By

Divya Thakur

Mpharmacy

Kaktiya university

INTRODUCTION:-

Para: outside

Enteron: intestine (i.e. beside the intestine)

Definition:-

According to the USP 24/ NF 19 “As those preparations intendedfor injection through the skin or other external boundary tissue,rather than through the alimentary canal”

SMALL VOLUME PARENTRALS:-

Defination:-According to USP “ an injection that is packaged in containerslabelled as containing 100 ml or lessAll the sterile products packaged in vials, ampoules, cartridges,syringes, bottles or any other container that is 100ml or less fallunder the class of SVP

CLASSIFICATION OF SVP:-

1) Single dose ampoules(glass/plastic )

2) Multiple dose vials

3) Prefilled syringes

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

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

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 hydroxyanisole,ascorbyl palmitate alpha tocopherol 9.

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

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.

MANUFACTURING

Planning and

scheduling function

management

-ingrediants

-material -packing

components

-labels

personal Documentation controlEquipment and

facilities

management

Preperation of facilities

Preperation of equipment

Online testing

Caping &outer sealing

inspection

quarantine

finishingLabeling &packing

Aseptic sub

divisional sealingsterilizationmanufacturing

Ware house

Leak testing

Terminal

sterilization

Filteration

of solutes

Compounding

of product

Ingrediants,

Vehicle,

sterilizationcleaningProcessing

equipment

sterilizationCleaning container

component

filling

sealing

packing

Product

storage

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

Pharmaceutically important

factorsBasic factors

Criteria for selection

1)Site selection:-

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

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

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 cGMPZone 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

Zones as per Gazzete of india:-

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.

GRADES Maximum permitted number of particles/m3 equal or above

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

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

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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SPACE REQUIREMENTS:-

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.

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

cabinetCold storage Hepa filters

Laminar flow

hoods

Vial labelling

machine

Vial inspection

machineVial fillinng

machine

Rubber stopper

washing machine

Vial washing

&sterilization

machine

Ampoule filling

machineAmpoule washing

machine

Fully automated

inspection system

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

Visual method:

-Filled container are examined against strong illuminated screen

by holding neck & rotating it slowly or inverted it to keep out the

foreign matter

Coulter counter method:

-It is 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

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 a procedure carried out to detect and conform absence of

any viableform of microbes in or pharmacopeia preperation or

product

methods:-

1)membrane filtration method

2)direct inoculation method

Membrane filtration method

all steps of this procedure are performed aseptically in a

class 100 laminar flow hood

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 quantityofpreperation 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

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