2. Definitions related to the topic:
 Parenteral Products
 Sterilization & Sterile Product
 Pyrogen
 SVP
 LVP
 Light Resistant Containers
 Well closed containers
 Tightly closed containers
 Single dose container
 Multiple dose container
 Hermetically sealed container

3. PARENTERALS
para: outside
enteron: intestine (i.e. beside the intestine)
These are the preparations which are given other than
oral routes.
Injections:
These are
Sterile,
Pyrogen free preparations intended to be
administered parenterally (outside alimentary tract).

4. Why Parenteral?
Parenteral Route Is Used bcoz
1) Rapid action
2) Oral route can not be used
3) Not effective except as injection
4) Many new drugs particularly those derived from
new development in biotechnologically can only
be given by parenteral coz they are inactivated in
GIT if given orally.
5) New drugs require to maintain potency &
specificity sodium that they are given by
parenteral.

5. Advantages:
Quick onset of action
Suitable for the drugs which are not administered by
oral route
Useful for unconscious or vomiting patients.
Duration of action can be prolonged by modifying
formulation.
Suitable for nutritive like glucose & electrolyte.
Suitable for the drugs which are inactivated in GIT or
HCl (GI fluid)

6. Disadvantages:
Once injected cannot be controlled (retreat)
Injections may cause pain at the site of injection
Only trained person is required
If given by wrong route, difficult to control adverse
effect
Difficult to save patient if overdose
Sensitivity or allergic reaction at the site of injection
Requires strict control of sterility & non pyrogenicity
than other formulation.

7. Necessities of Parenteral preparations:
Sterility (must)
Pyrogen (must)
Free from particulate matter (must)
Clarity (must)
Stability (must)
Isotonicity (should)
Solvents or vehicles used must meet special purity and other
standards.
 Restrictions on buffers, stabilizers, antimicrobial preservative. Do
not use coloring agents.
Must be prepared under aseptic conditions.
Specific and high quality packaging.

8. Parental Routes of Administration:
Most Common: 1. Subcutaneous (SC; SQ ;Sub Q)
2. Intramuscular (IM)
3. Intravenous (IV)
Others: 4. Intra-arterial (IA)
5. Intrathecal
6. Intraarticular
7. Intrapleural
8. Intracardial
9. Intradermal (Diagnostic)

9. Subcutaneous (SC; SQ ;Sub Q):
The injection is given under the skin
Need to be isotonic
Upto 2 ml is given
Using ½ to 1 inch 23 gauge needle or smaller needle
Given:
Vaccines
Insulin
Scopolamine
Epinephrine

10. Intramuscular (IM):
Striated muscle fibre
0.5 to 2 ml sometimes upto 4 ml
1 to 1.5 inch & 19 to 22 gauge needle is used
Preferably isotonic
Principle sites:
Gluteal (buttocks)
Deltoid (upper arms)
Vastus lateralis (lateral thigh)
Given:
Solutions
Emulsions
Oils
Suspension

11. Intravenous (IV):
Into the vein
1 to 1000 ml
1 inch ,19 to 20 gauge needle with injection rate 1ml/ 10
sec. for volume upto 5 ml & 1 ml/ 20 sec. for volume
more than 5 ml.
Given:
Aqueous solutions
Hydro alcoholic solutions
Emulsions
Liposome

12. Intra-arterial (IA):
Direct into the artery
2 to 20 ml
20 to 22 gauge
Solutions & emulsions can be administered
Given:
Radio opaque media
Antineoplastic
Antibiotics

13. Intrathecal:
Also called intra-spinal
Directly given into the spinal cord
1 to 4 ml
24 to 28 gauge
Must be isotonic
Given:
LA
Analgesics
Neuroleptics

14. Intraarticular:
Given directly into the joints
2 to 20 ml
5 inch 22 gauge
Must be isotonic
Given:
Morphine
LA
Steroids
NSAID’s
Antibiotics

15. Intrapleural:
Given directly into the pleural cavity or lung
Used for fluid withdrawal
2 to 30 ml
2 to 5 inch, 16 to 22 gauge needle
Given:
LA
Narcotics
Chemotherapeutic agents

16. Intracardial:
Directly given into the heart
0.2 to 1 ml
5 inch , 22 gauge needle
Given:
Cadiotonics
Calcium salts as a calcium channel blockers

17. Intradermal:
Also called as diagnostic testing
0.05 ml
½ inch, 25 to 26 gauge needle
Should be isotonic
Given:
Diagnostic agents

18. Official Types of Injections:
1. Solutions of Medicinal
Example: Codeine Phosphate Injection
Insulin Injection
2. Dry solids or liquid concentrate does not contain
diluents etc.
Example: Sterile Ampicillin Sodium
3. If diluents present, referred to as.....for injection
Example: Methicillin Sodium for injection

19. 4. Suspensions
"Sterile....Suspension"
Example: Sterile Dexamethasone Acetate Suspension
5.Dry solids, which upon the addition of suitable
vehicles yield preparations containing in all respects
to the requirements for sterile suspensions.
Title: Sterile....for Suspension
Example: Sterile Ampicillin for Suspension
6. Injectable Emulsions:
Example: Propofol injection

20.  Formulation of Parenteral:
1. Therapeutic agents
2. Vehicles
i. Water
ii. Water miscible vehicles
iii. Non- aqueous vehicles
3. Added substances (Additives)
i. Antimicrobials
ii. Antioxidants
iii. Buffers
iv. Bulking agents
v. Chelating agents
vi. Protectants
vii. Solubilizing agents
viii. Surfactants
ix. Tonicity- adjusting agents

21. General steps involved
1. Cleaning
2. Preparation of bulk products
3. Filtration
4. Filling of solution in or product in ampoule or vial
5.Sealing
7. Tests for Quality control
6. Sterilization

22. Formulation of Parenteral
Solvents:
o Water
o Should meet compendial requirements
o Water miscible vehicles
o Ethyl alcohol
o PEG
o PG
o Non aqueous vehicles
o Fixed oils

23. Solvents
Solvents used must be:
Non-irritating
Non-toxic
Non-sensitizing
No pharmacological activity of its own
Not affect activity of medicinal

24. Added substances (Additives)
 Antimicrobials:
 Added for fungistatic or bacteriostat action or
concentration
 Used to prevent the multiplication of micro-organisms
 Ex..
 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 %

25. Preservatives: Multidose containers must have
preservatives unless prohibited by monograph.
Large volume parenteral must not contain
preservative becoz it may be dangerous to human
body if it contain in high doses.

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

27.  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 %

28.  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 - .05 %
 Disodium calcium edetate - 0.04 %
 Tetrasodium edetate – 0.01 %

29. 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 %

30.  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
 Glycerin
 Lecithin
 PEG – 40 castor oil
 PEG – 300
 Polysorbate 20, 40, 80

31.  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
semipermaeable membrane
 Hypotonic : swelling of cells (enlargement)
 Hypertonic: shrinking of cells (reduction)
 Example:
 Glycerin
 Lactose
 Mannitol
 Dextrose
 Sodium chloride
 Sorbitol

32. LABELING:
Name of product
Quantity of the product
% of drug or amount of drug in specified volume of
amount of drug and volume of liquid to be added
Name and quantity of all added substances
Mfg. license no.
Batch no.
Manufacturer/Distributor
Mfg. & Expiration date
Retail price (incl. of all taxes)
Mfger. address
Veterinary product should be so labeled

33. Must check each individual monogram for:
 Type of container:
 Glass
 Plastic
 Rubber closure
 Type of glass
 Type I
 Type II
 Type III
 NP
Tests for glass containers
 Powdered Glass test
 Water Attack test
 Package size
 Special storage instructions

34. Production facilities
Types :
Emulsion
Suspension
Solutions
Preparation of
IV fluids
IV admixtures
TPN
Dialysis fluids
QC tests for parenteral

35. Production facilities:
Clean- up area
Preparation area
Aseptic area
Quarantine area
Finishing and packaging area

36. LAY OUT OF PARENTERAL MANUFACTURING AREA
STOCK ROOM
COMPOUNDING
AREA
CLEAN UP
AREA
ASEPTIC
AREA
STERILIZATION
QUARANTINE
AREA
QUARANTINE
AREA
STORAGE
AND
TRANSPORT

38. Working area
Incoming goods are stored in special areas for Quarantine,
Released and Rejected status.
A cold room is available for storage of temperature-sensitive
products. Entrance into the warehouse and
production areas is restricted to authorized personnel.
Sampling and weighing of the raw material is performed in
a dedicated sampling area and a central weighing suite,
respectively.
The route for final products is separated from the
incoming goods; storage of final products is done in
designated areas in the warehouse while they are awaiting
shipment.
Several clothing and cleaning procedures in the controlled
transport zone and production area ensure full quality
compliance.
In addition, a technical area is located in between the
production zone and the area for formulation
development.
Here, the water for injection equipment is located, as well
as the technical installation of the lyophilizer.

39. Clean- up area:
Non aseptic area
Free from dust ,fibres & micro-organisms
Constructed in such a way that should withstand moisture,
steam & detergent
Ceiling & walls are coated with material to prevent
accumulation of dust & micro-organisms
Exhaust fans are fitted to remove heat & humidity
The area should be kept clean sodium that to avoid
contamination to aseptic area
The containers & closures are washed & dried in this area.

40. Preparation area:
The ingredients are mixed & preparation is prepared for
filling
Not essential that the area is aseptic
Strict precaution is taken to prevent contamination
from outside
Cabinets & counters: SS
Ceiling & walls : sealed & painted

41. Aseptic area:
Filtration & filling into final containers & sealing is
done
The entry of outside person is strictly prohibited
To maintain sterility, special trained persons are only
allowed to enter & 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 & walls & floors : sealed & painted or treated
with aseptic solution and there should not be any toxic
effect of this treatment

42. Cabinets & counters: SS
Mechanical equipments : SS
AIR:
 Free from fibres, dust & 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 & 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

43. Quarantine area:
After filling, sealing & 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..

44. 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 & handling.
The labeled container should be packed in cardboard
or plastic containers
Ampoules should be packed in partitioned boxes.

45. Class

46. Air Handling System (Central Air-Conditioning)
 filling operations shall take place under Grade A conditions - HEPA filters.
 aseptic filling area – B conditions.
 sterilized components unloading area, Manufacturing and component
preparation areas – C conditions.
 change room conforming – D conditions.
 Differential pressure - at least 15 Pascal.
 Temperature – not more than 27 degree unless specified.
 relative humidity not more than 55%.
AIRBORNE PARTICULATE CLASSIFICATION FOR MANUFACTURE OF STERILE PRODUCTS
Grade At rest (b) In Operation (a)
Maximum number of permitted particles per cubic metre equal to or above.
0.5μm 5μm 0.5μm 5μm
A 3520 29 3500 29
B (a) 35,200 293 3,52,000 2,930
C (a) 3,52,000 2930 35,20,000 29,300
D (a) 35,20,000 29,300 Not defined (c) Not defined (c)

47. For Grade A, B and C, the maximum permitted number of particles in the “at rest”
condition shall approximately be as under:
 Grade A corresponds with Class 100 or M 3.5 or ISO Class 5.
 Grade B with Class 1000 or M 4.5 ISO Class 6.
 Grade C with Class 10,000 or M 5.5 or ISO Class 7.
 Grade D with Class 100,000 or M 6.5 or ISO Class 8.
TYPES OF OPERATIONS TO BE CARRIED OUT IN THE VARIOUS GRADES FOR ASEPTIC PREPARATIONS
Grade Types of operations for aseptic preparations
A Aseptic preparation and filling
B Background room conditions for activities requiring Grade A
C Preparation of solution to be filtered (Terminal sterilization required)
D Handling of components after washing
TYPES OF OPERATIONS TO BE CARRIED OUT IN THE VARIOUS GRADES FOR TERMINALLY STERILIZED PRODUCTS.
Grade Types of operations for terminally sterilized products
A Filling of products, which are usually at risk
C Placement of filling and sealing machines, preparation of solutions when usually at risk. Filling of
product when unusually at risk.
D Moulding, blowing (pre-forming) operations of plastic containers, preparations of solutions and
components for subsequent filling

48. Environmental Control & Monitoring
Tied to facility design and operation but carefully
designed and evaluated.
HVAC – controls the quality of air, airborne variables,
temp., humidity, air flow direction, and air pressure.
HEPA – controls the air quality.

49. cont…
periodic monitoring shall be as follows:-
Particulate monitoring in air . 6 Monthly.
HEPA filter integrity testing (smoke testing) . Yearly
Air change rates . 6 Monthly.
Air pressure differentials . Daily.
Temperature and humidity . Daily
Microbiological monitoring by settle plates and/or swabs in
aseptic areas daily, and at decreased frequency in other
areas

50. Monitoring methods
Methods Operation Principle Adv Dis Adv
Biologic evaluation
settling plates
Slit sampler
Centrifugal sampler
Gravitational fallout
in a given time on a
given area
Known volume of air
drawn through slit &
impacted on nutrient
agar as plate turns
Known volume of air
centifugally blown on
nutrient agar strip.
Uncomplicated
Low cost
Known amt of
air sampled.
Sampling
related to time
as plate turns.
Measured vol. of
air sampled.
Unit handled by
hand or batery
operated.
Heaver particle
settle and are
collected.
Irregularities in
counts.
Velocity, Drying
effect – lethal
effect on veg.
cells.
Must be used
with ele. &
vaccum.
Velocity, Drying
effect – lethal
effect on veg.
cells.

51. Cascade sieve
sampler
Mebrane
filter sampler
Particulate
matter
Mebrane
filter
Known volume of
air cascade through
upto six plates of
decreasing pore size
impacted on
nutrient plate, last
receives sr mall size
particles .
Measured volume of
air pass through
membrane filter.
Particles retained on
surface is incubated
on agar plate.
Measured volume of
air pass through
filter.
Particles retained on
surface.
Measured volume
of air sampled.
Permits gradation
of particles by
size.
Measured volume
of air sampled.
Used for
microscopic
particle counting.
Measured volume
of air sampled.
Particles
microscopicaly
visible&counting
possible.
Velocity– lethal
effect on veg.
cells.
Must be used in
vaccum.
Dry condition
gives best reslt.
Vaccum
required.
Drying – lethal
effect on veg.
cells.
Air pockets
prevents mic.
Growth.
Required trained
person for
counting.
Time consuming
process.

52. Light scattering
instrumental
counter
Right angle/Near
forward
Particles viewing
cell scatter light
from the
incident light to
photodetector
tube.
Qantitative
count is possible
from measured
volume of air.
Instant result.
Ranges of sizes is
measured.
Sizing affected
by light
scattering
charecteristics of
particle surface.
No
differentiation
between viable
and non-viable
matter.

53. Personnel - Garments
use by personnel working only in aseptic area and outdoor
clothing shall not be brought into the sterile areas.
made of non-shedding and tight weave material (no fibers or
particulate matter).
to protect the product from contamination
single piece with fastenings at cuffs, neck and at legs to ensure
close fit. Trouser legs shall be tucked inside the cover boots.
clean, sterilized and protective garments shall be used
mask and gloves shall be changed at every work session
footwear shall be of suitable plastic or rubber material, daily
cleaned with bactericide.

54. Sanitation
SOP for the sanitation of sterile processing facilities. Employees to
be trained specifically for this purpose.
Records of rotational use of sanitizing agents shall be maintained.
Purified water or maintained at 70°C distilled water to be used for
dilution of disinfectants.
alcohol or isopropyl alcohol is used for dilution of disinfectants for
use as hand sprays.
Formaldehyde or any other equally effective fumigant is
recommended for the fumigation of aseptic areas.
Air particulate quality shall be evaluated on a regular basis and
record maintained.

55. Equipment
Arrangement of equipments depending upon the utilities.
Unit-sterilizers shall be double-ended with suitable inter-locking
arrangements between the doors.
Filling machines shall be challenged initially and then at periodic
intervals by simulation trials including sterile media fill.
direct contact with products and the manufacturing vessels may be
stainless steel 316 or Boro-silicate Glass for easy washing and
autoclaving.
Equipment for critical processes like aseptic filling and sterilizers
shall be suitably validated according to a written program before
putting them to use.
SOP shall be available for each equipment for its calibration and
operation and cleaning.

56. Facility Design
To provide the control of microbial, pyrogen and
particles controls over the production
environment are essential.
Warehousing:
All samples should be aseptically taken, which
mandates unidirectional airflow and full operator
gowning.
These measures reduce the potential for
contamination ingress into materials that are yet
to receive any processing at any site.

57. Preparation Area:
The materials utilized for the production of the sterile
products move toward the preparation area through a
series of progressively cleaner environments.
First the materials are passed through class 100,000 i.e. grade D
environment for presterilization.
Transfer of materials are carried out in air-locks to avoid cross contamination
The preparation areas are supplied with HEPA filters. There should be more than
20 air changes per hour
The preparation place is Class 100 area.

58. Compounding area:
The manufacture of parenterals is carried out in
class 10,000 (Grade C) controlled environments in
which class 100 unidirectional flow hoods are
utilized to provide greater environmental control
during material addition.
These areas are designed to minimize the
microbial, pyrogen, and particulate contamination
to the formulation prior to sterilization.

59.  Aseptic filling rooms:
The filling of the formulations is performed in an Class 100
environment.
• Capping and Crimp sealing areas:
The air supply in the capping line should be of Class 100
• Corridors:
They serve to interconnect the various rooms. Fill rooms, air
locks and gowning rooms are assessed from the corridor.
• Aseptic storage rooms.
• Air-locks and pass-throughs:
Air locks serve as a transition points between one
environment and another.
They are fitted with the UltraViolet lights, spray systems, or
other devices that may be effectively utilized for
decontamination of materials.

60. Instrumentation
Mixer
Homogenizer
Filtration assembly
Filling machinery

61. Mixer/Homogenizer

62. Filtration assembly

63. Bottling/Filling machinery

64. Production Area

65. 65
Sterilization and Depyrogenation
Steam sterilization
Dry-heat sterilization and depyrogenation
Gas and vapour sterilization
Radiation sterilization
Sterilization by filteration

66. 66
Aseptic processing control and evaluation
In-process Testing:
End-product Testing:
Process simulations:
Quality Assurance
Particulate matter
Pyrogen test
Stability test

67. 67
Particulate matter detector