UNIT-4 PARENTERAL PRODUCTS. FIFTH SEM B. PHARM

Definition, types, advantages and limitations. Preformulation factors and essential
requirements, vehicles, additives, importance of isotonicity
production facilities and controls,
aseptic processing, Formulation of injections, sterile powders, large volume parenterals and
lyophilized products. Quality control tests of parenteral products.

1. PARENTERAL
PRODUCTS
MR. MADHAVB. KORDE

2. INDEX
➢INTRODUCTION
➢ADVANTAGES/ DISADVANTAGES
➢TYPES
➢ESSENTIAL REQUIREMENTS
➢FORMULATION CONSIDERATION
➢IMPORTANCE OF ISOTONICITY
➢PRODUCTION PROCESS/PROCEDURE
➢PRODUCTION FACILITIES AND CONTROLS
➢ASEPTIC PROCESSING
08-10-2024

3. Parenteral Products
➢ The term is derived from the Greek word 'para' outside & 'enterone' intestine.
➢Parenteral preparations are pyrogen-free preparations intended to be administered other
than oral routes.
➢Parenterals are sterile solutions or suspensions of the drug in an aqueous or oily
vehicle.
➢According to I.P. “parenterals are injectable preparations, sterile products
intended for administration by injection, infusion or implantation into the
body.”
➢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 implantationintothebody."08-10-2024

4. ➢Parenteral drugs are administered directly into the veins, muscles or
under the skin or more specialized tissues suchasthe spinalcord.
➢Term parenteral used for any drug/fluid whose delivery doesn't
utilize the alimentary canal for entering in to the body tissues.
➢So it is a route of administration other than the oral route. This route
of administration bypasses the alimentary canal
➢Parenteral routes of administration usually have a more rapid onset
of action than other routes ofadministration.
08-10-2024
Parenteral Products

5. Advantages
1)If the drug is not absorbed orally it can be given parenterally.
2)Drug which is unstable in GIT can be given parenterally.
3)Drugs which are undergoing extensive first-pass metabolism are
given parentally which avoid the first pass metabolism.
4)Rapid drug action in emergencies as the onset of action of
parenteral is rapid.
5)Patient is uncooperative/unconscious (accident, surgeryetc.)
6)Complete drug bioavailability (upto 100%) is possible.
08-10-2024

6. Advantages
7)Prolonged drug action is possible.
8)Parenteral therapy provides the means of correcting serious disturbances of fluid
and electronic balances
9)When food cannot be taken by mouth, total nutritional requirements can be
supplied by the parenteral route.
10)Targeted drug delivery.
11)Useful for delivering fluids, electrolytes or nutrients.
12)They may give rise to local effects. E.g. Local anesthesia.
13)Patient compliance problems are largely avoided.
08-10-2024

7. disAdvantages
1)Most inconvenient route of administration /pain upon injection.
2)Generally need a medical expert for administration (like a physician or nurse
usually in a hospital or clinic).
3) It requires strict adherence to aseptic procedures.
4) It is more expensive than other routes.
5) Chances of adverse effects are more.
6)Side effects are quicker than that of drug given by any other routes
08-10-2024

8. disAdvantages
7)Danger of blood clot formation is there.
8)Impossible to retrieve if an adverse reaction occurs even immediately after
administration.
9)More expensive and costly to produce(Manufacturing & Packaging).
10)Potential for infection at the site of injection.
11)Psychological distressbythepatient.
12)Require specialized equipment, devices, and techniques to prepare and
administer drugs.
13)Potential for tissue damage upon injection.
08-10-2024

9. Intravenous (IV) Vein
Intramuscular (IM) Mucle
Subcutaneous (SC) under the Skin
Intradermal(ID) into the Skin
Intraarticular Joints
Intrasynovial Joint-fluid area
Intraosseous Bones
Intracerebral Brain
Intraspinal Spinal column
Intrathecal Spinal fluid
Intra-arterial Arteries
Intracardiac Heart
Endotracheal down the Trachea
08-10-2024
1. Based on route of administration:

10. TYPES OF PARENTERALS
08-10-2024
1. Based on route of administration:

11. Intravenous
The injection of a drug directly into the patient's veins, resulting in
the most rapid onset of action.
Site of injection: median basilic vein near the anterior surface of the
elbow.
08-10-2024

12. Intradermal
The drug is injected into the top few layers of the skin.
Ideally, the drug is placed within the dermis. Used for
diagnostic agents.
Site of injection- skin of fore arm.
08-10-2024

13. Subcutaneous
The injection of the drug under the skin into the fatty layer, but not into the muscle.
Absorption of the drug is rapid.
Site of injection: upper arm
E.g. insulin

08-10-2024

14. Intramuscular
➢Drugs are injected deeply into muscle tissue. If the drug is in aqueous (water)
solution, absorption is rapid. However, if the drug is in an oily liquid or in the form
of a suspension, it can prolong the release of the drug.
➢Site of injection: shoulder, thigh, buttock, & may vary with multiple injections.
➢Syringe: 0.5 - 5 ml
➢Volume: max. 5ml in gluteus & 2ml in deltoid
➢Less rapid than IV but has longer duration of action.
➢Note: during administration plunger of the syringe withdrawn back to assure
absence of blood
08-10-2024

15. TYPES OF PARENTERALS
2. BASED ON VOLUME:
1.Large volume parenterals (LVP’s)
2.Small volume parenterals (SVP’s)
08-10-2024

16. 1.SMALL VOLUME PARENTERALS (SVP)
An injection that is packed and labeled in container as containing 100ml or less
2.LARGE VOLUME PARENTERALS (LVP)
Volume: 101 to 1000ml
They generally provide electrolytes and nutrition to the body
They are given iv route
2. BASED ON VOLUME:

17. Large volume parenteral (LVP’s)
Four types of LVPs
1.Hyper alimentation solution/TPN
2.Cardioplegia solution
3.Peritoneal dialysis solution
4.Irrigating solution
08-10-2024

18. 2. BASED ON VOLUME:
Large volume parenterals (LVP’s)
➢These solutions are usually administered by intravenous infusion
to replenish body fluids or electrolytes or to provide nutrition.
➢They are usually administered in volumes of 100ml to 1L or more
per day.
➢Because of the large volumes administered, these solutions must
not contain bacteriostatic agents or other pharmaceutical additives.
➢They are packaged in large single dose containers.
08-10-2024

19. ➢Electrolytes, vitamins are frequently incorporated into large volume parenteral for
coadministration to the patient.
➢It is the responsibility of the pharmacist to understand the physical and chemical
compatibility of the additive in the solution in which it is placed.
➢Common uses may include;
➢Correction of electrolyte and fluid balance disturbance
➢Nutrition
➢Vehicle for administrating other drugs
08-10-2024
Large volume parenterals (LVP’s)

20. Large volume parenterals (LVP’s)
Container for LVP
Large volume parenteral solutions are packaged in containers holding 100ml or more. LVP
packaged in
❖Glass bottle with an air vent tube
❖Glass bottle without an air vent tube
❖Plastic bags
08-10-2024

21. 2. BASED ON VOLUME:
Small volume parenterals (SVP’s)
➢USP defn: an injection that is packed in containers labeled as containing 100 ml or less.
➢May be given single dose or multiple dose. Mostly given in multiple doses.
➢Different types are: Solution
Suspension
Emulsion
Dry powders
Ampules
Vials
08-10-2024

22. 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 colored 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.
08-10-2024
Small volume parenterals (SVP’s)

23. 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.
08-10-2024
Small volume parenterals (SVP’s)

24. 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.
08-10-2024
Small volume parenterals (SVP’s)

25. comparison BASED ON VOLUME


08-10-2024

26. 3. BASED ON types:
a.Solution or emulsions of medicaments suitable for injections
Commonly called injections
Supplies in single dose or multiple dose containers
Volume varies from 0.5ml to 1 litre
b.Sterile solid
It is a 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.
Prepared immediately before its administration.
08-10-2024

27. 3.BASED ON types:
c.Sterile suspension
They should be sterile, pyrogen-free, stable, re-suspendable, syringeable, isotonic,
and non-irritant.
These are sterile suspensions of drugs in a suitable solvent which are administered
by IM or subcutaneous route.
d.Transfusion fluids
Parenteral solutions which are administered by IV route
08-10-2024

28. Consideration in parenteral preparation:
1)Stability :
1)Must be physically and chemically stable during storage.
2) All products must be stable.
2)Sterility: Aseptic environment must be maintained during preparation &
administration to prevent microbial contamination.
1)It should be free from all types of microorganisms.
2) Should pass test for sterility
3) Specific gravity:
1) The product meant for intra spinal injections should have the same specific
gravity as that of spinal fluid which the same are to be injected.
08-10-2024

29. Consideration in parenteral preparation:
4)Free from Foreign Particles:
1)Should be free from fibers and dust .
2)Must pass clarity test
5)Isotonicity:
1)Should be isotonic with blood plasma & body fluids.
2) It is very important, in order to avoid any complications on the administration of
parenteral products.
6)Free from pyrogen:
1)The parenteral preparations should be free from toxin & pyrogens.
2)The parenteral product must pass the test for pyrogen, because contaminated
parenteral product causes rise in body temperature after itsadministration.
08-10-2024

30. Consideration in parenteral preparation:
7)Chemical purity:
1)Should be free from chemical impurities.
2)Should be within a certain limit as specified in the monograph.
8)Containers:
1)Usually supplied in glass ampoules, bottles, vials in plastic bottles or bags or
in prefilled syringes.
2)They do not adversely affect the quality of preparations.
9)Closures:
Equipped with a firm seal to prevent entry of microorganisms & other
contaminants
08-10-2024

31. ISOTQNICITY
➢Isotonicity is determined by investigating the conc. of solute at which the cells remain in
their normal shape and size.
➢Isotonicity adjustment helps to reduce pain in areas near nerve endings.
➢NaCl, Glycerin and Lactose are used in parenteral preparations.
08-10-2024

32. ISOTQNICITY
➢Hypertonic : Hypertonic means that the environment outside of the cell has a
higher concentration of solutes than the cell itself.
That will attract water molecules from cell leading to shrinking of cell.
➢Isotonic : Solutions that contain the same concentration of water and solutes as
the cell cytoplasm are called isotonic solutions.
Cells placed in an isotonic solution will neither shrink nor swell since there
is no net gain or loss of water.
➢Hypotonic : A solution that contains fewer dissolved particles (such as salt and
other electrolytes) than is found in normal cells and blood.
Hypotonic solutions are commonly used to give fluids intravenously to hospitalized
patients in order to treat or avoid dehydration.
08-10-2024

33. IMPORTANCE OF ISOTQNICITY
1.The formulations of the parenteral product should be isotonic with invivo body fluids.
2.If any isotonicity and pH differences n1ay cause irritation, hemolysis, necrosis and
tissue toxicity.
3.Ophthalmic solutions should be isotonic with lachrymal fluid (tears) to prevent irritation
and pain.
4.Similarly injectable solutions should be isotonic with blood plasma.
5.This solution do not cause cell to absorb water from surrounding to lose water from cell.
6.Isotonicity also helps to determine the capacity of various route of injectons.
08-10-2024

35. FORMULATION (EXCIPEINTS) OF PARENTERALS
1.Vehicles:
Aqueous vehicle
Non aqueous vehicle
2.Preservatives
3.Antioxidants
4.Adjuvants
5.Solubilising agents and surfactants
6.Buffering agents
7.Antibacterial agents
8.Tonicity agents
9.Chelating agents
10.Stabilizers
11.Suspending agents
12.Emulsifying agents
13.Wetting agents
08-10-2024

36. 1.vehicles
a)Aqueous vehicle
b)Non aqueous vehicle
a)AQUEOUS VEHICLE
The aqueous vehicle used are
◦Water for injection
◦Bacteriostatic water for injection
◦Water for injection free from carbon dioxide
◦Water for injection free from dissolved air
08-10-2024

37. WATER FOR INJECTION (WFI)
➢Sterile water is free from volatile and non-volatile impurities and pyrogens.
➢Pyrogens are the byproduct of bacterial metabolism, they are polysaccharides,
thermostable, soluble in water, unaffected by bactericide, and can pass through bacteria-
proof filters.
➢They are removed from water by simple distillation process.
➢WFI contaminated with pyrogen may cause an increase in body temperature if injected.
➢Method of preparation a) Distillation b) Reverse osmosis
➢Total solid content in WFI-10ppm
➢Should be used within 24hrs.
FORMULATION (EXCIPEINTS) OF PARENTERALS

38. Bacteriostatic Sodium Chloride Injection U.S.P.
➢Bacteriostatic Water (Bacteriostatic water for injection) is sterile water containing
0.9% benzyl alcohol that is used to dilute or dissolve medications.
➢The container can be reentered multiple times (Usually by a sterile needle) and
the benzyl alcohol suppresses
Ringer’s Injection U.S.P.
➢A sterile solution of sodium chloride, potassium chloride, and calcium chloride in
water for injection.
➢Used as a vehicle for other drugs or alone as an electrolyte replenisher and plasma
volume expander.
Lactated Ringer’s Injection U.S.P.
A sterile solution of sodium chloride, potassium chloride, calcium chloride, and
sodium lactate in water for injection.
FORMULATION (EXCIPEINTS) OF PARENTERALS

39. b)NON AQUEOUS VEHICLE
Commonly used non-aqueous vehicles are-
Oils- fixed oils
Alcohols –ethyl alcohol, propylene glycol
FIXED OIL
Eg: Arachis oil, cotton seed oil, almond oil, sesame oil
Used when drug or medicament is insoluble or slightly soluble in water
ALCOHOL
Ethyl alcohol- preparation of hydrocortisone injection
Propylene glycol ; preparation of digoxin injection
FORMULATION (EXCIPEINTS) OF PARENTERALS

40. 2.Adjuvants
These are substances added to increase the stability or quality of the preparation
3. Solubilising agents
Used to increase the solubility of drugs which are slightly soluble in water
Eg: surfactants like tweens and polysorbates
4. Stabilizers
They are added to prevent oxidation and hydrolysis
Oxidation can be prevented by adding antioxidants
Eg: thiourea, ascorbic acid, sodium meta bisulfite
Hydrolysis can be prevented by using a nonaqueous vehicle or adjusting the pH of the preparation
FORMULATION (EXCIPEINTS) OF PARENTERALS

41. 5.Buffering agents
The degradation of preparation which is due to change in pH can be prevented
by adding suitable buffer to maintain desired pH
Eg: citric acid, sodium citrate, acetic acid, and sodium acetate
6.Antibacterial agents
They prevent the growth of microorganisms during storage
They act as preservatives
Eg: phenylmercuric nitrate, methylparaben
FORMULATION (EXCIPEINTS) OF PARENTERALS

42. 7.Chelating agents
They chelate the metallic ions present in the formulation
To remove trace elements. Eg: EDTA Sodium or potassium salt of citric acid
8.Suspending agent
Improve the viscosity of the preparation Eg: methylcellulose, CMC, gelatin, acacia
9.Emulsifying agent
They are used in sterile emulsion Eg: lecithin
FORMULATION (EXCIPEINTS) OF PARENTERALS

43. 10.Wetting agents
➢Reduce the interfacial tension between the solid particles and liquid
➢Prevent the formation of lumps
➢Act as antifoaming agents
11.Tonicity adjusters
➢Should be isotonic with blood plasma and other body fluids
➢Thus avoid destruction of RBC, irritation and tissue damage
➢Reduce the pain on injection
➢Eg: sodium chloride, dextrose, boric acid
FORMULATION (EXCIPEINTS) OF PARENTERALS

44. Processing of parenteral
1.Cleaning of containers ,closures and equipments
Rubber closure are washed with hot solution of 0.5% sodium pyrophosphate in
water
2.Collection of materials
Should be pure
WFI free from pyrogens and microorganism
3.Preparation of parenteral product
Under aseptic condition.
The ingredients are accurately weighed separately and dissolved 1n
vehicle as per method of preparation to be followed.

45. 4.Filtration
Parenteral solution passed through bacteria proof filters such as filter candle, membrane
filter, and sintered glass filter
Primary objective of filtration is to clarify the solution by removing foreign particles
5.Filling the preparation in final containers
Ampoule are used for filling single doses
Vials used for filling multiple doses
Both are used for filling transfusion fluids
6.Sealing of containers
Ampoules are sealed by rotating the neck in the flame of bunsen burner
Transfusion bottle and vials by closing with rubber closure

46. 6.Sealing of containers
Glass Vial Filling and sealing Procedure:
i.Similar to ampoules filling, an excess volume is needed for specific dose withdrawal.
ii.Vial openings sealed with rubber closures and aluminium sealing.
iii.Vials are more susceptible to contamination due to larger openings.
iv.Rubber closures should be sealed immediately after filling.
v.Open containers protected with HEPA-filtered airflow during exposure time.
vi.Rubber closure should fit tightly to seal irregularities.
vii.Closures inserted mechanically via automated process, with halogenation or silicone
treatment reducing friction.
viii.Manual stoppered vials used for small batches, but pose higher contamination risk.

47. 7.Sterilisation
For thermostable medicament
Autoclave can be used
Temperature 115
o
C to116
o
C for 30minutes
OR
121
o
C for 20minutes
Hot air oven 160
o
C for 2hr
For thermolabile preparations
Using bacteria proof filters

48. Evaluation of Parenterals
1.Sterility Test
2.Clarity Test
3.Leakage Test
4.Pyrogen Test
5.Assay

49. 1.Sterility Test
Sterility is defined as free from the presence of viable microorganisms.
Sterility testing is a procedure carried out to detect and conform absence of any viable
form of microbes in or on pharmacopeia preparation or product. Sterility test is performed
to check the presence of aerobic and anaerobic viable forms of bacteria, fungi and yeast in
parenteral products.
Types of media used
a)Fluid thioglycollate media- for anaerobic bacteria
b)Soya-bean casein digest media-for fungi and aerobic bacteria
Methods of sterility testing
i.Membrane filtration method
ii.Direct inoculation method

50. i.Membrane filtration method
It is more popular and widely used method over direct inoculation
method. It requires more skill and knowledge than the direct
inoculation method.
Procedure:
1.This method involves filtration of a sample through membrane filters of
porosity 0.22 microns
2.The filtration is assisted under vacuum.
3.After filtration completion, the membrane is cut into two half, and one
half is placed in two test tubes containing FTM, and SCDM.
4.Incubate the at 20-25°C (aerobic) and 30-35°C (anaerobic) for not less
than 14 days.
5.Check for microbial growth to determine sterility.

51. ii.Direct transfer/inoculation method
It is a traditional sterility test method that involves a direct inoculation of
required volume of a sample in two test tubes containing a culture
medium that is, a Fluid thioglycolate medium and soya bean casein
digest medium.
Procedure:
i. A suitable amount of material under test is transferred into sterile nutrient media
and incubated for a suitable period(14 days) at optimum temperature.
ii.After incubation, the media is examined for the presence or absence of any
microbes.
iii.If not, any growth of microbes is seen, the product is considered to be sterile.
iv.If growth of microbes occurs, test is repeated 2
nd
and 3
rd
time to account for
any accidental contamination.
v.If test fails after 2
nd
and 3
rd
time, product is declared nonsterile and
discarded.

52. 2.Clarity test
Clarity test is performed to detect presence of any particulate matter.
Also called particulate matter monitoring. Particular matter is defined as unwanted mobile insoluble
matter other than gas bubble present in the given product.
By clarity test apparatus- This method involves visual inspection of the container’s direct lighting
on container against black and white background to check the presence of any particulate matter.
Other methods: light absorption, light scattering, change in electrical resistance is also used to detect
particulate matter
The USP standards are met if the LVP's under test contain NMT 50 particles per ml of 10
µm, and NMT 5 particles per ml of size 25 µm 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 size 25 µmin an effective
spherical diameter.

53. ➢The sealed ampoules are subjected to small cracks which occur due to rapid
temperature changes or due to mechanical shocks.
Procedure:
Filled & sealed ampoules

Dipped in 1% Methylene blue solution

Under negative pressure in vacuum chamber


Vacuum released
colored solution enter into the ampoule, Defective sealing
➢Vials & bottles are not suitable for this test because the sealing material used is not rigid
3.Leaker Test

54. ➢The leak test can be carried out during autoclaving cycles by immersing the
ampoules in a dye bath.
➢This method achieves two objectives, firstly it evaluates the presence of any
leakage and secondly, it sterilises the product .
➢The leak test is not suitable for vials and bottles because they have rubber
closures that are not rigid.
3.Leaker Test

55. 4.Pyrogen test
Pyrogenic - means fever producing
Pyrogens – fever-inducing substances
Pyrogens are fever-producing organic substances ar1s1ng from microbial
contamination and are responsible for many of the febrile reactions that occur in
patients.
This test is used to detect the presence of pyrogenic substances in parenteral preparations.
In this test, rabbits are used as test animals because they show same physiological response
to pyrogenic substances like that of man.
If pyrogenic substance present in the product, it causes increase in body temperature of test
animal.
Procedure: Test sample is injected into ear vein of three rabbits.3 hours after injection, body
temperature of test animals are measured by rectal thermocouple inserted into rabbits and
temperature is measured by employing electronic thermometer.

56. 4.Pyrogen test
Rabbits test:
The test involves measurement of the rise in body temperature of rabbits following
intravenous injection of a sterile solution of the substance under examination.
Procedure:
i.Record temperature of each animal at intervals of not more than 30 mins. beginning at least 90
minutes before the injection of the solution under examination and continuing for 3 hours after the
injection.
ii.Not more than 40 minutes immediately preceding the injection of the test dose, record the initial
temperature of each rabbit, which is the mean of two temperatures recorded for that rabbit at interval
of 30 mins in 40-minute period.
iii.Rabbits showing a temperature variation greater than 0.2°C between two successive readings in the
determination of initial temperature should not be used for the test.
iv.In any one group of test animals, only those animals are used, whose initial temperatures do not vary
by more than 1°Cfrom each other.
v.Rabbits having a temperature higher than 39.8°C and lower than 38°C should not be used.

57. Rabbits test:
Interpretation:
If no single rabbit shows rise in temperature, product is declared as
nonpyrogenic
But if any one rabbit shows the rise in temperature of 0.6ºC or more above the
normal temperature, then the test is repeated on 5 additional rabbits.
Test requirements are met if not more than 3 of 8 rabbits show an individual rise
in temperature of 0.6°C and sum of maximum rise in temperature of 8 rabbits is
not more than 3.7ºC

58. LAL test
➢Limulus amebocyte lysate [LAL] test-In vitro pyrogen test.
➢Limulus Amebocyte Lysate (LAL) test measures the concentration of
bacterial endotoxins that maybe present in the sample, or on the article, to
which the test is applied, using LAL reagent.
➢Limulus amebocyte lysate is obtained from aqueous extracts of the
circulating amebocytes of the horseshoe crab, Limulus polyphemus.
➢It is especially processed and characterized for use as a LAL reagent for gel-
clot formation.

59. LAL test
Procedure:
i.In this method the 0.1ml test solution is combined with a cell lysate from the
amebocyte [blood cells] of horseshoe crab (Limulus Polyphemus family) .
ii.Incubate for 1 hour at 37°C.
iii.After incubation for 1 hour at 37°C, the mixture is analyzed for the presence of
gel clot.
iv.Gel clot forms, indicating endotoxins are present.
v.No clot formation, indicating the sample is endotoxin-free.
vi.Any endotoxin that might be present will be coagulated with the protein
fraction of the amoebocytes and results in the formation of a gel.
This test is considered to be simple, rapid, and of greater sensitivity than the
rabbit test

60. Packaging and Labelling
➢Packaging refers to the process of designing and developing a suitable package for
enclosing & holding product so that it can be easily covered and secured.
➢Parenteral formulations are packed in glass or plastic containers.
➢Container systems include ampoules, vials, syringes, cartridges, bottles, and bags.
Glass-
➢Type-I: Highly Resistant Borosilicate Glass.
➢Type II: Treated Soda lime Glass.
➢Type III: Regular Soda Lime Glass.
➢Type IV: N.P (Non parenteral) Glass
08-10-2024

61. Packaging and Labelling
➢Rubber materials are used in these containers, such as rubber stoppers for vials and bottles,
plungers, and rubber seals for syringes and cartridges.
➢Siliconisation is used to prevent product interaction with glass surfaces, minimizing
adsorption of active ingredients and solids.
➢Plastics are used for packaging parenteral products, with polyethylene or polypropylene
being the most common.
➢Rubber closures are used for multiple-dose vials, intravenous fluid bottles, plugs for
disposable syringes, and bulbs for ophthalmic pipettes.
➢Rubber closures may contain a vulcanising agent, accelerator, activator, fillers, antioxidants,
lubricants, etc.
➢Coring, the generation of rubber particles from the closures when needles are inserted, is a
common problem of rubber closures.
08-10-2024

62. Packaging and Labelling
✓In parenteral, labeling refers to the text, design, symbol, logo, instructions & suggestions
for usage, etc.
✓Labelling refers to all written, printed, or graphic matter on immediate container or product
packaging.
✓Label should include necessary information for safe product use.
✓Information cannot be readable on the container, hence add-on printed matter is required.
✓Label should not be placed on outer shipping container.
Labeling Guidelines for Dialysis, Haemofiltration, and Irrigation Solutions:
➢Labels should cover the entire container for product examination.
➢Labels should meet injection requirements, not just volume.
➢Labels should indicate they're not for intravenous injection.
➢Labels for veterinary use should also be included.
08-10-2024

63. 08-10-2024
Packaging and Labelling

64. Production Facilities for Parenteral Products
1.Cleanliness Standards: Aseptic filling rooms maintain near-perfect cleanliness. Surrounding areas with
slightly lower cleanliness standards. Aims to prevent contamination with easily cleanable, non-porous
materials.
2.Facility Construction: Epoxy finish for walls and ceilings; ceramic-plastic cement for floors. Movable
partitions and glass for supervision and flexibility. Recessed lighting, stainless steel furniture.
3.Air & Utilities Control: HEPA-filtered laminar airflow in aseptic areas. Non-sterilizable equipment kept
outside aseptic zones. Services like gas, water, and air in separate corridors to prevent contamination.
4.Personnel Management:
▪Hygiene: Personnel must maintain high hygiene standards.
▪Training: Formal training in aseptic techniques, with regular re-training.
▪Uniforms: Sterile, lint-free uniforms, gloves, and goggles.
5.Functional Areas & Workflow:
▪Functional Areas: Warehousing, compounding, filtration, aseptic filling, packaging.
▪Flow Plan: Components move from warehouses, to compounding, then aseptic areas, and finally
packaging.
▪Quality Control: Testing and records review before final shipment.

65. Production procedure
1.Clean-up area
2.Compounding section
3.Aseptic area
4.Packing and labeling section
08-10-2024

66. Production procedure
1.Clean-up area
➢Clean-up area should withstand moisture, soap, and detergents and Inward air leaks and dirt accumulation
should be avoided.
➢Ceiling and walls should be coated with epoxy and vinyl polymeric continuous film.
➢Clean rooms control airborne particles using HEPA filters, continuous air circulation, and physical barriers.
➢Clean rooms establish appropriate environmental levels for airborne particulates, temperature, humidity, air
pressure, and airflow patterns.
➢Air changes should be related to room size, equipment, and personnel.
➢After 15-20 minutes of clean-up, an unmanned state should be received.
➢A alert and action limits should be fixed for particulate and microbiological monitoring results.
➢Other parameters like temperature and relative humidity depend on the product nature and manufacturing
procedure.
➢Components after washing should be handled in grade D environment. Solutions to be sterile filtered should
be prepared in grade C environment.
➢Aseptically prepared products should be handled and filled in grade A environment with grade B background.
08-10-2024

67. Production procedure
1.Clean-up area.
Classifications: Cleanrooms are classified based on the permissible number of particles per cubic
meter of air.
1.Class 100 (ISO 5): For critical areas where the product is exposed (e.g., filling stations).
2.Class 10,000 (ISO 7): For less critical areas such as buffer zones.
Environmental Monitoring: Routine checks of particulate matter, viable microorganisms, and air
quality.
08-10-2024

68. Production procedure
08-10-2024

69. Air Control
✓Air Filtration: Fresh or recycled air is filtered using a series of prefilters, starting with larger pores
and ending with smaller ones.
✓HEPA Filters: Removes 99.97% of particles ≥0.3 μm, ensuring air free of contaminants.
✓Blowers: Installed upstream of filters to keep dirt away from the air ventilation system.
✓Air Distribution: Clean air is dispersed through stainless steel ducts or a plenum system to
controlled rooms.
✓Positive Pressure: Maintains aseptic conditions by preventing unclean air from entering sterile areas
through cracks or open doors.
08-10-2024

70. Aseptic Processing
08-10-2024
Traffic Control in Aseptic Areas:
➢Aseptic areas should be designed to control and limit traffic.
➢Only personnel's wash rooms, non-sterile manufacturing area, and packaging area should
have direct access from the outside.
➢Personnel should enter the aseptic areas after following a rigid protocol including washing
their hands and removing street clothing.
➢Unofficial personnel should not enter these areas.
Laminar Flow Benches:
➢The aseptic area environment can be controlled using laminar airflow from a HEPA filter.
➢The airflow direction can be horizontal or vertical and occupy either a limited area or an
entire room.
➢Vertical flow from the ceiling-mounted HEPA filters is often used to protect critical sections
of processing lines.

71. Aseptic Processing
08-10-2024

72. Aseptic Processing
08-10-2024
➢Utilizes laminar airflow from HEPA filters to control the aseptic area environment.
➢Airflow direction can be horizontal or vertical, occupying either a limited area or an entire room.
➢This method is the only way to achieve a Class 100 clean room with a particle count of less than
100 per cubic foot.
➢Airflow uniformly blows out of the entire back or top of a workbench or room, ensuring uniform
velocity and direction.
➢Contaminants entering downstream from the filter can transfer to working areas, reducing
contamination risk.
➢Vertical flow from ceiling-mounted HEPA filters is often used to protect critical sections of
processing lines.

73. Containers and Closures
✓The container-closure system is an essential part of the final presentation of
pharmaceutical product.
✓It defines the closure, protection, and functionality of a container while ensuring the
safety and quality of the drug product over the product shelf life.
✓Parenteral formulations are packed in glass or plastic containers.
08-10-2024

74. Containers and Closures
✓Glass is composed of Silicon dioxide & a varying amount of oxides Sodium,
Potassium, Calcium, Magnesium, Aluminium, Boron etc.
✓Basic structure network silicon dioxide tetrahedron.
✓Boric oxide easily enters into network structure of silicon dioxide & does
not leach into solution of container.
✓But other oxides do not enter into the network structure of Silicon
dioxide & loosely bound (other oxides).
✓Relatively free to migrate which result in leached into sol
n
in container, especially during
thermal Sterilization process.
✓The leached oxide may hydrolyze & finally result in Raise pH & may catalyze
or enter into the undesired reaction.
08-10-2024

75. Containers and Closures
TYPES OF GLASS
1.Type I/Borosilicate: Also, know as Neutral Glass
✓Composition- 81% -silicon dioxide; 13% -Boric oxide; other oxide (Na & Al etc) -
non network forming oxide.
✓Used for all types of preparation whethe parenteral
preparation or not & for all acid & Alkaline preparation or whether buffered or not.
2.Type II/Soda lime treated: Also known as Sodalime treated glass
✓Composed of Silicon dioxide & high proportional of Sodium oxide (14%)& Calcium
oxide ( 18%).
✓Also high hydrolytic resistance.
✓Treated with Silicon dioxide & other dealkalizers to neutralize
interior surface of the container [under controlled te1np & hu1nidity] to increases
chemically resistance of glass.
✓Used for Acidic & Neutral or pH<7 buffered preparation

76. Containers and Closures
TYPES OF GLASS
3.Type III/Sodalime glass:
•Moderate hydrolytic resistance
•Used for Non . Aqueous Parenteral & powdered for injection preparation.
4.Type IV/Non-Parenteral glass
• Not used for parenteral preparation.
•Used for Oral dosage form.

77. Containers and Closures
CLOSURES:
Rubber closures:
➢Rubber closures are used to seal the opening of cartridges, vials, and
bottles, providing a material soft and elastic enough to permit entry and withdrawal of
a hypodermic needle without loss of the integrity of the sealed container.