Classification, Types of vehicles, Selection of vehicles and added substance, Processing and manufacturing of SVPs

1. Small Volume Parenterals
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2. Contents…
• Classification,
• Types of vehicles,
• Selection of vehicles and added substance,
• Processing and manufacturing of SVPs,
• Pilot plant scale up for SVPs.
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3. Small Volume Parenteral
• According to USP: “ an injection that is packaged in containers labelled as containing
100 ml or less”.
• All the sterile products packaged in vials, ampoules, cartridges, syringes, bottles or
any other container that is 100 ml or less fall under the class of SVP.
• Ophthalmic products packaged in squeezable plastic containers, although topically
applied to the eye rather than administered by injection, also fall under the
classification of Small Volume Injections (SVI) as long as the container size is 100 ml
or less.
• SVP aqueous solutions can be administered by intravenous route because of local
irritation.
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4. Small Volume Parenteral
• Small volume parenteral products can be formulated and packaged in several
ways and include a wide variety of products like:
• Pharmaceutical products, Biological products, Allergenic extracts,
Radiopharmaceutical products, Genetically engineered or biotechnology
products, Liposome and lipid products.
• An injection is a preparation intended for parenteral administration and/or
for constituting or diluting a parenteral article prior to administration.
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5. Small Volume Parenteral
• Types of preparations:-
• Drug injection
• Drug for injection
• Drug injectable emulsion
• Drug injectable suspension
• Drug for injectable suspension
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6. Classification of SVP
• Single dose ampoules (glass/plastic),
• Single dose vials
• Multiple dose vials,
• Prefilled syringes.
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7. Single Dose Ampoules
• A single-dose or single-use vial is a vial of liquid medication intended for parenteral
administration (injection or infusion) that is meant for use in a single patient for a
single case, procedure, injection.
• Single-dose or single-use vials are labeled as such by the manufacturer and typically
lack an antimicrobial preservative.
• Vials that are labeled as single-dose or single-use should be used for only a single
patient as part of a single case, procedure, injection.
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8. Single Dose Vials
• A Single-Dose Vial (SDV) is approved for use on a single patient for a single
procedure or injection.
• SDVs typically lack an antimicrobial preservative.
• Do not save leftover medication from these vials.
• Harmful bacteria can grow and infect a patient.
• Discard after every use!
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9. Multiple Dose Vials
• A Multiple-dose Vial (MDV) is recognized by its FDA-approved label.
• MDVs can be used for more than one patient when aseptic technique is followed,
ideally even MDVs are used for only one patient.
• MDVs typically contain an antimicrobial preservative to help limit the growth of
bacteria.
• Preservatives have no effect on bloodborne viruses (i.e. hepatitis B, hepatitis C, HIV).
• Discard MDVs when the beyond-use date has been reached, when doses are drawn
in a patient treatment area, or any time the sterility of the vial is in question!
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10. Prefilled syringes
✓ A prefilled syringe is a single-dose packet of parental drug to which a needle has
been fixed by the manufacturer.
✓ Prefillable syringes have become an increasingly important option in the
packaging and delivery of injectable drug products.
✓ Humira®, Enbrel®, Copaxone®, Lovenox® and Rebif® are examples of
blockbuster drugs that are being extensively administered via prefilled syringes
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11. Vehicles for Injection
• Aqueous vehicles:
• Frequently, isotonic (to blood) to which drug may be added at time of use.
• Water-miscible vehicles:
• Portion of the vehicle in the formulation,
• used primarily to effect solubility of drugs and/or reduce hydrolysis
• ethyl alcohol; polyethylene glycol (liquid) and propylene glycol
• Nonaqueous vehicles:
• Fixed oils (vegetable origin, and rancid resistance) used in hormone preparations
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12. Aqueous vehicles
• Water for Injection (WFI) USP
• Sterile Water for Injection (SWFI)
• Bacteriostatic Water for Injection USP
• Sterile Water for Irrigation USP
• Sterile Water for Inhalation USP
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13. Water for Injection (WFI) USP
• Highly purified water used as a vehicle for injectable preparations which will be
subsequently sterilized.
• USP requirement: NMT 10 ppm (1 mg/100 ml) of total solids.
• pH of 5.0 – 7.0 .
• WFI may be prepared by either distillation or reverse osmosis.
• Stored in chemically resistant tank.
• Used as solvent for preparation of parenteral solutions.
• It is not required to be sterilized and pyrogen free.
• It is intended to be used within 24 hours after collection.
• The water should be collected in sterile and pyrogen free containers.
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Specifications for WFI as per USP

14. Sterile Water for Injection (SWFI)
• Sterile Water for Injection is Water for Injection packaged and rendered sterile.
• Is water for injection that is sterilized and packaged in single dose container of type1 and 2 glass.
• It is used for extemporaneous prescription compounding and as a sterile diluent for parenteral
products.
• It may also be used for other applications when
• Access to a validated water system is not practical, or
• Where only a relatively small quantity is needed.
• Sterile Water for Injection is packaged in single-dose containers not larger than 1 L.
• 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. 14
Why TDS in
SWFI is more
than WFI?

15. Bacteriostatic Water for Injection USP
• Water for Injection, packaged and rendered sterile, to which one or more suitable
antimicrobial preservatives are added or Is sterile water for injection that contains
one or more suitable antimicrobial agents.
• Sterile water containing 0.9% benzyl alcohol that is used to dilute or dissolve
medications.
• It is intended to be used as a diluent in the preparation of parenteral products.
• These are typically for multi-dose products that require repeated content
withdrawals.
• It also packaged in single or multiple dose container of type 1 and 2 glass.
• It may be packaged in single-dose or multiple-dose containers not larger than 30 mL. 15

16. Sterile Water for Irrigation USP
• Water for Injection packaged and sterilized in single-dose containers which
may be larger than 1 L.
• Is water for injection that is sterilized and suitably packaged.
• They allow rapid delivery of their contents.
• Due to its usage, Sterile Water for Irrigation is not required to meet Particulate
Matter in Injections.
• It contains no antimicrobial agents or other added substances.
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17. Sterile Water for Inhalation USP
• Is Water for Injection that is packaged and rendered sterile.
• It is intended for use in inhalators and in the preparation of inhalation
solutions.
• This monograph has no requirement to meet.
• It carries a less stringent specification for bacterial endotoxins than Sterile
Water for Injection.
• Therefore is not suitable for parenteral applications.
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18. Water-miscible vehicles
• A number of solvents that are miscible with water have been used as a portion
of the vehicle in the formulation of parenterals.
• These solvents are used to solubilize certain drugs in an aqueous vehicle and
to reduce hydrolysis.
• The most important solvents in this group are ethyl alcohol, liquid
polyethylene glycol and propylene glycol.
• Ethyl alcohol is used in the preparation of solutions of cardiac glycosides and
the glycols in solutions of barbiturates, certain alkaloids, and certain
antibiotics.
• Such preparations are given intramuscularly.
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19. Water-miscible vehicles
• There are limitations with the amount of these co-solvents that can be
administered, due to toxicity concerns, greater potential for
hemolysis, and potential for drug precipitation at the site of injection.
• Formulation scientists needing to use one or more of these solvents
must consult the literature and toxicologists to ascertain the
maximum amount of co-solvents allowed for their particular product.
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20. Non-Aqueous Vehicles
• The most important group of non-aqueous vehicles is the fixed oils.
• The USP provides specifications for such vehicles, indicating that the fixed oils must
be of vegetable origin so they will metabolize, will be liquid at room temperature,
and will not become rancid readily.
• The USP also specifies limits for the free fatty acid content, iodine value, and
saponification value (oil heated with alkali to produce soap, i.e., alcohol plus acid
salt).
• The oils most commonly used are corn oil, cottonseed oil, peanut oil, and sesame oil.
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21. Non-Aqueous Vehicles
• Fixed oils are used as vehicles for certain hormone (e.g., progesterone,
testosterone, deoxycorticosterone) and vitamin (e.g., Vitamin K,
Vitamin E) preparations.
• The label must state the name of the vehicle, so the user may beware
in case of known sensitivity or other reactions to it.
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Antimicrobials
• Added for fungistatic or bacteriostat action or concentration.
• Used to prevent the multiplication of micro-organisms.
• Examples:
• Benzyl alcohol -- 0.5 – 10 %
• Benzethonium chloride -- 0.01 %
• Methyl paraben -- 0.01 – 0.18 %
• Propyl paraben -- 0.005 – 0.035 %
• Phenol -- 0.065 – 0.5 %
Preservatives
 Multidose containers must have
preservatives unless prohibited by
monograph.
 Large volume parenteral must not
contain preservative b’coz it may
be dangerous to human body if it
contain in high doses.

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Antioxidants
• Used to protect product from oxidation.
• Acts as reducing agent or prevents oxidation.
A) Reducing agent:
 Ascorbic acid -- 0.02 – 0.1 %
 Sodium bisulphate -- 0.1 – 0.15 %
 Sod. Metabisulphite -- 0.1 – 0.15 %
 Thiourea -- 0.005 %
C) Synergistic:
 Ascorbic acid ,
 Citric acid ,
 Tartaric acid.
B) Blocking agents:
 Ascorbic acid esters -- 0.01 – 0.015%
 BHT -- 0.005 – 0.02 %
D) Chelating agent:
 EDTA -- 0.01- 0.075 %
Example

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Buffers• Added to maintain pH,
• Change in pH may causes degradation of the products
• Acetates, citrates, phosphates are generally used.
Factors affecting selection of buffers:
• Effective range,
• Concentration
• Chemical effect on the total product
Examples:
• Acetic acid, adipic acid, benzoic acid, citric acid, lactic acid
• Used in the conc. of 0.1 to 5.0 %

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Stabilizers
• As parenterals are available in solution form they are most prone to unstabilize.
• Used to stabilize the formulation
• Maintain stable
Examples:
• Creatinine – 0.5- 0.8 %
• Glycerin – 1.5 – 2.25 %
• Niacinamide – 1.25 -2.5 %
• Sodium saccharin – 0.03 %
• Sodium caprylate – 0.4 %

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Chelating agents
• Used to form the complex with the metallic ions present in the formulation so that the
ions will not interfere during mfg. of formulation.
• They form a complex which gets dissolved in the solvents.
Examples:
• Disodium edetate – 0.00368 - 0.05 %
• Disodium calcium edetate - 0.04 %

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Solubilizing agents
• Used to increase solubility of slightly soluble drugs
• They acts by any one of the following:
• Solubilizers,
• Emulsifiers or
• Wetting agents.
Examples:
• Dimethylacetamide, Ethyl alcohol, Glycerine, Lecithin, PEG – 40 + Castor oil, PEG – 300,
Polysorbate 20, 40, 80

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Inert gases
• Another means of enhancing the product integrity of oxygen sensitive medicaments is
by displacing the air 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 and may also be
topped off with gas before sealing.

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Tonicity adjusting agents
• Used to reduce the pain of injection.
• Buffers may acts as tonicity contributor as well as stabilizers for the pH.
• Isotonicity depends on permeability of a living semipermeable membrane
• Hypotonic : swelling of cells (enlargement)
• Hypertonic: shrinking of cells (reduction)
Examples:
• Glycerin, Lactose, Mannitol, Dextrose, Sodium chloride, Sorbitol

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Surfactants
• Used:
• to dispose a water-insoluble drug as a colloidal dispersion.
• for wetting powder.
• to prevent crystal growth in a suspension.
• to provide acceptable syringability.
• for Solubilizing steroids and fat-soluble vitamins.
• Example:
• Polyethylene 0.1 to 0.5%
• Sorbitan monooleate 0.05 to 0.25%

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Protectants
• Used to protect against loss of activity caused by some stress
• Used to prevent loss of active ingredients by adsorption to process equipment or
to primary packaging materials
• Protectants primarily used in protein formulations.
Examples:
• Sucrose, glucose, lactose, maltose, trehalose (2 to 5%)
• Human serum albumin (0.1 to 1%)

32. Processing and manufacturing of SVPs
• The production area where the parenteral preparation are
manufactured can be divided into five sections:
• Clean-up area
• Preparation area
• Aseptic area
• Quarantine area
• Finishing & packaging area
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33. Layout showing various activities in
parenteral manufacturing
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34. Clean- up area
• Non aseptic area.
• Free from dust, fibers and micro-organisms.
• Constructed in such a way that should withstand moisture, steam and detergent.
• Ceiling and walls are coated with material to prevent accumulation of dust and micro-organisms.
• Exhaust fans are fitted to remove heat and humidity.
• The area should be kept clean so as to avoid contamination to aseptic area.
• The containers and closures are washed and dried in this area.
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35. Preparation area
• The ingredients are mixed and preparation is prepared for filling.
• Not essential that the area is aseptic.
• Strict precaution is taken to prevent contamination from outside.
• Cabinets and counters: SS.
• Ceiling and walls : sealed and painted.
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36. Aseptic area
• Filtration and filling into final containers and sealing is done.
• The entry of outside person is strictly prohibited.
• To maintain sterility, special trained persons are only allowed to enter and work.
• Person who worked should wear sterile cloths.
• Should be subjected for physical examination to ensure the fitness.
• Minimum movement should be there in this area.
• Ceiling and walls and floors : sealed and painted or treated with aseptic solution and there should not
be any toxic effect of this treatment.
• Cabinets and counters: SS.
• Mechanical equipments : SS. 36

37. Air in aseptic area
• Free from fibers, dust and micro organisms.
• HEPA filters are used which removes particles upto 0.3 micron.
• Fitted in laminar air flow system, in which air is free from dust and micro
organisms flows with uniform velocity.
• Air supplied is under positive pressure which prevents particulate contamination
from sweeping.
• UV lamps are fitted to maintain sterility.
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38. Quarantine area
• After filling, sealing and sterilization the products or batch is kept in this
area.
• The random samples are chosen and given for analysis to QC dept.
• The batch is send to packing after issuing satisfactory reports of analysis
from QC.
• If any problem is observed in above analysis the decision is to be taken for
reprocessing or others.
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39. Finishing and packaging area
• After proper label, the product is given for packing.
• Packing is done to protect the product from external environment.
• The ideal Packing is that which protects the product during transportation,
storage, shipping and handling.
• The labeled container should be packed in cardboard or plastic containers.
• Ampoules should be packed in partitioned boxes.
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40. Stainless steel used in Pharm. Industry
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41. Stainless steel used in Pharm. Industry
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