This document discusses sterile products and clean room classifications. Sterile products must be free from microorganisms and pyrogens. They include parenterals, ophthalmics, and irrigation fluids. Several factors are important for sterile compounding including clean facilities, trained personnel, and sterilization/stability principles. Clean rooms are classified based on particulate levels, with grades A through D (or classes 100 through 100,000) used in pharmaceutical facilities. Grade A/class 100 areas are needed for high-risk aseptic operations.

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Chapter: 7
STERILE PRODUCTS
Lecture - 17

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Sterile products
 Sterile products are dosage forms of
therapeutic agents that are free from viable
microorganisms.
 Sterility is an absolute term, means the absence
of living microorganisms.
1. Microbe is a microscopic organisms such as a
bacteria, fungus, protozoa or virus.
2. Pyrogens are metabolic by-products of live or
dead microorganisms that cause a pyretic
response (i.e., a fever) upon injection

3.  Pharmaceutical dosage forms that are sterile.
 These include;
1. Parenterals
2. Opthalmics
3. Irrigation fluids
 Sterile product compounding requires cleaner
facilities, personnel training and testing, and a
sound of knowledge of sterilization and stability
principles and practices.
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4. 1- Parenterals
 Parenteral (Gk, para enteron, beside the intestine) dosage
forms differ from all other drug dosage forms, because they
are injected directly into body tissue through the primary
protective systems of the human body, the skin, and
mucous membranes.
 Must be exceptionally pure and free from physical,
chemical, and biological contaminants.
 These requirements place heavy responsibility on
pharmaceutical industry to practice current good
manufacturing practices (cGMPs) in the manufacture of
parenteral dosage forms & on pharmacists and other
health care professionals to practice good aseptic practices
(GAPs) in dispensing parenteral dosage forms for
administration to patients. 4

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 Bypass the highly efficient first line of body defense –
skin and mucous membranes, they must be;
i. Free from microbial contamination.
ii. Free from toxic components.
iii. Possess exceptionally high level of purity.
 Components and processes involved in preparation of
these products must be selected & designed to
eliminate as much as possible contaminations of all
types like;
i. Physical origin.
ii. Chemical origin.
iii. Microbiological origin.

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 Preparations must be sterile to enter veins
and arteries, otherwise anaphylactic shock or
other abnormalities may result.
 Sterility: Complete destruction of all living
organisms & their spores or their complete
removal from formulation.
 Aseptic Technique: Technique for preparation
and manipulation of compounded sterile
products and parenteral preparations that
prevents contamination.

7.  Contamination: Any effect or action that has a
negative impact on a product's integrity making it
unfit for use;
i. Chemical composition
ii. pH
iii. Sterility (e.g. microorganism contamination)
iv. Pyrogenicity
v. Physical appearance
vi. Particulate matter (e.g. dust, glass or precipitation)
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2- Ophthalmic Preparations
 Preparations for eye, although not
introduced into the internal body cavities,
but are placed with the tissues which are
extremely sensitive to contamination.
 Due to this reason, similar standards are
required for ophthalmic preparations as for
the parenterals.

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3- Irrigating Solutions
 Irrigating solutions are also required to
meet the same standards as the parenteral
solutions, b/c during an irrigation
procedure, substantial amounts of these
solutions can enter the bloodstream
directly through;
i. Open blood vessels of wounds.
ii. Abraded mucous membranes.

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Types
 Sterile products are most frequently;
i. Solutions
ii. Suspensions
iii. Emulsions
iv. Solid pellets for tissue implantations (not
common).
 Control of a process to minimize contamination
for a small quantity of sterile product can be
achieved easily.
 As the quantity of the product increases, the
problems of controlling the process to prevent
contamination go on multiplying.

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 The preparation of sterile products has
become a highly specialized area in
Pharmaceutical industry.
 It requires a superior level of;
i. Established Standards.
ii. Attitude of Personnel.
iii. Process control.

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 The organizational divisions normally
responsible for the preparation of sterile
products in the Pharmaceutical Industry
are;
1. Product Development
2. Production
3. Q.C.
4. Packaging

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Particulate
 Simply airborne particles are solids suspended in
the air.
 The size of contaminants and particles are usually
described in microns.
 Air, whether it is from outside or re-circulated, acts
as a vehicle for bacterial and gaseous
contaminants brought in by the movement of
people, material, equipment etc.
 Since many of these air borne contaminants are
harmful to products & people, their removal is
necessary on medical, legal, social or financial
grounds.

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SOURCES
 There are two main sources of particulates.
1. External
2. Internal sources
1- External sources
 These consist of the following:
i. Outside air introduced into the room.
 This is typically the largest source of external
particulates.
ii. Infiltration through doors, windows and other
penetrations through the clean room barriers.

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Control Action
i. Make-up air filtration
ii. Room pressurization
iii. Sealing of all penetrations into the space.
2- Internal sources
 Internal sources consist of the following:
i. People in the clean area – people are potentially
the largest source of internally generated
particulates (Touch contamination & Generation
of particulates from shedding cells or hair)
ii. Clean room surface shedding
iii. Process equipment
iv. Material and ingredients
v. Manufacturing processes

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Control Action
 Design airflow path to shield humans from
surroundings.
 Use of air showers [to continually wash occupants
with clean air].
 Using hard-surfaced, non-porous materials such as
polyvinyl panels, epoxy painted walls, & glass board
ceilings.
 Proper gowning procedures, head wear mask etc.
 A super clean environment with controlled
temperature & relative humidity has now become
an essential requirement for a wide range of
applications in Pharmaceutical Plants.
 More critical in case of Sterile products.

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20. Types of sterile products processing
1) Terminally sterilised
 → prepared, filled and sterilised
2) Sterilised by filtration
3) Aseptic preparation
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21. 1. Terminally sterilised
 Usually involves filling and sealing product containers
under high-quality environmental conditions.
 Products are filled and sealed in this type of
environment to minimize the microbial and
particulate content of the in-process product and to
help ensure that the subsequent sterilization process
is successful.
 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.
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22. 2. Sterilisation by Filtration
 Previously sterilized container are taken.
 Filters having nominal pore size 0.22 μm or less
are used for filtration
 Remove bacteria and moulds but Not viruses &
Mycoplasmas
 Double filter layer or second filtration
 No fibre shedding or asbestos filters
 Filter integrity testing
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23. 3. Aseptic Preparation
 In an 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 product in its final
container, it is critical that containers be filled and
sealed in an extremely high-quality environment.
 Before aseptic assembly into a final product, the
individual parts of the final product are generally
subjected to various sterilization processes.
 Any manual or mechanical manipulation of the sterilized
drug, components, containers, or closures prior to or
during aseptic assembly poses the risk of contamination
and thus necessitates careful control. 23

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Clean rooms
 The production of sterile preparations should be
carried out in clean areas, entry to which should be
through airlocks for personnel and/or for goods.
 Clean areas should be maintained to an appropriate
standard of cleanliness & supplied with air that has
passed through filters of an appropriate efficiency.
 Various operations of component preparation, product
preparation, filling & sterilization should be carried out
in separate areas within a clean area.
 Clean areas for production of sterile products are
classified according to the required characteristics of
the air, in grades A, B, C & D or Classes 100, 10,000 &
10o,000.

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 A clean room is defined as a room in which the
concentration of airborne particles is controlled.
 The clean rooms have a defined environmental control
of particulate and microbial contamination, and are
constructed, maintained, and used in such a way as
to minimize the introduction, generation, and
retention of contaminants inside the room & and in
which other relevant parameters, e.g. temperature,
humidity, and pressure, are controlled as necessary.

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Clean room Classification
 Clean room classifications are established by
measurement of the number of particles 0.5
micron and larger that are contained in 1 ft³ 0r 1 m³
of sampled air.
 Generally class 100 to 100,000 rooms are used in
the pharmaceutical industry.
 Rooms may be classified as clean as class 1 or 10 for
other applications, particularly in the microchip
/semiconductor industry.

29.  As built : condition where the installation is complete
with all services connected and functioning but with no
production equipment, materials, or personnel
present.
 At rest : condition where the installation is complete
with equipment installed and operation in a manner
agree upon by the customer and supplier, but with no
personnel present.
 Operational : condition where the installation is
functioning in the specified manner, with the
specified number of personnel and working in the
manner agreed upon.
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30. Four grades of clean areas:
 Grade D (equivalent to Class 100,000, ISO 8):
 Clean area for carrying out less critical stages in manufacture of
aseptically prepared products eg. handling of components after
washing.
 Grade C (equivalent to Class 10,000, ISO 7):
 Clean area for carrying out less critical stages in manufacture of
aseptically prepared products eg. preparation of solutions to be filtered.
 Grade B (equivalent to Class 100, ISO 5):
 Background environment for Grade A zone, eg. Clean room in which
laminar flow workstation is housed.
 Grade A (equivalent to Class 100 (US Federal Standard
209E), ISO 5 (ISO 14644-1):
 Local zone for high risk operations eg. product filling, stopper bowls,
open vials, handling sterile materials, aseptic connections, transfer of
partially stoppered containers to be lyophilized.
 Conditions usually provided by laminar air flow workstation. 30

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 Class 100 is the area where particle count must not
exceed a total of 100 particles per cubic foot (3,500
particles per m³) of a size 0.5 microns & larger.
 Class 10,000 is the area where particle count must not
exceed a total of 10,000 particles per cubic foot
(350,000 particles per m³) of a size 0.5 microns &
larger or 70 particles per cubic foot (2,470 particles per
m³), of a size 5.0 microns & larger.
 Class 100,000 is the area where particle count must
not exceed a total of 100,000 particles per cubic foot
(3,500,000 particles per m³) of a size 0.5 micron &
larger or 700 particles per cubic foot (24,700 particles
per m³ ) of a size 5.0 microns and larger.

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 All pharmaceutical facilities belong to one or other
class of clean room.
 General acceptance is:
 Tabletting facilities - Class 100,000
 Topical & oral liquids - Class 10,000
 Injectables class - Class 100