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LAYOUT OF PARENTRAL FACILITIES

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INTRODUCTION:-

Parenterals :-

Are Sterile, Pyrogen free preparations injected through

skin or mucous membrane into internal body compartment.

Parentral drugs are administered directly into the vein,

muscles, or under the skin or more specialised tissues such

as the spinal cord.

Thus they should be free from microbial contamination

and should have high purity.

Small Volume Parentral: A parentral prepration sealed in container of 100ml or less volume.Large Volume Parentral: A liquid intended for infusion sealed in container of greater than 100ml volume.

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TYPICAL LAYOUT OF PARENTERAL PLANT:

MAINTENANCE AND UTILITIES

SHIPPING WAREHOUSE

PRODUCTION

DISPENSING

RECEIVINGWAREHOUSE

MATERIAL UNPACK & PREPARATION

GOWNING AREA

QUALITY CONTROL

ADMINISTRATION

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SPACE REQUIREMENT:-

Function

Area Square meter

Percentage

Production 11,094 45.1

Warehouse 7,606 30.9

Utility 1,016 4.1

Quality Control 1,716 7.0

Administration 1,018 4.1

Maintenance 1,104 4.5

Employee services 1,104 4.1

Security 39 0.9

Total 24,607 100

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GENERAL

Sterile products, being very critical and sensitive in nature, a very high degree of precautions, prevention and preparations are needed to ensure aseptic conditions in all areas. Strict compliance is maintained under standards to maintain hygiene.

BUILDING AND CIVIL WORKS

Proper foundation is maintained to avoid any cracks. The manufacturing area is separated into different areas like

Washing area. Component preparation area. Storage area. Preparation area – Blending Manufacturing Area. Non aseptic Area etc.

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General points to be in consideration for ASEPTIC

Areas:

→ Walls, floors and ceiling-impervious, non-shedding,

non-flaking and non-cracking.

→ Flooring-unbroken, provided with a cove both at the

junction between the wall and the floor & wall and

ceiling. Epoxy should done in aseptic area, Walls-

shall be flat.

→ Light-fittings and air-grills-shall flush with the walls

and not hanging from ceiling.

→ Doors & Windows-made of non-shedding material

preferably Aluminium or Steel material.

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CONT...

→ Doors shall open towards the higher-pressure area

so that they close automatically due to air pressure.

→ The furniture-smooth, washable and made of

stainless steel or any other appropriate material

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ENVIRONMENTAL MONITORING:• All environmental parameters shall be verified and established at the time of

installation and there after monitored at periodic intervals and recorded. The recommended frequencies of periodic monitoring shall be as follows :-

A Particulate monitoring in air MonthlyDaily

B HEPA filter integrity testing Yearly

C Air change rate Monthly

D Temperature and Humidity Daily

E Air pressure differentials Daily

F Microbiological monitoring Daily

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CONT...

After major engineering modification to the HVAC

system of any area, all monitoring shall be re-performed

before production commences.

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WAREHOUSE

ZONE 2

GENERAL PRODUCTION

ZONE 3

CLEAN AREA

ZONE 4

WEIGHING,MIXING,TRANSFER

ZONE 5

FILLING AREA

ZONE 6

FILLING LINE

ZONE 7

EXTERIOR

ZONE 1Fig -Environmental Control Zones

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ENVIRONMENT CONTROL NEEDS:-

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GARMENTS:

• Only clean, sterilized and protective

garments shall be used at each work

session.

• The garments shall be made of

non-shedding and tight weave

material.

• Head cover and gloves should be

used once only.

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CONT....

Footwear should be suitably plastic or

rubber material and cleaned with

bactericide.

Safety goggles and numbered glass

should be sanitized.

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SANITATION:

• This includes written procedures ,performed by trained employee.

• Different Sanitizing agents are used.

• Formaldehyde may be used normally for fumigation of aseptic area.

• Cleaning of sterile processing facilities shall be undertaken with air

suction devices or with non-linting sponges or clothes.

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EQUIPMENT:

The special equipment required for manufacturing sterile products includes –

• component washing machines,

• Steam sterilizers,

• Dry heat sterilizers,

• Membrane filter assemblies,

• Manufacturing vessels, blenders,

• Liquid filling machines,

• Powder filling machines,

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CONT.....

Sealing and labeling machines,

Vacuum testing chambers,

Inspection machines,

Lyophilisers,

Pressure vessels etc

may be provided with SOP, depending upon the type and

volume of activity.

The construction material used - stainless steel 316 or Boro-silicate

glass (if glass containers) and the tubing shall be capable of being

washed and autoclaved.

Installation qualification should be performed.

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WATER AND STEAM SYSTEMS :

TYPE OF WATER

MICROBIOLOGICAL SPECIFICATIONS

USES STORE

Purified Water 100cfu/100ml Hand washing in changing room,

washing containers, closures before

washing with suitable filtered water.

Stainless steel tank / plastic

Water for injection

10cfu/100ml Bulk liquid parenterals Steam jacketed stainless steel tanks

of suitable size and the tanks shall have

hydrophobic bacterial retention with 0.2 µ

ventfilters.

Water for non-injectables

10 cfu per 100ml and absence of

Pseudomonas aeruginosa and

Enterobacter coli

For eye drops same

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DESIGN CONCEPTS:-

CHANGE ROOM

Entrance to a change room is normally through

vestibules whose doors are electrically

interlocked so that both can not open

simultaneously,

Thus maintaining the necessary air pressure

differential to prevent the entry of airborne

contamination.

Upon entry in the change room, wash sinks are

provided for scrubbing hands and forearms.

Automatic or foot operated controls for water

and soap eliminate hand contact with

contaminated surfaces.

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Hand Wash Station

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CONT...

Next, hands are dried by hot air blowers.

Commercial hand driers may create

undesired airflow patterns. Special filtered

driers are available to minimize the

creation of particulate contamination.

After the hands are dry, garments are

taken from dispensers and donned

while moving across a dressing bench.

As a final gowning step, aseptic gloves

are put on and sanitized.

Hand Blower

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CHANGE ROOM

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CLEAN ROOM:-

An area with defined environmental control of

particulate and microbial contamination,

constructed and used in such a way as to reduce the

introduction, generation and retention of contaminants

within the area. QUALITIES OF CLEAN ROOM :-

•The room should undergo 15-20 air changes per hour.

• HEPA filters are to clean the air entering the room.

•HEPA filters remove all airborne particles of size 0.3 or

larger with an efficiency of 99.97%.

• Maintaining higher air pressure(+ve pressure) within the

critical area to minimize infiltration of airborne

contaminants from outside.

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CONT... Care should be taken to ensure that air flows do not

distribute particles from a particle-generating person,

operation or equipment to a zone of higher product

risk.

A warning system should be provided to indicate

failure in the air supply.

Counters in the clean room should be made of

stainless steel or other non-porous, easily cleaned

material.

Walls and floors should be free from cracks or

crevices and have rounded corners. If the walls or

floors are to be painted, epoxy paint is used.

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CONT...

The air flow should move with uniform velocity along

parallel lines.

Providing temp. & humidity controls appropriate to the

product being manufactured.

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FEDERAL STANDARD:-

Clean

Room Class

Class Limits "not to exceed" particles per cu ft for particle size shown

0.1μm 0.2μm 0.3μm 0.5μm 5 μm

1 35.0 7.50 3.0 1.0 --

10 350 75.0 30.0 10.0 --

100 -- 750 300 100 --

1000 -- -- -- 1000 7.0

10000 -- -- -- 10000 70.0

100000 -- -- -- 100000 700

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HVAC SYSTEM:

1. Temprature:This has to be product specific but normally in critical area(A,

B,&C) it may be 27°c ± 2°c. However depending upon specific requirement it

may be less.

2. Relative Humidity: Same as temperature, this is product specific but

gengerally a relative humidity of 45% ± 5% is recommended.

3. Air Velocity: In case of HEPA filters the air velocity normally required in

between 80 and 120 feet per minute.

4. Differential Pressure &Room to Room Air Balancing: Normally

pressure between adjecent room is recommended to be 15 pascals .

(it may Vary in certain cases but less than 10pascals is not acceptable)

Higher differential pressure may result in door opening & closing problems.

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CONT...

5. HEPA Filter: HEPA Filter composed of mat of randomly arranged

fibers (poly vinylidene fluoride-PVDF), integrity of HEPA filter is very

important, hence it may be tested regularly by DOP testing.

6.Laminar Air Flow Unit: All class-A installation should have L.A.F unit

working. They can be either vertical or horizontal.

Laminar Flow Hoods:

These are clean air work benches are specially designed to

ensure the aseptic preparation of sterile products. Laminar air

flow hoods are generally used in conjunction with clean rooms.

For laminar air flow work station the air flow rates shall be 0.3

meter per second (vertical) and 0.45 (horizontal)

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CONT...

Introduction of personnel, equipment, and material into

the work area provides sources of particulate matter

which may contaminate the product.

Very small particles are not heavy enough to settle due

only to the force of gravity, but instead are carried and

directed by air currents and if there is turbulent air,

particles may be driven into product.

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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

D Handling of components after washing

CRITICAL AREAS GRADES

Aseptic feeling area B

Sterilized component unloading area C

Change room D

AIR HANDLING SYSTEM (AHU):

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PERSONNEL MOVEMENT :-

The movement of personnel should be planned during

the design of individual plant areas.

Discontinuous and crowded flow patterns can

decrease production efficiency, increase security

problems, and increase the problems 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

change rooms, gowning rooms, locker rooms, or other

areas as may be required to prepare the personnel for the

cleaner area.

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FLOW OF MATERIAL THROUGH PRODUCTION DEPARTMENT:-

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OVERVIEW OF MANUFACTURING PROCESS OF PARENTRALS:-

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Documentation: The manufacturing records relating to manufacture of sterile

products shall indicate the following details:-

(1) Serial number of the Batch Manufacturing Record.

(2) Name of the product

(3) Reference to Master Formula Record.

(4) Batch/Lot number

(5) Batch/Lot size.

(6) Date of commencement of manufacture and date of completion of

manufacture.

(7) Date of manufacture and assigned date of expiry.

(8) Date of each step in manufacturing.

(9) Names of all ingredients with the grade given by the quality control department.

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(10) Quality of all ingredients.

(11) Control reference numbers for all ingredients.

(12) Time and duration of blending, mixing, etc. whenever applicable.

(13) pH of solution whenever applicable.

(14) Filter integrity testing records

(15) Temperature and humidity records whenever applicable

(16) Records of plate-counts whenever applicable.

(17) Results of pyrogen and/or bacterial endotoxin & toxicity.

(18) Results of weight or volume of drug filled in containers.

(19) Bulk sterility in case of aseptically filled products.

(20) Leak test records.

Cont…

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Cont…

(24) Total number of containers filled.

(25) Total numbers of containers rejected at each stage

(26) Theoretical yield, permissible yield, actual yield and variation thereof.

(27) Clarification for variation in yield beyond permissible yield.

(28) Reference numbers of relevant analytical reports.

(29) Details of reprocessing, if any.

(21) Inspection records.(22) Sterilization records including autoclave leakage test records, load details,date, duration, temperature, pressure, etc.(23) Container washing records.

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CONT …

(30) Name of all operators carrying out different activities.

(31) Environmental monitoring records.

(32) Specimens of printed packaging materials.

(33) Records of destruction of rejected containers printed packaging and testing.

(34) Signature of competent technical staff responsible for manufacture and testing.

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SOME IMPORTANT PARENTRAL PREPRATIONS:-

IV Admixture IV Fluids Electrolyte Prepration Dialysate Irrigating Solutions

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REFERENCES:

1. Pharmaceutical dosage forms (Parenteral Preparation) by Kenneth Avis, Leon Lachman, Vol-2 ,page no-235-263.

2. Good manufacturing practices for pharmaceuticals ,6th edition, Joseph D.Nally, page no-37-113

3. www.GMP.online.coms

4. B. VenkateReddy, B.Rasmitha Reddy, K.Navaneetha, V.Sampath Kumar, A REVIEW ON PARENTERAL,swara PRODUCTION TECHNOLOGY, volume-3, Sree Datta Institute of Pharmacy.