MA N U F A C T U R I N

G
L A Y OUT
E Q U I P ME N T S
 Introduction
 Sterile - Absolute term as the state of freedom from all viable
organism.

Type of sterile preparations

 OPTHALMIC
 PARENTERAL
 IRRIGATING PREPARATION
 DIAGNOSTIC AGENTS
 ALLERGIC EXTRACTS
 SURGICALS
 RADIO PHARMACEUTICALS
Parenteral : The dosage form for conveying a drug
by means of injection through the skin or mucous
membranes.

Parenteral drugs are administered directly into the

veins, muscles or under the skin, or more
specialized tissues such as the spinal cord.

Circumvented the highly efficient first line body

defense that is skin and mucus membrane.

Thus they should be free from microbial

contamination and should have high purity.
Aseptic- “without sepsis” Used to designate a practical level of sterility.
Parenteral

Sterile

Alert level- An established microbial or airborne particle level giving

early warning of potential drift from normal operating conditions.

Action Level- An established microbial or airborne particle level that,

when exceeded, should trigger appropriate investigation and corrective
action based on the investigation.

HVAC- Heating, ventilation, and air conditioning.

Laminar flow of air- Airflow moves in a single direction and in parallel

layers at constant velocity.
ULPA filter : Ultra-low penetration air filter with minimum 0.3
µm particle retaining efficiency of 99.999 percent.

LVP : A liquid intended for infusion and hermetically sealed in a

container of greater than 100 ml volume.

SVP : A parenteral preparation hermetically sealed in a container

of 100 ml or less volume.

Pyrogen : The fever producing lipid associated with polysaccharide

or polypeptide of microbial origin.

Sterilization : A process designed to completely eliminate or

destroy all living microorganism.

Process validation:
SAL :
A. IV Admixtures consist of one or more sterile drug
products added to an IV fluid.
Used for
• Drugs intended for continuous infusion
• For drugs that may cause irritation or toxicity when
given by direct IV injection.

B. IV fluids
These fluids have multiple uses,
• Vehicles in IV admixtures
• Provide means for reconstituting sterile powders
• Serve as the basis for correcting body fluids and
electrolyte disturbances
• For administering parenteral nutrition
 Dextrose : Generally, a solution of 5% dextrose in water
• pH of 5% dextrose ranges from 3.5-6.5. Instability may result if it
is combined with an acid sensitive drug.
• In higher conc. (e.g. 10% solution in water), dextrose provides a
source of carbohydrate in parenteral nutrition solutions.
• Should used cautiously in patients with diabetes mellitus.

Sodium chloride : usually given as 0.9% solution called as

normal saline solution.
 Sterile sodium chloride for injection:
• Used as vehicle in IV admixtures and fluid for electrolyte
replacement.
 Bacteriostatic sodium chloride for injection:
• It contains an agent that inhibits bacterial growth (e.g. Benzyl
alcohol, Propyl paraben. Methyl papaben), allowing its use in multiple
dose preparation.
 Water
• Used for reconstitution and for dilution of IV solutions such as
dextrose and sodium chloride.
• Water suitable for parenteral preparations include sterile water
for injection and bacteriostatic water for injection.

Ringer solutions
• Used for fluid and electrolyte replacement.
• Commonly administered to post surgical patients.
• It contains sodium lactate, sodium chloride, potassium
chloride, and calcium chloride.
C. Electrolyte preparation
• Ions present in both intracellular and extracellular fluid.
• Surgical and medical patients who can not take food by
mouth or who need nutritional supplementation require the
addition of electrolytes in hydrating solutions or parenteral
nutrition solutions.

D. Dialysate
• Used in paients with disorder as renal failure, poisoining, and
electrolyte disturbances.
• In peritoneal dialysis, a hypertonic dialysis is infused directly
into peritoneal cavity via a surgically implanted catheter. It
contains Dextrose and electrolyte, which removes the
harmful substances by osmosis and diffusion.
E. Irrigating solutions
• Not intended for infusion into the venous system.
 Topical administration
• Used in irrigating wounds, moistening dressings, and
cleaning surgical instruments.

 Infusion of irrigating solutions

• Surgeons performing urological procedure often use
irrigating solution to perfuse tissues in order to
maintain the integrity of surgical field, remove blood,
and provide a clear field of view.
 Parenteral preparation
Intravenous, Intraspinal, Intramuscular, Subcutaneous, and
Intradermal.
No absorption
is necessary
Intravascular route complete drug availability
occurs immediately
 For all other routes, at least a blood vessel wall, and usually one or
more tissue cell walls, must be permeated before the drug can enter the
circulation.
 Most often this occurs by passive diffusion and is most favourable when
the drug has both lipophilic and hydrophilic properties, with the former
being predominant.
 So with nonvascular injection, absorption is also affected by such factors
o Size and number of blood vessels supplying the tissue,

o Physical & chemical properties of drug

o Characteristic of the dosage form as whether it is a

solution, suspension or emulsion
o Nature of vehicle & its pH
and package components
 •TYPES OF PROCESSING
Terminal sterilization
• The product in its final container is subjected to a sterilization
process such as heat or irradiation.
• In most cases, the product, container, and closure have low bio-
burden, but they are not sterile.

Aseptic process
• The 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.
•Types of Operations for Terminally Sterilized Products

Types of Operations for Terminally Sterilized

Grade
Products
A Filling of products, when unusually at risk
Placement of filling and sealing machines, preparation of
C
solutions, when unusually at risk.
moulding, blowing (pre-forming) operations of plastic containers,
D
Preparation of solutions and components for subsequent filling

Note

Grade A and B correspond to with class 100, M 3.5, ISO 5

Grade C correspond to with class 10000, M 5.5, ISO 7
Grade D correspond to with class 100000, M 6.5, ISO 8
Types of Operations for Aseptic preparations

Grade Types of Opeartions 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

Note
Grade A and B correspond to with class 100, M 3.5, ISO 5
Grade C correspond to with class 10000, M 5.5, ISO 7
Grade D correspond to with class 100000, M 6.5, ISO 8
 Parameters to be taken into consideration in the Design
of a Parenteral Production Facility:
• Environmental factors such as site selection, area
planning, space planning, design and construction
features, traffic flow of personnel and supplies, and
service features.
1. Site selection
Criteria for site selection

Basic factors Pharmaceutically important factors

land availability, land cost,

Requires special consideration
construction cost, taxes,
because of unique
utility costs, labor availability,
pharmaceutical needs.
labor cost and so on.
• Basic plant requirement includes an adequate supply of raw
materials, transportation availability, market proximity,
adequate utilities, and labor supply.
• Minimizing shipping may aid in minimizing potential
contamination, material degradation due to ageing or lack of
environmental control (e.g. temp. & humidity).

2. Area planning it depends on

a) Type of production
Batch operations -Suited to small production volume &
minimum financial investment is necessary.

Advantages
• Product quality, consistency, and homogeneity are relatively
easily controlled.
• Production documentation is easy.

Disadvantages
• Economically undesirable because it is labor intensive and
does not exploit the economies of volume.
 Continuous operations: It is suited to very high volume
production requirements.
• It requires more space and more complex equipments.

Advantages
• Minimizes shortcoming of batch operations; labor, production
time, and environmental exposure of the product.
• Since the intermediate material handling steps are eliminated,
the potential for product contamination during those steps is no
longer exists.

Disadvantages
• Product quality assurance is difficult.

• It is very difficult to document the ingredients or process

cyclefor a product produced in a continuous process.
b)Container size
SVPs and LVPs obviously requires different space considerations.
All the production equipment has container size limitations- large
container requires large equipments and more space.

c) Environment control needs

Sterilization and
Depyrogenation of
For aseptic filling process
containers before filling,
Provision must normally hot air oven
be made for or autoclave.

Filling requires

An aseptic environment with

Inspection and Packaging the attendant support rooms
• Non aseptic filling, followed by terminal sterilization, normally
requires less rigid environmental control.

Eliminates the
Terminal sterilization
sterilization prior
to filling

Following to
filling and sealing

An accumulation and segregation

area is required to accumulate
the product for transfer to the
next process step
d) Product characteristics
Liquids are probably the easiest product to handle.

Emulsion may require compounding areas close to filling lines to

ease transfer problems. Pumping systems will be very critical.

Suspension will require a means of maintaining a homogenous

mixture prior to filling.
To minimize the time the suspension resides in
piping, reservoir, and pump system, filling rate should be kept
high and the distance from compounding to filling should be
minimized.
e) Environmental control zone groupings
Zones as per cGMP
Zone 7:- Filling line
Zone 6:- Filling area
Zone 5:- Weighing, mixing &
transfer area. Zone 7
7
Zone 4:- Clean area
Zone 3:-General production
Zone 2:- Warehouse
Zone 1:- Exterior 1

Zones as per Gazette of India

White zone:-Final step ( filling of
parenteral)
WHITE
Grey zone:-weighing, Dissolution &
BLACK
filtration.
GRAY
Black zone:-Storage, Worst area from
contamination view point
f) Space requirements
FUNCTION Area
Square meter Percentage
Production 11,094 45.1
Warehouse 7,606 30.9
Administration 1,018 4.1
Utility 1,716 4.1
Quality control 1,716 7.0
Maintenance 1,014 4.5
Employee services 1,014 4.1

Security 39 0.9
Total 24,607 100.0
g) Personnel flow
Design
• Discontinuous and crowded flow patterns can
decrease production efficiency, increase 1 3
security problems, and increase the problems of
maintaining a clean environment.
4 2
• 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
√ Design
to prepare the personnel for the cleaner area.
• Access should be restricted. 1 2

3
4
• CHANGE ROOM
 FILLING AREA
The product & sterilized components are exposed to room
environment.
Therefore these areas are specially constructed, filtered, and
maintained to prevent environmental contamination.

Clean room must meet several requirements:

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.
Adjacent rooms of different grades should have a pressure
differential of 10 - 15 Pascals.
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.
The air flow should move with uniform velocity along parallel lines. The
velocity of the air flow is 90 20 ft/m3.
Providing temp. & humidity controls appropriate to the product being
manufactured.
 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.
 PERSONNEL & GOWNING
No. of workers should kept to a minimum.
Training of personal
Personal hygiene:-All employees should be in good
health, Subjected to Physical examination, Understood their
responsibilities to report own illness like cold, a sore throat, or
other infection.

Clothing
Uniform is made up of Dacron and Span polyethylene.
Hats & masks are sometimes made of special parchment paper.
Foot wears plastic and rubber material.
1. Air Classification as per Schedule M

handling system
Maximum permitted number of particles/m3 equal or above
Grade
•Air
at rest in operation
0.5µm 5.0µm 0.5µm 5.0µm
A
B
C
D not defined not defined

2. Air Classifications by USFDA guideline on Sterile Drug Products

Clean Area <0.5 µm <0.5 µm Microbiological Limit
Classification Particles/ft3 Particles/mt3 cfu/ft3 cfu/m3
3. Air Classifications as per WHO 2002
Maximum Number Permitted / M3
Grade Particles
Microorganisms
0.5µm 5.0µm
A (LAF)
B
C
D

4. As per ISO
Grade ISO Class Particle/cum Class(SI)
A 5 100 3.5 M 3.5(filling)
B 6 1000 35 M 4.5
C 7 10000 350 M5.5 (preparation)
D 8 100000 3500 M 6.5
5. As per British Pharmacopoeial Codex

Class Maximum microorganism

1(A)HEPA filter every <1
where
1(B)only at station 5
2 100
3 500
•QUALITATIVE LAYOUT OF PARENTERAL
MANUFACTURING (circular flow)
•QUALITATIVE LAYOUT OF PARENTERAL MANUFACTURING
(parallel flow)
 Layout for Aseptic Production

Pdt. Material
Exit Entry
Soln
Unidirectional Prepn
Clean Zone Area

Aseptic
Filling zone
Clean
Changing
Entry Room
Oven Equipment &
Component
Auto Prepn
clave Area
Aseptic
Receiving
Area Comp.
Hatch Entry
 Layout for Terminal Sterilization
Terminal Solution
Prepn Material
Sterilization Entry
Unidirectional
lamimar Area
flow
Clean Zone

Clean Filling Area

Clean
Changing
area

Equipment &
Component prepn
Area

Comp.
Entry
•EQUIPMENTS
 •The following equipments as pre Schedule-M are recommended:

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.
• The tanks or containers shall be made of either glass or such
materials as will not react with the liquid.
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 Garment Cabinet
Stainless steel
Ensure a clean storage
space by making use of
UV disinfectant and
heating through IR
lamps.
These cabinets may be
designed in horizontal air
flow system and clean air
through HEPA filters
Cooler or Cold Storage
 HEPA Filter
HEPA filters can remove at least 99.97% of airborne particles
0.3 µm in diameter.
HEPA filters are composed of a mat of randomly arranged fibres
(poly-vinylidene fluoride -PVDF)
Key metrics affecting function are fibre density and
diameter, and filter thickness.
The air space between HEPA filter fibres is much greater than
0.3 μm. The common assumption that a HEPA filter acts like a
sieve where particles smaller than the largest opening can pass
through is incorrect.
Smaller pollutants and particles are mainly trapped (they stick
to a fibre) by one of the following three mechanisms
1. Interception
2. Impaction
3. Diffusion
 Laminar flow hoods
• Clean air work benches are specially
designed to ensure the aseptic
preparation of sterile products.
• Air flow rates
• 0.3 m/s (vertical)
• 0.45 m/s (horizontal)
• 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.
• Laminar air flow velocity satisfactorily
sweeps the area yet does not create
unacceptable turbulence.
•Types of containers

Ampoules
• They are intended for single
use only.
• Because glass particles may
become dislodged during
ampoule opening, the
product must be filtered
before it administered.
Limitation
• Unsuitability for multiple-
dose use
• The need to filter solutions
before use
• Other safety considerations
 •Vials
Glass or plastic containers are closed with
a rubber stopper and sealed with an
aluminum crimp.

Advantages over ampoules.

They can be designed to hold
multiple doses (if prepared with a
bacteriostatic agent).
It is easier to remove the product.
They eliminate the risk of glass
particle contamination during
opening.

Drawbacks
• Multiple withdrawals (as with
multiple-dose vials) may result in
microbial contamination.
 •Double Chambered Vials
• Some drugs that are unstable in solution
are packaged in vials in powder form
and must be reconstituted with sterile
sodium chloride for injection before use.

• Some of this drugs come in vials that

contain a double chamber.
• Top chamber - sterile water for
injection
• Bottom chamber- unreconstituted
drug
• Both chambers are separated by a
rubber closure.
• To dislodge the inner closure and mix
the contents of the compartments,
external pressure is applied to the outer
rubber closure.
 •Prefilled syringes

Designed for quickest

administration and
maximum convenience.

Drugs administered in an
emergency (e.g.atropine,
epinephrine) may be
available for immediate
injection when packaged
in prefilled syringes.
•Rubber Stopper Washing Machine
 •Syringe Filling Machine
Characteristics
• Barrier isolators
• In-process check weighing
• Filling : rotary piston pumps.
• 0.2 to 29 ml.

Filling :
-- All types of syringe including
glass, plastic can be filled.
-- 300 to 600 syringes in a
minute.
 •Ampoule Washing Machine
PROCESS
 Water is sprayed onto the
ampoules.
 Turned to an angle of 180 degree
with their mouth downward to
remove water.
 Finally the ampoules are filled with
compressed air to remove residual
water.
 Certain machines have a high
temperature zone meant for killing
any bacteria.
•Vial Washing And Sterilizing Machine
•Automatic Intelligent Light Inspection Machine
 •Vial Filling Machine

• Fill vials and bottles

• liquids, viscous material and
suspensions and powders.

PROCESS
 The machine comprises of an intake
section which loads the vials.
 Transferred through an intermittent
transport section.
 liquid filling section which fill the vials
with predetermined quantity.
 Finally the filled and rubber stoppered
vials are released and discharged.
•Fully automated inspection systems

58/94
•Vial Inspection Machine
•Vial Labeling Machine
 •Ampoule Filling Machine
Note = vertical laminar air flow, plastic
curtain.
 Filling range of these machines is
normally between 1ml to 20 ml.
Features of Ampoule Filling
Machines
 Accommodate a variety of ampoules in
terms of shapes and size.
 'no ampoule no fill' capability
 Check weight mechanism of the machine
helps to maintain consistency in each
batch.
 Sealing is done either by laser sealing
system or conventional gas flame.
Application of Ampoule Filling
Machine
• Pharmaceutical
• Neutraceutical
 •SIP System
• For in-line sterilization of various
processing equipments.

• Handling various biological

solutions and mixtures requires
cleaning and sterilizing these
equipments from time to time as
they are susceptible to
contamination.

• Proper SIP integration with

pharmaceutical equipment is very
important for the overall success
of the operation.
 •ANTIMICROBIAL EFFICACY OF A SILVER-ZEOLITE
MATRIX COATING ON STAINLESS STEEL

• A silver and zinc-containing zeolite matrix (AgION) used as

a coating for stainless steel.

• Test against- e coli, s aereus, p aeroginosa etc.

• Result:- The silver-zeolite mixture reduced microbial colony-

forming units upto 84.536 – 99.999% after 4 h exposure, and
upto 99.992-100% after24 h in all cases.
•FILTERS IN FILTRATION STERILIZATION
Millipore’s Airvent filters
• Constructed with a PTFE membrane.

• These filters have been qualified to

withstand at least 40 SIP cycles at 135
C for 30 minutes.

Millipore’s Durapore filters

• Constructed with a PVDF membrane

• These filters have been qualified to

withstand 5 to 30 SIP cycles at 135 C
for 30 minutes

Verification of integrity of filter

• Bubble point method

• Diffusive flow

• Pressure hold test

•Bubble Point Test
Test Method

1. Record the filter part number(s), lot number, and product information.
Also include physical observations.
2. Wet the filter to be tested with the appropriate solvent (water for
hydrophilic filters, alcohol for hydrophobic filters).
3. Place the wetted filter in the appropriate housing.
4. Connect the outlet fitting from the compressed air pressure regulator to
the upstream side of the test filter.
6. Connect a piece of flexible tubing from the downstream port of the test
filter into a beaker filled with water.
7. Starting from zero pressure, gradually increase the pressure to the test
filter using the pressure regulator.
8. Observe the submerged end of the tubing for the production of bubbles as
the upstream pressure is slowly increased in 0.5 psig increments. Note the
rate that the bubbles appear for the end of the submerged tube.
9. The bubble point of the test filter is reached when bubbles are produced
from the tube at a steady rate. Record the pressure to the nearest 0.5 psig
as indicated on the pressure gauge.
 •STANDARAD OPERATION PROCEDURE

For aseptic filling:-

Check allsterilized material has indicator and expiration date.
Open sterilized container, filling assembly and tubing on LAF bench.
Connect the tubing of filling lines.
Connect solution tank to the inlet of the filling assembly.
Connect the nitrogen over lay in tank for pre and post flushing.
Pump the solution in filling tubing up to the filling nozzle (remove any air
bubble)
After that wipe the filling nozzle with 70%alcohol.
Switch on the machine.

S.O.P FOR OTHER MENUFACTURING PROCESSES IS SAME AS THAT OF NON STERILE

DOSAGE FORMS
 •VALIDATION
Purpose : To minimize this reliance on end product sterility
testing.

Three principle involved in validation process.

• To built sterility in the product.

• To demonstrate the maximum level of probability that the

processing and sterilization method have establish
sterility to all units of product batch.
• To provide greater assurance and support to the result of

the end product sterility.

 •Validation
a) Pre-processing quality control test
b) In process quality control test
c) Finished product quality control test

Pre-processing quality control test:-

a) Raw material testing and assays
b) Packaging material test (glass, plastic, rubber etc)
c) sterility test and media fill (process simulation test )
 •Tests for containers
(a). For Glass containers.
(i). Test for hydrolytic resistance.
(ii). Arsenic test.
(b). For Plastic container.
(i). Non volatile matter.
(ii). Sulphated ash.
(iii). Heavy metals.
(iv). Buffering capacity.
(v). Biological test. (Adverse reaction or toxicity)
 •Media fill (process simulation test):-
 Evaluation
of the environment along with the process, the operator
and the equipment is the media fill.

Procedure
 Sterile
Trypticase soy broth is filled into sterile container under
condition simulating as for a product.
 Entire lot at least 3000 units is incubated at suitable temp for 14
days .
 To pass the test not more than 0.1% of the unit may show growth.
 This
is very stringent evaluation of an aseptic fill process and is
considered to be the most evaluative test available.
 •In Process Quality Control Test
Conductivity measurement
Volume filled
Temp for heat sterilized product

Environmental control tests

Visual inspection
 •Finished product quality control test

Leaker test
Pyrogen test

Particulate test

Sterility test.

Uniformity of weight.

Uniformity of content
 •Leak test
• To detect incompletely sealed
ampoules.
Principle
10% methylene blue or 0.1% FDC red
one or red two.
Generally combined with autoclave.

Disadvantage
Leakage of 15 micron in diameter or
smaller is not detected.
Vial and bottles are not subjected to
this test.
 •Pyrogen test

Pyrogen test

LAL test Rabbit test (IP, BP, USP, EP)

 •LAL test
Limulus amoebocyte test or bacterial Endotoxin test for the validation of
depyrogenation process.
Reagent - LAL reagent (limulus Polyphemus)
Reaction - In presence of Endotoxin a firm gel is formed within 60 min when
incubated at 370 C.

CHARACTERISTIC
• Test tube scale.
• Only pyrogen of gram negative bacteria detected.
• Semi quantitative test.
• Sensitivity in terms of Endotoxin unit.
• In-vitro test.
• Doesn’t measure fever producing potential of Endotoxin.
• Sensitivity varies with different microbial source of LAL.
•LAL TESTER
 •Pyrogen test- Fever response of rabbit
• Sham test is performed to select the proper animals for the main tests.
• Rabbit test - Qualitative fever response test.
Procedure
• Test solution is injected into the vein of rabbit. Temperature elevation is
seen for 3 hrs.

Disadvantage
 Biological variation
 Expensive
 Laborious
 Dose dependent.
 Not for anti pyretic drug.
 • Particulate test

USP
Visually inspected- all (WHITE AND BLACK )
Any with visible particle is discarded.
Large volume parental
 50 particles of 10μm
 5 particulates of 25 μm per ml

1. Light obscuration particle count test

2. Microscopic particle count test
 •HVAC Validation
Features of HVAC affect product quality (sterility).
1. HEPA integrity
a) Certification: by filter manufacturer indicates that filter is capable of removing all
particulate matter equal to or greater than 0.3 in size with an efficiency of 99.97%.
b) Installation: a certified filter if improperly installed will not perform its function &
provides a false sense of security.
c) Integrity testing: A popular method for certifying integrity of filter installation uses
polydisperse aerosol, created by blowing air through liquid Dioctyl phthalate,
introduced into upstream of HEPA filter followed by scanning the entire downstream of
filter face with a probe nozzle of an aerosol photometer.
• This testing will indentify “leaks” caused by damage due to mishandling or faulty
construction.
• Small leaks can be repaired with a suitable silicone based compound without
removing filter.
 •HVAC Validation (Cont.)
d) Airflow resistance : Caused by dirty filter may reduce airflow volume, thereby
reducing the air change rate in critical areas.
Airflow resistance is expressed as pressure differential between the air pressure
upstream of the filter and the downstream air filter.
If the filters are not changed when they reach the maximum resistance as
specified by manufacturer, they may begin to lose their physical integrity or
rupture, thereby releasing some of the dust they have accumulated.

2. Airborne particle control

Particle count surveys should be performed at regular intervals.

3. Airflow direction
Determination of unidirectional flow involves measuring the parallelism of air flow
generating from HEPA filter throughout the work zone.
This can be accomplished using an isokinetic smoke generator & measuring
devices to determine offset from straight line flow.
 HVAC Validation (Cont.)
4. Room pressure difference
• Special monitoring devices which measure the pressure differential are
connected directly to an alarm system that will cause a visual signal (flashing
light) or an audible signal (Alarm buzzer) to report a deviation outside a
prescribed range of pressure differential.

5. Temp. & Humidity control

Cleanroom Environmental Monitoring

Sr.No Test Frequency
Particle Monitoring in air 6 monthly
HEPA Filter Integrity Testing Yearly
Air Changes Rate Calculation 6 Monthly
Air Pressure Differentials Daily
Temperature and Humidity Daily
Daily, and at decreased
Microbiological monitoring by settle plates and / or swabs in
frequency in other
aseptic areas
areas
 •Packaging of finished product
Packaging material.
(1) Glass
(2) Plastic
• Plastic is more preferred over glass as packaging material
for no of reasons.
- Ease to form
- High quality
- Freedom of design

E.g.--Polypropylene, PVC, Polystyrene, Nitrile polymers.

 •USP requirements for packaging.

• Single dose container should not be more than 1 liter.

• Intra-spinal and intra-cisternal administered product
must be in single dose container.
• In case of multiple dose container dose should not be

more than 30 ml.

 BFS Technology
• It refers to the technology and related
equipment and procedures in which
the formation of the container, its
filling with liquid pharmaceutical
material, and subsequent formation
and application of a seal for container
are achieved aseptically in an
uninterrupted sequence of operations
without exposure to nonsterile
environments between poerations.
 •BFS Technology
1. Extrusion
• An endless sterile plastic tube is
continuously extruded from the
melted granulate in the filling cavity of
the mould.

2. Blowing
• Final container is produced by
sterile air pressure from Blow
and Fill nozzle.
 BFS Technology

3. Filling
• After the container is formed
inside the mould, sterile liquid
product is introduced into the
container.

4. Sealing
• Final container is sealed in
place by closing of the seal-
mould form onto the
container top.
BFS Technology

5. Mould opening
• Upon completion of filling and
sealing steps, the mould is
separated, producing the sterile
filled and sealed container.
 •ADVANTAGE OVER CONVECTIONAL ASEPTIC FILLING

• There is no need to purchase and stock a range of pre-fabricated container and

closures.
• Cleaning and sterilizing pre-fabricated container and closures are not required. A
clean sterile container is made with in the BFS machine.
• The cost of material transport, storage and inventory control is reduced.
• Validation requirement are reduced.
• There is a large choice of neck and opening device shapes.
• Saving floor space.
• Less labour intensive than conventional one.
• The code number and variables can be moulded into container it-self
• With blow-fill-seal, you produce a one-piece, aseptically filled container with a built-
in safety seal..
• The blow-fill-seal process is suitable for heat-sensitive products.
.

•Asep-Tech ® Model 603 Blow/Fill/Seal

Packaging Machine System
 •QUESTIONS ASKED
1) Differentiate Master formula record (MFR), Batch manufacturing record (BMR) and standard operating
procedure (SOP) by giving a suitable example of a compendia injection product (MARCH- 2004 ).
2) Give qualitative and quantitative lay out, manufacturing steps with suitable equipments, important IPQC
parameter, and packaging records and post marketing surveillance reports for sterile products. (JULY-
2004 )
3) Discuss the department layout, schedule ‘M’ requirement, validation parameters, and PMS report for
sterile LVPs?(29th September, 2004 )
4) What is the importance of Bio film removal on product quality?( march 2005)
5) What are the facilities, environment control and air handling system with different types of classification
?( march 2005)
6) Discuss clean room concept and level of protection in brief?(2005)
7) How will you evaluate the package for different sterile DF? Give the legal requirement for keeping their
records and reports? (sep 2006)
8) Discuss the qualities , national ,international standard for clean room? Discuss the pressure differential in
the pharma. plant ?(sep 2006)
9) Validation of the steam sterilizer and importance of the D, Z, F value? (sep 2006)
10) QC. Of aseptic area (may 2003)
11) Give detail lay-out of SVP and area and equipment requirement as per CGMP ? (may 2003)
 •REFERENCES
1. Pharmaceutical dosage forms (Parenteral Preparation) by Kenneth E. Avis, Leon
Lachman, Vol-1.
2. Pharmaceutical dosage forms (Parenteral Preparation) by Kenneth E. Avis, Leon
Lachman, Vol-2.
3. Drugs & Cosmetics Act 1940.
4. The theory and Industrial pharmacy by Leon Lachman, Third edition
5. Pharmaceutical science by Remington, 20th edition
6. Pharmaceutical process Validation by Loftus & Nash: 29-90.
7. Sterile Pharmaceutical Manufacturing by Groves Gisan.
8. www.fda.gov.
9. American Journal of Hospital Pharmacy, Vol. 38, Issue 8, 1144-1147
10. Dispensing for pharmaceutical students; 10 th edition; by:-S J Carton
11.www.GMP.online.coms
12.www.ispc.org
13.www.whqlibdoc.who.org
14.www.dwscientific.co.uk
15.www.pharmamachines.com
16.www.bascotech.com
17.www.getthatmag.com
18.www.fabtecheng.com
19.www.ahind.com
20.www.nkambica.com