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INDUSTRIAL PHARMACY- I
PARENTERAL PRODUCTS
Prepared by: Komal Pramod Sathe
College: HSBPVTs GOI College of Pharmacy, Kashti.
Roll no.: 117
 Parenterals
The term is derived from the Greek word ‘Para’ (outside) & ‘Enterone’ (intestine).
These are the preparations which are given other than oral routes.
Definitions
 According to B.P. : “Parenteral preparations are sterile preparations intended
for administration by injection, infusion or implantation into human or animal
bodies”
 According to WHO : “Parenteral preparations are sterile, pyrogen-free liquids
(solutions, emulsions, or suspensions) or solid dosage forms containing one or
more active ingredients, packaged in either single-dose or multi dose
containers. They are intended for administration by injection, infusion, or
implantation into the body.”
 Advantages
1. Rapid onset of action
2. Localized drug delivery
3. Useful for patients who cannot take drug orally (Patients who are vomiting or
unconscious)
4. Useful for emergency situations
5. Avoid first pass metabolism as drug directly enters the systemic circulation by parenteral
route.
6. Irritation of stomach by the drug is avoided
7. Complete bioavailability
8. Providing sustained drug delivery (implants)
9. Useful for delivering fluids, electrolytes or nutrients.
10. The drug action can be prolonged by modifying the formulation
11. Injection ensures accurate dosage of the medicament
 Disadvantages (Limitations)
1. Pain on injection
2. Sensitivity or allergic reactions at the site of injection
3. Trained person is required for administration of drug. Self medication is difficult.
4. Drug directly reaches to the systemic circulation hence it is difficult to reverse an
administered drug’s effect. Difficult to save patient if overdose.
5. These routes are not very convenient and economical for the patient.
6. It is essential to follow strict aseptic technique in order to avoid possibility of infections.
7. Side effects are quicker than that of drug given by any other route.
 Parenteral routes:
Classification of parenteral products:
 On the basis of Volume
Small volume parenteral Large volume parenteral
An injection that is packed in containers
labelled as containing 100 mL or less
An injection that is packed in containers
labelled as containing 101 mL-1000 mL
Single or multiple use Single use
Used for administration of drug Used to provide calories, electrolytes, fluid
Preservatives are used Preservatives are not used
Administered through various parenteral
routes
Administered through IV infusion technique
e.g. Insulin injection, Procaine penicillin G
injection
e.g. Saline solution, Mixture of dextrose,
amino acids, lipids, vitamins, etc.
Types of large volume parenteral-
1. Hyper alimentation solutions
2. Cardioplegic solutions
3. Peritoneal dialysis solution
4. Irrigating solution
Types based on the mode of delivery
The different categories of parenteral preparations include:
1. - injections;
2. - intravenous infusions;
3. - powders for injections or intravenous infusions;
4. - concentrates for injections or intravenous infusions;
5. - implants.
1. Injections
“Injections are sterile, pyrogen- free solutions or dispersions (emulsions or suspensions) of
one or more active ingredients in a suitable vehicle.”
They are prepared using an aqueous vehicle.
• Single dose injections: They should not contain antimicrobial preservatives unless justified
and authorized.
• Multi dose preparations: They contain a suitable antimicrobial preservative in appropriate
concentrations except in cases where the preparations themselves have adequate
antimicrobial properties. Multi dose preparation should normally not exceed 30 mL
2. Intravenous infusions
• Intravenous infusions are sterile, pyrogen- free aqueous solutions or emulsions with
water as continues phase, usually prepared to be isotonic.
• They are intended for administration in large volumes & do not contain any antimicrobial
preservatives.
3. Powders for injection or Intravenous infusion
They are sterile, pyrogen- free solid substances (including freeze-dried materials), distributed
in their final containers & which when the prescribed volume of the appropriate sterile liquid
is added, rapidly from either clear and practically particle-free solutions or uniform
suspensions.
4. Concentrates for injections or intravenous infusions
They are sterile, pyrogen- free solutions intended for injection or infusion after dilution.
They are diluted to a prescribed volume with a prescribed liquid before administration.
5. Implants
• Implants are sterile solid preparations containing one or more active ingredients.
• They are of a size and shape suitable for parenteral implantation & provide release of the
active ingredients over an extended period of time.
• They are presented in individual sterile containers.
 Classification based on the type of Formulation
Types of formulation
Solution
Suspensions
Injectable emulsions
Freeze dry powders
1) Solutions: A solution is a liquid preparation that contains one or more soluble chemical
substances dissolved in a specified solvent.
Aqueous solvents are compatible physiologically compatible with body tissues, biologic
response is reasonably predictable.
2) Suspensions: They should be sterile, pyrogen- free, stable, re-suspendable, syrringeable,
isotonic & non-irritant.
Administered usually by subcutaneous or intramuscular route.
3) Emulsion: Parenteral emulsions are rare because it is necessary & difficult to achieve stable
droplet of less than 1 micron to prevent emboli in blood vessels, which is difficult to prepare for
such a preparation. Very limited selection of emulsifier & stabilizers is there to choose from.
4) Dry powders: It is formulation of lyophilized or freeze-dried powders that must be
reconstituted with some suitable solvent to make a liquid formulation before being withdrawn
from the vial.
 General requirements for parenteral dosage forms:
1. Sterility- All parenteral products must be sterile. Preparation should be free from all types of
microorganisms. An aseptic conditions are required to maintain during the preparation of
parenteral products & its administration. The parenteral product must pass the test for sterility.
2. Stability- All products must be stable. The physical as well as chemical stability of parenteral
preparation must be maintained during storage.
3. Isotonicity- The parenteral preparations should be isotonic with blood plasma & body fluids.
It is very important, in order to avoid any complications on the administration of parenteral
products.
4. Free from pyrogen- The parenteral preparations should be free from toxin & pyrogens. The
parenteral product must pass the test for pyrogen, because contaminated parenteral product
causes rise in body temperature after its administration.
5. Free from foreign particles- The parenteral products should be free from foreign particles
such as dust & fibres. To ensure this, the product must pass the clarity test.
6. Specific gravity- The parenterals meant for intra- spinal injections should have the same
specific gravity as that of spinal fluid into which the same are to be injected.
7. Chemical purity- The parenteral preparation should be free from chemical impurities or it
should be within certain limit as specified in the monograph of that preparation in the
pharmacopoeia.
8. Containers- Parenteral products are usually supplied in glass ampoules, bottles or vials, in
plastic bottles or bags, or in prefilled syringes. In case of light- sensitive substances the
container should protect the contents. They do not adversely affect the quality of the
preparation.
9. Closures- Closures for parenteral preparation containers are equipped with a firm seal to
prevent entry of microorganisms & other contaminants.
 Importance of Isotonicity
o Isotonicity- Solutions that have the same osmotic pressure as that of a 0.9% sodium chloride
solution (=normal saline) are considered to be isotonic to blood, tears & other body fluids.
o Isotonicity is important for parenteral preparation because the possibility that the product
may penetrate red blood cell & cause hemolysis is greatly reduced if the solution is isotonic
with blood i.e. the cells maintain their tone.
o Isotonic products reduce the pain of injection in areas with nerve endings.
o Solution that has less osmotic pressure than the blood plasma called hypotonic &
o Solution that has more osmotic pressure than the blood plasma called hypertonic.
o When introduce hypotonic solution cell may swell & offers burst because of diffusion of
water into the cell i.e. hemolysis,
o If introduce hypertonic solution, the cell may lose water & shrink.
o Tonicity adjusting agents are added to injectable preparations to prevent osmotic shock
at the site of injection upon administration, & thereby reduce local irritation.
o Three ingredients are generally used to adjust the tonicity of solutions: Dextrose,
Glycerine, & sodium chloride.
o Isotonic solutions are used: to increase the extracellular fluid volume due to blood loss,
surgery, dehydration, fluid loss that has been loss extracellularly.
o Isotonicity calculations based on freezing point depression-
W= 0.52-a/b
Where,
− W is the % w/v of adjusting substance in the final solution
− a is the freezing point depression of unadjusted solution (i.e. freezing point depression
of 1% solution × strength in & w/v) &
− b is the freezing point depression of water due to 1% w/v of adjusting substance, usually
sodium chloride or glucose.
 Preformulation factors:
 Preformulation studies are of various types:
1. Physicochemical properties of new drug substance
2. Stability testing
3. Mechanism of drug degradation
4. Testing for packaging material
o Molecular structure & weight: The first & most important step in preformulation is
determination of the molecular structure & weight.
o Colour: Appearance of colour change is indicative of physicochemical instability which may
decrease the shelf life of the product.
o Thermal analysis: The drug may undergo physical or chemical changes due to variations of
temperature which may be associate with loss or gain. The change analyzed by DTA &v DSC.
o Solubility
• A clear solution for injectable that are to be administered either infusion or via
intramuscular route mainly depends on solubility.
• Solubility of drug substances can be determined by spectrophotometric method or from pH
profile.
• Non aqueous solvents like ethyl alcohol, glycerin, polyethylene glycol are used.
o Partition coefficient
• It is used to determine the rate & extent of drug absorption. It is the ratio of unionized drug
distributed between the organic phase & aqueous phase.
• It is explained by equation
P= Co/CW
Test for stability
Light stability
• Drug solution placed in the petri plate & glass ampoules respectively
• Drug substance placed in light resistant container such as carbon box which act as controller.
• The samples are placed & maintain lighting condition such as 500 foot candles for a period
of 4 weeks.
• Consider light extremely any changes discoloration, precipitation, decomposition observe in
the sample to consider light sensitive & require light protection in both solid & liquid form.
Mechanism of drug degradation
• It is the most common reaction which is responsible for
the degradation of compounds. e.g. sodium
phenobarbital
Hydrolysis
• Oxidation may lead to discoloration of the parenteral
solution. E.g. Ascorbic acid, adrenaline etc.
Oxidation
• This reaction is commonly observed in compounds
containing carboxylic acid functional group.
Decarboxylation
Testing for packaging components
o Glass- Powdered glass test, Water attack test
o Plastic- Leakage test, collapsibility test, clarity of aqueous test, transparency
o Rubber- Penetrability, fragmentation, self sealibility test, extractive test
◊ Formulation of parenterals:
In the preparation of parenteral products, the following substances are added to make a stable
preparation-
A) Vehicles-
1. Aqueous
2. Non-aqueous
B) Additives-
1. Antimicrobial agents
2. Solubilizing agents
3. Buffers
4. Antioxidants
5. Tonicity agents
6. Chelating agents
7. Suspending agents
8. Emulsifying agents
9. Wetting agents
10. Inert gases
A) Vehicles
There are two types of vehicles which are commonly used for the preparation:
1. Aqueous vehicles-
Water is used as vehicle for majority of injections because water is tolerated well by the body
& is safest to administer.
─ Water for Injection (WFI) USP- Highly purified water is used as a vehicle for injective
preparations which will be subsequently sterilized.
• pH: 5.0-7.0
• WFI may be prepared by either distillation or reverse osmosis.
• Stored in chemically resistant tank.
• Test for pyrogens is done to ensure that water for injection is free from pyrogens.
― Bacteriostatic Water for Injection-
• This type of water is used for making parenteral solutions prepared under aseptic
conditions & not terminally sterilized.
• It can contain an added bacteriostatic agent when in containers of 30 mL or less.
― Sterile water for Injection-
• Contains one or more suitable bacteriostatic agent
• Multiple- dose containers not exceeding 30 mL
• They are permitted to contain higher levels of solid than WFI because of possible leaching.
• Used for washing wounds, surgical incisions, or body tissues.
2. Non- aqueous vehicles
• The commonly used non-aqueous vehicles are oils and alcohols.
• The oily vehicles are generally used when a depot effect of drug is required or the
medicaments are insoluble or slightly soluble in water or the drug is soluble in oil.
Example: dimercaprol injection- using arachis oil as vehicle.
• Fixed oils- Arachis oil, cottonseed oil, almond oil, and sesame oil are used as vehicle.
• Ethyl alcohol, Propyl glycol, propylene glycol and glycerin are used as vehicles.
B) Additives
• These substances are added to increase the stability or quality of the product. They should
be added in minimum possible quantity.
• While selecting the additives, care must be taken that-
-They should be compatible both physically and chemically with the entire formulation.
-They should be non- toxic.
-They should not adversely affect the product
-They should not interfere with the therapeutic efficacy of the active compound.
1. Antimicrobial agents
• These agents are added in adequate quantity to prevent the growth of micoorganisms
during storage and withdrawal of individual doses. So these agents are acts as preservatives.
• Preservatives are added in single dose parenteral products which are sterilized by filtration
method. e.g. Benzalkonium chloride 0.01 %
Phenol: 0.065- 0.5%
Benzyl alcohol: 0.5-10.0 %
Chlorobutanol: 0.25- 0.5 %
Metacresol: 0.1-0.25 %
Methyl paraben: 0.01-0.18 %
Propyl paraben: 0.005-0.035 %
2. Solubilizing agents
These are used to increase the solubilty of drugs which are slightly soluble in water.
e.g. Ethyl alcohol 0.61-49.0
Glycerin 14.6- 25.0 %
Lecithin 0.5- 2.3 %
Polysorbate 20: 0.01%
Polysorbate 40: 0.05 %
• The solubility of drug is increased by using surface active agents.
e.g. Polyethylene 0.1-0.5 %
Sorbitan monooleate 0.05-0.25
3. Buffers
• Drug solubility is strongly depends on the pH of the solution.
• The acceptable pH range is 3-10.5 for i.v. preparations & 4-9 for other routes.
• The degradation of the preparation occurs due to change in pH.
• Buffers are added to maintain the pH of solution.
e.g. Acetic acid 0.22 %
Citric acid 0.5 %
Lactic acid 0.1 %
Maleic acid 1.6 %
Tartaric acid 0.65 %
Sodium citrate 4.0 %
4. Antioxidants
• Many drug in solution are subject to oxidative degradation.
• The oxidation can be prevented by adding a suitable antioxidant.
e.g. Ascorbic acid 0.02-0.1 %
Thiourea 0.005 %
Sodium metabisulphite 0.1-0.15 %
5. Tonicity adjusting agents
• Parenteral preparations should be isotonic with blood plasma or other body fluids to avoid
the destruction of red blood cells, irritation & tissue damage.
• The isotonicity of the solution may be adjusted by adding tonicity adjusting agents.
e.g. Sodium Chloride- Concentration varies
Dextrose 3.75-5.0 %
Mannitol 0.4-2.5 %
Sodiium sulphate 1.1 %
Lactose 0.14-5.0 %
6. Chelating agents
• Chelating agents are added to chelate & thereby inactivate metals such as copper, iron, zinc
present in the formulation. They form a complex which get dissolved in the solvent.
e.g. Edetate disodium 0.00368- 0.05 %
Edetate calcium disodium 0.04 %
Edetate tetrasodium 0.01 %
7. Suspending agents
Suspending agents are used to improve the viscosity & to suspend the particles for a long time.
e.g. Methyl cellulose
Carboxymethyl cellulose
Gelatin
Acacia
8. Emulsifying agents
• These are used in sterile emulsions.
• They reduce the interfacial tension between oily phase & aqueous phase & thus make them
miscible with each other & form a stable emulsions.
e.g. Lecithin
Polysorbate 80
9. Wetting agents
• The reduce the contact angle between the surface of the particle & wetting liquid in
suspension.
• Useful when hydrophobic powders are suspended in aqueous systems.
e.g. Non aqueous solvents (Glycerin, alcohol, & propylene glycol)
Non ionic surfactants (Polysorbate 20, 40, 80)
10. Inert gases
• Another means of enhancing the product integrity of oxygen sensitive medicaments is by
displacing the air of the solution with Nitrogen or Argon.
• This technique may be made more effective by first purging with Nitrogen or boiling the
water to reduce dissolved oxygen.
• The container is also purged with Nitrogen or Argon before filling & may also be topped off
with gas before sealing.
₪ Production procedure:
The following steps are involved in the processing of parenteral preparations:
1. Cleaning of containers, closures & equipment
• All the containers, closures & equipment are thoroughly cleaned with detergents with
tap water, followed by clean distilled water &finally rinsed with water for injection.
• Rubber closures are washed with 0.5% sodium pyrophosphate in water, then removed
from the solution, washed with water followed by rinsing with filtered water for
injection.
• On small scale washing is done manually but on a large scale automatic washing
machines (rotary rinsers, automatic washers) are used.
2. Handling & collection of materials
• The wet, clean containers must be handled in such a way that contamination is not
reintroduced. These containers must be protected by a laminar flow of clean air until
covered, within a stainless steel box, or within a sterilizing tunnel.
• The various ingredients of the formulation of parenteral preparations are collected in
the preparation room. The raw material should be pure.
3. Preparation of parenteral product
• The parenteral preparation must be prepared in aseptic condition.
• All measurements of quantities should be made as accurately as possible & checked by
a second qualified person. The ingredients are accurately weighed separately &
dissolved in the vehicle as per method of preparation to be followed.
• The order of mixing of ingredients may affect the product significantly, particularly
those of large volume, where attaining homogeneity requires considerable mixing time.
4. Filtration
• After a product has been compounded, it must be filtered, if it is a solution. The solution is
passed through bacteria proof filter such as membrane filter, Seitz filter, filter candle &
sintered glass filters.
• The primary objective of filtration is to clarify a solution.
• Membrane filters are used exclusively for parenteral solutions due to their particle-
retention effectiveness, non- shedding property, non- reactivity, & disposable
characteristics. Filters are available as flat membranes or pleated into cylinders to increase
surface area &, thus flow rate.
• Each filter in its holder should be tested for integrity before & after use.
Membrane filter
5. Filling the preparation in final containers
• The filtered product is filled into final containers such as ampoules, vials, & transfusion
bottles, which are previously cleaned & dried.
• The filling is carried out under strict aseptic precautions.
• On small scale, filling is done manually by using hypodermic syringe & needle. On large scale,
filling is done by automatic filling machine.
• Ampoules- single doses
• Vials- Multi doses
• Transfusion bottles- Transfusion fluids.
6. Sealing the containers
• Sealing should be done immediately after filling to prevent contamination.
• Ampoules are sealed by melting a portion of the glass neck.
• Glass or plastic vials & bottles are sealed by closing the opening with a rubber closure
(stopper).
7. Sterilization
The parenteral preparation should be immediately sterilized after sealing in its final container.
• For thermostable substances the parenteral products are sterilized by autoclaving method at
different temperature & pressure.
 Autoclave: At 115°C to 116°C for 30 min
At 121°C for 20 min
 Hot air Oven: At 160°C for 2 hours
• Thermolabile preparations are sterilized by filtration through a suitable bacteria proof filter.
8. Evaluation of the parenteral preparation
The finished parenteral products are subjected to the following tests, in order to maintain
quality control:
1. Sterility test
2. Clarity test
3. Leakage test
4. Pyrogen test
5. Assay
9. Labelling & Packaging
After evaluation of the parenteral preparation, the ampoules, vials & transfusion bottles are
properly labelled & packed. The label should state-
1. Name of the preparation
2. Quantity of the preparation
3. Mfg. Lic. No.
4. Batch No.
5. Date of manufacture
6. Date of expiry
7. Storage conditions
8. Retail price
9. Manufacturer’s address
The packaging provide ample protection for the product against physical damage from
shipping, handling, & storage as well as protecting light-sensitive materials from UV radiation.
 TYPES OF PACKAGING
1. Primary Packaging
• Primary packaging is the material that first envelops the product and holds it.
• Primary packaging is in direct contact with the contents.
• Examples: Ampoules, Vials, Bottles, Closures (rubber, plastic, metal), Syringe,
(for Tablets/Capsules- Strip package, Blister packaging).
2. Secondary Packaging
• Secondary packaging is outside the primary packaging – perhaps used to group
primary packages together.
• Example: Paper and boards, Cartons ,Corrugated fibers, Box, Injection trays etc.
3. Tertiary Packaging
• Tertiary packaging is used for bulk handling , warehouse storage and transport shipping.
• The most common form is a palletized unit load that packs tightly into containers.
• Examples of tertiary packaging might include brown cardboard boxes, wood pallets and
shrink wrap
e.g. Barrel, Container, Edge protectors, Shipping containers etc.
 Production facilities & controls, aseptic processing
Store room
for material
&
equipment
Preparation
area
Clean up area
Aseptic filling
area
Sterilization
Quarantine
area
Packaging &
finishing
Storage & its
disposal
Fig. Flow chart of parenteral products preparation facilities
 Production area can be divided into 5 sections:
1. Clean up area
2. Preparation area
3. Aseptic area
4. Quarantine area
5. Finishing & packaging area
The manufacture of parenteral preparation requires special precautions & facilities in order
to maintain sterility & freedom from particulate matter.
1. Clean up area
 It is not an aseptic area
 The area & atmosphere of the room must be free from dust, fibers
 & microorganism.
 Clean up area should be constructed to withstand moisture, steam & detergent.
 Ceilings & walls can be coated with materials which prevent the accumulation of dust &
microorganisms.
 Exhaust fans should be fitted to remove humidity & heat
 This area should be kept clean so that contaminants may not be carried into aseptic area.
 The containers & closures are properly washed & dried in this area.
2. Preparation area
 The ingredients of the parenteral products are mixed & preparation is made for filling
operation.
 Strict precautions are required to prevent any contamination from outside.
 Cabinets & counters should be made of stainless steel & they are filled in such a way that
no space is left for the dirt to accumulate.
 Ceilings, walls & floor should be sealed & suitably painted to keep them thoroughly
clean.
3. Aseptic area
 From preparation area the parenteral formulation will be transferred to aseptic filling
area.
 The parenteral preparations are filtered, filling into final containers & subsequently
sealed.
 The entry of personnel into aseptic area should be through an air lock.
 To maintain sterility, specially trained persons should be selected to work. They required
to wear sterile clothes & should be subjected to physical examination at regular intervals
to ensure that they are not carrier of any infectious disease.
 There should be minimum movement in aseptic area.
 Ceiling, walls & floor of aseptic area should be sealed & painted, so that they can be
washed or treated with aseptic solution or sprayed before use.
 Stainless steel counters should be fitted on the walls.
 Mechanical equipment should be housed in stainless steel cabinet in order to prevent
dirt to accumulate on it. Mechanical parts that will come in contact with the parenteral
product should be separated so that they can be sterilized.
 The air in aseptic area should be free from fibres, dust & microorganism. This can be
achieved by the use of High Efficiency Particulate Air (HEPA) filters which can remove
particles upto 0.3 μ. The HEPA filter can theoretically remove at least 99.97% of dust,
pollen, mold, bacteria, & any airborne particles.
 HEPA filters are fitted in laminar air flow system, in which air free from dust &
microorganism flows with uniform velocity.
 The air is supplied under positive pressure which prevents particulate contamination from
sweeping from adjoining areas.
 Ultra violet lamps are fitted in order to maintain sterility.
4. Quarantine area
 A batch of parenteral products after its filling, sealing & sterilization are held up in this
area.
 The random samples of parenteral product of different batches are in the analytical
laboratory for its evaluation.
 Those parenteral products which passes all the quality control tests are transferred into
finishing & packaging area.
5. Finishing & packaging area
 The parenteral products are properly labelled & packed.
 Proper packaging is essential to provide protection against physical damage from
transportation, handling & storage.
 The labelled containers should be packed in cardboard or plastic containers. Ampoules
should be packed in partitioned boxes
 The packed parenteral products are temporarily stored till it is finally disposed off.
o Lyophilization & Sterile powders
• Sterile powders or powders for injections (PFI) are
sterile, solid substances (including freeze dried materials)
which are distributed in their final containers & which,
when shaken with the prescribed volume of the
appropriate sterile liquid, rapidly form clear & practically
particle-free solutions or uniform suspensions.
• Injections are packaged as dry solids rather than in conjunction with solvent or vehicle
because therapeutic agent is unstable in the presence of liquid component. Such drugs
can be filled as solutions, placed in a chamber, where the combined effects of freezing &
drying under low pressure will remove the solvent & residual moisture from the solute
components, resulting in a dry powder that has sufficient long term stability.
• Dry sterile powder is aseptically added to a sterile vial
• The dry drug powder is reconstituted with a sterile vehicle before use.
• Example: Amphotericin B, Ampicillin, Ceftriaxone PFI
There are other technologies available to produce sterile dry powder drug products besides
freeze-drying, such as sterile crystallization or spray-drying and powder filling. However,
freeze-drying is the most common unit process for manufacturing drug products too
unstable to be marketed as solutions.
The term ‘lyophilization’ describes a process to produce a product that ‘loves the dry state.’
Equipment used to freeze-dry products are called freeze-dryers or lyophilizers.
For small molecules the highest secondary drying temperature used is 40°C, whereas for
proteins it is no more than 30°C.
Small scale lyophilization
1. The product may be frozen on the shelf in the chamber by circulating refrigerant
(usually silicone) from the compressor through pipes within the shelf. After freezing is
complete, which may require several hours, the chamber and condenser are evacuated
by the vacuum pump, the condenser surface having been chilled previously by
circulating refrigerant from the large compressor.
2. Heat then is introduced from the shelf to the product under graded control by electric
resistance coils or by circulating silicone or glycol.
3. Heat transfer proceeds from the shelf into the product vial and mass transfer (ice)
proceeds from the product vial by sublimation through the chamber and onto the
condenser.
4. The process continues, until the product is dry (usually 1% or less moisture, except for
some proteins that require a minimum amount of water for conformational stability),
leaving a sponge-like matrix of the solids originally present in the product, the input of
heat being controlled so as not to degrade the product.
For most pharmaceuticals and biologicals, the liquid product is sterilized by filtration
before being filled into the dosage container aseptically.
The containers must remain open during the drying process to allow water vapor to
escape; therefore, they must be protected from contamination during transfer from the
filling area to the freeze-drying chamber, while in the freeze-drying chamber and at the end
of the drying process until sealed.
 Freeze drying process phases
1. Freezing- Liquid- solid conversion of the product.
2. Primary drying- Removal of the frozen solvent by sublimation
3. Secondary drying- Removal of unfrozen solvent by diffusion & desorption
Freeze
dryer
 Containers & closures
 Containers
Ampoules Vial Transfusion bottles Collapsible bags
Injectable formulations are packaged into containers made of glass or
plastic. Container systems include ampoules, vials, syringes, cartridges,
bottles, and bags.
Ampoules are all glass, whereas bags are all plastic. The other containers
can be composed of glass or plastic and must include rubber materials,
such as rubber stoppers for vials and bottles and rubber plungers and
rubber seals for syringes and cartridges.
Irrigation solutions are packaged in glass bottles with aluminum screw
caps.
Prefilled syringes
 Ampoules
• An ampoule is a small sealed vial which is used to contain & preserve a sample, usually
liquid. Ampoules are commonly made of glass, although plastic ampoules do exist.
• For single use.
• There are 3 types of ampoules-
One point cut ampoules Flat bottom constricted neck ampoules Flame cut ampoules
 Vials
A glass or plastic container closed with a rubber stopper & sealed with an aluminium crimp
Single use or multiple use
 Transfusion bottles
A bottle of neutral glass either clear or amber color. Glass bottles with big rubber stoppers.
 PVC collapsible bags/ polyethylene packets
Theses are used to pack infusion fluids. Used for large volume parenterals.
 The pharmacopoeia requires the following conditions for a container & closure to be
used for parenteral preparations:
1. It should not yield foreign substances to the product
2. It should be sufficient transparent to allow visual inspection of the content in it.
3. It should not have any adverse effect on the product
4. It should prevent diffusion in or across the walls.
5. It must protect the content from external environment & mechanical shocks
6. It must have a pharmaceutically elegant appearance
7. Must be cheap & economical
◌ Container types
A) Glass
Glass is employed as the container material of choice for most SVIs.
It is composed, principally, of silicon dioxide, with varying amounts of other oxides, such as
sodium, potassium, calcium, magnesium, aluminum, boron, and iron.
The original Parenteral packaging material, has superior clarity, facilitating visual inspection
for particulate matter.
 The USP provides a classification of glass
1. Type I, a borosilicate glass;
2. Type II, a soda-lime treated glass;
3. Type III, a soda-lime glass; and
4. NP, a soda-lime glass not suitable for containers for parenterals.
Container type Type of formulation can be
packed
Glass type that can be
used
Ampoule
Aqueous injectables of any pH Type I
Aqueous injectables of pH less
than 7
Type II
Non- aqueous injectables Type III
Vial
Aqueous injectables of any pH Type I
Aqueous injectables of pH less
than 7
Type II
Non- aqueous injectables Type III
Dry powders for parenteral use Type IV
The glass types are determined from the results of two USP tests:
1. Powdered Glass Test
2. Water Attack Test.
ᴥ Characteristics
1. Glass containers must be strong enough to withstand the physical shocks of handling and
shipping and the pressure differentials that develop, particularly during the autoclave
sterilization cycle.
2. They must be able to withstand the thermal shock resulting from large temperature
changes during processing, for example, when the hot bottle and contents are exposed to
room air at the end of the sterilization cycle. Therefore, a glass with a low coefficient of
thermal expansion is necessary.
3. The container must also be transparent to permit inspection of the contents.
4. Preparations that are light-sensitive must be protected, by placing them in amber glass
containers or by enclosing flint glass containers in opaque cartons labeled to remain on the
container during the period of use.
 Advantages of Glass
 They are transparent
 Available in various shapes & sizes
 Can withstand the variation in temperature & pressure during sterilization
 Economical & easily available
 Protect the photosensitive medicaments from light during storage
 Neutral after proper treatment
 Impermeable to atmospheric gases & moisture
 Good protection power
 Do not deteriorate with age
 Can be easily labelled
 Can be sealed hermetically or by removable closures.
 Disadvantages
 Danger of breakage
 Traces of heavy metal
 Costly manufacturing
 Heavy weights
B) Plastic
• A plastic is a material that contains an essential ingredient one or more polymeric organic
substances of large molecular weight.
• Plastic are either thermosetting or thermoplastic type.
• Thermosetting consist of those plastics that, when subjected to heat, normally will become
infusible or insoluble, & as such cannot be remelted.
• Used for construction of closure
• Thermoplastic consist of those plastics that normally are rigid at operating temperatures
but can be remelted & reprocessed.
• Choice of material for LVPs.
 Thermosetting Plastics-
• Phenol formaldehyde
• Urea formaldehyde
• Melamine formaldehyde
 Thermoplastics-
• Polyethylene (PE)
• Polypropylene (PP)
• Polyethylene Terephthalate (PET)
• Polyvinyl chloride (PVC)
• Polyvinylidene chloride
• Polystyrene (PS)
• Polycarbonate
 Advantages of plastics
1. Lightweight storage options
2. Economical
3. Flexible
4. Molding
5. unbreakable
6. Available in various size & shapes
7. Transported easily
8. Good shock absorption capacity
9. Durability
 Disadvantages
1. Low melting point & low heat
resistant
2. Harmful for nature
3. Relatively expensive
4. May absorb chemical substances,
such as preservative for solution
5. Permeation of vapors & other
molecules
6. Leaching of constituents from the
plastic into the product
 Closures
Containers are equipped with a firm seal to prevent entry of microorganisms & other
contaminants while permitting the withdrawal of a part or the whole of the contents.
1. Rubber closures
• To permit introduction of needle from a hypodermic syringe into a multiple dose vials &
provide resealing as soon as needle is withdrawn.
• It has elasticity, reseal ability & adaptability to many shapes
• To reduce leaching coating of Teflon is applied to closure.
• There are 2 types
1. Natural rubber- suitable for multiple use containers
2. Synthetic rubber- less suitable for multiple use
• Examples of rubbers/ elastomers- Butyl rubber, Chloroprene rubbers (Neoprene), Silicon
rubbers
Rubber closures
Metal caps
Composition of rubber closure
Ingredients Examples
Elastomer Natural rubber, Butyl rubber, Neoprene
Vulcanizing agent Sulfur, peroxides
Accelerator Guanidine's, sulfides
Activator zinc oxide, stearic acid
Filler Carbon black, kaolin
Plasticizer / Lubricant Paraffin oil, silicone oil, Dibutyl phthalate
Antioxidant Aromatic amines
Pigments Carbon black, Inorganic oxides
 Advantages
 Heat resistant
 Permeability of water vapor & air is low
 Water absorption is very low
 Oil resistant
 Disadvantages
 Absorption of bactericide & leaching of
extractives
 Silicon rubbers are expensive
2. Metals
The metals commonly used are aluminium, tin plated steel, stainless steel, tin & lead.
Advantages-
a. Sturdy
b. Impermeable to light, moisture & gases
c. They can be Made into rigid unbreakable containers by impact extrusion
d. They are light in weight as compared to glass containers
Disadvantages
a. Expensive
b. They may shed metal particles into the pharmaceutical product.
 Filling & Sealing of Ampoules, vials, & bottles
 Filling
During the filling operation, the product must be transferred from a bulk container or tank
and subdivided into dose containers.
Most frequently, the compounded product is in the form of a liquid. However, products are
also compounded as dispersed systems (e.g., suspensions and emulsions) and as powders.
 Liquids
There are three main methods for filling liquids into containers with high accuracy:
1. Volumetric filling,
2. Time/pressure dosing,
3. Net weight filling.
• Volumetric filling machines, employing pistons or peristaltic pumps, are most commonly
used.
• When high-speed filling rates are desired but accuracy and precision must be maintained,
multiple filling units are often joined in an electronically coordinated machine.
• Time-pressure (or time-gravity) filling machines are gaining popularity in filling sterile
liquids. A product tank is connected to the filling system equipped with a pressure sensor.
The sensor continuously measures pressure and transmits values to the PLC system
controlling the flow of product from tank to filling manifold. Product flow occurs when
tubing is mechanically unpinched and stops when tubing is mechanically pinched.
• The main advantage of time/pressure filling operations is that these filling apparatuses do
not contain mechanical moving parts in the product stream.
• The product is driven by pressure (usually nitrogen) with no pumping mechanism
involved. Thus, especially for proteins that are quite sensitive to shear forces,
time/pressure filling is preferable.
• The filling of a small number of containers may be accomplished with a hypodermic
syringe and needle, the liquid drawn into the syringe and forced through the needle into
the container. An example of such a device that provides greater speed of filling is the
Cornwall Pipette (Becton Dickinson)
Product filling & closing of vials & infusion bottles
Cornwall Pipette
 Solids
• Sterile solids, such as antibiotics, are more difficult to subdivide evenly into containers
than are liquids. The rate of flow of solid material is slow and often irregular.
• Some sterile solids are subdivided into containers by individual weighing. A scoop is
usually provided to aid in approximating the quantity required, but the quantity filled into
the container is finally weighed on a balance. This is a slow process. When the solid is
obtainable in a granular form, so it will flow more freely, other methods of filling may be
employed.
• In general, these involve the measurement and delivery of a volume of the granular
material that has been calibrated in terms of the weight desired. In the machine shown in
Figure an adjustable cavity in the rim of a wheel is filled by vacuum and the contents held
by vacuum, until the cavity is inverted over the container. The solid material is then
discharged into the container by a puff of sterile air.
High speed powder filling &
closing machine
 Sealing
 Ampoules sealing
• Ampoules are sealed by melting a portion of the glass neck.
• Two types of seals are employed normally:
1. Tip-seals (bead-seals) or
2. pull-seals.
1. Tip seals
• Tip-seals are made by melting enough glass at the tip of the neck of an ampoule to form a
bead and close the opening. These can be made rapidly in a high-temperature gas-oxygen
flame. To produce a uniform bead, the ampoule neck must be heated evenly on all sides,
such as by burners on opposite sides of stationary ampoules or by rotating the ampoule in
a single flame.
• An incompletely sealed ampoule is called a ‘leaker’.
2. Pull seals
• Pull-seals are made by heating the neck of the ampoule below the tip, leaving enough of
the tip for grasping with forceps or other mechanical devices.
• The ampoule is rotated in the flame from a single burner. When the glass has softened,
the tip is grasped firmly and pulled quickly away from the body of the ampoule, which
continues to rotate.
• The small capillary tube, thus, formed is twisted closed. Pull-sealing is slower, but the
seals are more secure than tip-sealing.
• Ampoules having a wide opening must be sealed by pull-sealing.
Ampoule filling & sealing
 Vials & bottles sealing
• Glass or plastic vials and bottles are sealed by closing the opening with a rubber closure
(stopper). This must be accomplished as rapidly as possible after filling to prevent
contamination of the contents.
• Preferably, closures are inserted mechanically, using an automated process, especially
with high-speed processing. To reduce friction, so the closure may slide more easily
through a chute and into the container opening, the closure surfaces are halogenated or
treated with silicone.
• When the closure is positioned at the insertion site, it is pushed mechanically into the
container opening.
• When small lots are encountered, manual stoppering with forceps may be used, but such
a process poses greater risk of introducing contamination than automated processes.
• Container-closure integrity testing has become a major focus for the industry, due to
emphasis by regulatory agencies. Container- closure integrity measures the ability of the
seal between the glass or plastic container opening and the rubber closure to remain tight
and fit and to resist any ingress of microbial contamination during product shelf life.
Container-closure integrity test requirements are covered in USP <1207>.
• Rubber closures are held in place by means of aluminum caps. The caps cover the closure,
crimped under the lip of the vial or bottle to hold them in place. The closure cannot be
removed without destroying the aluminum cap; it is tamperproof. Therefore, an intact
aluminum cap is proof that the closure has not been removed intentionally or
unintentionally.
Capping
Vial sealing machine Manual sealing
Prefilled
cartridge
Prefilled Syringe
 PREFILLED SYRINGES & CARTRIDGES
These are designed for maximum convenience.
a. Prefilled Syringes:
Drugs administration in an emergency are available for immediate injection when packaged
in prefilled syringes.
e.g.: Atropine, epinephrine
b. Prefilled cartridges
•Are ready-to-use parenteral packages that offer improved sterility and accuracy.
•They consist of a plastic cartridges holder and prefilled .
•The medication is premixed and premeasured
E.g. Enoxaparin
Inova
syringe
filling
machine
needle &
plunger
assemblies
 Advantages
• Less or no breakage: Prefilled cartridges are much less prone to crack or break in
comparison to their standard, glass counterparts.
• Accuracy: Prefilled syringe cartridges assure that patients receive accurate dosages.
• Self-inject medication possible: This is especially advantageous for patients who need to
self-inject medication, but have no medical training.
 Disadvantages
• Expensive
• Not compatible with all drugs
BLOW-FILL-SEAL TECHNOLOGY
• Blow-Fill Seal technology refers to the manufacturing technique used to produce small,
and large volume, (500mL+) liquid filled containers.
• The basic concept of blow fill seal (BFS) is that a container is formed, filled, and sealed in a
continuous process without human intervention, in a sterile enclosed area inside a
machine.
Blow – fill- seal process
 The BFS cycle can be divided into the following main steps:
 Step 1: Parison Extrusion
 Step 2: Container Molding
 Step 3: Container Filling
 Step 4: Container Sealing
 Step 5: Container Discharge
https://youtu.be/6Lauct3ZmsQ
Material used for container:
• Polyethylene
• Polyvinyl chloride
• Polyester
• Polypropylene
 Step 1: Parison extrusion
Firstly pharmaceutical plastic resin is vertically heat extruded through a circular throat to
form a tube called the Parison.
 Step 2: Container Molding
This extrused tube is then enclosed within a 2 part- mould, & the tube is cut above the
mould.
 Step 3: Container Filling
The mould is transferred to the filling zone, or sterile filling space where filling needle
manderlas lowered space & used to enflate the plastic to form container within the
mould.
 Step 4: Container Sealing
The Manderel is used to fill the container with liquid, following filling, the manderels are
remove & a secondary top mould seals the container.
 Step 5: Container Discharge/ De-flashing
To remove the flash or scrap, trimming the containers & delivering the container outside the
machine.
• All action takes place inside the sterile chamber inside the machine. The product is then
discharged to a non sterile area for labelling, packaging & distribution
 Advantages
 Reduce personal intervention
 No need to purchase and stock a range of prefabricated containers and their closures.
 Cleaning and sterilization of prefabricated containers and closures is not required.
 The code numbers and variable data such as batch number and expiry date can be
 embedded onto the container itself.
 The cost of material transport, storage and inventory control is reduced.
 Validation requirements are reduced.
 There is a large choice of neck and opening device shapes.
 A single compact BFS machine takes the place of several conventional machines, saving
 floor space.
 Quality control tests
○ IPQC Tests for Sterile Formulations
1. •Leakage Test
2. •Clarity Test
3. •pH
4. •Particulate Matter Injection
5. •SterilityTest
6. •PyrogenTest
7. •Content Uniformity & Weight
8. •Volume Filled
1. Leakage test
•Leakage test is employed to detect incompletely sealed ampoule so that they may be
discarded.
•To test the package integrity.
•Package integrity reflects its ability to keep the product in and to keep potential
contamination out.
Leakage tests are 4 types:
a) Visual inspection
b) Bubble test
c) Dye test
d) Vacuum ionization
a) Visual inspection
 Visual inspection is the easiest leaker test method to perform.
 The method is used for the evaluation of large volume parenterals.
 To increase the sensitivity of the method the visual inspection of the sample container
may be coupled with the application of vacuum to make leakage more readily observable.
 This method is simple and inexpensive.
 Disadvantage: less sensitive
 Sensitivity is increased by applying pressure/vacuum
b) Bubble test
• The test package is submerged in liquids.
• A differential pressure is applied on the container.
• The container is observed for bubbles.
• Sometimes, surfactant added liquid is used for immersion of test package.
• Any leakage is evident after the application of differential pressure as the generation of
foaming in immersion liquid.
• The method is simple and inexpensive.
• The location of the leaks can be observed in this method.
• Generation of a differential positive pressure of 3 psi inside the vial and observation of any
leakage using magnifying glass within a maximum test time of 15 minutes.
• However, it is relatively insensitive and the findings are operator dependent and are
qualitative.
• The optimized conditions can be achieved using a surfactant.
C) Dye test
•The test container is immersed in a dye bath.
•Vacuum and pressure is applied for sometime.
•The container is removed from the dye bath and washed.
•The container is then inspected for the presence of dye either visually or by means of UV
spectroscopy.
•The dye used is usually 0.5% to 1% methylene blue.
•The dye test is widely accepted in industry and is approved in drug use.
•The test is inexpensive and is requires no special equipment required for visual dye detection.
•However, the test is qualitative, destructive and slow.
•The test is used for ampoules
d) Vacuum ionization test
•Vacuum ionization test is useful for testing leakage in the vials or bottled sealed under
vacuum.
•This test is used for testing of the lyophilized products.
•High voltage, high frequency field is applied to vials which to cause residual gas, if present to
glow.
•Glow intensity is the function of headspace vacuum level.
•The blue glow is the indicative of vacuum while the purple glow indicative of no vacuum. The
sensitivity of the method is not documented.
•This test is rapid and is non destructive test.
•However, the proteins present in test sample may be decomposed.
•This method is used of for the lyophilized vials in biopharmaceuticals
2. CLARITY TEST
(PARTICLE CONTAINMENT TEST)
•
• Definition: Clarity is a relative term, its mean a clear solution having a high polish
conveys to the observer that the product is of exceptional quality and purity.
• Clarity test is carried out to check the particulate matter in the sample.
• It is practically impossible that every unit of lot is perfectly free from visible particulate
matter, that is, from particles that are 30 to 40 micrometer and large in size.
PRINCIPLE:
• This test is performed to check the particulate contamination of injections and infusions
consists of extraneous, mobile and undissolved particles, other than gas bubbles,
unintentionally present in the solution.
USP limits for large volume infusion
Particle size Particle limit
10 μm or larger/ mL 50
25 μm or larger/ mL 5
3. pH
Checking the bulk solution, before filling for drug content, pH, color, clarity and
completeness of solution.
The pH of a formulation must be considered from following standpoint:
• The effect on the body when the solution is administered
• The effect on stability of the product
• The effect on container-closure system
 pH measurement
 pH is measured by using a pH meter .
 pH meter is initially calibrated with respective buffer capsule then the pH of
the preparation is measured
4. PARTICULATE MATTER IN INJECTIONS
•The preparations intended for parenteral use should be free from particulate matter
and should be clear when inspected visually.
•Two methods are described by USP according to the filled volume of the product to be
tested.
•For large volume parenterals (LVP's), a filtration followed by microscopical examination
procedure is used.
• For small volume parenterals (SVP's) a light obscuration based sensor containing
electronic liquid borne particle counter system is used.
• The USP standards are met if the LVP's under test contain NMT 50 particles per ml of
10μ m, and NMT 5 particles per ml of 25μm in an effective linear dimensional fashion.
•The USP standards are met if the SVP's under test contain NMT 10,000 particles per
container of 10 μm, and NMT 1000 particles per container of 25μm in an effective
spherical diameter.
Table 1: Limits for particle number as per IP, BP, EP and JP
Volume of
solution
Particle size ≥ 10
μm
Particle size ≥25
μm
Small volume
injections (< 100 ml)
3000 per container 300 per container
Large volume
injections (> 100 ml)
12 per ml 2 per ml
5. STERILITY TESTING
• 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.
• Sterility testing attempts to reveal the presence or absence of viable microorganisms in a
sample number of containers taken from batch of product.
• Based on results obtained from testing the sample a decision is made as to the sterility of
the batch.
 Major factors of importance in sterility testing:
The environment in which the test is conducted
The quality of the culture conditions provided
The test method
The sample size
The sampling procedure
Environmental conditions:
Environmental conditions avoid accidental contamination of the product during the test.
The test is carried out under aseptic conditions regular microbiological monitoring
should be carried out.
Culture conditions:
Appropriate conditions for the growth of any surviving organism should be provided by
the culture media selection.
 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.
 The 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
Samples size to be taken
No. of articles in batch
(injectables)
No. of articles to be tested
Not more than 100 articles 10% /4 articles whichever is
greater
More than 100 but not more
than 500
10 articles
For more than 500 2%/20 articles whichever is less
For large volume parenterals 2%/10 containers whichever is
less
[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.
o Interpretation of results
At the end of the incubation period the following observations are possible:
 No evidence of growth; hence the preparation being examined passes the test for
sterility.
 If there is evidence of growth, retesting is performed using the same number of
samples, volumes to be tested and the media as in the original test. If no evidence of
microbial growth is then found, the preparation being examined passes the test for
sterility.
 If there is again evidence of the microbial growth then isolate and identify the
organisms. If they are not readily distinguishable from those growing in the containers
of the first test then the preparation being examined fails the test for sterility.
 If they are distinguishable from the organisms of the first test then again do the test
using twice the number of samples. The preparation being examined passes the test for
sterility in case there is no evidence of microbial growth. In case there is evidence of
growth of any microorganisms in second re –test, the preparation being examined fails
the tests for sterility
6. PYROGEN TESTING
o Pyrogens are fever producing substances.
o Pyro means ‘pyrexia’, Gen means ‘producing’.
o Pyrogens are the by-products of microorganisms mainly of bacteria, molds and viruses.
o During the processing these pyrogens may come from water, active constituent or the
excipient or from the equipments.
o Chemically these pyrogens are lipid substances associated with carrier usually
polysaccharides or may be proteins
o Parenteral solutions are officially tested for the presence of pyrogens by a biological
test in which “FEVER” response of rabbits is used as criteria.
Types of Pyrogen test :
 For Detection and quantification of Pyrogens:
 Basically there are 2 tests performed to detect the presence of pyrogens in sterile
parenteral products they are-
1. In Vivo pyrogen test (Rabbit Test)- SHAM test
2. In Vitro pyrogen test(Limulus Amebocyte Lysate Test)
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.
Interpretation of Result (Rabbit Test)
No. of Rabbits Individual Temp.
size (ᵒC)
Temp. rise in
groups (ᵒC)
Test
3 Rabbits 0.6 1.4 Passes
If above not passes
3+5= 8 rabbits
0.6 3.7 Passes
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.
CONTENT UNIFORMITY AND WEIGHT :
•Determine the content of the active ingredient of each of 10 containers taken at random.
•The preparation under examination complies with the test if the individual values thus
obtained are all between 85 and 115 percent of the average value.
•The preparation under the examination fails to comply with the test if more than one
individual value is outside the limits 85 to 11 percent of the average value or if any one
individual value is outside the limits 75 to 125 percent of the average value.
•If one individual value is outside the limits 85 to 115 percent but within the limits 75 to
125 percent of the average value, repeat the determination using another 20 containers
taken at random.
•The preparation under examination complies with the test if in the total sample of 30
containers not more than one individual value is outside the limits 85 to 115 percent and
none is outside the limits 75 to 125 percent of the average value.
Table 3: Limits for Uniformity of Weight
Pharmaceutical
Formulation
Average Mass Percentage Deviation (%)
Powders for parenteral use More than 40 mg 10
Powders for eye drops Less than 300 mg 10
Powders for eye lotions 300 mg or more 7.5
Parenteral Products

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Parenteral Products

  • 1. INDUSTRIAL PHARMACY- I PARENTERAL PRODUCTS Prepared by: Komal Pramod Sathe College: HSBPVTs GOI College of Pharmacy, Kashti. Roll no.: 117
  • 2.  Parenterals The term is derived from the Greek word ‘Para’ (outside) & ‘Enterone’ (intestine). These are the preparations which are given other than oral routes. Definitions  According to B.P. : “Parenteral preparations are sterile preparations intended for administration by injection, infusion or implantation into human or animal bodies”  According to WHO : “Parenteral preparations are sterile, pyrogen-free liquids (solutions, emulsions, or suspensions) or solid dosage forms containing one or more active ingredients, packaged in either single-dose or multi dose containers. They are intended for administration by injection, infusion, or implantation into the body.”
  • 3.  Advantages 1. Rapid onset of action 2. Localized drug delivery 3. Useful for patients who cannot take drug orally (Patients who are vomiting or unconscious) 4. Useful for emergency situations 5. Avoid first pass metabolism as drug directly enters the systemic circulation by parenteral route. 6. Irritation of stomach by the drug is avoided 7. Complete bioavailability 8. Providing sustained drug delivery (implants) 9. Useful for delivering fluids, electrolytes or nutrients. 10. The drug action can be prolonged by modifying the formulation 11. Injection ensures accurate dosage of the medicament  Disadvantages (Limitations) 1. Pain on injection 2. Sensitivity or allergic reactions at the site of injection 3. Trained person is required for administration of drug. Self medication is difficult. 4. Drug directly reaches to the systemic circulation hence it is difficult to reverse an administered drug’s effect. Difficult to save patient if overdose. 5. These routes are not very convenient and economical for the patient. 6. It is essential to follow strict aseptic technique in order to avoid possibility of infections. 7. Side effects are quicker than that of drug given by any other route.
  • 5. Classification of parenteral products:  On the basis of Volume Small volume parenteral Large volume parenteral An injection that is packed in containers labelled as containing 100 mL or less An injection that is packed in containers labelled as containing 101 mL-1000 mL Single or multiple use Single use Used for administration of drug Used to provide calories, electrolytes, fluid Preservatives are used Preservatives are not used Administered through various parenteral routes Administered through IV infusion technique e.g. Insulin injection, Procaine penicillin G injection e.g. Saline solution, Mixture of dextrose, amino acids, lipids, vitamins, etc. Types of large volume parenteral- 1. Hyper alimentation solutions 2. Cardioplegic solutions 3. Peritoneal dialysis solution 4. Irrigating solution
  • 6. Types based on the mode of delivery The different categories of parenteral preparations include: 1. - injections; 2. - intravenous infusions; 3. - powders for injections or intravenous infusions; 4. - concentrates for injections or intravenous infusions; 5. - implants. 1. Injections “Injections are sterile, pyrogen- free solutions or dispersions (emulsions or suspensions) of one or more active ingredients in a suitable vehicle.” They are prepared using an aqueous vehicle. • Single dose injections: They should not contain antimicrobial preservatives unless justified and authorized. • Multi dose preparations: They contain a suitable antimicrobial preservative in appropriate concentrations except in cases where the preparations themselves have adequate antimicrobial properties. Multi dose preparation should normally not exceed 30 mL
  • 7. 2. Intravenous infusions • Intravenous infusions are sterile, pyrogen- free aqueous solutions or emulsions with water as continues phase, usually prepared to be isotonic. • They are intended for administration in large volumes & do not contain any antimicrobial preservatives. 3. Powders for injection or Intravenous infusion They are sterile, pyrogen- free solid substances (including freeze-dried materials), distributed in their final containers & which when the prescribed volume of the appropriate sterile liquid is added, rapidly from either clear and practically particle-free solutions or uniform suspensions. 4. Concentrates for injections or intravenous infusions They are sterile, pyrogen- free solutions intended for injection or infusion after dilution. They are diluted to a prescribed volume with a prescribed liquid before administration. 5. Implants • Implants are sterile solid preparations containing one or more active ingredients. • They are of a size and shape suitable for parenteral implantation & provide release of the active ingredients over an extended period of time. • They are presented in individual sterile containers.
  • 8.  Classification based on the type of Formulation Types of formulation Solution Suspensions Injectable emulsions Freeze dry powders 1) Solutions: A solution is a liquid preparation that contains one or more soluble chemical substances dissolved in a specified solvent. Aqueous solvents are compatible physiologically compatible with body tissues, biologic response is reasonably predictable. 2) Suspensions: They should be sterile, pyrogen- free, stable, re-suspendable, syrringeable, isotonic & non-irritant. Administered usually by subcutaneous or intramuscular route.
  • 9. 3) Emulsion: Parenteral emulsions are rare because it is necessary & difficult to achieve stable droplet of less than 1 micron to prevent emboli in blood vessels, which is difficult to prepare for such a preparation. Very limited selection of emulsifier & stabilizers is there to choose from. 4) Dry powders: It is formulation of lyophilized or freeze-dried powders that must be reconstituted with some suitable solvent to make a liquid formulation before being withdrawn from the vial.  General requirements for parenteral dosage forms: 1. Sterility- All parenteral products must be sterile. Preparation should be free from all types of microorganisms. An aseptic conditions are required to maintain during the preparation of parenteral products & its administration. The parenteral product must pass the test for sterility. 2. Stability- All products must be stable. The physical as well as chemical stability of parenteral preparation must be maintained during storage. 3. Isotonicity- The parenteral preparations should be isotonic with blood plasma & body fluids. It is very important, in order to avoid any complications on the administration of parenteral products. 4. Free from pyrogen- The parenteral preparations should be free from toxin & pyrogens. The parenteral product must pass the test for pyrogen, because contaminated parenteral product causes rise in body temperature after its administration.
  • 10. 5. Free from foreign particles- The parenteral products should be free from foreign particles such as dust & fibres. To ensure this, the product must pass the clarity test. 6. Specific gravity- The parenterals meant for intra- spinal injections should have the same specific gravity as that of spinal fluid into which the same are to be injected. 7. Chemical purity- The parenteral preparation should be free from chemical impurities or it should be within certain limit as specified in the monograph of that preparation in the pharmacopoeia. 8. Containers- Parenteral products are usually supplied in glass ampoules, bottles or vials, in plastic bottles or bags, or in prefilled syringes. In case of light- sensitive substances the container should protect the contents. They do not adversely affect the quality of the preparation. 9. Closures- Closures for parenteral preparation containers are equipped with a firm seal to prevent entry of microorganisms & other contaminants.  Importance of Isotonicity o Isotonicity- Solutions that have the same osmotic pressure as that of a 0.9% sodium chloride solution (=normal saline) are considered to be isotonic to blood, tears & other body fluids.
  • 11. o Isotonicity is important for parenteral preparation because the possibility that the product may penetrate red blood cell & cause hemolysis is greatly reduced if the solution is isotonic with blood i.e. the cells maintain their tone. o Isotonic products reduce the pain of injection in areas with nerve endings. o Solution that has less osmotic pressure than the blood plasma called hypotonic & o Solution that has more osmotic pressure than the blood plasma called hypertonic. o When introduce hypotonic solution cell may swell & offers burst because of diffusion of water into the cell i.e. hemolysis, o If introduce hypertonic solution, the cell may lose water & shrink.
  • 12. o Tonicity adjusting agents are added to injectable preparations to prevent osmotic shock at the site of injection upon administration, & thereby reduce local irritation. o Three ingredients are generally used to adjust the tonicity of solutions: Dextrose, Glycerine, & sodium chloride. o Isotonic solutions are used: to increase the extracellular fluid volume due to blood loss, surgery, dehydration, fluid loss that has been loss extracellularly. o Isotonicity calculations based on freezing point depression- W= 0.52-a/b Where, − W is the % w/v of adjusting substance in the final solution − a is the freezing point depression of unadjusted solution (i.e. freezing point depression of 1% solution × strength in & w/v) & − b is the freezing point depression of water due to 1% w/v of adjusting substance, usually sodium chloride or glucose.
  • 13.  Preformulation factors:  Preformulation studies are of various types: 1. Physicochemical properties of new drug substance 2. Stability testing 3. Mechanism of drug degradation 4. Testing for packaging material o Molecular structure & weight: The first & most important step in preformulation is determination of the molecular structure & weight. o Colour: Appearance of colour change is indicative of physicochemical instability which may decrease the shelf life of the product. o Thermal analysis: The drug may undergo physical or chemical changes due to variations of temperature which may be associate with loss or gain. The change analyzed by DTA &v DSC.
  • 14. o Solubility • A clear solution for injectable that are to be administered either infusion or via intramuscular route mainly depends on solubility. • Solubility of drug substances can be determined by spectrophotometric method or from pH profile. • Non aqueous solvents like ethyl alcohol, glycerin, polyethylene glycol are used. o Partition coefficient • It is used to determine the rate & extent of drug absorption. It is the ratio of unionized drug distributed between the organic phase & aqueous phase. • It is explained by equation P= Co/CW Test for stability Light stability • Drug solution placed in the petri plate & glass ampoules respectively • Drug substance placed in light resistant container such as carbon box which act as controller. • The samples are placed & maintain lighting condition such as 500 foot candles for a period of 4 weeks. • Consider light extremely any changes discoloration, precipitation, decomposition observe in the sample to consider light sensitive & require light protection in both solid & liquid form.
  • 15. Mechanism of drug degradation • It is the most common reaction which is responsible for the degradation of compounds. e.g. sodium phenobarbital Hydrolysis • Oxidation may lead to discoloration of the parenteral solution. E.g. Ascorbic acid, adrenaline etc. Oxidation • This reaction is commonly observed in compounds containing carboxylic acid functional group. Decarboxylation Testing for packaging components o Glass- Powdered glass test, Water attack test o Plastic- Leakage test, collapsibility test, clarity of aqueous test, transparency o Rubber- Penetrability, fragmentation, self sealibility test, extractive test
  • 16. ◊ Formulation of parenterals: In the preparation of parenteral products, the following substances are added to make a stable preparation- A) Vehicles- 1. Aqueous 2. Non-aqueous B) Additives- 1. Antimicrobial agents 2. Solubilizing agents 3. Buffers 4. Antioxidants 5. Tonicity agents 6. Chelating agents 7. Suspending agents 8. Emulsifying agents 9. Wetting agents 10. Inert gases A) Vehicles There are two types of vehicles which are commonly used for the preparation: 1. Aqueous vehicles- Water is used as vehicle for majority of injections because water is tolerated well by the body & is safest to administer. ─ Water for Injection (WFI) USP- Highly purified water is used as a vehicle for injective preparations which will be subsequently sterilized.
  • 17. • pH: 5.0-7.0 • WFI may be prepared by either distillation or reverse osmosis. • Stored in chemically resistant tank. • Test for pyrogens is done to ensure that water for injection is free from pyrogens. ― Bacteriostatic Water for Injection- • This type of water is used for making parenteral solutions prepared under aseptic conditions & not terminally sterilized. • It can contain an added bacteriostatic agent when in containers of 30 mL or less. ― Sterile water for Injection- • Contains one or more suitable bacteriostatic agent • Multiple- dose containers not exceeding 30 mL • They are permitted to contain higher levels of solid than WFI because of possible leaching. • Used for washing wounds, surgical incisions, or body tissues. 2. Non- aqueous vehicles • The commonly used non-aqueous vehicles are oils and alcohols. • The oily vehicles are generally used when a depot effect of drug is required or the medicaments are insoluble or slightly soluble in water or the drug is soluble in oil. Example: dimercaprol injection- using arachis oil as vehicle. • Fixed oils- Arachis oil, cottonseed oil, almond oil, and sesame oil are used as vehicle. • Ethyl alcohol, Propyl glycol, propylene glycol and glycerin are used as vehicles.
  • 18. B) Additives • These substances are added to increase the stability or quality of the product. They should be added in minimum possible quantity. • While selecting the additives, care must be taken that- -They should be compatible both physically and chemically with the entire formulation. -They should be non- toxic. -They should not adversely affect the product -They should not interfere with the therapeutic efficacy of the active compound. 1. Antimicrobial agents • These agents are added in adequate quantity to prevent the growth of micoorganisms during storage and withdrawal of individual doses. So these agents are acts as preservatives. • Preservatives are added in single dose parenteral products which are sterilized by filtration method. e.g. Benzalkonium chloride 0.01 % Phenol: 0.065- 0.5% Benzyl alcohol: 0.5-10.0 % Chlorobutanol: 0.25- 0.5 % Metacresol: 0.1-0.25 % Methyl paraben: 0.01-0.18 % Propyl paraben: 0.005-0.035 % 2. Solubilizing agents These are used to increase the solubilty of drugs which are slightly soluble in water. e.g. Ethyl alcohol 0.61-49.0
  • 19. Glycerin 14.6- 25.0 % Lecithin 0.5- 2.3 % Polysorbate 20: 0.01% Polysorbate 40: 0.05 % • The solubility of drug is increased by using surface active agents. e.g. Polyethylene 0.1-0.5 % Sorbitan monooleate 0.05-0.25 3. Buffers • Drug solubility is strongly depends on the pH of the solution. • The acceptable pH range is 3-10.5 for i.v. preparations & 4-9 for other routes. • The degradation of the preparation occurs due to change in pH. • Buffers are added to maintain the pH of solution. e.g. Acetic acid 0.22 % Citric acid 0.5 % Lactic acid 0.1 % Maleic acid 1.6 % Tartaric acid 0.65 % Sodium citrate 4.0 % 4. Antioxidants • Many drug in solution are subject to oxidative degradation. • The oxidation can be prevented by adding a suitable antioxidant. e.g. Ascorbic acid 0.02-0.1 %
  • 20. Thiourea 0.005 % Sodium metabisulphite 0.1-0.15 % 5. Tonicity adjusting agents • Parenteral preparations should be isotonic with blood plasma or other body fluids to avoid the destruction of red blood cells, irritation & tissue damage. • The isotonicity of the solution may be adjusted by adding tonicity adjusting agents. e.g. Sodium Chloride- Concentration varies Dextrose 3.75-5.0 % Mannitol 0.4-2.5 % Sodiium sulphate 1.1 % Lactose 0.14-5.0 % 6. Chelating agents • Chelating agents are added to chelate & thereby inactivate metals such as copper, iron, zinc present in the formulation. They form a complex which get dissolved in the solvent. e.g. Edetate disodium 0.00368- 0.05 % Edetate calcium disodium 0.04 % Edetate tetrasodium 0.01 % 7. Suspending agents Suspending agents are used to improve the viscosity & to suspend the particles for a long time. e.g. Methyl cellulose Carboxymethyl cellulose
  • 21. Gelatin Acacia 8. Emulsifying agents • These are used in sterile emulsions. • They reduce the interfacial tension between oily phase & aqueous phase & thus make them miscible with each other & form a stable emulsions. e.g. Lecithin Polysorbate 80 9. Wetting agents • The reduce the contact angle between the surface of the particle & wetting liquid in suspension. • Useful when hydrophobic powders are suspended in aqueous systems. e.g. Non aqueous solvents (Glycerin, alcohol, & propylene glycol) Non ionic surfactants (Polysorbate 20, 40, 80) 10. Inert gases • Another means of enhancing the product integrity of oxygen sensitive medicaments is by displacing the air of the solution with Nitrogen or Argon. • This technique may be made more effective by first purging with Nitrogen or boiling the water to reduce dissolved oxygen. • The container is also purged with Nitrogen or Argon before filling & may also be topped off with gas before sealing.
  • 22. ₪ Production procedure: The following steps are involved in the processing of parenteral preparations:
  • 23. 1. Cleaning of containers, closures & equipment • All the containers, closures & equipment are thoroughly cleaned with detergents with tap water, followed by clean distilled water &finally rinsed with water for injection. • Rubber closures are washed with 0.5% sodium pyrophosphate in water, then removed from the solution, washed with water followed by rinsing with filtered water for injection. • On small scale washing is done manually but on a large scale automatic washing machines (rotary rinsers, automatic washers) are used. 2. Handling & collection of materials • The wet, clean containers must be handled in such a way that contamination is not reintroduced. These containers must be protected by a laminar flow of clean air until covered, within a stainless steel box, or within a sterilizing tunnel. • The various ingredients of the formulation of parenteral preparations are collected in the preparation room. The raw material should be pure. 3. Preparation of parenteral product • The parenteral preparation must be prepared in aseptic condition. • All measurements of quantities should be made as accurately as possible & checked by a second qualified person. The ingredients are accurately weighed separately & dissolved in the vehicle as per method of preparation to be followed. • The order of mixing of ingredients may affect the product significantly, particularly those of large volume, where attaining homogeneity requires considerable mixing time.
  • 24. 4. Filtration • After a product has been compounded, it must be filtered, if it is a solution. The solution is passed through bacteria proof filter such as membrane filter, Seitz filter, filter candle & sintered glass filters. • The primary objective of filtration is to clarify a solution. • Membrane filters are used exclusively for parenteral solutions due to their particle- retention effectiveness, non- shedding property, non- reactivity, & disposable characteristics. Filters are available as flat membranes or pleated into cylinders to increase surface area &, thus flow rate. • Each filter in its holder should be tested for integrity before & after use. Membrane filter
  • 25. 5. Filling the preparation in final containers • The filtered product is filled into final containers such as ampoules, vials, & transfusion bottles, which are previously cleaned & dried. • The filling is carried out under strict aseptic precautions. • On small scale, filling is done manually by using hypodermic syringe & needle. On large scale, filling is done by automatic filling machine. • Ampoules- single doses • Vials- Multi doses • Transfusion bottles- Transfusion fluids. 6. Sealing the containers • Sealing should be done immediately after filling to prevent contamination. • Ampoules are sealed by melting a portion of the glass neck. • Glass or plastic vials & bottles are sealed by closing the opening with a rubber closure (stopper). 7. Sterilization The parenteral preparation should be immediately sterilized after sealing in its final container. • For thermostable substances the parenteral products are sterilized by autoclaving method at different temperature & pressure.  Autoclave: At 115°C to 116°C for 30 min At 121°C for 20 min  Hot air Oven: At 160°C for 2 hours • Thermolabile preparations are sterilized by filtration through a suitable bacteria proof filter.
  • 26. 8. Evaluation of the parenteral preparation The finished parenteral products are subjected to the following tests, in order to maintain quality control: 1. Sterility test 2. Clarity test 3. Leakage test 4. Pyrogen test 5. Assay 9. Labelling & Packaging After evaluation of the parenteral preparation, the ampoules, vials & transfusion bottles are properly labelled & packed. The label should state- 1. Name of the preparation 2. Quantity of the preparation 3. Mfg. Lic. No. 4. Batch No. 5. Date of manufacture 6. Date of expiry 7. Storage conditions 8. Retail price 9. Manufacturer’s address The packaging provide ample protection for the product against physical damage from shipping, handling, & storage as well as protecting light-sensitive materials from UV radiation.
  • 27.  TYPES OF PACKAGING 1. Primary Packaging • Primary packaging is the material that first envelops the product and holds it. • Primary packaging is in direct contact with the contents. • Examples: Ampoules, Vials, Bottles, Closures (rubber, plastic, metal), Syringe, (for Tablets/Capsules- Strip package, Blister packaging). 2. Secondary Packaging • Secondary packaging is outside the primary packaging – perhaps used to group primary packages together. • Example: Paper and boards, Cartons ,Corrugated fibers, Box, Injection trays etc.
  • 28. 3. Tertiary Packaging • Tertiary packaging is used for bulk handling , warehouse storage and transport shipping. • The most common form is a palletized unit load that packs tightly into containers. • Examples of tertiary packaging might include brown cardboard boxes, wood pallets and shrink wrap e.g. Barrel, Container, Edge protectors, Shipping containers etc.
  • 29.  Production facilities & controls, aseptic processing Store room for material & equipment Preparation area Clean up area Aseptic filling area Sterilization Quarantine area Packaging & finishing Storage & its disposal Fig. Flow chart of parenteral products preparation facilities  Production area can be divided into 5 sections: 1. Clean up area 2. Preparation area 3. Aseptic area 4. Quarantine area 5. Finishing & packaging area
  • 30. The manufacture of parenteral preparation requires special precautions & facilities in order to maintain sterility & freedom from particulate matter. 1. Clean up area  It is not an aseptic area  The area & atmosphere of the room must be free from dust, fibers  & microorganism.  Clean up area should be constructed to withstand moisture, steam & detergent.  Ceilings & walls can be coated with materials which prevent the accumulation of dust & microorganisms.  Exhaust fans should be fitted to remove humidity & heat  This area should be kept clean so that contaminants may not be carried into aseptic area.  The containers & closures are properly washed & dried in this area. 2. Preparation area  The ingredients of the parenteral products are mixed & preparation is made for filling operation.  Strict precautions are required to prevent any contamination from outside.  Cabinets & counters should be made of stainless steel & they are filled in such a way that no space is left for the dirt to accumulate.  Ceilings, walls & floor should be sealed & suitably painted to keep them thoroughly clean.
  • 31. 3. Aseptic area  From preparation area the parenteral formulation will be transferred to aseptic filling area.  The parenteral preparations are filtered, filling into final containers & subsequently sealed.  The entry of personnel into aseptic area should be through an air lock.  To maintain sterility, specially trained persons should be selected to work. They required to wear sterile clothes & should be subjected to physical examination at regular intervals to ensure that they are not carrier of any infectious disease.  There should be minimum movement in aseptic area.  Ceiling, walls & floor of aseptic area should be sealed & painted, so that they can be washed or treated with aseptic solution or sprayed before use.  Stainless steel counters should be fitted on the walls.  Mechanical equipment should be housed in stainless steel cabinet in order to prevent dirt to accumulate on it. Mechanical parts that will come in contact with the parenteral product should be separated so that they can be sterilized.
  • 32.  The air in aseptic area should be free from fibres, dust & microorganism. This can be achieved by the use of High Efficiency Particulate Air (HEPA) filters which can remove particles upto 0.3 μ. The HEPA filter can theoretically remove at least 99.97% of dust, pollen, mold, bacteria, & any airborne particles.  HEPA filters are fitted in laminar air flow system, in which air free from dust & microorganism flows with uniform velocity.  The air is supplied under positive pressure which prevents particulate contamination from sweeping from adjoining areas.  Ultra violet lamps are fitted in order to maintain sterility.
  • 33. 4. Quarantine area  A batch of parenteral products after its filling, sealing & sterilization are held up in this area.  The random samples of parenteral product of different batches are in the analytical laboratory for its evaluation.  Those parenteral products which passes all the quality control tests are transferred into finishing & packaging area. 5. Finishing & packaging area  The parenteral products are properly labelled & packed.  Proper packaging is essential to provide protection against physical damage from transportation, handling & storage.  The labelled containers should be packed in cardboard or plastic containers. Ampoules should be packed in partitioned boxes  The packed parenteral products are temporarily stored till it is finally disposed off.
  • 34. o Lyophilization & Sterile powders • Sterile powders or powders for injections (PFI) are sterile, solid substances (including freeze dried materials) which are distributed in their final containers & which, when shaken with the prescribed volume of the appropriate sterile liquid, rapidly form clear & practically particle-free solutions or uniform suspensions. • Injections are packaged as dry solids rather than in conjunction with solvent or vehicle because therapeutic agent is unstable in the presence of liquid component. Such drugs can be filled as solutions, placed in a chamber, where the combined effects of freezing & drying under low pressure will remove the solvent & residual moisture from the solute components, resulting in a dry powder that has sufficient long term stability. • Dry sterile powder is aseptically added to a sterile vial • The dry drug powder is reconstituted with a sterile vehicle before use. • Example: Amphotericin B, Ampicillin, Ceftriaxone PFI There are other technologies available to produce sterile dry powder drug products besides freeze-drying, such as sterile crystallization or spray-drying and powder filling. However, freeze-drying is the most common unit process for manufacturing drug products too unstable to be marketed as solutions.
  • 35. The term ‘lyophilization’ describes a process to produce a product that ‘loves the dry state.’ Equipment used to freeze-dry products are called freeze-dryers or lyophilizers. For small molecules the highest secondary drying temperature used is 40°C, whereas for proteins it is no more than 30°C. Small scale lyophilization 1. The product may be frozen on the shelf in the chamber by circulating refrigerant (usually silicone) from the compressor through pipes within the shelf. After freezing is complete, which may require several hours, the chamber and condenser are evacuated by the vacuum pump, the condenser surface having been chilled previously by circulating refrigerant from the large compressor. 2. Heat then is introduced from the shelf to the product under graded control by electric resistance coils or by circulating silicone or glycol. 3. Heat transfer proceeds from the shelf into the product vial and mass transfer (ice) proceeds from the product vial by sublimation through the chamber and onto the condenser. 4. The process continues, until the product is dry (usually 1% or less moisture, except for some proteins that require a minimum amount of water for conformational stability), leaving a sponge-like matrix of the solids originally present in the product, the input of heat being controlled so as not to degrade the product.
  • 36. For most pharmaceuticals and biologicals, the liquid product is sterilized by filtration before being filled into the dosage container aseptically. The containers must remain open during the drying process to allow water vapor to escape; therefore, they must be protected from contamination during transfer from the filling area to the freeze-drying chamber, while in the freeze-drying chamber and at the end of the drying process until sealed.  Freeze drying process phases 1. Freezing- Liquid- solid conversion of the product. 2. Primary drying- Removal of the frozen solvent by sublimation 3. Secondary drying- Removal of unfrozen solvent by diffusion & desorption
  • 38.  Containers & closures  Containers Ampoules Vial Transfusion bottles Collapsible bags Injectable formulations are packaged into containers made of glass or plastic. Container systems include ampoules, vials, syringes, cartridges, bottles, and bags. Ampoules are all glass, whereas bags are all plastic. The other containers can be composed of glass or plastic and must include rubber materials, such as rubber stoppers for vials and bottles and rubber plungers and rubber seals for syringes and cartridges. Irrigation solutions are packaged in glass bottles with aluminum screw caps. Prefilled syringes
  • 39.  Ampoules • An ampoule is a small sealed vial which is used to contain & preserve a sample, usually liquid. Ampoules are commonly made of glass, although plastic ampoules do exist. • For single use. • There are 3 types of ampoules- One point cut ampoules Flat bottom constricted neck ampoules Flame cut ampoules  Vials A glass or plastic container closed with a rubber stopper & sealed with an aluminium crimp Single use or multiple use  Transfusion bottles A bottle of neutral glass either clear or amber color. Glass bottles with big rubber stoppers.  PVC collapsible bags/ polyethylene packets Theses are used to pack infusion fluids. Used for large volume parenterals.
  • 40.  The pharmacopoeia requires the following conditions for a container & closure to be used for parenteral preparations: 1. It should not yield foreign substances to the product 2. It should be sufficient transparent to allow visual inspection of the content in it. 3. It should not have any adverse effect on the product 4. It should prevent diffusion in or across the walls. 5. It must protect the content from external environment & mechanical shocks 6. It must have a pharmaceutically elegant appearance 7. Must be cheap & economical ◌ Container types A) Glass Glass is employed as the container material of choice for most SVIs. It is composed, principally, of silicon dioxide, with varying amounts of other oxides, such as sodium, potassium, calcium, magnesium, aluminum, boron, and iron. The original Parenteral packaging material, has superior clarity, facilitating visual inspection for particulate matter.
  • 41.  The USP provides a classification of glass 1. Type I, a borosilicate glass; 2. Type II, a soda-lime treated glass; 3. Type III, a soda-lime glass; and 4. NP, a soda-lime glass not suitable for containers for parenterals.
  • 42. Container type Type of formulation can be packed Glass type that can be used Ampoule Aqueous injectables of any pH Type I Aqueous injectables of pH less than 7 Type II Non- aqueous injectables Type III Vial Aqueous injectables of any pH Type I Aqueous injectables of pH less than 7 Type II Non- aqueous injectables Type III Dry powders for parenteral use Type IV The glass types are determined from the results of two USP tests: 1. Powdered Glass Test 2. Water Attack Test.
  • 43. ᴥ Characteristics 1. Glass containers must be strong enough to withstand the physical shocks of handling and shipping and the pressure differentials that develop, particularly during the autoclave sterilization cycle. 2. They must be able to withstand the thermal shock resulting from large temperature changes during processing, for example, when the hot bottle and contents are exposed to room air at the end of the sterilization cycle. Therefore, a glass with a low coefficient of thermal expansion is necessary. 3. The container must also be transparent to permit inspection of the contents. 4. Preparations that are light-sensitive must be protected, by placing them in amber glass containers or by enclosing flint glass containers in opaque cartons labeled to remain on the container during the period of use.  Advantages of Glass  They are transparent  Available in various shapes & sizes  Can withstand the variation in temperature & pressure during sterilization  Economical & easily available  Protect the photosensitive medicaments from light during storage  Neutral after proper treatment  Impermeable to atmospheric gases & moisture  Good protection power  Do not deteriorate with age
  • 44.  Can be easily labelled  Can be sealed hermetically or by removable closures.  Disadvantages  Danger of breakage  Traces of heavy metal  Costly manufacturing  Heavy weights B) Plastic • A plastic is a material that contains an essential ingredient one or more polymeric organic substances of large molecular weight. • Plastic are either thermosetting or thermoplastic type. • Thermosetting consist of those plastics that, when subjected to heat, normally will become infusible or insoluble, & as such cannot be remelted. • Used for construction of closure • Thermoplastic consist of those plastics that normally are rigid at operating temperatures but can be remelted & reprocessed. • Choice of material for LVPs.
  • 45.  Thermosetting Plastics- • Phenol formaldehyde • Urea formaldehyde • Melamine formaldehyde  Thermoplastics- • Polyethylene (PE) • Polypropylene (PP) • Polyethylene Terephthalate (PET) • Polyvinyl chloride (PVC) • Polyvinylidene chloride • Polystyrene (PS) • Polycarbonate  Advantages of plastics 1. Lightweight storage options 2. Economical 3. Flexible 4. Molding 5. unbreakable 6. Available in various size & shapes 7. Transported easily 8. Good shock absorption capacity 9. Durability  Disadvantages 1. Low melting point & low heat resistant 2. Harmful for nature 3. Relatively expensive 4. May absorb chemical substances, such as preservative for solution 5. Permeation of vapors & other molecules 6. Leaching of constituents from the plastic into the product
  • 46.  Closures Containers are equipped with a firm seal to prevent entry of microorganisms & other contaminants while permitting the withdrawal of a part or the whole of the contents. 1. Rubber closures • To permit introduction of needle from a hypodermic syringe into a multiple dose vials & provide resealing as soon as needle is withdrawn. • It has elasticity, reseal ability & adaptability to many shapes • To reduce leaching coating of Teflon is applied to closure. • There are 2 types 1. Natural rubber- suitable for multiple use containers 2. Synthetic rubber- less suitable for multiple use • Examples of rubbers/ elastomers- Butyl rubber, Chloroprene rubbers (Neoprene), Silicon rubbers Rubber closures Metal caps
  • 47. Composition of rubber closure Ingredients Examples Elastomer Natural rubber, Butyl rubber, Neoprene Vulcanizing agent Sulfur, peroxides Accelerator Guanidine's, sulfides Activator zinc oxide, stearic acid Filler Carbon black, kaolin Plasticizer / Lubricant Paraffin oil, silicone oil, Dibutyl phthalate Antioxidant Aromatic amines Pigments Carbon black, Inorganic oxides
  • 48.  Advantages  Heat resistant  Permeability of water vapor & air is low  Water absorption is very low  Oil resistant  Disadvantages  Absorption of bactericide & leaching of extractives  Silicon rubbers are expensive 2. Metals The metals commonly used are aluminium, tin plated steel, stainless steel, tin & lead. Advantages- a. Sturdy b. Impermeable to light, moisture & gases c. They can be Made into rigid unbreakable containers by impact extrusion d. They are light in weight as compared to glass containers Disadvantages a. Expensive b. They may shed metal particles into the pharmaceutical product.
  • 49.  Filling & Sealing of Ampoules, vials, & bottles  Filling During the filling operation, the product must be transferred from a bulk container or tank and subdivided into dose containers. Most frequently, the compounded product is in the form of a liquid. However, products are also compounded as dispersed systems (e.g., suspensions and emulsions) and as powders.  Liquids There are three main methods for filling liquids into containers with high accuracy: 1. Volumetric filling, 2. Time/pressure dosing, 3. Net weight filling. • Volumetric filling machines, employing pistons or peristaltic pumps, are most commonly used. • When high-speed filling rates are desired but accuracy and precision must be maintained, multiple filling units are often joined in an electronically coordinated machine. • Time-pressure (or time-gravity) filling machines are gaining popularity in filling sterile liquids. A product tank is connected to the filling system equipped with a pressure sensor. The sensor continuously measures pressure and transmits values to the PLC system controlling the flow of product from tank to filling manifold. Product flow occurs when tubing is mechanically unpinched and stops when tubing is mechanically pinched.
  • 50. • The main advantage of time/pressure filling operations is that these filling apparatuses do not contain mechanical moving parts in the product stream. • The product is driven by pressure (usually nitrogen) with no pumping mechanism involved. Thus, especially for proteins that are quite sensitive to shear forces, time/pressure filling is preferable. • The filling of a small number of containers may be accomplished with a hypodermic syringe and needle, the liquid drawn into the syringe and forced through the needle into the container. An example of such a device that provides greater speed of filling is the Cornwall Pipette (Becton Dickinson) Product filling & closing of vials & infusion bottles Cornwall Pipette
  • 51.  Solids • Sterile solids, such as antibiotics, are more difficult to subdivide evenly into containers than are liquids. The rate of flow of solid material is slow and often irregular. • Some sterile solids are subdivided into containers by individual weighing. A scoop is usually provided to aid in approximating the quantity required, but the quantity filled into the container is finally weighed on a balance. This is a slow process. When the solid is obtainable in a granular form, so it will flow more freely, other methods of filling may be employed. • In general, these involve the measurement and delivery of a volume of the granular material that has been calibrated in terms of the weight desired. In the machine shown in Figure an adjustable cavity in the rim of a wheel is filled by vacuum and the contents held by vacuum, until the cavity is inverted over the container. The solid material is then discharged into the container by a puff of sterile air. High speed powder filling & closing machine
  • 52.  Sealing  Ampoules sealing • Ampoules are sealed by melting a portion of the glass neck. • Two types of seals are employed normally: 1. Tip-seals (bead-seals) or 2. pull-seals. 1. Tip seals • Tip-seals are made by melting enough glass at the tip of the neck of an ampoule to form a bead and close the opening. These can be made rapidly in a high-temperature gas-oxygen flame. To produce a uniform bead, the ampoule neck must be heated evenly on all sides, such as by burners on opposite sides of stationary ampoules or by rotating the ampoule in a single flame. • An incompletely sealed ampoule is called a ‘leaker’.
  • 53. 2. Pull seals • Pull-seals are made by heating the neck of the ampoule below the tip, leaving enough of the tip for grasping with forceps or other mechanical devices. • The ampoule is rotated in the flame from a single burner. When the glass has softened, the tip is grasped firmly and pulled quickly away from the body of the ampoule, which continues to rotate. • The small capillary tube, thus, formed is twisted closed. Pull-sealing is slower, but the seals are more secure than tip-sealing. • Ampoules having a wide opening must be sealed by pull-sealing.
  • 54. Ampoule filling & sealing  Vials & bottles sealing • Glass or plastic vials and bottles are sealed by closing the opening with a rubber closure (stopper). This must be accomplished as rapidly as possible after filling to prevent contamination of the contents. • Preferably, closures are inserted mechanically, using an automated process, especially with high-speed processing. To reduce friction, so the closure may slide more easily through a chute and into the container opening, the closure surfaces are halogenated or treated with silicone.
  • 55. • When the closure is positioned at the insertion site, it is pushed mechanically into the container opening. • When small lots are encountered, manual stoppering with forceps may be used, but such a process poses greater risk of introducing contamination than automated processes. • Container-closure integrity testing has become a major focus for the industry, due to emphasis by regulatory agencies. Container- closure integrity measures the ability of the seal between the glass or plastic container opening and the rubber closure to remain tight and fit and to resist any ingress of microbial contamination during product shelf life. Container-closure integrity test requirements are covered in USP <1207>. • Rubber closures are held in place by means of aluminum caps. The caps cover the closure, crimped under the lip of the vial or bottle to hold them in place. The closure cannot be removed without destroying the aluminum cap; it is tamperproof. Therefore, an intact aluminum cap is proof that the closure has not been removed intentionally or unintentionally. Capping
  • 56. Vial sealing machine Manual sealing Prefilled cartridge Prefilled Syringe
  • 57.  PREFILLED SYRINGES & CARTRIDGES These are designed for maximum convenience. a. Prefilled Syringes: Drugs administration in an emergency are available for immediate injection when packaged in prefilled syringes. e.g.: Atropine, epinephrine b. Prefilled cartridges •Are ready-to-use parenteral packages that offer improved sterility and accuracy. •They consist of a plastic cartridges holder and prefilled . •The medication is premixed and premeasured E.g. Enoxaparin Inova syringe filling machine needle & plunger assemblies
  • 58.  Advantages • Less or no breakage: Prefilled cartridges are much less prone to crack or break in comparison to their standard, glass counterparts. • Accuracy: Prefilled syringe cartridges assure that patients receive accurate dosages. • Self-inject medication possible: This is especially advantageous for patients who need to self-inject medication, but have no medical training.  Disadvantages • Expensive • Not compatible with all drugs BLOW-FILL-SEAL TECHNOLOGY • Blow-Fill Seal technology refers to the manufacturing technique used to produce small, and large volume, (500mL+) liquid filled containers. • The basic concept of blow fill seal (BFS) is that a container is formed, filled, and sealed in a continuous process without human intervention, in a sterile enclosed area inside a machine.
  • 59. Blow – fill- seal process  The BFS cycle can be divided into the following main steps:  Step 1: Parison Extrusion  Step 2: Container Molding  Step 3: Container Filling  Step 4: Container Sealing  Step 5: Container Discharge https://youtu.be/6Lauct3ZmsQ
  • 60. Material used for container: • Polyethylene • Polyvinyl chloride • Polyester • Polypropylene  Step 1: Parison extrusion Firstly pharmaceutical plastic resin is vertically heat extruded through a circular throat to form a tube called the Parison.  Step 2: Container Molding This extrused tube is then enclosed within a 2 part- mould, & the tube is cut above the mould.  Step 3: Container Filling The mould is transferred to the filling zone, or sterile filling space where filling needle manderlas lowered space & used to enflate the plastic to form container within the mould.  Step 4: Container Sealing The Manderel is used to fill the container with liquid, following filling, the manderels are remove & a secondary top mould seals the container.
  • 61.  Step 5: Container Discharge/ De-flashing To remove the flash or scrap, trimming the containers & delivering the container outside the machine. • All action takes place inside the sterile chamber inside the machine. The product is then discharged to a non sterile area for labelling, packaging & distribution  Advantages  Reduce personal intervention  No need to purchase and stock a range of prefabricated containers and their closures.  Cleaning and sterilization of prefabricated containers and closures is not required.  The code numbers and variable data such as batch number and expiry date can be  embedded onto the container itself.  The cost of material transport, storage and inventory control is reduced.  Validation requirements are reduced.  There is a large choice of neck and opening device shapes.  A single compact BFS machine takes the place of several conventional machines, saving  floor space.
  • 62.  Quality control tests ○ IPQC Tests for Sterile Formulations 1. •Leakage Test 2. •Clarity Test 3. •pH 4. •Particulate Matter Injection 5. •SterilityTest 6. •PyrogenTest 7. •Content Uniformity & Weight 8. •Volume Filled 1. Leakage test •Leakage test is employed to detect incompletely sealed ampoule so that they may be discarded. •To test the package integrity. •Package integrity reflects its ability to keep the product in and to keep potential contamination out. Leakage tests are 4 types: a) Visual inspection b) Bubble test c) Dye test d) Vacuum ionization
  • 63. a) Visual inspection  Visual inspection is the easiest leaker test method to perform.  The method is used for the evaluation of large volume parenterals.  To increase the sensitivity of the method the visual inspection of the sample container may be coupled with the application of vacuum to make leakage more readily observable.  This method is simple and inexpensive.  Disadvantage: less sensitive  Sensitivity is increased by applying pressure/vacuum b) Bubble test • The test package is submerged in liquids. • A differential pressure is applied on the container. • The container is observed for bubbles. • Sometimes, surfactant added liquid is used for immersion of test package. • Any leakage is evident after the application of differential pressure as the generation of foaming in immersion liquid. • The method is simple and inexpensive. • The location of the leaks can be observed in this method. • Generation of a differential positive pressure of 3 psi inside the vial and observation of any leakage using magnifying glass within a maximum test time of 15 minutes. • However, it is relatively insensitive and the findings are operator dependent and are qualitative. • The optimized conditions can be achieved using a surfactant.
  • 64. C) Dye test •The test container is immersed in a dye bath. •Vacuum and pressure is applied for sometime. •The container is removed from the dye bath and washed. •The container is then inspected for the presence of dye either visually or by means of UV spectroscopy. •The dye used is usually 0.5% to 1% methylene blue. •The dye test is widely accepted in industry and is approved in drug use. •The test is inexpensive and is requires no special equipment required for visual dye detection. •However, the test is qualitative, destructive and slow. •The test is used for ampoules d) Vacuum ionization test •Vacuum ionization test is useful for testing leakage in the vials or bottled sealed under vacuum. •This test is used for testing of the lyophilized products. •High voltage, high frequency field is applied to vials which to cause residual gas, if present to glow. •Glow intensity is the function of headspace vacuum level. •The blue glow is the indicative of vacuum while the purple glow indicative of no vacuum. The sensitivity of the method is not documented. •This test is rapid and is non destructive test. •However, the proteins present in test sample may be decomposed. •This method is used of for the lyophilized vials in biopharmaceuticals
  • 65. 2. CLARITY TEST (PARTICLE CONTAINMENT TEST) • • Definition: Clarity is a relative term, its mean a clear solution having a high polish conveys to the observer that the product is of exceptional quality and purity. • Clarity test is carried out to check the particulate matter in the sample. • It is practically impossible that every unit of lot is perfectly free from visible particulate matter, that is, from particles that are 30 to 40 micrometer and large in size. PRINCIPLE: • This test is performed to check the particulate contamination of injections and infusions consists of extraneous, mobile and undissolved particles, other than gas bubbles, unintentionally present in the solution. USP limits for large volume infusion Particle size Particle limit 10 μm or larger/ mL 50 25 μm or larger/ mL 5
  • 66. 3. pH Checking the bulk solution, before filling for drug content, pH, color, clarity and completeness of solution. The pH of a formulation must be considered from following standpoint: • The effect on the body when the solution is administered • The effect on stability of the product • The effect on container-closure system  pH measurement  pH is measured by using a pH meter .  pH meter is initially calibrated with respective buffer capsule then the pH of the preparation is measured
  • 67. 4. PARTICULATE MATTER IN INJECTIONS •The preparations intended for parenteral use should be free from particulate matter and should be clear when inspected visually. •Two methods are described by USP according to the filled volume of the product to be tested. •For large volume parenterals (LVP's), a filtration followed by microscopical examination procedure is used. • For small volume parenterals (SVP's) a light obscuration based sensor containing electronic liquid borne particle counter system is used. • The USP standards are met if the LVP's under test contain NMT 50 particles per ml of 10μ m, and NMT 5 particles per ml of 25μm in an effective linear dimensional fashion. •The USP standards are met if the SVP's under test contain NMT 10,000 particles per container of 10 μm, and NMT 1000 particles per container of 25μm in an effective spherical diameter.
  • 68. Table 1: Limits for particle number as per IP, BP, EP and JP Volume of solution Particle size ≥ 10 μm Particle size ≥25 μm Small volume injections (< 100 ml) 3000 per container 300 per container Large volume injections (> 100 ml) 12 per ml 2 per ml
  • 69. 5. STERILITY TESTING • 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. • Sterility testing attempts to reveal the presence or absence of viable microorganisms in a sample number of containers taken from batch of product. • Based on results obtained from testing the sample a decision is made as to the sterility of the batch.  Major factors of importance in sterility testing: The environment in which the test is conducted The quality of the culture conditions provided The test method The sample size The sampling procedure
  • 70. Environmental conditions: Environmental conditions avoid accidental contamination of the product during the test. The test is carried out under aseptic conditions regular microbiological monitoring should be carried out. Culture conditions: Appropriate conditions for the growth of any surviving organism should be provided by the culture media selection.  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.
  • 71.  The 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 Samples size to be taken No. of articles in batch (injectables) No. of articles to be tested Not more than 100 articles 10% /4 articles whichever is greater More than 100 but not more than 500 10 articles For more than 500 2%/20 articles whichever is less For large volume parenterals 2%/10 containers whichever is less
  • 72. [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.
  • 73. o Interpretation of results At the end of the incubation period the following observations are possible:  No evidence of growth; hence the preparation being examined passes the test for sterility.  If there is evidence of growth, retesting is performed using the same number of samples, volumes to be tested and the media as in the original test. If no evidence of microbial growth is then found, the preparation being examined passes the test for sterility.  If there is again evidence of the microbial growth then isolate and identify the organisms. If they are not readily distinguishable from those growing in the containers of the first test then the preparation being examined fails the test for sterility.  If they are distinguishable from the organisms of the first test then again do the test using twice the number of samples. The preparation being examined passes the test for sterility in case there is no evidence of microbial growth. In case there is evidence of growth of any microorganisms in second re –test, the preparation being examined fails the tests for sterility
  • 74. 6. PYROGEN TESTING o Pyrogens are fever producing substances. o Pyro means ‘pyrexia’, Gen means ‘producing’. o Pyrogens are the by-products of microorganisms mainly of bacteria, molds and viruses. o During the processing these pyrogens may come from water, active constituent or the excipient or from the equipments. o Chemically these pyrogens are lipid substances associated with carrier usually polysaccharides or may be proteins o Parenteral solutions are officially tested for the presence of pyrogens by a biological test in which “FEVER” response of rabbits is used as criteria. Types of Pyrogen test :  For Detection and quantification of Pyrogens:  Basically there are 2 tests performed to detect the presence of pyrogens in sterile parenteral products they are- 1. In Vivo pyrogen test (Rabbit Test)- SHAM test 2. In Vitro pyrogen test(Limulus Amebocyte Lysate Test)
  • 75. 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. Interpretation of Result (Rabbit Test) No. of Rabbits Individual Temp. size (ᵒC) Temp. rise in groups (ᵒC) Test 3 Rabbits 0.6 1.4 Passes If above not passes 3+5= 8 rabbits 0.6 3.7 Passes
  • 76. 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.
  • 77. CONTENT UNIFORMITY AND WEIGHT : •Determine the content of the active ingredient of each of 10 containers taken at random. •The preparation under examination complies with the test if the individual values thus obtained are all between 85 and 115 percent of the average value. •The preparation under the examination fails to comply with the test if more than one individual value is outside the limits 85 to 11 percent of the average value or if any one individual value is outside the limits 75 to 125 percent of the average value. •If one individual value is outside the limits 85 to 115 percent but within the limits 75 to 125 percent of the average value, repeat the determination using another 20 containers taken at random. •The preparation under examination complies with the test if in the total sample of 30 containers not more than one individual value is outside the limits 85 to 115 percent and none is outside the limits 75 to 125 percent of the average value. Table 3: Limits for Uniformity of Weight Pharmaceutical Formulation Average Mass Percentage Deviation (%) Powders for parenteral use More than 40 mg 10 Powders for eye drops Less than 300 mg 10 Powders for eye lotions 300 mg or more 7.5