WHAT IS STERILE

“Any material that is free from bacteria or other living microorganisms”.

But now a days sterile refers to the probability of survival of
microorganisms (i.e. Sterility Assurance Level-SAL)
 STERILITY ASSURANCE LEVEL (SAL)
“Any material that is free from bacteria or other living microorganisms”.
But now a days sterile refers to the probability of survival of
microorganisms (i.e. Sterility Assurance Level-SAL)
 STERILIZATION
“a term referring to any process that eliminates or kills all forms of
life from an item or field”
 TYPES OF STERILE PRODUCTS

Sterile Injectables

Sterile Opthalmic preparation

Sterile solution for Irrigation

Sterile medical devices

Sterile Diagnostics

 Dialysis solutions

Sterile meter dose inhalers

 Sterile Implants

 Intraocular inserts
 STERILE INJECTABLES
CLASSIFICATION BASED ON FILL /RE-CONSTITUTION VOLUME

Type SVP LVP

Fill volume ≤50 mL ≥50 mL

Example Pre-filled syringe, Infusion bags, parenteral hyper
single/multiple dose vials etc…. alimentation solution for infusion
etc….
 STERILE INJECTABLES

CLASSIFICATION BASED ON FILL /RE-CONSTITUTION VOLUME

Manufacturing process Description Example

Aseptic Processing The product is manufactured such Most SVP’s are

a way that every step of aseptic manufactured
processing ensure complete following aseptic
removal of microorganism to processing
render the final product sterile
Terminally sterilized All precautions are taken as for LVP’s & some SVP’s
sterile products but the final are manufactured
product is sterilized after by terminal
sterilization
 STERILE INJECTABLES

Basic difference between aseptic processing & terminal sterilization

Aseptic processing Terminal sterilization

Final product is not sterilized Final product is sterilized

Generally thermo labile products or
products that deteriorate with
sterilization process are
manufactured by this process
Final sterilization assurance is not as
much high as terminal products
Chance of contamination is high so
more precaution should be taken
during processing
Endotoxin level is low
Thermo stable products are manufactured
by this way
Final sterilization assurance is high
Processing is relax relative to aseptic
processing
Endotoxin level is higher
 COMMON ROUTES OF ADMINISTRATION
OF INJECTIONS
Routes of Feature Site of Diagram
administration Injection
Most Arms,
Intravenous commonly use, hands,
Convenient, legs, feet
Less pain

Intramuscular Painful, May

cause abscess

Subcutaneous Convenient for

self
administration
 ADVANTAGES OF INJECTABLE DOSAGE FORMS
 Injectable preparations are applied directly to the blood stream or adjacent to the
blood stream thus promotes 100 % to near 100 % bioavailability
 They provide rapid onset of action
 Small amount medication is required to produce the desired therapeutic effect
compared to other dosage forms (i.e. tablet, capsules etc)
 Drug products that are not stable in other routes of administration can be formulated
as injectable dosage forms
e.g. Penicilling is unstable in GI tract that is given by intravenous route
Injectables are ideal preparations to meet emergency medical conditions….e.g. glucose
is given intravenously in case of severe hypoglycemia…..nitroprusside is given for severe
heart failure
 Injections are widely used in anaesthesiology
 Post operative pain mangent
 Most of the bio-therapeuticals are given through injectables routes of administration
for disese management…e.g. mAb, erythropietin, insulin etc
 ADVANTAGES OF INJECTABLE DOSAGE FORMS
 Injectable preparations are applied directly to the blood stream or adjacent to the
blood stream thus promotes 100 % to near 100 % bioavailability
 They provide rapid onset of action
 Small amount medication is required to produce the desired therapeutic effect
compared to other dosage forms (i.e. tablet, capsules etc)
 Drug products that are not stable in other routes of administration can be formulated
as injectable dosage forms
e.g. Penicilling is unstable in GI tract that is given by intravenous route
Injectables are ideal preparations to meet emergency medical conditions….e.g. glucose
is given intravenously in case of severe hypoglycemia…..nitroprusside is given for severe
heart failure
 Injections are widely used in anaesthesiology
 Post operative pain mangent
 Most of the bio-therapeuticals are given through injectables routes of administration
for disese management…e.g. mAb, erythropietin, insulin etc
 DISADVANTAGES OF INJECTABLE DOSAGE
FORMS
 Injectable preparations are applied directly to the blood stream or adjacent to the
blood stream thus promotes 100 % to near 100 % bioavailability
 They provide rapid onset of action
 Small amount medication is required to produce the desired therapeutic effect
compared to other dosage forms (i.e. tablet, capsules etc)
 Drug products that are not stable in other routes of administration can be formulated
as injectable dosage forms
e.g. Penicilling is unstable in GI tract that is given by intravenous route
Injectables are ideal preparations to meet emergency medical conditions….e.g. glucose
is given intravenously in case of severe hypoglycemia…..nitroprusside is given for severe
heart failure
 Injections are widely used in anaesthesiology
 Post operative pain mangent
 Most of the bio-therapeuticals are given through injectables routes of administration
for disese management…e.g. mAb, erythropietin, insulin etc
 STERILE INJECTABLES

1. Site selection:

A. Basic plant requirements: Basic plant requirements includes supply of raw

materials, transportation availability, market proximity, adequate utility and
labour supply.

B. Energy: A parenteral facility is not a fuel-intensive operation but does a

require a reliable source of energy for both domestic uses, such as heating,
cooling, hot water, lighting & production uses, such as sterilization and
distillation.

Special consideration must be given to the reliability of electrical power.

Because loss of electrical power can often lead to costly or dangerous situations
with in a pharmaceuticals facility. Plants should have at least one standby
generator which should be sized handle only critical safety & process loads such
as emergency lighting, alarm systems, communication systems, lyophilizers,
fermentors clean room circulation fans, WFI circulation pumps etc……
 STERILE INJECTABLES
1. Site selection:

C. Water: Water is a common ingredient to most parenteral formulations &

copious amounts are needed for equipment cleaning, container washing &
rinsing, process & personnel cooling, & steam generation etc. Given some
range of supply quality, the in-plant treatment must be able consistently to
produce water of a desired quality. e.g. Surface water temperature will tend
to vary seasonally, as well its quality, due to contamination by floods,
industrial accidents, or even sabotage.

D. Air quality, waste disposal & nontechnical factors:

 The ambient air quality is a significant design concern. Very small airborne
particles (less than 1µm), excessive humidity, odors, industrial waste gases
are difficult to remove & therefore can create discomfort to the control
environment
 Environmental concerns about the disposal hazardous wastes are more
serious. Waste disposal method should be included in the design feature
 Site selection may also be influenced by company’s philosophy may dictate
the all facilities be built on a common site
 STERILE INJECTABLES
2. Facility area use planning: Planning for a production facility requires
determination of the functions necessary & the size & location for each
function. After these needs are determined , a review of the functional needs
will lead to a determination of area requirements & relative location for each
function. The area use planning may influenced by:
A. General operational assessments
• Type of production line:
 It may be batch operations
 It may continuous batch operations
 Or it may be integrated operations
 Diversity of product line
 Container size
 Environmental control needs
 Product characteristics etc………….

B. Area planning:

• Environmental control zone groupings:

 STERILE INJECTABLES
• Functional groupings:
 Production functions
 Warehousing
 Administrative areas
 Utilities
 Quality control
 Engineering & maintenance
 Employee services..e.g. cafeteria, locker rooms, rest rooms, personnel service
s such as interviewing, benefits, & health facilities etc……..
 Security etc………

• Proximity groupings: Proximity priority should be addressed during facility

design. It is important to define a type of proximity priority to aid in choosing
the optimum location for the various functions.
Over the life of plant there may be change in areas required to accommodate
increased in capacity, therefore the ability to renovate the plant without the
need to shut down all of the operations must addressed during the initial design
of the facility. This allows for flexibility of future operations so that areas such as
utility rooms, office, etc. , do not become fixed constraints & limit expansion
 STERILE INJECTABLES
• Man & material flow: The movement of man & materials should be planned
during the design of individual plant areas, but because of its importance it
should also be reviewed periodically during the planning process as a total
facility need

3. Design concepts: The progression from operational concepts and floor plans
to working drawings & then to a functioning plant requires grappling with
the real problems of just how something is to be done. Often, basic concepts
are involved, dictated by parenteral need or state of the art. Basic concepts
can be influenced by:
A. No. of filling suits.: It may a single filling line, two filling line, four filling ine or
multiple filling line operations.
B. Wall & floor treatments:
• The wall & floor should be smooth, cleanable.
• Exposed columns, wall stud, bracings & so on are unacceptable
• Walls & floors should withstand the cleaning & disinfectants
• To aid sanitization all wall & ceiling junctions must be coved or rounded
C. Miscellaneous:
 Doors are preferred with push plates plates or arm hooks which replace usual
door knobs
 STERILE INJECTABLES
 Doors are preferred with push plates or arm hooks which replace usual door
knobs
 Lighting fixtures should be recessed flush with the ceiling
 Light fixture should be tightly sealed with the ceiling
 Lamps should be replaced from outside room
 The cleanability of the exposed sprinkler heads should be improved by use of
semirecessed heads & protective caps, although these caps cannot be sealed
 Clean room telephones should be used instead of usual PABX to enhance
cleanabilty & to reduce contamination
 There should be LAF aided dynamic pass boxes for material entry/exit form
the clean room
D. Mechanical services:

 Utility equipment location & there distribution to production areas

 Utility should be supplied according to product requiremnts
 Evaluate the point of use requirements
 Maintenance procedures of utility must be determined
 STERILE INJECTABLES
E. Utility system component details: The need for absolute control of utility
systems in a parenteral facility requires that attention be given to details of
system design which might otherwise be considered unimportant. To completely
design, specify, & install a utility system, specifically a piped system, requires
attention to details such as materials & alloy selection, surface finish, sizig,
joining technique, types of valving, cleanability, insulation & so on.

• Selection of type of distribution system:

 Design the distribution system to provide required utilities in the most
efficient manner

Loop distribution system, Branch distribution system with e.d

• Materials:
STERILE INJECTABLES
 Carbon steel: Commonly available & manufactured according to ASTM A 53 or
A106. They can be used for CA distribution system. But they rusts quite
readily, so they should not be used in clean area purpose
 Copper: Two types. Type K & Type L. They are relatively corrosion resistant.
But thy lose strength in high temperature so, they should not be used in
steam
 304 stainless steel: Contain approx. 18% chromium & 8% nickel.
Nonmagnetic, nonhardenable. Resistant to nitric acid but not to sulfuric acid
or hydrochloric acid
 316/316L stainless steel: Similar to 304 but have 2 to 4 % higher nickel
contain, 2% less chromium, & has 2 to 3% molybdenum. Corrosion resistant.
316 L contain 0.03% les alloy carbon than 316 which makes it more weilding
resistant. They can be used in WFI, clean steam etc….
• Surface finishing: Mechanical or electropolishing with passivation is preferred
• Joining techniques: Piping systems can be joined by threding, welding or
clamping. Threaded connections are used for non critical uses. For critical
purpose high quality welding are used that produce smoothest internal
surface in a piping system. Any welds have defects such as crevices or voids
should be rejected or rewelded. Piping which requires frequent disassembly, a
clamped & gasketed flange is used. Although sanitary clamp produce a rather
internal surface, it is prone to leakage and must be disassembled for complete
 STERILE INJECTABLES
• Valving:There are various types of valve as ball valve, diaphragm valve, gate
valve etc. For acceptabiliy proper valve should be selected according to the
purpose.
• Utility service connection arrangement: The arrangement of services within
the production area and the connection of services to the points of use &
equipment can have a significant impact on the plant environment. Utilities
must be carefully connected to avoid stagnant areas & to avoid difficult to
clean areas just as would be done for the utility distribution system. So it
must be considered during designing.
 CLEAN ROOM DEFINITION, CLASSIFICATION
, TESTING & MONITORING

A ROOM IN WHICH THE CONCENTRATION OF AIRBORNE PARTICLES IS

CONTROLLED, AND WHICH IS CONSTRUCTED AND USED IN A MANNER
TO MINIMISE THE INTRODUCTION, GENERATION, AND RETENTION
OFPARTICLES INSIDE THE ROOM AND IN WHICH OTHER RELEVANT
PARAMETERS, E.G. TEMPERATURE, HUMIDITY, AND PRESSURE, ARE
CONTROLLED AS NECESSARY.
CLEAN ROOM CLASSIFICATION BASED ON
DESIGN
1. TURBULENTLY VENTILATED CLEANROOMS
CLEAN ROOM CLASSIFICATION BASED ON
DESIGN
1. TURBULENTLY VENTILATED CLEANROOMS
CLEAN ROOM CLASSIFICATION BASED ON
OPERATION
1. TURBULENTLY VENTILATED CLEANROOMS
 PRINCIPLES OF CLEANROOM TESTING
The air supplied to the cleanroom is of sufficient quantity to dilute or
remove the contamination generated in the room.

The air within the cleanroom suite moves from clean to less-clean areas
to minimise the movement of contaminated air. Air should move in the
correct direction through doorways and the fabric of the room.

The air supplied to the cleanroom is of a quality that will not add significantly
to the contamination within the room.

The air movement within the cleanroom should ensure that there are no
areas within the room with high concentrations of contamination

If these principles are satisfied then the concentration of particles, and

where necessary microbe-carrying particles, should be measured to ascertain
that the specified cleanroom standard has been achieved.
CLEAN ROOM TEST SEQUENCES

ADDITIONAL TEST
temperature
relative humidity
heating and cooling capabilities of the room
sound levels
lighting levels
vibration levels.
RE-TESTING TO DEMONSTRATE COMPLIANCE
MONITORING OF CLEANROOMS
air pressure difference
airborne particle count
where appropriate, microbiological counts.
AIRBORNE PARTICLE COUNTS
AIRBORNE PARTICLE COUNTS
AIRBORNE PARTICLE COUNTS
PARTICLE COUNTING IN DIFFERENT
OCCUPANCY STATES
As built: complete and ready for operation,
with all services connected
and functional, but without equipment or
operating personnel in the
facility
0 At rest: complete, with all services
functioning and with equipment
installed and operable or operating, as
specified, but without operating
personnel in the facility;
0 Operational: in normal operation, with all
services functioning and
with equipment and personnel, if applicable,
present and performing
their normal work functions in the facility.