than the pressure outside the room. So that , when a door to clean room is opened, the
air flow is outward.
Diagrammatic view of LAF
Departments of Layout of sterile area
Steps of Production Planning Of Parenterals / Sterile
Products

1. Formulation of Parenteral

2. Processing of Parenteral

3. Evaluation/ Quality control test for Parenteral

 1. Formulation of Parenteral

• Additives used in formulation

1. Vehicle
2. Non- aqueous vehicle / solvents
3. Antibacterial agents
4. Antioxidants
5. Buffers
6. Tonicity contributors
7. Preservatives and Stabilizers
 A. Vehicles
• Water is the best vehicle used in preparation parenteral formulation
• Types of water:
1. Water for Injection (WI) : It is a sterile water free from volatile, non- volatile impurities
and pyrogens. It is prepared by Distillation or by Reverse Osmosis process.

water for injection

Sterile Water for Injection Bacteriostatic Water for Injection

It is again sterilized It is prepared by adding any
in an autoclave after distillation bacteriostatic agents in sterile water
Conti..

2. Water for Injection free of CO2 : It is used for some preparations and prepared by
removing CO2 from sterile water.

3. Dissolved Air: It is removed from sterile water to prepare sterile water for
injection.
 B. Non –aqueous vehicles/ solvents

• Selection criteria for Non –aqueous vehicles/ solvents

It must not be irritating and toxic.
It must not exerts an adverse effects on the ingredients in formulations.
For fixed oils, they should satisfy the requirements of Degree of saturation, Saponification
value, Iodine number, and Free fatty acids.
They are selected on the basis of solubility, stability and safety.
Commonly used fixed oils are peanut oil, cotton seed oil, corn oil, arachis oil and almond
oil.
Frequently , alcohol is not a choice as a vehicle for parenteral, because it causes pain
during administration and tissue damage the site of injection.
Propylene glycol and glycerin are used vehicles that are added as a solvents in water and
prepared.
 C. Antibacterial agents

• Antibacterial agents prevents the growth of Bacteria and Microorganisms during storage.
They are added in only single dose containers.

• Examples: 1. Phenol 0.5%

2. Cresol 0.3%
3. Chlorocresol 0.2 %
4. Phenyl mercuric nitrate 0.002%
5. Benzethonium chloride
6. Benzalkonium chloride 0.001%
 D. Antioxidants
• These are the agents that prevent oxidation, when thermal sterilization of parenteral
products is done.
• They become oxidized and acts as a reducing agents of medicaments.
• They block oxidative chain in the given formulation.
• Examples : 1. Ascorbic acid
2. Sodium bisulphate
3. Sod. Metabisulphite
4. Thiourea
5. Tocopherol
 E. Buffers , Tonicity contributors, Preservatives and Stabilizers

• Buffers are used to maintain the required pH of the formulations.

Examples : acetate, citrates, phosphates etc.
• Tonicity contributors are used to maintain isotonicity of given formulations with blood
plasma.
Examples : 0.9% w/v NaCl and borax
• Preservatives and Stabilizers preserve the drugs and make products stable.
Examples : benzyl alcohol, methyl paraben, propyl paraben, phenol etc.
 Containers and Closures for Parenteral.
• The selection of containers for parenterals is based upon, Bleaching, Permeation and
Adsorption.
• Thermoplastic polymers are used as a packaging material for SVP, LVP and
Ophthalmic preparations.
1. Plastic materials.
• Advantages: i.No risk of any breakage.
ii.They are easily squeezable.
• Disadvantages: i. Permeation of vapours.
ii. Non- clarity.
iii. Melting under heat sterilization.
Conti..
2. Glass materials:
Glass is mainly composed of silicone dioxide. Type I and Type II glasses are as a containers for
parenterals.
Advantages
• Glass containers are mainly used in packaging liquid preparations due to their rigidity and their
superior protective qualities.
• Its high transparency allows easy inspection of its contents.
• It offers better protection because it is relatively impermeable to air and moisture.
• It is chemically resistance to most medicinal products.
• Coloured glass (amber glass and red coloured glass) can protect its content from ultraviolet rays and
certain wavelengths.
• Glass containers can be easily sterilized using heat.
Disadvantages
• Glass containers are expensive to manufacture
• They are fragile and relatively heavy
• During heat sterilization, some types of glass containers
have the tendency of shedding some part of the silica into the formulation.
Conti..
3. Rubber:
It is used as a closure for multi-dose and single –dose containers for SVPs and LVPs.
Rubber is generally made up of from natural rubber, latex or synthetic polymer.
Advantages :
• It makes easy to introduce a needle in to the container to withdraw the required
dose and is again resealed properly.
• Rubber has elasticity to fit the container.
 2. Processing of Parenteral

• Production of parenterals involve following steps.

1. Cleaning of equipment
• All equipments are dissembled first by unscrewing.
• It is scrubbed with the hand or with a stiff brush.
• Detergents, soaps or dichromate solution are used for cleaning the equipments.
• For large tanks and equipments, pipelines that may be isolated from process , can
be cleaned at that place.
• Glass or metal equipments are placed in inverted positions and subjected to high
pressure treatment, hot tap water and finally rinsed with distilled water.
2. Cleaning of containers and closures:
• The glass containers are rinsed alternatively with hot and cold water and final
rinsing is done with cold water for injection.
• After cleaning, the containers are placed in clean stainless steel boxes for the
sterilization to avoid the dust, dirt contamination during handling.
• Rubber closures are washed by mechanical agitation in a tank of hot detergent
solution, 0.5% sodium pyrophosphate and finally rinsed with WI.
3. Compounding the formula or Product:
• The product should be compounded under clean environmental conditions.
• Homogenecity should be maintained while preparing the solution, suspensions,
emulsion or mixture.
4. Filtration:
• Solutions must be filtered through bacteria- proof filters i.e. Seitz filter and
Membrane filter.
• Membrane filters can be effective, non-reactive and disposable.

Seitz filter membrane filter

5. Filling:
• The filtered product is filled in to ampoules or vials with the help of automatic or
semi automatic machines under aseptic conditions,

• Small scale filling can be done with the help of hypodermic syringes attached with
long needles..

• Filling can also be done on LAF bench.

• LVPs can be filled in bottles using pressure or by vacuum filling devices.

6. Sealing :
• Containers should be sealed in the aseptic area immediately adjacent to the filling
machine.
• Sealing can be done by the two methods.
Tip sealing Pull sealing
1. Tip of ampoule neck is heated to form a bead 1. Little below the tip, the ampoule neck is heated. The
which closes the opening. tip is grasped firmly and pulled quickly with continuous
rotation of ampoule neck over flame. The capillary tube
thus formed twisted closed.
2. It is fact but not sure. Excessive heating may 2. It is slower but more sure.
cause bubble on the tip.
Conti…

• Closures are inserted by machines, usually treated with halogen gas or coated with
silicone to reduce friction.

• Aluminium caps are used to hold the rubber closure in place.

• Single Aluminium caps may be sealed by applying hand crimping devices.

7. Sterilization :

• The parenteral product should be sterilized immediately after its sealing in final
container.

• The sterilization is the process of making the product free from microbes.
 Sr. Sterilizing method Products
no
1. Dry heat ( Hot air oven) Dry solid are not affected by the heat,
temperature and requiring long heating
period. It also effective for sterilization of
glass wares.
2. Moist heat under pressure ( Autoclave) Aqueous solutions or substances can be
penetrated by steam
3. Ionizing radiation Dry solid such as streptomycin,
poly-vitamins, penicillin, sutures etc.
4. Gaseous sterilization ( Ethylene oxide) Syringes, disposable needles, plastic and
stainless steel equipments.

5. Bacteria proof filtration Thermoliable products.

6. Lyophillisation ( freeze drying) Preservation of human tissue.

 3. Evaluation /Quality control tests for Parenteral

• Evaluation of parenteral products can be done by following methods,

1. Sterility test

2. Pyrogen test

3. Leaker test

4. Clarity test or particulate matter evaluation

 Sterility Test
• Sterility can be defined as the freedom from the presence of viable microorganisms.
It is done for detecting the presence of viable forms of bacteria, fungi and yeast in parenteral
products.
The test for Sterility must be carried out under strict aseptic conditions in order to avoid accidental
contamination of the product during test.
All glassware's required for the test must be Sterile.
Based on results obtained from testing the sample a decision is made as to the sterility.
• Culture media used for sterility testing:
1. Fluid thioglycolate medium
2. Soybean casein digest medium
1. Fluid thioglycolate medium (FTM):
FTM provides both aerobic and anaerobic environments within the same medium. FTM is an
excellent medium for the detection of bacterial contamination. Thioglycolate has the advantage of
neutralizing the bacteriostatic properties of mercurial preservatives.
• Composition:
L-cysteine, trypticase peptone, dextrose, yeast extract, sodium chloride, sodium thioglycolate,
resazurin, agar, purified water, final pH 7.1.
• Incubation of the media: 14 days at 30 -35°C
2. Soybean casein digest medium:
• Soya-bean casein digest medium primarily intended for the culture of both fungi and
aerobic bacteria specific role of some ingredients.
• Incubation of the media: 14 days at 20 -25°C
• Composition
• Trypticase soya broth, trypticase peptone, phytone peptone, sodium chloride,
dipotassium phosphate, dextrose, purified water, final pH 7.3
• Sterility test methods
[1] Direct inoculation method
[2] Membrane filtration method
[1] Membrane filtration methods
• Selection of filters for membrane filtration: Pore size of 0.45μ effectiveness established
in the retention of microorganism’s appropriate composition the size of filter discs is
about 50 mm in diameter.
Procedure of membrane filtration
Sterilization of filtration system and membrane filtration of
examined solution under aseptic conditions.

Filtration of the sample through a membrane filter having the

nominal size of 0.45μ and a diameter of 47mm.

After filtration the membrane is removed aseptically from

the metallic holder and divided into two halves.

The first half is transferred into 100 ml of culture media

meant for fungi and incubated at 20˚ to 25 ˚c for not less
than seven days.

The other half is transferred into 100ml of fluid thioglycolate

medium and incubated at 30 to 35 ˚c for not less than 7 days.
[2] Direct inoculation method
Required quantities of liquid is removed from the test
containers with a sterile pipette / sterile syringe.

Aseptically transfer the specified volume of the material from

each container to vessel of culture medium

Mix the liquid with medium but not aerate excessively.

Incubate the inoculated media for not less than 14 days, unless
otherwise specified in the monograph at 300c - 350c in the case of
fluid thioglycolate medium and 200c - 250 c for soybean casein digest
medium.

When materials examined renders the medium turbid so presence / absence of

microbial growth cannot be determined readily by visual examination transfer
suitable portions of medium to fresh vessels of the same medium between 3 rd.
and 7 th day after test is started.

Continue incubation of the transfer vessel for not less than 7 additional days after
transfer and total of NLT 14 days.
 Pyrogen Test
• Pyrogen: “Pyro” (Greek = Fire) + “gen” (Greek = beginning). i.e Fever producing, metabolic by-products
of microbial growth and death.
• Bacterial pyrogens are called “Endotoxins”. Gram negative bacteria produce more potent endotoxins than
gram + bacteria and fungi.
• Endotoxins are heat stable lipopolysaccharides (LPS) present in bacterial cell walls, not present in
cell-free bacterial filtrates.
• Stable to at least 175ºC; steam sterilization ineffective.
• Water soluble; monomer unit of LPS can be 10,000 Daltons (1.8 nm) so endotoxins can easily pass
through 0.22μm filters.
Sources: Water (main), raw materials, equipment, process environment, people, and protein expression
systems if using gram negative bacteria.
Other Source: Equipment, Containers (Glass, plastic, metal), Solvent and Solute.
• Elimination of pyrogens:
1. Dry heat sterilization: For glass wares, metal equipments, powders, waxes, oils, heat stable drugs.
650 o C temp - 1 min 250 o C temp - 30 min 180 o C temp - 240 min
2. Ultra filtration
3. Reverse osmosis: RO membrane is composed of cellulose acetate phthalate/ polyamide
4. Distillation
5. Adsorption method
1. Rabbit Test:
• This test basically involves the injection Sample solution which is to be tested into a
Rabbits which are used as test animals through ear vein.
• The Temperature sensing probe (Clinical Thermometer, Thermosestor or similar
probe) into a rectum cavity of Rabbit at the depth of 7.5 cm, the test solution must be
warmed at 37º prior to injection.
• Then Rectal temperature is recorded at 1, 2, 3 hr. subsequent to injection.
• This test is performed in separate area designed solely for this purpose under
environmental conditions similar to animal house should be free from disturbances
that likely to excite them.
• Initially this test is performed on 3 Rabbits but if required results are not obtained
this test is repeated on 5 additional Rabbits with same sample solution administer to
initial 3 rabbits.
• Prior to 1hr of injecting sample solutions the control temperatures of rabbits are
determined.
• Use only those rabbits whose control temperature is no vary by more than 1 ºc.
2. Bacterial endotoxin test:
• LAL (Limulus Amebocyte Lysate) test is used to characterize the bacterial
endotoxin that may be present. The USP reference standard contains 10,000 USP
endotoxins per vial. The LAL reagent is used for gel-clot formation.
• The test is performed using stated amounts of volumes of products, standard,
positive control, negative control of endotoxin. The tubes are incubated at 37±1ºC
FOR 60 ±2 minutes. When the tubes are inverted at 180ºC angle, formation of
firm gel confirms positive reaction.
• While formation of a viscous gel that doesn't maintain its integrity or absence of a
firm gel confirms negative reaction.
• The test is invalid if the standard endotoxin or positive product control doesn't
show end point within ± 1. Two fold dilution from label claim sensitivity of LAL
reagent or if the negative control shows gel-clot end point.
 Leaker test
• Leakage test is employed to test the package integrity. Package integrity reflects its ability
to keep the product in and to keep potential contamination out”.
• It is because leakage occurs when a discontinuity exists in the wall of a package that can
allow the passage of gas under pressure or concentration differential existing across the
wall.
• Leakage test can be done by dye bath test:
Dye Bath Test:
• This test is usually performed by producing a negative pressure within a sealed ampoule.
• The ampoule is dipped entirely in a coloured dye solution.it is performed in a vacuum
chamber by producing negative pressure.
• Then the ampoules are dipped in 1 % sodium methylene blue solution, in vacuum
chamber.
• After some time the ampoule is checked to see if the dye has entered the parenteral
preparation.
• Observation : If the presence of dye in the ampoule then it confirms the leakage and is
 Clarity Test or Particulate matter evaluation

• Clarity testing is carried out to check the particulate matter in the sample. In this test
transparent particles or white particles observed against the black background and the
black or dark particles observed against the white background.

• Procedure : Any ampoule, bottle or vial can be seen under the light, and against a dark
background, by the naked eyes. To perform this test, the neck of filled container can be
held against a strongly illuminated screen, if some particles are visible, then the sample is
rejected.

Clarity test apparatus

 NON–STERILE MANUFACTURE
• Definition : The product or drug that do not require sterilization are called as non
sterile manufacture.

• Examples: Tablets, Capsules, Ointments, Liquid orals etc.

• The non – sterile manufacturing unit in the hospital do not have any stringent rules
compared with sterile manufacturing. But they have license from FDA.

• The unit must follow the rules of Good Manufacturing Practice ( GMP ) gives in D
and C act 1945 in schedule M PART I , where as schedule M PART II deals with the
Requirements, Equipments, Processing, Packaging, Labelling and Testing.
Classification
Non sterile manufactured

Tablets, capsule,
Solid dosage pills, powders etc.
form
products

Solutions, syrup, mixture

Liquid dosage Monophasic liquids
etc
form
Biphasic liquids Emulsions, Suspensions
Semisolid dosage Ointments , creams,
form paste, suppository
etc
 Requirements of Solid Dosage Forms
Manufacturing of Solid dosage form have the following requirements:
1. Weighing Room: Where ingredients are weighed under the supervision of QC
chemists.
2. Mixing section: The compounding formula is mixed together to reduce the particle size
and uniform distribution of all ingredients. Then the binding of bulk is done by the
adding suitable wetting agents and disintegrators.
3. Drying section: The wet bulk or sludge is subjected to drying so as to achieve hardness
and disintegration as per recommended in pharmacopoeia.
4. Granulating section: Sifters are used to get uniform particle size and lubricants are
applied at the same stage.
5. Tableting section: Where tablets are pressed by tablet compression machine and there
is a storage cabinet for purchase, dyes, spammers and brushes etc.
6. Coating section: Various coatings are done in this area where pan coating, spray
coating, film coating machines are installed.
 Equipments required for Solid Dosage Form
• Weighing balance
• Mixture or Blender
• Ball mill
• Grinder like Cutter mill, Hammer mill etc.,
• Sifter or Sieve machine
• Granulator
• Dryers
• Compression machine
• Coating machine- Pan coating, Spray coating, Film coating and Polishing pan
• Capsule sealing and filling machine
• Disintegrator
• Packaging machine.
 Manufacture of Liquid Orals
• Manufacturing of liquid orals must comply with the equipment and facilities
specified under D and C act.

• Equipments for liquid orals are as follows:

• Storage tank for aqueous vehicle

• Mixing vessel or tank

• Filtration assembly

• Bulk storage tank

• Bottle sealing and filling machine

• Advantages of liquid dosage forms

1. Used for patients who can not swallow the solid dosage forms.

2. Has fast absorption rate.

3. it is more flexible in achieving the proper dosing.

4. Best choice for young children and elders.

• Disadvantages of liquid dosage forms

1. Has short shelf life due to low stability.

2. Has less accuracy.

3. Needs special storage and transferring conditions.

4. It is easily infected by microorganisms.

5. Has special storage requirements.

The liquid formulations are meant for internal as well as external use:

Oral solutions, elixirs,

Internal use linctuses, syrups,
mixtures, drops etc.
Liquid orals
Lotions, liniments, ENT
External use preparations, enemas,
inhalations liquids etc.
 PLANNING
• SOLUTIONS : Simple solutions are prepared by dissolving the solute in the solvent or solvent
mixture. Colorants, flavourants, stabilizers and preservatives may be added to these solutions.

• SYRUPS: These are concentrated aqueous preparations of sugar and medicinal substances with
or without added flavoring agents. Most of syrups contains sugar ( usually sucrose) ,
preservatives, colouring agents, flavouring agents, and may be solubilizes and stabilizers.

• Preparation of syrup:

• Syrup can be prepared by the following methods: solution of the ingredients

• With the aid of heat

• By agitation without use of heat

• By addition of sucrose to prepared medicated liquid

• Preparation of Elixirs:

• Elixirs are prepared by simple method of solution by agitation and by the admixture
of two or more liquid ingredients.

• The water soluble ingredients are dissolved in water and alcohol soluble ingredients
are dissolved in alcohol and then the aqueous solution is added to the alcoholic
solution.

• After complete mixing of two solutions, volume of mixture is adjust with specified
solvents.

• If mixture becomes cloudy , allow it to stand for few hours and filtrate .
 Bulk Concentrate
• Many dosage forms i.e. Solutions and Semisolid dosage forms which can be used
as pharmaceutical aid are compounded in bulk quantity is called as bulk
concentrate.

• The bulk concentrate i.e. liquid orals includes Syrups, Elixirs, Mixture etc.

• The bulk concentrate Semisolid preparation includes Ointments , Creams, and

Suppositories etc.

• The entire procedure is carried out in bulk compounding lab with adequate
facilities like washing, cleaning, processing and storage.
 Manufacture of Externals
OINTMENTS
Preparation of ointments: The ointment may either be medicated or non-
medicated. The non- medicated ointments are the ointment bases and are used as
emollient, lubricants or as a vehicle in preparation of medicated ointments.

Types of ointments bases:

1. Absorption bases

2. Water soluble bases

3. Hydrocarbon bases

4. Water miscible bases

• Absorption bases:
1. Non- emulsified: These bases absorb water to produce w/o emulsion
• Examples: Wool fat, Wool alcohol, Bees wax, and Cholesterol
2. Emulsion bases:These are already w/o emulsions which prepared by incorporation of
small quantities of water or aqueous solutions.
• Examples: Hydrous wool fat ( lanolin) , Cold cream
• Water-soluble bases:
• These are developed from Polyethylene Glycols.
• Advantages: Non- occlusive, miscible with exudates, non staining, easily removable by
washing, non-toxic and non- irritant to the skin.
• Disadvantages : It reduces the activity of anti microbial substances like phenol,
quaternary ammonium compounds and hydroxybenzoates.
• Examples: 1. Bentonite+Glycerin+Water, 2. Gelatin+Glycerin+Water
• Hydrocarbon bases( Water insoluble bases):
• These bases absorb very little water from skin exudates or formulations and not
absorbed by skin.by improving the hydration of the skin , enhances the absorption of
medicament.
• Examples: Soft paraffin, Hard paraffin and Liquid paraffin
• Water miscible bases:
• These bases can emulsify large quantities of water they are immiscible with an
excess of water. These can be easily removed after use.
• Examples: Emulsifying wax, Liquid paraffin, White soft paraffin etc. .
• Preparation of ointments
The ointments are prepared by two methods,
A) Fusion method
B) Incorporation method
A) Fusion method: By the fusion method, all or some of the components of an
ointment are combined by being melted together and cooled with constant stirring until
congealed. Components not melted are added to the congealing mixture as it is being
cooled and stirred. Naturally, heat-labile substances and any volatile components are
added last when the temperature of the mixture is low enough not to cause
decomposition or volatilization of the components.
B) incorporation method
• By the incorporation method, the components are mixed until a uniform
preparation is attained, on a small scale the pharmacist may mix the components
using a mortar and pestle or a spatula and slab (a glass or porcelain plate).
• Incorporation of Solids: The ointment base is placed on one side and the
powdered components previously reduced to fine powders on the other side. A
small portion of the powder is mixed with a portion of the base until uniform
mixture is obtained. The process is continued until all portions of the powder and
the base are combined and thoroughly and uniformly blended. It is often desirable
to reduce the particle size of a powder or crystalline material before incorporation
into the ointment base, so that the final product will not be gritty. This may be
done by Levigation process (i.e. mixing the solid material in a vehicle to make a
smooth dispersion).
• Incorporation of Liquids : Liquid substances or solutions of drugs are added to an
ointment according to ointment base’s capacity to accept the volume required. For
example, only very small amounts of an aqueous solution may be incorporated into an
oleaginous ointment, whereas hydrophilic ointment bases readily accept aqueous
solutions. When it is necessary to add an aqueous preparation to a hydrophobic base,
the solution first may be incorporated into a minimum amount of a hydrophilic base
and then that mixture added to the hydrophobic base. However, all bases even if
hydrophilic have their limit to retain liquids beyond which they become too soft or
semiliquid. Alcoholic solutions of small volume may be added well to oleaginous
vehicles or emulsion bases. - On large scale, roller mills force ointments through
stainless steel rollers to produce ointments that are uniform in composition and
smooth in texture.
EMULSIONS
 Requirements
• The D and C act 1945, recommended the following equipment for the manufacture of
Ointments and Emulsions :

• Mixing tank

• Kettle, steam, gas or electrically heated

• A suitable power driven mixer

• Storage tanks

• Colloid mill

• A triple roller mill liquid filling equipments.

• Jar or tube filling equipment

• An area of 30 square meters is recommended for the basic installations.

 Facilities
The risk of microbial growth is greater in aqueous system than others. The sources of contamination
during manufacturing and filling of these products are numerous such as:
• Storage of water in tanks which are not adequately cleaned.
• Badly designed piping system for the supply of distilled water at the site of use.
• The manufacturing equipment have the cavities where the water gets trapped resulting improper
cleaning.
• Insufficient space and facility for cleaning and storage of equipment.
• Use of contaminated disinfectants.
• Inadequate ventilation at the site of manufacture.
• Overcrowding of product and personnel.
• Improper hygienic procedures for manufacturing of the products.
• Inadequate facilities for the control of manufacturing process.
 SUPPOSITORIES
• Suppositories are Solid dosage forms intended for insertion into body orifices where they melt,
soften, or dissolve and exert localized or systemic effects.
• The most common aspect in formulation of suppositories is the selection of base.
I. Fatty or Oleaginous bases : Designed to melt at body temperature. 1- Theobroma oil (Cocoa
butter) ` It is a yellowish-white solid with an odour of chocolate and is a mixture of glyceryl esters of
different unsaturated fatty acids.
• ` Advantages: a- A melting range of 30 - 36°C
b- Readily melted on warming, rapid setting on cooling.
c- Miscible with many ingredients.
d- Non-irritating.
• Disadvantages: a- Polymorphism
b- Adherence to the mould:
c- Softening point too low for hot climates.
d- Melting point reduced by soluble ingredients
e- Rancidity on storage:
f- Poor water-absorbing ability
g- Leakage from the body
h- Expensive
 II Water-soluble bases:
1. Glycero-Gelatin base: It is used in the preparation of viginal suppositories.

Disadvantages:
❖ A physiological effect: Osmosis occurs during dissolving in the mucous secretions of
the rectum, producing a laxative effect.
❖ Can cause rectal irritation due to small amount of liquid present.
❖ Unpredictable solution time.
❖ Hygroscopic: So, they should be packaged in tight containers and also have dehydrating
effects on the rectal and vaginal mucosa leading to irritation.
❖ Microbial contamination
❖ Long preparation time.
❖ Lubrication of the mould is essential.
•Polyethylene Glycol base (PEG):
• Polyethylene glycols are polymers of Ethylene oxide and Water, prepared to various
chain lengths, molecular weights, and physical states.
• Polyethylene glycols (PEGs) having average molecular weights of 300, 400, and 600
are clear, colorless liquids, while those with molecular weights of 600- 1000 are
semisolids.
Advantages
a. PEG suppositories are easily made by fusion.
b. When formulated with an appropriate PEG blend, they dissolve in body cavity fluids
and release the active ingredients, both hydrophilic and hydrophobic drugs.
c. Because their melting points are easily controlled by appropriate blending, these bases
and their suppositories do not require carefully monitored storage temperatures.
Disadvantages
a. PEG suppositories are irritating to body cavity tissues, so they have less patient
acceptance than do fatty-base suppositories.
b. They are incompatible with a long list of drugs, especially those prone to oxidation.
c. They interact with polystyrene, the plastic often used for prescription vials, so they
should not be dispensed in these containers unless the suppositories are first wrapped
with foil.
 Preparation of Suppositories
Suppositories are prepared by four methods:
I . Hand molding:
• Hand molding is useful when we are preparing a small number of suppositories:
1. The drug is made into a fine powder.
2. It is incorporated into the suppository base by kneading with it or by trituration in a
mortar.
3. The kneaded mass is rolled between fingers into rod shaped units.
4. The rods are cut into pieces and then one end is pointed.
II . Compression molding:
The cold mass of the base containing the drug is compressed into suppositories using a
hand operated machine.
III . Pour moulding:

• Using a supp. mould which is made of metal or plastic. Traditional metal moulds are in two halves
which are clamped together with a screw.

• Steps:

1. The base is melted and precautions are taken not to overheat it.

2. The drug is incorporated in it.

3. The molten liquid mass is poured into chilled(lubricated if cocoa butter or glycrogelatin is the
base) molds.

4. After solidification the cone shaped suppositories are formed.

IV. Automatic Moulding machine: All the operations in pour moulding are done by automatic
machines. Using this machine, up to about 10,000 suppositories per hour can be produced.
 Requirements
• The D and C act 1945, recommend the following equipment for the manufacture of
suppositories.

1. Mixing and Pouring equipment.

2. Molding equipment.

An area of 20 sq. /meters is recommended for the basic installations.

 Procurement ( Purchasing) of Store
• Purchasing is the process of buying. It is the learning of the requirement, identifying
and selecting a supplier, negotiation price.

• Purchasing is an element of the wider function of procurement and it includes many

activities such as ordering, expediting, receipt and payment.

• Purchasing is responsible for obtaining the materials, parts, supplies and services needed
to produce of a product or provide a service.

Inventory : “ It’s an itemized list of goods with their estimated worth.”

 Role of Pharmacist in Purchasing of Drugs
• The drugs for hospital use may be purchased as follows:

• Directly from manufacturer.

• Directly from wholesaler.

• from either manufacturer or wholesaler by bid.

• From local retail pharmacy ( in emergency only)

• By contract purchase management with manufacturer.

• By contract purchase through a hospital purchase bureau or corporation.

• In case of bid purchasing, when bids from manufacturers are opened, the lowest bidder should receive the
purchase order, however he should assure that the hospital gets the best quality if items.

• The hospital pharmacist should discuss with the purchasing agents ( officer) and method for purchasing the
drugs.
 Duties of Pharmacist in Purchasing of Drugs
• Maintain a list of names, addresses, and telephone numbers of the drug
manufacturer, wholesaler and their local agents.

• Prepares “ request for purchase” forms

• Prepares detailed specifications required for drugs, chemicals, and biological.

• Prepares “ receiving memo” if drugs are received directly by the pharmacy.

• Prepares “ returns goods memo” whenever applicable.

 Role of Purchasing Officer in Drug Procurement
• Role of purchasing officer for drug procurement vary from small to large hospitals.

• In small hospitals purchasing functions may be a part time and may be handled by
administrator and he may have person like storekeeper.

• In large hospitals where purchasing functions is full time work the following duties
should be performed by purchasing officer.

• Issuing purchase orders.

• Maintaining purchase records.

• Follow up on the orders which are delayed.

• Obtaining quotations from specified sources.

• Execution of competitive bidding procedures.

 Objectives in Purchasing
• The general areas in which purchasing objectives must be established can be under the
“ seven rights of purchasing” . These are- the pharmacy manager should buy:
• The Right Variety of merchandise(items)
• The Right Quality of merchandise to meet the target markets expectations and demands.
• The Right Quantity of goods at a particular point in time to ensure that the stock –outs
are balanced against the costs of tying up funds in excess inventory,.
• At then Right Time, so that the supply of incoming merchandise roughly coincides the
customer purchases.
• From the Right Sources to obtain the most favorable terms possible and dependable
sources of supply.
• At the Rights Price, so that the cost of good will not be too high to allow reasonable
gross margin.
• At the Right Cost to the pharmacy in terms of minimizing the expenses with purchasing
 Objectives of Inventory Control
• To ensure a continuous supply of materials and stock so that production should not suffer at
the time of customers demand.
• To avoid both overstocking and under-stocking of inventory.
• To maintain the availability of materials whenever and wherever required in enough
quantity.
• To maintain minimum working capital as required for operational and sales activities.
• To optimize various costs indulged with inventories like purchase cost, carrying a cost,
storage cost, etc.
• To keep material cost under control as they contribute to reducing the cost of production.
• To eliminate duplication in ordering stocks.
• To minimize loss through deterioration, pilferage, wastages, and damages.
• To ensure everlasting inventory control so that materials shown in stock ledgers should be
physically lying in the warehouse.
• To ensure the quality of goods at reasonable prices.
• To facilitate furnishing of data for short and long-term planning with a controlled inventory.
• To supply the required material continuously.
 Procedure for Purchasing Drugs
• Purchase Request Form
• Quotation Invitation
• Purchase Order Form
• Return of Goods

1. Purchase Request Form

• The pharmacist or a person authorized by him should complete a purchase
request form. This form provides the purchase department with the data
concerning description specifications, packing, price quantity needed and also
information about the inventory balance and anticipated monthly use.
2. Quotation Invitation
• On receipt of “request for purchase”, invites competitive rates (quotations)
from different suppliers. To prevent delay in supply, an annual rate contract
can also be undertaken.
Conti. .
3. Purchase Order Form
• The purchase officer scrutinizes quotations received, checks the quality expected to be
supplied in consultation with pharmacists and prepares a purchase order.
• The purchase order may take the form of any different type- it may consist of two page
or a many page or a many page “snap out” form.
• However, a multi-copy snap out form is suitable as it provides a copy for the supplier,
accounts department, purchasing number file, department which has sent the purchase
requisition, two receiving reports and a copy which indicates the history of the
purchase.

4. Return of Goods
• If for any reason, any portion of the articles received are to be returned to the supplier a
“Returned Goods Memorandum” must be prepared because it is by its means that the
hospital can be assured of receiving credit for the goods.
• This form is of the snap out type and provides four copies first to account department,
second to the purchasing officer, third to the store room, fourth to the pharmacy and the
supplier.
 Purchase Request Form
Purchase/ repair request
XYZ Hospital, Mumbai.

No . 1234
Date :
Repair of equipment
Purchase
Purchasing department use only
Department Account name
name charge to
Charge code Suggested vendor Terms Purchaser order number

Date needed ………………… Price per unit Number of Total price Quantity
………………… units needed
On hand Used per

Commodity Description –
number Specifications-
Packaging-

Requested by………. Approved by…….

 Purchase Order Form

DEPARTMENT OF PHARMACY
XYZ Hospital, Mumbai.
PURCHASING REQUISITION
Vendor……………….. Vendor No………………… Purchase order
no……………….…
Vendor contact …………………
Date placed…………….. Ordering frequency……………….. Date
prepared………………………
Next ordering date ………………………. Shipping date…………….. Cost center
no……………….
Prepared by ………………. Order taken by ………………….

No. Quantity Unit Description Cost each Extension Contract price

 Out of Stock Form

XYZ Hospital, Mumbai.

Pharmacy
Date ……………….
Department ………………………
Name on original request ………………………..
We are temporarily out of stock for the following.

Quantity Items

1. Charged
2. Not charged

When these items are available , your order will be completed

PLEASE DO NOT REORDER
List of Questions
1) Which economic factors are consider for make or buy decision?
2) Describe the processing of parenteral.
3) Enlist and Explain evaluation tests for parenteral preparations.
4) Give the difference between LVP and SVP.
5) Draw and Explain layout of Sterile area.
6) What do you mean by aseptic technique ? Write its requirements.
7) Describe the steps required for purchase of material in hospital.
8) Explain estimation of demand for product in hospital.
9) Define parenteral. Enlist the requirement to fulfill.
10) Define Sterilization and classify the stages of sterilization.
11) Enlist and explain additives added in parenteral preparation.
12) Describe various requirements to manufacture of tablets in hospitals.
Conti. .
13) Define non- sterile manufacturing of drugs. What are equipments and facilities required for
liquid orals?

14) Write a note on Bulk concentrate.

15) What is HEPA Filter? Draw the diagram of LAF Bench.

16) Describe the facilities required for manufacture of ointment and emulsions.

17) Write a short note on i) Ointment bases ii) Suppository bases

18) Describe the preparation of suppositories by moulding.

19) Describe the methods of preparation for ointments.

20) Define sterile products.

21) What do you mean by WFI, SWFI and BWFI?

Conti ..
22) Write in brief about the aseptic area for the manufacture of sterile products.

23) Give the basic requirements for the manufacture of parenteral preparation.

24) Explain the role of pharmacist in purchasing of drugs.

25) Explain the duties of purchasing officers.

26) Give the objectives of Purchasing and Inventory control.

27) Describe the procedure for purchasing of drugs.

28) Give the format for

i) Purchase request form

ii) Out of stock form

iii) Purchase order form.