Sterile preparation techniques involve maintaining cleanliness levels from grades A through F to minimize contamination. Grade A areas have the highest level of protection for aseptic processing. Various sources of possible contamination like premises, air, personnel and materials are controlled. Personnel follow hygiene procedures and wear protective clothing appropriate for the cleanliness grade. Sampling locations are chosen based on factors like criticality and proximity to products to monitor environmental quality.

1. 1
Sterile Preparation Techniques:
The most prior requisite to understand Sterile or
Aseptic Manufacturing/Preparation Activities is to know
- - - - -

2. 2
GMP
Sterile Preparation Techniques:

3. 3
Sterile Preparation Techniques:
GMP is a ----------
• Concept
• Philosophy
• Law (Rules and Regulations)
• Commitment

4. 4
Aseptic operations are always dependent on the followings:
• Premises and Equipment
• Air
• Personnel
• Materials
• Methods/Techniques
• Above create an environment for certain controlled activity
Sterile Preparation Techniques:

5. 5
Sterile Preparation Techniques:
But also - - - - - - - -
Possible contamination sources from the environment are:
• Premises and Equipment
• Air
• Personnel
• Materials
To minimize the contamination risk to acceptable
levels, manufacturing areas are classified into six
cleanliness classes (A-F) with graded requirements:

6. 6
Sterile Preparation Techniques:
Cleanliness Classes and Monitoring of Controlled
Environment:
• Grade F: non-classified (no specification for microbial
contamination or total airborne particles), clean areas in
which product is not exposed to the environment. These
areas are appropriate for storage (warehouse), secondary
packaging and for other operations requiring controlled
access and pest controlled environment.
• Grade E: classified area (specification for microbial
contamination) appropriate for the manufacturing of non-
sterile products that are usually not at risk of microbial
contamination.

7. 7
• Grade D: classified area (specification for microbial
contamination and total airborne particles) appropriate
for the manufacturing of products usually not at risk
but requiring a controlled microbial environment.
• Grade C: classified area (specification for microbial
contamination and total airborne particles) appropriate
for the manufacturing of products unusually at risk
requiring environments with low levels of
contamination.
Sterile Preparation Techniques:

8. 8
• Grade B: classified area (specification for microbial
contamination and total airborne particles) appropriate
as surrounding area for the area/zone in which aseptic
processes are performed requiring direct operator
interventions (Grade A).
• Grade A: classified area (specification for microbial
contamination and total airborne particles). These
areas are not necessarily separated rooms but
represent zones protected by unidirectional air flow,
barrier- or isolator technology for the manufacturing of
products requiring the highest protection against
microbial and particulate contamination (aseptic
processing).
Sterile Preparation Techniques:

9. 9
Premises and Equipment:
• Their layout and design must aim to permit effective
cleaning and maintenance in order to avoid cross-
contamination, build up of dust or dirt and, in general,
any adverse effect on the quality of products.
• Premises are preferably laid out in such a way as to
allow the production to take place in areas connected
in a logical order and to the requisite cleanliness levels,
to avoid cross contamination and to minimize the risk in
manufacturing or control steps. Plants, food, drink,
smoking material and personal medicines are not
permitted in manufacturing areas cleanliness class A to
F.
Sterile Preparation Techniques:

10. 10
Premises and Equipment:
• Premises must be designed and equipped so as
to afford maximum protection against the entry
of insects or other animals.
Sterile Preparation Techniques:

11. 11
Air:
For critical processes, like aseptic filling, airflow
patterns are evaluated for turbulence or eddy flow that
can act as a channel or reservoir for air contaminants
(e.g., from an adjoining lower classified area). In situ air
pattern analysis must be conducted at the critical area
to demonstrate unidirectional airflow and sweeping
action over and away from the product under dynamic
conditions. The studies must be well documented with
written conclusions.
Sterile Preparation Techniques:

12. 12
Personnel:
• Steps must be taken to ensure as far as is practicable
that no person affected by an infectious disease or
having open lesions on the exposed surface of the body
is engaged in the manufacture of drug products.
• Direct contact must be avoided between the operator’s
hands and the exposed product as well as with any part
of the equipment that comes into contact with the
products. If this is inevitable, personnel must wear
gloves. Gloved hands are disinfected regularly and
before each intervention under cleanliness class A.
Sterile Preparation Techniques:

13. 13
Personnel:
• Personal hygiene procedures including the use of
appropriate protective clothing applies to all persons
entering cleanliness class A to E. Hands must be always
washed and disinfected before entering cleanliness
class B to D areas.
• The type and quality of clothing in classified areas has
to be suitable for the work routine, safety and
environment. Clothing must be worn correctly at all
times to avoid contamination of pharmaceutical
products. Use of clothes of different colors or types is
useful to make a clear differentiation between
cleanliness classes.
Sterile Preparation Techniques:

14. 14
Personnel:
• Used protective clothing can be a source of cross
contamination.
• Protective clothing must be laundered and dried in such
a way that it does not gather additional contaminants,
which can be later shed in the controlled environment.
In addition and based on manufacturer’s
recommendation, a maximum number of washing and
cleaning cycles must be defined for critical clothing.
Sterile Preparation Techniques:

15. 15
Personnel:
• Changing and washing must follow a written procedure
designed to minimize contamination of clean area
clothing or carry-through of contaminants to the clean
areas.
• No make-up, no wrist-watches, no jewelry, no artificial,
long or pointed fingernails are accepted in cleanliness
class E or higher.
• For aseptic gowning, a qualification program must
assess the ability of a cleanroom operator to maintain
the cleanliness of the gown at least once per year. The
assessment includes microbiological surface sampling
of several locations on a gown (glove fingers, forearm,
facemask/hood, chest and shoes).
Sterile Preparation Techniques:

16. 16
Zone Dependent Personnel Activity:
• Maintain controlled access. Only trained persons with
proper gowning
• Minimize the frequency of entries and exits
• Minimize the number and density of people
• Minimize the movements and traffic flow
Sterile Preparation Techniques:

17. 17
Zone Dependent Personnel Activity:
• Avoid excessive/loud talking. Sanitize the gloved hands
frequently. Exclude personnel with infectious illness
• In critical areas, minimize the air turbulence and
disruption of LFH by hands and other objects
Sterile Preparation Techniques:

18. 18
Zone Dependent Personnel Activity:
• Avoid to touch any critical object under LFH
• Reduce direct human manipulation of critical objects
such as sterile stoppers and parts
• Avoid simultaneous doors opening
Sterile Preparation Techniques:

19. 19
Materials:
• Operations on different products are not being carried
out simultaneously or consecutively in the same room
unless there is no risk of cross-contamination (or mix-
up).
• When working with dry powders, special precautions
have to be taken to prevent the generation and
dissemination of dust.
• Dedicated premises and equipment are necessary
during handling of following materials:
• Penicillin and other ß-lactams
Sterile Preparation Techniques:

20. 20
Materials:
• Segregated premises and equipment are necessary
during handling of following materials:
• Biological preparations from live micro-organisms
• Genotoxic compounds that are known to be, or highly likely
to be, carcinogenic to humans
• Compounds that can produce reproductive and/or
teratogenic effects at low dosage* as well as that can
produce serious target organ toxicity or other significant
adverse effects at low dosage*
Sterile Preparation Techniques:

21. 21
Materials:
Certain highly active hormones or other highly active
drug substances**
• * low dosage=clinical doses<10mg/day or dosages in
animal studies<1mg/kg/day)
• ** highly active drug substances=clinical
doses<1mg/day
Sterile Preparation Techniques:

22. 22
Sampling Site Selection for Microbiological
Monitoring:
• Sampling reflects the actual usage of the environmental
system and is therefore taken from representative
locations and critical areas.
• Sampling site selection is based at least on the following
criteria:
• Criticality of production process
• Proximity to the product (for class A maximal 30 cm
distance)
• Size and geometry of the room
Sterile Preparation Techniques:

23. 23
Sampling Site Selection for Microbiological
Monitoring:
• Personnel traffic patterns
• Material traffic patterns
• Cleanliness class
• Air visualization studies where appropriate
• Visual inspection of the facility with particular attention
to areas posing potential risk to the product
• Personnel monitoring following each aseptic handling.
Sterile Preparation Techniques:

24. 24
Active Air Sampling:
• Sampling is performed with a suitable impaction
sampler (e.g., such brands as Reuter-Centrifuge-
Sampler, MAS-100-Sampler, Slit-to-Agar Air Sampler or
Anderson Air Sampler)
Passive Air Sampling:
• Sampling is performed using settling plates of a suitable
size, e.g., dishes with a diameter of 90 to 100mm.
Exposure of single plates does not exceed 4 hours.
Where necessary the sum of multiple plates from one
sampling site is used to reach the overall exposure
time.
• Results are reported in Colony Forming Units
(CFU)/plate x time.
Sterile Preparation Techniques:

25. 25
Documentation and Trending of Monitoring Data:
• All monitoring activities are documented properly. The
results from critical sampling locations must be
assignable to the respective activity at the time of
sampling.
• Monitoring data must be summarized on a periodic
basis.
Sterile Preparation Techniques:

26. 26
Documentation and Trending of Monitoring Data:
• Based on this summary trends (for total particulate
monitoring, if applicable) have to be evaluated and
summaries have to be issued to the responsible senior
management on a periodic basis.
• Where necessary the environmental monitoring data must
have a formal linkage to product releases as defined by
procedures.
Sterile Preparation Techniques:

27. 27
Investigation Procedures:
• Written procedures are established assigning
responsibility for and describing in sufficient detail the
necessity for initiating corrective actions when the
specified levels of a controlled environment are
exceeded.
• Monitoring critical and associated clean areas as well as
personnel includes routine identification of
microorganisms to the species (or, where appropriate,
genus) level when Alert and Action Levels are
exceeded. In classes A and B all microorganisms found
are identified to the species or, where appropriate
genus level.
Sterile Preparation Techniques:

28. 28
Gowning Procedures:
• Wear sterile white uniform taking care to touch only
the inside surface of uniform to prevent contamination.
Put on sterile white suit in following sequence (clean
hands with 70% IPA at every sequence and every time
take care to touch only the inside surface of every part
of uniform):
1. Sterile Surgical Gloves
2. Sterile Trouser and Gown
3. Sterile Head Mask
4. Sterile Nose Mask
5. Sterile Shoe Covers
Sterile Preparation Techniques:

29. 29
Gowning Procedures:
• Enter Buffer Room, pick up a wrapped Tyvik Suit,
unwrap and wear it in the following sequence:
1. Tyvik Suit with Head Cover
2. Shoe Cover
• Put on a 2nd pair of surgical glove
• Swab the gloved hands with 70% IPA and enter the
main filling room, again clean the gloved hands with
70% IPA and straight away go to the working place. If
hands touched with anything with swab hands again
with 70% IPA. Start filling operation.
Sterile Preparation Techniques:

30. 30
Precautions During Work in Sterile Area:
• Do not touch any part of body with wall, door or filling
machine etc.
• Do not move fast or excessively in the sterile area.
Avoid excessive talking during work in Sterile Fill Room
• Use fresh sterilized uniform after every interval
• Do not Lean over the Critical Sterile Items
• Do not put your Elbow and Legs while sitting on stool
Sterile Preparation Techniques:

31. 31
• Once product become non-sterile (contaminated)
• Patient Safety At Risk
• Manufacturing Process is Irreversible – Cost
• Confidence Shaken
Sterile Preparation Techniques:

32. 32
Gowning Requirement
Requirement/Cleanliness Class A B C D E
F
1)
F
2)
• Suitable work suit and plant footwear
• Cap complete covering head hair
• Gloves (non powdered and free of components which may produce allergic reactions either
to patients or to personnel such as latex proteins), mouth and if necessary beard covering are
worn when working with open product or cleaned surfaces coming into contact with products
• In manufacturing areas covering mask for moustache/beard is always worn
• One or two piece work suit with closed cuffs and collar
• No exterior, unlocked pockets and utensils above waist line
• One/two piece work suit with closed cuffs and collar made of texture which sheds few
fibers and particles
Sterile Preparation Techniques:

33. 33
Gowning Requirement
Requirement/Cleanliness Class A B C D E
F
1)
F
2)
• Sterilized overalls made of synthetic monofilament material worn onto clean room
underwear or on the work suit of cleanliness class D or higher
• A cap covering the hair completely and tucked into the overalls and a face mask covering
mouth and nose as well as sterilized clean room helmets if necessary
• No bare skin between gloves and cuffs
• Sterilized cover shoes (“booties”) worn on sterilized/disinfected cleanliness class B
dedicated shoes
• Sterilized, non powdered rubber or plastic gloves (free of components which may produce
allergic reactions either to patients or to personnel (e.g., latex proteins)
• Sterilized forearm protection or gloves covering forearm
• Sterilized or disinfected goggles/shields
• Working clothes have to be changed every time the area is entered
• Working clothes are changed at least once a week or if dirty
• Working clothes are changed at least twice a week or if dirty
F 1) = Secondary packaging areas F 2) = Warehouse/API production
Sterile Preparation Techniques:

34. Sterile products
• Sterile products" are dosge forms of therapeutic agents that are free
from viable microorganism
• Sterile products include
 Intravenous injections and admixtures
 IM, SC, and Epidural (preservative-free) injections
 Ophthalmic preparations
 Intrathecal preparation
• Two categories of sterile products
– those that can be sterilized in final container (terminally
sterilized)
– those that cannot be terminally sterilized and must be aseptically
prepared

35. Cont.…….
• Examples of Sterile Products Provided:
• Intrathecal pump medications: e.g., morphine, fentanyl,
clonidine, hydromorphone, bupivacaine,etc.
• Ophthalmic preparations
• Compounding for Retina Specialists: Bevacizumab
(Avastin®) Injection
• Anterior Chamber Injections: Injections may
contain: Ceftazidime, Vancomycin, Dexamethasone,
Triamcinolone, Hydrocortisone

36. Parenteral products:
• Parenteral products are products that are administered
to the body by injection
• Because this route of administration bypasses the
normal body defense mechanisms, it is essential that
these products are prepared with a high degree of care
and skills than utilized in preparing conventional oral or
topical products.
• The finished product must be sterile, non-pyrogenic and
free from extraneous insoluble materials. These products
must satisfy a number of requirements for parenteral
products.

37. Ophthalmic preparation
• They are specialized dosage forms designed to be
instilled onto the external surface of the eye (topical),
administered inside (intraocular) or adjacent (periocular)
to the eye or used in conjunction with an ophthalmic
device.
• The most commonly employed ophthalmic dosage forms
are solutions, suspensions, and ointments. But these
preparations when instilled into the eye are rapidly
drained away from the ocular cavity due to tear flow and
lacrimal nasal drainage.
• The newest dosage forms for ophthalmic drug delivery
are: gels, gel-forming solutions, ocular inserts ,
intravitreal injections and implants.

38. Intrathecal preparation
• Intrathecal administration is a route of
administration for drugs via an injection into
the spinal canal, or into the subarachnoid
space so that it reaches the cerebrospinal
fluid(CSF) and is useful in spinal
anesthesia, chemotherapy, or pain
management, applications.

39. Advantages
• Quick onset of action
• Suitable for drug which are not administered by oral
route
• Useful for unconscious or vomiting patients
• Suitable for drugs which are inactivated in GIT tract
• Suitable for nuitritive like glucose and electrolyte.

40. Disadvantages
• Injection may cause pain at site of injection site.
• Only trained person required
• If given through wrong route ,difficult to control
adverse effects
• Sensitivity and allergic reaction may occur at
site of injection
• Require strict control of sterility and non
pyroginicity more than other formulation

41. Ideal Requirements
• Sterility
• Particulate material
• Pyrogen free
• Stability
• pH
• Osmotic pressure

42. During the formulation of sterile products
the following factors are critical
• The vehicle in which the drug is dissolved or
dispersed
• Volume (dose) of the injection
• Adjustment of isotonicity
• Adjustment of pH
• Stabilisers
• Preservatives
• Adjustment of specific gravity (for spinal
anaesthesia)
• Concentration units

43. Difference between parenterals and
other products
• Limits to the level of pyrogens present and of
particulate matter
• The injection route dictates the volume of
formulation. Hence the solubility of the drug in
the selected vehicle is critical in the formulation

44. Vehicle
• The preferred vehicle is water as it is well
tolerated by the body, easy to administer and a
large solvent capacity
• Water for injection must be sterile and free from
pyrogens
• Cellulose, glass, rubber cores, cloth or cotton
fibers may constitute the contaminants list.
• Suitable filtration media for removal of particulate
material are sintered glass filters or membrane
filters with a pore size of 0.45-1.2 microns

45. PH and Buffers
• As parenteral products are administered directly to
tissues and systemic circulation, formulations prepared
should not vary significantly from physiological pH, which
is about 7.4.
• The acceptable pH range is 3-10.5 for i.v preparations and
4-9 for other routes.
• Buffers are included in injections to maintain the pH of
the packaged product.
• The buffers used in the injection must allow the body
fluids to change the product pH after injection.
• Acetate, citrate and phosphate buffers are commonly
used in parenteral products.

46. Osmotic pressure
• The osmotic pressure of the blood is approx.
300 milli Osmoles/L and ideally any sterile
solution would be formulated to have the same
osmolarity
• For eg: 0.9% w/v NaCl i.v solution has an
osmolarity of 308 milli Osmoles/L .
• 5% w/v Dextrose i.v solution has an osmolarity
of 280 milli Osmoles/L .
• NaCl, Mannitol or glucose can be used to adjust
osmolarity.

47. Antimicrobial agents
• Aqueous preparations which are prepared using
aseptic preparations and which cannot be
terminally sterilized may contain a suitable
antimicrobial preservative in an appropriate
concentration.
• Antimicrobial agents are added to multiple dose
vials to inhibit the growth of microbial organisms
which may occur accidentally and contaminate
the product during use.
• Antimicrobial agents must be effective in the
parenteral formulation

48. Antimicrobial preservatives
S.NO ANTIMICROBIAL
AGENT
CONCENTRATION (%w/v)
1 Benzalkonium
chloride
0.01
2 Benzyl alcohol 1- 2
3 Chlorobutol 0.25 – 0.5
4 Phenol 0.5
5 Chlorocresol 0.1 – 0.3
6 Phenyl mercuric
salts
0.002

49. Antioxidants
• Aqueous solutions are more susceptible to
oxidation
• Bisulphites and metabisulphites are commonly
used antioxidants in aqueous injections.
• Injection formulations may in addition also
contain chelating agents, such as EDTA or citric
acid, to remove trace elements, which catalyse
oxidative degradation.

50. Sterilization
• Sterility : Absence of life or absolute freedom
from biological contamination.
• Sterilization : inactivation or elimination of all
viable organism and their spores.
• Disinfectant : substance used on non- living
objects to render them non- infectious; kills
vegetative bacteria, fungi, virus but not spores.
Eg: Formaldehyde
• Bactericide : ( Germicide) substance that kills
vegetative bacteria and spores

51. Sterilization-Methods
Commonly used methods of sterilization
– Moist Heat
– Dry Heat
– Gas (Ethylene oxide)
– Radiation (Gamma or Electron)
– Filtration
– Others - UV, Steam and formaldehyde, hydrogen
peroxide

52. Moist Heat
• Saturated steam
• Common cycles:
– 121°C for 15 minutes
– 134°C for 3 minutes
– Other cycles of lower temperature and longer
time may be used (e.g. 115°C for 30 minutes)
• Used for sterilization of:
– terminal sterilization of aqueous injections,
ophthalmic preparations, irrigation &
haemodialysis solutions, equipment used in
aseptic processing

53. Moist Heat
• Not suitable for non-aqueous/dry preparations
• Preferred method of sterilization

54. Pasteurization
• Moist heat at temperature below 1000 C.
• Heat labile fluids may be disinfected not sterilized
by heating at 560 C for 30 min.
• Sufficient to kill mesophilic bacteria but not spores.
• For serum, or other body fluids containing
proteins, temp to rise above 59o C.
• UHT; 140o C less than 1 sec.
• Cold Pasteurization.
• High pressure pasteurization.

55. Dry Heat
• Lethality due to oxidative processes
• Higher temperatures and longer exposure times
required
• Typical cycles:
– 160°C for 120 minutes
– 170°C for 60 minutes
– 180°C for 30 minutes
– tunnels used for the sterilisation of glass vials may
use much higher temperatures (300°) for a much
shorter period

56. Dry Heat
• Used for:
– glassware and product containers used in aseptic
manufacture, non aqueous thermostable powders and
liquids (oils)
• also used for depyrogenation of glassware (250°C)
– (Pyrogens - substances found in cell wall of some
bacteria which can cause fever when introduced into
the body)

57. Ethylene Oxide Gas
• Either pure or in mixtures with other inert gases
• Requires presence of moisture
• Complex process
• Typical cycles:
– 1-24hours
– 25-1200 mg/L gas
– 25-65°C
– 30-85% relative humidity

58. Ethylene Oxide
• Used for:
– heat labile product containers
– surface sterilization of powders
• Adequate aeration to reduce toxic
residues

59. Radiation
• Gamma rays generated by Cobalt 60 or Caesium 137
radionuclides; or
• Accelerated electrons from an electron generator
• 25 kilograys (kGy) usual dose
– dose dependent on bioburden (resistance of
organisms not predictable)
• process must be properly validated
• used for:
– dry pharmaceutical products
– heat labile product containers
• can cause unacceptable changes

60. Filtration
• Removes organisms from liquids and gasses
• 0.2 - 0.22 micron for sterilization
• composed of cellulose esters or other polymeric
materials
• filter material must be compatible with liquid
being filtered
• used for bulk liquids, gasses and vent filters

61. Autoclaves
• Invented by Charles
Chamberland in
1879.
• Precursor was the
Steam digester
invented by Denis
Papin in 1679.
• At correct temp
lethal to all bacteria,
viruses, fungi &
protozoa.

62. Cont.……
• Example of usage of autoclaves are:
• Hospitals & OPD- Porous load autoclaves.
• Mortuary- Bench top autoclaves.
• Microbiology Lab: Media preparators or fluid
cycle steam sterilizers.
• Pharmaceutical- Fluid Cycle Sterilizer

64. Sterile Area Lay Out
• The production of sterile preparations should be carried
out in clean areas, entry to which
• should be through airlocks for personnel and/or for
equipment and materials.
• Clean areas should be maintained to an appropriate
standard of cleanliness and supplied with air that has
passed through filters of the required efficiency
• Manufacturing operations are divided here into two
categories: first, those where the productis terminally
sterilized, and second, those which are conducted
aseptically at some or all stages.

65. Quality control
• The sterility test applied to the finished product should only be
regarded as the last in a series of
• control measures by which sterility is assured. The test should be
validated for the product(s) concerned.
• Samples taken for sterility testing should be representative of the
whole of the batch, but
• should, in particular, include samples taken from parts of the batch
considered to be most at risk of contamination, for example:
(a) for products that have been filled aseptically, samples should
include containers filled at the
beginning and end of the batch and after any significant interruption
of work;
(b) for products that have been heat sterilized in their final containers,
consideration
should be given to taking samples from that part of the load that is
potentially the coolest

66. Cont.…..
• The sterility of the finished product is assured by
validation of the sterilization cycle in the
• case of terminally sterilized products, and by “media
simulation” or “media fill” runs for aseptically
• processed products. Batch processing records and, in
the case of aseptic processing, environmental
• Working document QAS/09.295 Rev.1
• page 5
• quality records, should be examined in conjunction with
the results of the sterility tests.

67. Sanitation
• The sanitation of clean areas is particularly
important. They should be cleaned frequently
• and thoroughly in accordance with an approved
written programmed.
• Monitoring should be regularly undertaken in
order to detect the contamination or the
presence of an organism against which the
cleaning procedure is ineffective.

68. Manufacture of sterile
preparations
• Clean areas for the manufacture of sterile
products are classified according to the required
• characteristics of the environment. Each
manufacturing operation requires an appropriate
• environmental cleanliness level in the operational
state in order to minimize the risks of particulate
or microbial contamination of the product or
materials being handled.

69. Manufacture of sterile
preparations
• For the manufacture of sterile pharmaceutical
preparations, four grades are distinguished
• here, as follows:
• Grade A: The local zone for high-risk operations, e.g.
filling and making aseptic connections.
• Normally such conditions are achieved by using a
unidirectional airflow workstation. Unidirectional
• airflow systems should provide a homogeneous air
speed of 0.36–0.54 (guidance value) at a defined
• test position 15-30 cm below the terminal filter or air
distributor system.

70. Manufacture of sterile
preparations
• Grade B: In aseptic preparation and filling, the
background environment for the grade A zone.
• Grades C and D: Clean areas for carrying out less
critical stages in the manufacture of sterile
• products.

71. Manufacture of sterile
preparations
• Clean room and clean air device classification
• Classification should be clearly differentiated
from operational process environmental
monitoring.
• The maximum permitted airborne particle
concentration for each grade is given in Table 1.

72. Grade
Maximum number of
particle
Permitted per m3
Maximum number of
viable micro-organism
per m3
0.5–5 μm > 5 μm
A
(Laminar airflow
workstation)
3 500 None Less than 1
B 3500 None 5
C 350,000 2000 100
D 3500,000 20000 500

73. Cont.……
• Manufacturing operations are here divided into
three categories
• first, those in which the preparation is seal in its final
container and terminally sterilized;
• second, those in which the preparation is sterilized
by filtration; and
• third, those in which the preparation can be
sterilized neither by filtration nor terminally and
consequently must be produced from sterile starting
materials in an aseptic way

74. Cont.……
• Manufacturing operations are here divided into
three categories
• first, those in which the preparation is seal in its
final container and terminally sterilized;
• second, those in which the preparation is sterilized
by filtration; and
• third, those in which the preparation can be
sterilized neither by filtration nor terminally and
consequently must be produced from sterile starting
materials in an aseptic way

75. ASEPTIC PROCESSING
• Aseptic processing presents a higher risk of microbial
contamination of the product than terminal sterilization.
In an aseptic filling process, the drug product, containers
and closures are sterilized separately and then brought
together under an extremely high quality environmental
condition designed to reduce the possibility of a non-
sterile unit. Aseptic processing involves more variables
than terminal sterilization. Any manual or mechanical
manipulation of the sterilized drug, containers, or closures
prior to or during aseptic filling and assembly poses the
risk of microbial contamination

76. OVERVIEW OF MANUFACTURING PROCESS OF
PARENTERALS
Equipment &
facility Manufacturing
requirement
docume
ntation
personal
Finishing
Manufacturing
Bulk analysis
Sterilization
Q.C. Testing
Aseptic filling
Visual inspection
Labeling
&
packing
Planning &
scheduling
Material
management
-Raw material &
API
-Packaging material
Wareho
using

77. ENVIRONMENTAL CONTROL ZONE GROUPING
• Zone 1:- Exterior
• Zone 7:- Filling line
• Zone 6:- Filling area
• Zone 5:- Weighing, mixing & transfer area
• Zone 4:- Clean area
• Zone 3:- General production
• Zone 2:- Warehouse

78. AREA PLANING AND
ENVIRONMENTAL CONTROL:
-
Area planning may be addressed by functional
groups ground this critical area with particular attention
given to maintaining cleanliness.
Functional groupings:-
Warehousing:-
o The storage of spare parts, air filters, change parts, water
treatment chemicals, office supplier, janitorial supplies,
uniforms, an so on may be handled as central storage or
individually by department.
o Finished product and certain raw materials need special
environmental storage conditions, such as, temperature
and humidity control.

79. WALL & FLOOR TREATMENT
:
• The design of filling areas or more generally,
controlled environment areas involves attention to
many seemingly minor details. The basic clean ability
requirement includes smooth, cleanable walls, floors,
ceilings, fixtures, and partition exposed columns, wall
studs, bracing, pipes, and so on are unacceptable.
The need for clean ability also eliminates the
open floor system commonly used in the
microelectronics industry for laminar airflow rooms.

80. LIGHTNING FIXTURES
Lighting fixtures should be reduced flush with the ceiling. Areas
having a full HEPA ceiling obviously cannot accommodate recessed
lighting fixtures. In these areas, fixtures are of a special “tear drop”
shape which minimizes disruption to the laminar airflow pattern.
4. CHANGE ROOMS :
• Personnel access to all controlled areas should be through change
rooms. Change rooms concepts and layouts
vary from single closet size rooms to
expensive multi-room complexes.

81. Entrance to a change area is normally through
vestibules whose doors are electrically interlocked
so that both cannot be opened simultaneously, thus
maintaining the necessary air pressure differential
to prevent the entry of airborne contamination.
Upon entry into the change room wash skins
are provided for scrubbing hands and forearms.
Further control may be achieved by using
filtered and heated compressed air for drying to
reduce further particular potential.

82. Cont.……
• After hands are dry, garments are taken from
dispensers and donned while moving across a
dressing bench.
• As a final growing step, aseptic gloves are put
on and sanitized. Exit from the change room to
the controlled area is, like entrance, through an
interlocked vestibule.

83. Personnel flow :-
The movement of personnel should be planned
during the design of individual plant areas. Each
individual production area may have a smooth and
efficient personnel flow pattern, a discontinuous or
crowded pattern may develop when several
individual production area plants are combined.
The flow of material and personnel through
corridors are inefficient and unsafe paths for
moving materials, particularly if heavy forklifts are
required.

84. UTILITES AND UTILITY EQUIPMENT
LOCATION :-
Utilities :-
Piping system in particular, must be initially and
often periodically cleaned and serviced. Exposed
overhead piping is not acceptable from a cleanliness or
contamination stand point since it collects dirt, is
difficult to clean and may leak. Buried or concealed pipe
may require unacceptable demolition for cleaning or
repair.
Utilities equipment location :-
Public utilities require space for metering. In
addition to meeting, electrical power system require for
switchgear and transformer.

85. Cont…..
Water systems usually require treatment to ensure
consistent quality. Plant generated utilities typically
require steam boilers, air compressors, and
distillation, the typical “boiler room” approach.
Proper equipment maintenance is difficult in foul
weather, especially winter.
Heavy equipment may damage the roof-
structure, particularly if the equipment location
requires numerous penetrations through the roof
which, coupled with equipment vibration, will
invariable lead to leakage.

86. .
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