Introduction to the principles of sterile and aseptic

Aseptic is the term used to show that

an item or a substance is free of pathogenic
microorganisms which is proven through sterility
tests. Sterile is a term that describes the state
where a substance or item is free of all
microorganisms which is also proven through
sterility tests.
Sterile manufacturing facilities
In regards to pharmaceutical manufacturing
facilities , the injectable product manufacturing
facilities are the most sophisticated and challenging
to design, build, qualify and operate. The most
important factors of sterile manufacturing facilities
include highly controlled room environments(ISO
5) , unidirectional flow of materials and personnel,
clean in place (CIP) and steam in place (SIP)
systems, highly sophisticated and controlled sterile
or aseptic filling systems, complex equipment and
components, and intensive utilities of heating,
ventilation, and air conditioning (HVAC) systems.
The sterile manufacturing facilities perform two
types of processing operations.
1.Primary bulk processing of the drug substance.
2.The formulation filling and finishing of the drug
product.
Process equipment
Major design consideration in process
equipment includes operability, cleanability of the
system, ability to sterilize the system, drainability,
consistent and repeatable functions, closed versus
open process systems, ability to control the
manufacturing environment.
Process design
Two steps of process design are being carried out.
Open process design
This system is exposed to the background
environment in the processing facility such as open
transfer of product within a clean room. In this
sensitive processes are carried out such as
injectables that cannot be maintained in a closed
state. These sensitive processes are carried out with
the specification of ISO5.
Closed process design
Closed system affect the development, size,
Cost, and operation of a sterile manufacturing
project. A closed system is defined as a isolated
system. A closed system can be opened initially for
cleaning or parts changeover, but it is intrinsically
closed. Closed system might be made up of glass,
plastic or stainless steel. Glass panels easily
facilitate visual inspection and also the compatibility
of formulation. Stainless steel is difficult to handle
because of visualization issues. closed system are
more appropriate and expensive.
Processing in barrier and isolation system
 Barrier and isolation system is the most
common approach in the design and
operation of sterile facilities.
 A restricted access barrier (RAB) isolation
system is a barrier system consisting of a set
of glass doors fixed into a stainless steel
 frame. Due to this system, interventions
during processing, as well as the loading and
unloading of the material, must be clearly
understood.
 An isolated system consists of a stainless
steel and a glass enclosure system, with
glove ports, creating a totally sealed system
for the critical environment.
 These technologies provide protection of
product, protection of personnel, and have
the ability to reduce the environmental
classification level of the background
environment.
Project philosophies
The team must develops the project
philosophies, which are the details or
statements about the factors that affect the
project. these philosophies are the part of
the basis of design (BOD). Some examples of
philosophies for a sterile manufacturing
facility are given below:
 Processing: it is important to know the
process operating conditions such as that
the process is open or closed,
multiproduct or single product etc
 Functional zoning: generally zones are
the preparative areas and the layout
depend on processes and nature of
services. These zones are provided with
different types of facilities.
 Product flow and management: the
general flow of critical and noncritical
materials and the overall product flow
throughout the facility must be
developed.
 Personnel flow: it defines that how
people enter and exit the operating areas
as well as how they move.
 Cleaning: this philosophy includes CIP
and COP that is clean in place and clean
out of place. It must be clear that how
the product and the nonproduct surface
must be cleaned.
  Sterilization: the general criteria for
sterilization must be defined in a simple
manner. A well developed sterilization
plans must be there to form a good
facility operating practice.
 Waste management: how the waste
should be managed in the sterile facility
operation must be developed.
AEROSOL BEHAVIOUR
It is important to know the behavior of the
particles present in the airstream in order to
control the contamination. These particles are
possess various physical forces.
 Gravitational forces: due to gravitational
force settling of particles occurs
 Electrostatic forces: particles have
different electrical charges due to which
attraction takes place.
 Frictional forces: the resisting forces
produced by rubbing.
  Inertial forces: the tendency of the
particles to follow the airflow.
 Diffusion forces: particles in continuous
and random motion.
 Thermal forces: difference in temperature
of the air masses cause the change in
kinetic energy.
AIR FILTERATION
Air filtration is a method to obtain the clean air in
the production area.
CLASSIFICATION OF FILTERS
The filtration mechanism involves a combination
of various effects such as
 INERTIAL IMPACTION:
 Their should be the change in the particle
direction in the airstream .
 By increasing the air velocity and by
decreasing the fiber’s diameter the
effectiveness of inertial impaction is
increased.
  This effect is more seen on particles larger
than 1 micrometer.
 DIRECT IMPACTION:
 The particles having negligible masses are
trapped by electrostatic forces or direct
impaction.
 Increase in the fiber’s and particle’s diameter
cause the decrease in the efficiency of
method.
 This effect is more seen on particles with the
diameters in the range of 0.5-1 micrometer.
 DIFFUSION:
 In this the particles are trapped because of
their random motion.
 Diffusion takes place in very small particles
in the range of 0.2-0.3 micrometer.
 ELECTROSTATIC:
 The controlled polarity of the filter medium
cause the retention of the particles by the
action of electrostatic forces.
  The attractive forces of particles vary
inversely with the air velocity and the
dimensions of the particles.
EVALUATION OF AIR FILLTER SYSTEMS:
To select the proper filter system, the
following characteristics must be evaluated.
 Evaluating air flow resistance
 Evaluating filter efficiency
 Evaluating service life
 Evaluating arrestance
1.EVALUATING AIR FLOW RESISTANCE:
 Air flow resistance is measured in inches by
using a water manometer.
 The instrument consist of two parts one is
located upstream of the filter and other on
downstream.
 The reading indicates the total resistance
of the flow of air by showing the difference
in static pressure from one side to the
other. This is known as pressure drop.
  The smaller the particles to be filtered out ,
the higher the airflow resistance.
 The efficiency of filter is proportional to the
pressure drop.
2.EVALUATING FILTER EFFICIENCY:
 Filter collection efficiency is the efficiency of
the air filters that show’s how much percent
of particles are retained by the filters.
 Granulometric methods are those method
that use synthetic dust composed of
mixtures of different types and size of
particles.
 Colorimetric test is used to check the
efficiency of intermediate air filters.
 The method which is use for the particles
of uniform size and weight is called DOP
test, which uses a photometric detection
device.
3.EVALUATING SERVICE LIFE:
 The life of the filter is directly proportional
to its capacity to retain contaminants.
  Filtration systems are set up in a way to
extend the life of higher efficiency filters.
 Nonaseptic controlled environment have
three stages: a primary filters, an
intermediate filters, and a final stage high
efficiency filters .
 The service life of the final or high efficiency
filters can be extended to 3 years with
adequate prefiltration.
4.EVALUATING ARRESTANCE:
 The capacity of the filter to retain dust is
called arrestance.
 The arrestance of the filter can be
determine by the design of filter.
 The more medium a filter has ,the greater
its dust-loading capacity.
HIGH-EFFICIENCY PARTICULATE AIR (HEPA) FILTER:
 HEPA filter has the capability to retain
particles as small s 0.3 micrometer with the
efficiency of 99.97%.
  HEPA filter medium consists of extremely
fine glass fibers.
CONSTRUCTION OF HEPA FILTER:
The basic components of HEPA filter are
1.Frame:
 frame selection is based on filter application.
 Possible frame materials are board, plastic,
metal.
 Metallic frames are free from particle emission.
 Plastic frames have been introduced recently.
2.Filter medium:
 Filter medium is made up of glass fibers.
 Filter media sustain the temperature from 4 to
250 degree centigrade.
3.Separators:

4.Adhesive
5.Gasket