This document discusses the formulation, manufacturing, and quality control of small volume parenterals (SVPs). It defines SVPs as injections packaged in containers of 100ml or less. The key points are: SVPs can be single dose ampoules, multiple dose vials, or prefilled syringes. Their formulations typically include an aqueous, water-miscible, or non-aqueous vehicle along with buffers, preservatives, antioxidants, and tonicity adjusters. Manufacturing involves preparation, sterilization, filling, and sealing in clean rooms with proper air filtration and personnel flow. Quality control tests include particulate matter, leakage, clarity, sterility, pyrogen and endotoxin tests.

1. By
Divya Thakur
Mpharmacy
Kaktiya university

2. INTRODUCTION:-
Para: outside
Enteron: intestine (i.e. beside the intestine)
Definition:-
According to the USP 24/ NF 19 “As those preparations intended
for injection through the skin or other external boundary tissue,
rather than through the alimentary canal”

3. SMALL VOLUME PARENTRALS:-
Defination:-
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 100ml or less fall
under the class of SVP
CLASSIFICATION OF SVP:-
1) Single dose ampoules(glass/plastic )
2) Multiple dose vials
3) Prefilled syringes

4. FORMULATION:-
1)vehicle:-
A)aqueous vehicle
B)water miscible vehicles
C)non aqueous vehicle
A)Aqueous vehicle:-
Types:-
Purified water, WFI,Sterile WFI, BacteriostaticWFI,
Sterile WF irrigation.
Preparation :-
 Distillation
 ion exchange
 reverse osmosis

5. B)Water-miscible vehicles :
primarily to effect solubility of drugs and or reduce hydrolysis.
C)Non-aqueous vehicles :
because of saftey,
purity
bio compatibility
several SVP are marketed as oily solutions
The oil must be vegitable in origin (sesame, olive, cotton seed
oil)
Product USP oil
Ampicillin(suspension) Vegitable
Diethyl stilbestrol Sesame, cotton
Epinephrine(suspension) Sesame
Pencillin G procaine(suspension) vegitable

6. Co solvents :-
These are used to increase the stability of poorly soluble drug
in water and prevent drug chemical degradation by
hydrolysis
Ex:-propylene glycol or in combination with ethanol and
polyethylene glycol.
Antimicrobial preservatives :
Maintain the stability of the product during storage.
ex:-Phenyl mercuric nitrate and Thiomersol 0.01%
Benzethonium chloride and benzalkonium chloride, Phenol
or cresol 0.5%, chlorobutanol 0.5%.
Antioxidants :-
ex:- water soluble: sulfurous acid salts, ascorbic acid
isomers, thiol derivatives.
oil soluble: propyl gallate, butylated hydroxy
anisole,ascorbyl palmitate alpha tocopherol 9.

7. Buffers :
Added to maintain pH Results in stability of drug
Common buffers used in SVPs
pH Buffer system Conc %
8.2-10.2 Aceticacid-acetate 1-2
2.5-6.0 Citricacid-citrate 1-5
8.2-10.2 Phosphoricacid-
phosphate
0.8-2
8.2-10.2 Glutamicacid-
glutamate
1-2

8. Tonicity adjusters :
 Electrolytes:
ex:-Nacl
 Non elecrolytes:
ex:-Glucose,Mannitol,Glycerine
 isotonic:
Dextrose injection 5%&Nacl injection 0.9%
 Tonicity can be measurement by: osmometer
Other ingredients :
 Bulking agents – for freeze dried preparations(solids) ex
mannitol, lactose sucrose, dextran.
 Suspending agents – CMC, methyl cellulose gelatin, sorbitol.
 Emulsifying agents – lecithin, polysorbate 80
 Ophthalmic ointments bases – petrolatum.

9. MANUFACTURING

Planningand
schedulingfunction
management
-ingrediants
-material-packing
components
-labels
personal Documentationcontrol
Equipmentand
facilities
management
Preperationof facilities
Preperationofequipment
Online testing
Caping &outer sealing
inspection
quarantine
finishingLabeling &packing
Asepticsub
divisionalsealing
sterilizationmanufacturing
Ware house
Leak testing
Terminal
sterilization

10. Filteration
of solutes
Compounding
of product
Ingrediants,
Vehicle,
sterilizationcleaning
Processing
equipment
sterilizationCleaning
container
component
filling
sealing
packing
Product
storage

11. PARAMETERS TO BE TAKEN INTO CONCIDERATION IN
DESIGH OF PARENTRAL PRODUCTION FACILITY
Requires special
considerations
because of unique
pharmaceutical needs
Land availability,Lnd coast,
construction cost, taxes,
utility cost, labour
availability, labour cost and
so on
Pharmaceuticallyimportant
factors
Basic factors
Criteria for selection
1)Site selection:-

12. 2)area planning :-
it depends on
i) Type of production
ii) Environmental control needs
iii) Product characteristics
iv) Environmental control zone grouping
v) space requirements personnel flow
i)Type of production
a)Batch operations
b)continuous operations

13. Environmental control needs
For aseptic filling process
Sterilization and
depyrogenation of
containers before filling
,normally hot air ovenor
autoclave
An aseptic environment
with the attendant support
rooms
Inspection and
packing
Filling
requirements
Provision must
be made for
Non aseptic filling :-
Terminal sterilization Eliminates the sterilization prior to filling
An accumilation and segregation area is
required to accumulate the product for
transfer to next process step
Following to filling
and sealing

14. Product characteristics:-
a)liquids:- easiest product to handle
b)emulsions:-ease transfer problems
c)Suspensions:- require maintaining a homogeneous mixture
Environmental control zone grouping:-
Zones as per cGMP
Zone 7:-filling line
Zone 6:-filling area
Zone 5:-weighing mixing
&transfer area
Zone 4:-clean area
Zone 3:-general production
Zone 2:-ware house
Zone 1:- exterior

15. Zones as per Gazzete of india:-

16.  Environmental control :
Sources Control
People Total body covering in critical area and partial covering in non
critical area.
Adequate personal flow and restricted access to aseptic and
critical environment.
Minimum movement of personal.
Adequate operation procedure for personal
Barrier Adequate sterilization procedure
Protective laminar flow equipment
Barrier and separation between high risk and low risk
operation.
Adequate operation procedure to assure proper handling,
cleaning, and sterilization of machinery and equipment
Material Adequate material control and selection
Adequate sterilization and filtration procedure
Air Adequate air filtration system
Adequate monitoring of air cleanliness level.
Adequate air system validation procedure.

17. GRADES Maximumpermittednumberofparticles/m3equalorabove
At rest in operation
0.5μm 0.5μm 0.5μm 0.5μm
A 3,520 29 3,500 29
B 35,200 293 3,52,000 2,930
C 3,52,000 2930 35,20,000 29,300
D 35,20,000 29300 Not defined Not defined
Air Classification as per Schedule M
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

18.  TYPES OF OPERATIONS TO BE CARRIED OUT IN THE
VARIOUS GRADES FOR ASEPTIC PREPARATIONS
 Types of operations to be carried out in the various Grades
for terminally sterilized products
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
D Handling of components after washing
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

19.  PERSONEL FLOW:-
 Discontinuous and crowded flow patterns can decrease
production efficiency, increases the problem of maintaining a
clean environment
 Personnel flow path from zone to zone must be such that
access to higher level of cleanliness is only through
changing rooms ,gowning rooms, locker rooms, or other
areas as may be required to prepare the personnel for the
cleaner area
 Access should be restricted
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20. SPACE REQUIREMENTS:-

23. EQUIMENTS EMPLOYED:-
a) Manufacturing area: -
 1. Storage equipment for ampoules, vials bottles and closures.
 2. Washing and drying equipment.
 3. Dust proof storage cabinet
 4. Water still.
 5. Mixing and preparation tanks or other containers.
 6. Mixing equipment where necessary.
 7. Filtering equipment.
 8. Hot air sterilizer.
b) Aseptic filling and sealing rooms -
 9. Benches for filling and sealing.
 10. Bacteriological filters.
 11. Filling and sealing unit under laminar flow work station.

24.  c) General Room.
 12. Inspection table.
 13. Leak testing table.
 14. Labeling and packing benches.
 15. Storage of equipment including cold storage and
refrigerators if necessary
Sterile garmet
cabinet
Cold storage Hepa filters

25. Laminar flow
hoods
Vial labelling
machine
Vial inspection
machine
Vial fillinng
machine
Rubber stopper
washing machine
Vial washing
&sterilization
machine

26. Ampoule filling
machineAmpoule washing
machine
Fully automated
inspection system

27.  Quality control
1)Particulate matter test
2)Leakage test
3)Clarity test
4)Pyrogen test
5)Sterility test
6)Bacterial endotoxin test
 Particulate matter test:-
Methods of monitoring particulate matter contamination
 Visual method
 Coulter counter method
 Filtration method
 Light blockage method

28.  Visual method:
-Filled container are examined against strong illuminated screen
by holding neck &rotating it slowly or inverted it tokeep out the
foreign matter
 Coulter counter method:
-Itis used for detection of particles less than 0.1 micrometer in
diameter
 Filtration method:
-Material is collected on filter & evaluated under microscope.
 Light blockage method:
used for hydraulic oils

29.  2) LEAKAGE TEST:
performed in vaccum chamber, ampoule dipped in 1%methylene
blue dye solution
 3) CLARITY TEST:
container held by neck against strong illuminated black and white
screen done by visual inspection
 4)sterility test:-
it is aprocedure carried out todetect and conform absence of
any viableform of microbes in or pharmacopeia preperation or
product
methods:-
1)membrane filtration method
2)direct inoculation method

30.  Membrane filtration method
all steps of this procedure are performed aseptically in a
class 100 laminar flow hood

31.  Direct inoculation method:-
 volume of produst is NMT10% volume of medium
 Suitable for aqueous solutions ,oily liquids , ointments
and creams
 Direct inoculation of culture medium suitable quantityof
preperation to be examined is transferred directly into
appropriate culture medium &incubate for NLT 14days
5) PYROGEN TEST
Rabbit test(old)
Lal test(new)
1)Rabbit test:-
The rabbit pyrogen test requires the injection of a small
amount of batched test material into a rabbit’s blood
stream, and monitoring for temperature increases

32. LAL TEST:-
There are three basic LAL test methodologies:
 gel-clot
 Turbidimetric
 Chromogenic
Limulus amebocyte lysate (lal) is an aqueous extract of blood
cells (amoebocytes) from the horseshoe crab, limulus
polyphemus. Lal reacts with
bacterial endotoxin or lipopolysaccharide (lps), which is a
membrane component of gram negative bacteria.
To test a sample for endotoxins it is mixed with lysate and water;
endotoxins are present if coagulation occurs