COLLEGE OF PHARMACY

Dr. Mohammad Javed Ansari Ph.D Contact info: mj.ansari@psau.edu.sa

STERILE PRODUCTS PHT 434

LECTURE OUTLINES • Manufacturing of Parenterals –considerations

• Building and Facility,

• Personnel,

• Garments,

• Change room, Clean rooms,

• Processes like cleaning, compounding, filling sealing and sterilization.

• Parenterals: Quality control test • Leaker test

• Clarity

• Pyrogen test

• Sterility

Building and Facility:

• The parenteral manufacturing areas should be clearly separated into several support, preparation, testing areas such as-

• Procurement / warehousing;

• Compounding /formulation;

• Materials preparation are (containers, closures, equipment);

• Filtration/Sterile receiving;

• Aseptic filling; stoppering;

• Lyophilization (required for dry powders);

• Packaging / labeling,

• Quarantine areas

• Quality assurance area.

• Walls, floors and ceiling-impervious, non-shedding, non-flaking and non-cracking.

• Doors shall open towards the higher-pressure area so that they close automatically due to air pressure.

• Distillation / reverse osmosis plants for production of WFI must be available with proper storage provisions.

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Manufacturing of PARENTERALS -considerations

• Personnel: Must be highly competent, healthy, neat & organized.

• Garments: Designed to confine the contaminants discharged from the body of the operator, thereby preventing their entry into the production environment.

• Sterile garments made of non-shedding and tight weave material, single piece with fastenings at cuffs, neck and at legs to ensure close fit. Trouser legs shall be tucked inside the cover boots.

• Design-include a hood (head-cover) or a separate hood which can be tucked inside the over-all.

• Gloves-made of latex or other suitable plastic materials & long enough to cover wrists completely and allow the over-all cuff to be tucked in.

• Personnel Movement: 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.

• Discontinuous and crowded flow patterns can decrease production efficiency, increase security problems, and increase the problems of maintaining a clean environment.

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Manufacturing of PARENTERALS -considerations

• 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.

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Manufacturing of PARENTERALS--considerations

• 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.

• The air entering a cleanroom from outside is filtered to exclude dust, and the air

inside is constantly recirculated through high-efficiency particulate air (HEPA)

and/or ultra-low penetration air (ULPA) filters to remove internally generated

contaminants.

• HEPA filters remove all airborne particles of size 0.3 or larger with an efficiency

of 99.99%. (air flow 90 ± 20 ft/m3, 15-20 air changes per hour).

• The velocity of the Maintaining higher air pressure(+ve pressure) within the

critical area to minimize infiltration of airborne contaminants from outside.

• Adjacent rooms of different grades should have a pressure differential of 10 - 15

Pascals.

• Staff enter and leave through airlocks (sometimes including an air shower stage),

and wear protective clothing such as hoods, face masks, gloves, boots and

coveralls.

• Cleanrooms are not sterile (i.e., free of uncontrolled microbes); only airborne

particles are controlled. Particle levels are usually tested using a particle

counter.

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Manufacturing of PARENTERALS-considerations

• US Federal Standard 209E:

• First published in 1963 dealt with cleanroom classification and monitoring.

• Large numbers like "class 100" or "class 1000" denote the number of particles of size 0.5 µm or larger permitted per cubic foot of air.

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Manufacturing of PARENTERALS-clean rooms

• European nations declared their own standards.

• GMP EU, clean rooms are classified as A, B, C & D where A contains not more than 3500 particles of 0.5µ per cubic meter hence equivalent to class 100 as 1 m³ is approximately 35 ft³).

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Manufacturing of PARENTERALS-clean rooms

• International Standard Organization (ISO) adopted a new standard of clean rooms in 1999 following the cancellation of FED-STD-209E.

• ISO14644-1, introduced 3 additional classes (ISO 1, ISO 2 and ISO 9).

• ISO clean room numbers refer to the decimal logarithm of the number of particles 0.1 µm or larger permitted per cubic meter of air.

• For example, an ISO class 2 cleanroom has at most 102 = 100 particles per cubic meter. ( as log 2 = 100)

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Manufacturing of PARENTERALS-clean rooms

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Manufacturing of PARENTERALS-clean rooms

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Manufacturing of PARENTERALS- processing zones

A

B

C

D

Facilities are divided into 4 grades of air quality:

Grade A:

Exposed Product

Grade B :

Adjacent to Product (Operators are fully gowned)

Grade C:

Non- Sterile Production area / Formulation

–Grade D:

General Corridors

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Manufacturing of PARENTERALS overview

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Manufacturing of PARENTERALS-overview

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Manufacturing of PARENTERALS -overview

START END

Performed within Grade “A” areas

To Packaging

Vial Trayof

f

Vial Inspecti

on

Vial Cappi

ng

Tank CIP

Tank SIP

Formulation/

Filtration

Incoming

Raw Materi

als

From Dispensing

Incoming

Stoppers

Stopper Steriliza

tion

From Component Warehouse

Incoming

Vials

Vial Wash

Vial Depyrogenat

ion

Vial Filling, Stoppering

• Raw materials

– Received → tested → approved → processed → tested

• Vehicle

– WFI must be stored in close system, filtered to remove M. O. dust etc., held at 80oC, should be used within 24 hrs

– Distribution by pipes system constructed of stainless steel, always circulating, no head space, means of cleaning & sanitation from time to time (clean steam, hot alkali).

• Cleaning / sterilizing equipment & containers (v. clean).

• Cleaning / sterilizing rubber & plastic components.

• Note: All components must be pyrogen free, as it is very difficult to remove if detected at later stage.

• Autoclaving will not destroy pyrogen, and it will filters also.

• Dry heat (180°C for 4 hours / 250°C for 45 min/ 650°C for 1 min). Plastics and rubber components cant be depyrogenated.

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Manufacturing of PARENTERALS-processes

• Compounding – Solution, Suspension, Emulsion, Dry powder – Lyophilized products, Frozen solutions

• Filling in aseptic area & inert environment (N2, CO2).

• Sealing in aseptic area & inert environment (N2, CO2).

• Sterilization

• Quality control testing

• Labeling and packaging

• Warehousing

• All process must be carried out with great care and as rapidly as possible, to minimize the risk of microbial contamination. Preferably, no more product should be prepared than can be processed completely within one working day, including sterilization.

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Manufacturing of PARENTERALS-processes

• Filling in aseptic area & inert environment (N2, CO2).

• Filling of liquids (ampoules)

– Equipment feature: repetitive forcing a measured volume of liquid through orifice of delivery tube to be inserted into the container

– Must freely enter the container & deep to let the air escape

• Filling of solids (vials)

• Machine: Adjustable cavity in the rim filling wheel is filled by vacuum as it passes under the hopper then vacuum is removed when & inverted in the container.

• Difficult to fill accurately as in liquids ; as powder flow irregular & slow (fine powder)

• If free flowing, machine can be used to deliver weight.

• Concerns: stratification of particles, electrostatic charge, air pockets, clumping. So uniform particle size and charge dissipation may be needed.

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Manufacturing of PARENTERALS- filling process

Sealing in aseptic area & inert environment (N2, CO2). • Sealing of ampoules: • By melting a portion of the neck • Bead seal (tip seal): • Bead of molten glass to close the opening (fast) • Pull seal: • Pulling tip away to form a small twisted capillary prior

to being sealed (cleaner but slow). • Concerns: • Distortion of container/seal. • Excessive heating cause air expansion & bubble

formation. • Fracture of the neck. • Wet glass increase chances of bubble formation

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Manufacturing of PARENTERALS-sealing process

Sealing in aseptic area & inert environment (N2, CO2).

Sealing of bottles (vials)

• Rubber closure must fit the opening (snugy but not very snugy):by hand using forceps

• By machine: surface of rubber halogenated (coated with silica to reduce friction) slide from a chute where it is positioned over the container then by plunger (pulling device) insertion take place.

• Aluminum caps are placed at the top of rubber to hold closure in place, sign as temper proof

• Aluminum caps have central hole that can be torn away.

• After filling & sealing sterilization of the product is carried out depending on the properties of the product.

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Manufacturing of PARENTERALS-sealing process

Terminally sterilized parenterals:

• In most cases, the product, container, and closure have low bio-burden, but they are not sterile.

• The product in its final container is then subjected to a sterilization process such as heat or irradiation.

Parenteral Sterilization by Filtration: • Previously sterilized container are taken. Then filters having nominal pore

size of 0.22 μm or less are used for filtration • Remove bacteria and moulds but Not viruses & Mycoplasmas.

Aseptic Preparation : • Drug product, container, and closure are first subjected to sterilization

methods separately, as appropriate, and then brought together. • Because there is no process to sterilize the product in its final container, it

is critical that containers be filled and sealed in an extremely high-quality environment.

• Note:- In area occupied by personal, the air must be exchanged with the frequent intervals. Fresh outside or recycled air must be first filtered to remove particulate matter and than HEPA filters are used to get CLASS-100 air systems.

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Manufacturing of PARENTERALS-sterilization processes

– Incoming raw material

• All, according to specification

– During processing

• Volume filled

• Time, pressure & temperature of sterilization

• Labels

– Finished product

• Leaker test

• Clarity

• Pyrogen test

• Sterility

• Others pharmacopeia tests: identity, assay, solid dissolution …etc.

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PARENTERALS: Quality control

Leaker test : 1. visual inspection: large volume parenterals

2. bubble test : Differential pressure is applied on the containers submerged in liquids.

3. dye test: test containers are immersed in a dye bath under vacuum.

Clarity: visually or by microscopic methods

Pyrogen test – In Vivo pyrogen test (Rabbit Test): Preliminary SHAM test

(injection of saline solution to screen animals, followed by injection of test sample: observe rise in rectal temperature.

– In Vitro pyrogen test(Limulus Amebocyte Lysate Test /bacterial endotoxin test (BET): Limulus Amebocyte Lysate enzyme agglomerates and gelled in presence of pyrogen.

Sterility test: filtering / culturing and observing growth

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PARENTERALS: Quality control

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