Manufacture of Pharmaceutical preparations a) Sterile formulations – large and small volume parenteral

1. DOCTOR OF PHARMACY
IV YEAR
Manufacturing of SVPS and LVPS
CHAPTER-6 a
MANUFACTURING OF PHARMACEUTICAAL
PREPARATIONS
Dr.V.Chanukya Pharm D

2. Student Learning Outcomes
• SVPS and LVPS
Types
Formulation aspects
Sterilization techniques
Quality control tests
Upon completion of the chapter, the student will be able to:

3. Small-Volume Parenterals
• The USP designation small-volume injection applies to an injection
packaged in containers labeled as containing 100 mL or less.
• Premixed IV delivery systems have simplified delivery for small-
volume parenterals in particular.
• A distinct advantage of these ready-to-use systems is that they require
little or no manipulation to make them patient specific.
• Thus, they are a viable alternative to the traditional labor-intensive
method of compounding parenteral medications from individual or
multiple doses of IV medications and an appropriate parenteral
solution.

4. • The traditional method for preparing small-volume parenteral
therapy from a partial- fill drug vial into a mini bag can be labor
intensive and costly in materials.
• The savings accrued through ready-to-use systems can be
• Significant.
• Another key advantage of these systems is extended stability dating
and reduced wastage.
• Doses can be put together (but not activated) in cycles, then activated
just prior to use, and delivered to the nursing station by the pharmacy
personnel.

5. Small-Volume Parenterals - Types
• Different types of SVPS are:
– Ampules
– Vials
– Dry powders
– Prefilled syringes

6. AMPULES
• Sealed glass containers with an elongated neck that must be broken
off.
• Most ampules are weakened around the neck for easy breaking; these
will have a coloured band around the neck.
• A 5 micron filter needle should be used when drawing the contents of
an ampule into a syringe since glass particles may have fallen inside
the ampule when the top was snapped off.
• In addition, it is useful to wrap an alcohol wipe or small piece of
gauze around the top of the ampule before breaking it
• This will provide some protection to the fingers if the ampule shatters
and will also reduce the possibility of glass splinters becoming
airborne.

7. Vials
• Drugs and other additives are packaged in vials either as liquids or
lyophilized powders.
• Made of glass or plastic and are sealed with a rubber stopper.
• A needle is used to add contents to or withdraw contents from the vial.
• Before withdrawing contents from a vial, an equal volume of air is
usually injected into the vial to pressurize the vial and aid in
withdrawing the contents.
• Vials may be designated for single-dose or multi-dose use.
• Multi-dose vials contain a preservative to inhibit bacterial
contamination once the vial has been used.

8. Vials

9. Dry powders
• Dry powder formulations are lyophilized or freeze-dried powders that
must be reconstituted with some suitable solvent to make a liquid
formulation before being withdrawn from the vial.
• Some drugs are not stable in liquid form and so these drugs are put
into the powder form and reconstituted just prior to use.
• There are several solvents that might be used to reconstitute the dry
powders;
• The most common solvents are Sterile Water for Injection,
Bacteriostatic Water for Injection, Sodium Chloride Injection etc.

10. Prefilled syringes
• It consists of syringes which are prefilled with the drug solution.
• There are two varieties of prefilled syringes.
• One type, a cartridge type package, is a single syringe and needle unit
which is to be placed in a special holder before use.
• Once the syringe and needle unit is used, they are discarded but the
holder is used again with a new unit.
• The other type of prefilled syringe consists of a glass tube closed at
both ends with rubber stoppers.
• The prefilled tube is placed into a specially designed syringe that has a
needle attached to it.
• After using this type or prefilled syringe, all of the pieces are
discarded.

11. Prefilled syringes

12. SVPS- Formulation asects
• Water for Injection (WFI)
• Solutes
• Added substances
• Antimicrobial agents
• Antioxidants
• Pyrogens
• Sterilization

13. 1) Water for Injection (WFI)
• Sterile Water for Injection, USP is a sterile, non-pyrogenic
preparation of water for injection which contains no bacteriostatic,
antimicrobial agent or added buffer and is supplied only in single
dose containers to dilute or dissolve drugs for injection.
• According to USP, it contains 10 CFU/100 ml water.
• For IV injection, add sufficient amount to a solute to make an
approximately isotonic solution-pH 5.0 to 7.0.
• No therapeutic activity and non-toxic.
• Water purified by reverse osmosis and distillation.

14. 2) SOLUTES:
• Added to give good stability and efficacy to the preparation.
Eg. Sucrose, Mannitol, Lactose.
3) ADDED SUBSTANCES:
• All substances that can safeguard quality of preparation.
• It may affect the solubility of the preparation, provide a preservative
effect and enhance isotonicity.
4) ANTIMICROBIAL AGENTS
• Eg. Phenol 0.5% w/v, Chlorobutanol 0.5% w/v

15. • 5) ANTIOXIDANTS:
• To preserve products because of the ease with which many drugs
get oxidized.
Eg. Sodium bisulphite 0.1%
6) BUFFERS:
• To stabilize pH.
Eg. Citrates, acetates etc.

16. Preparation
• Primary washing and sterilization
• Compounding
• Terminal sterilization

17. Pyrogens
• Metabolic products of microbial growth causing an increase in body
temperature.
• Come from sources like solvent, medicament, apparatus and improper
storage.
• It is very difficult to remove pyrogens because they are:
1) Thermostable
2) Water soluble
3) Unaffected by common bactericides.
• The bacterial substance lipopolysaccharide (LPS) in the cell wall of
bacteria is an example of pyrogen.

18. Sterilization
Sterilization of SVPS can be done by various methods like
• Moist heat sterilization
• Dry heat sterilization
• Sterilization by filtration
• Gas sterilization
• Sterilization by ionizing radiation

19. Moist heat sterilization
• Bacterial death by moist heat is due to denaturation and coagulation of
essential protein molecules (enzymes) and cell constituents.
• It can be used for a large number of injections, ophthalmic solutions
etc.
• Methods used: 1) Autoclave 2) Tyndallization
• Autoclaving used to sterilize anything, which is not injured by steam
and high temperature of sterilization.
• These include aqueous parenteral solutions e.g. distilled water, saline
solutions etc.

20. • Tyndallisation essentially consists of heating the substance to
boiling point (or just a little below boiling point) and holding it
there for 15 minutes, three days in succession.
• After each heating, the resting period will allow spores that have
survived to germinate into bacterial cells; these cells will be
killed by the next day's heating.

21. Dry heat sterilization
• The killing of microorganisms by heat is a function of the time-
temperature combination used. If the temperature is increased then the
time required for killing all the bacteria will be decreased.
• The vital constituents of cells such as proteins (enzymes) and nucleic
acids are denatured by oxidation.
• Cycles recommended as per BP 1988 are:
– A minimum of 1800C for not less than 30 minutes.
– A minimum of 1700 C for not less than 1 hour.
– A minimum of 1600 C for not less than 2 hours.
• Dry heat is used to sterilize glass ware( e.g. test tubes, petri dishes,
flasks, glass syringes etc. )

22. Hot air Oven

23. Sterilization by filtration
• This method is used for sterilizing thermo-labile solutions, which will
otherwise be degraded by other conventional heating methods.
• The drug solutions are passed through the sterile bacteria proof filter
unit and subsequently transferring the product aseptically into the
sterile containers which are then sealed.
• Different types are :
1. Sintered glass filter
2. Seitz filter
3. Ceramic filter
• They are suitable for sterilizing aqueous and oily solutions but not for
organic solvents such as alcohol, chloroform etc.

24. Filtration sterilization

25. Filtration sterilization
Ceramic filter Sintered glass filter

26. Gas sterelization
• This process involves exposure of materials to sterilizing gases such
as ethylene oxide, formaldehyde, glutaraldehyde, propylene oxide.
• Ethylene oxide is the only gas that is successfully used on a large
scale of industrial and medical applications.
• It works by alkylation

27. Radiation sterilization
• Different types of radiation used for sterilization are
1) Ultraviolet radiation
2) Gamma radiation
3) Infrared radiation
4) X-rays
5) Alpha and beta radiation
• Only a narrow range of wavelength (220 to 280 nm) of UV is
effective in killing micro-organisms, and wavelengths close to 253.7
nm are the most effective.
• Radiation from the radioactive isotope of Cobalt 60 Co, is used as a
source of gamma emission.
• Radiation sterilization causes damage to DNA and results in cell
death.

28. Quality control tests
• Quality control tests for svps includes :
1. Leaker's Test
2. Sterility Test
3. Clarity Test
4. Pyrogen Test

29. Leaker’s Test:
• It is performed by completely submerging the sealed ampule in a
deeply coloured dye solution.
• Generally 1% methylene blue solution is used.
• The ampules if not sealed properly, the dye solution present outside
the ampules will enter into the ampules and make the solution
coloured.
Clarity Test:
• The parenteral product to be evaluated is placed against a white and
black background with the contents set in motion in swirling action.
• It is kept in that motion until any particle becomes visible or not.
• Care is to be taken to avoid any air bubbles.

30. Sterility test
• Important to check if the product meets the
requirements of sterility according to the official books
or not.
• It has 2 methods:
• -The direct transfer of the samples to sterile culture
media.
• -The membrane filtration procedure.

31. Pyrogen test
• Samples of production batch are tested in rabbits for the presence of
pyrogens.
• It has 2 stages: 1) Sham test 2) Main test
• 1) Sham test:
• If the animals are being used for the first time in pyrogen testing,
then condition the animals for 1-3 days by injecting 10 mg/kg body
weight of pyrogen free solution IV.
• Maintain animals like that for 18 hrs in room maintained at a temp of
3ºC.
• Record the temperature of the animals beginning at least 90 mins
before injection and continuing for 3 hrs after injection.
• Any animal showing variation of 0.6ºC or more must not be used for
main test.

32. • 2) Main Test:
• Determine the control temperature of each rabbit by recording the
temperature not more than 30 mins prior to injection of test solution.
• Inject into an ear vein of each rabbit 10 ml of the test solution per kg
body weight, completing each injection within 10 mins after start of
administration.
• The test solution must be warmed upto 37±2ºC.
• Record the temperatures at 1, 2 and 3 hrs subsequent to the injection.
• Following are the requirements for passing the test:
1) Individual rise in temperature of 0.6ºC with respect to control and sum of
3 individual rabbits does not exceed 1.4ºC, the sample passes the test.
2) If anything above the above mentioned requirements, continue the test
with 5 other rabbits.
3) Individual rise in temperature not more that 0.6ºC and sum of all eight
does not exceed 3.7ºC, the sample passes the test.

33. Large-Volume Parenterals
• The USP designation large-volume IV solution applies to a single-
dose injection intended for IV use and is packaged in containers
labeled as containing more than 100 mL.
• They are usually administered in volumes of 100 mL to 1 L or more
per day by slow IV infusion with or without a controlled-rate
infusion system.
• They are packaged in large single-dose containers.
• It includes IV infusions, irrigating solutions, peritoneal dialysates
and blood collecting units with anticoagulant.

35. • As indicated previously, electrolytes, vitamins, and antineoplastics
are frequently incorporated into large-volume parenterals for
coadministration to the patient.
• It is the responsibility of the pharmacist to understand the physical
and chemical compatibilities of the additive in the solution or liquid
in which it is placed.
• Obviously, a combination that results in formation of insoluble
material or affects the efficacy or potency of the therapeutic agent of
the vehicle is not acceptable.

36. LVPS – Usage
• Large-volume parenteral solutions are employed in maintenance
therapy for the patient entering or recovering from surgery and for
the patient who is unconscious and unable to take fluids,
electrolytes, and nutrition orally.
• The solutions may also be used in replacement therapy for patients
who have suffered a heavy loss of fluid and electrolytes.

37. Characteristics of LVPS:
• LVPs Packaged in glass bottles or in large volume flexible containers.
• May contain greater than 100 ml to greater than 1 or 2 L sterile
Pyrogen-Free Essentially particulate free matter and be isotonic.
• The quality of the starting materials and solutes is critical to the
finished LVP’s product.
• Heat ,light, moisture and air can adversely effect many of these
materials.
• The containers for these drug substances can also be imp factors in
stability considerations.

38. LVPS –Formulation requirments
• Sterile, pyrogenic ,free from particulate matter.
• No preservative.
• Single dose unit.
• Clear solution except fat emulsion.
• Isotonic solution.
• LVPs volume is 100-1000 ml;up to 3000ml
• IV infusiontechnique is called VENOCLYSIS

39. TYPES OF LVPs:
• HYPER ALIMENTATION SOLUTIONS
• CARDIOPLAGIC SOLUTIONS
• PERITONEAL DIALYSIS SOLUTIONS
• IRRIGATING SOLUTIONS

40. Hyperalimentation solutions
• Administration of large amount of nutrients to patients who are
unable to take food orally,at caloric intake of 4000k cal/day.
• Subclavian vein cannulation: infusion of hypertonic solutions.
• Formulation: mixture of dextrose ,aminoacids,lipids, electrolytes,
and vitamins.
• Uses:
• Administration of life saving or sustaining drug to comatose patient.

41. Cardioplagic solutions
• These are the solutions used in heart solutions to prevent injury to
myocadium during reperfusion ,as well as to maintain bloodless
operating field.
• Maintains the diastolic arrest.
• Slightly alkaline to compensate metabolic acidosis.
• Hypertonic
• Uses:
• To minimise referfusion injury resulting from tissue edema.

42. Peritoneal dialysis solutions
• Infused continuously into the abdominal cavity , bathing peritoneum
and are then continuously with drawn.
• Formulation :
Glucose,
Antibiotics as prophylactic.
• Uses:
• Removal of toxic substances from the body.
• To aid and accelerate excrection normal.
• To treat acute reneal insufficiency.

43. Irrigating solutions
• To irrigate , flush and aid in cleaning body cavities and wounds.
• Certain IV solutions (NS) may be used as irrigating solution , but
solution designed as irrigating solution should not be used as
parenterally.
• Use:
• Treatment of serious wounds infused into blood stream.

44. Manufacture of LVPS
Commonly used carbohydrates are
 MONOSACHARIDES (dextrose , fructose)
 DISACHARIDES (sucrose , maltose)
 POLYSACHARIDES (dextran)
Nitrogen containing substances like lipid emulsions –vegetable oil
polyols like
 Glycerol-tonicity adjuster.
 Sorbital – irrigation product.
 Mannitol – osmotic agent.

45. Batch mixing
A.SIMPLE SOLUTION:
• With exception of o/w emulsion used in parenteral nutrition ,the
majority of large volume parenterals are simple aq. Solutions of
electrolytes , aminoacid or sugars.
EXAMPLES:
• Dextrose hydrous USP
• Sodium chloride USP
• Sodium lactate USP
• KCl USP
• CaCl2 USP

46. B.LIPID EMULSION:
• The productio of lipid emulsion is highly specialised process
because difficulty dealing
• With dispersed system in which average droplet diameter is
required below 500nm.
 Thermodynamically unsatble.
 ifficulty in heat sterilization.
EXAMPLE:
• 10% IV fat emulsion.
-fractioned soy oil.
-Fractioned egg phosphatides.
-Glycerol USP and
Water for injection USP

47. • C.SPECIALIZED PRODUCT:
• Specialized LVPs containing active ingredient that are not adequately
stable in solution or compatible with container when reconstituted as
aq.solution.
• EXAMPLE:
• Tris amino physiological buffer , urea , an osmotic diuretic in this
substance.
• -active ingredient provided as
• Sterile
• Non – pyrogenic solid.

48. MARCH -2019 170101 /Chapter-3 /S48
EDUCATION FOR PEACE & PROGRESS
COPY RIGHTS RESERVED
Santhiram College of Pharmacy, Nandyal
Formulation
AQUEOUS VEHICLE:
• Water for injection
• Bacteriostatic water for
injection
• Sterile water for injection
• Water miscible vehicles:
primariliy to effectsolubility
of drugs and or reduce
hydrolysis.
NON – AQUEOUS VEHICLES:
• Fixed oils
• Peanut oils
• Corn oils
• Cotton seed oils
• Sesame oils
• Ethyl oleate
• Isopropyl myristate

49. Filling of LVPS
LVPs are filled by
• Gravity filling
• Pressure filling
• Vacuum filling

50. Packing
• Large volume parenteral solutions are packaged in
containers holding 100 ml or more.
• There are three types of containers:
• Glass bottle with an air vent tube,
• Glass bottle without an air vent tube
• Plastic bags.

51. End of
Chapter
“Precipitate as weather, she appeared from somewhere, then
evaporated, leaving only memory.”
― Haruki Murakami