STERILE PRODUCTS

(Chapter 4 Part C) (Spring 2023)

 Sterile Manufacturing
 All pharmaceutical manufacturing operations are
complicated, requiring utmost organization &
control to ensure that every dosage form produced
meets all quality attributes and specifications.
 Sterile pharmaceutical manufacturing has added
complication of assuring that dosage forms produced
are free from microbial contamination, endotoxin
contamination & visible particulate matter.
 Unit processes involved in manufacturing include
compounding & mixing, filtration, filling, terminal
sterilization (when possible), lyophilization (freeze-
drying), closing & sealing, sorting & inspection,
labeling, and final packaging for distribution
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 cGMP Principles Involved
1. Ensure that personnel responsible for assigned duties
are capable & qualified to perform them. GMP
emphasizes need for personnel to have a combination
of education, experience & training to do their jobs.
2. Ingredients used in compounding the product have the
required identity, quality & purity.
3. Validating critical processes to be sure the
equipment used & processes followed ensure that the
finished product has the qualities expected.
4. Maintaining a production environment suitable for
performing critical processes required, addressing
such matters as orderliness, cleanliness, asepsis &
avoidance of cross contamination.
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5. Confirming, through adequate quality-control
procedures, that the finished products have the
required potency, purity, and quality.
6. Establishing, through appropriate stability
evaluation, that drug products retain their intended
potency, purity, and quality, until established
expiration date.
7. Ensuring that processes are always carried out in
accordance with established, written procedures.
8. Providing adequate conditions and procedures for the
prevention of mix-ups or cross-contamination.
9. Establishing adequate procedures, with supporting
documentation, for investigating & correcting
failures or problems in production or quality
control. 4
10.Providing adequate separation of quality-control
responsibilities from those of production to
ensure independent decision making.
11. Establishment of time limits for each phase of
production.
12.Requirements for the ability to reprocess unit
operations.
13.Requirements for label control.
14. Documentation requirements for master
production records & batch records.

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 (B) PRODUCTION
 All steps from accumulation and combining
of ingredients of the formula to enclosing
of product in the individual container for
distribution.
 Well planned processes can become
ineffective by;
1) Personnel – not having right attitude and
training.
2) Facilities – do not provide properly
controlled environment.
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 Requirement
 All processing steps found effective should be
written & always followed (SOPs).
 Only be changed through proper steps.
 Records to assure that production processes are
carried out as prescribed – requirement of GMP.
 In-process controls more important than even
product release testing.
 Quality product – efforts of personnel in
developing, performing and confirming SOPs.
 QA involved in preplanning those factors that
produce a quality product.
 QC concentrate on those operations & tests that
are designed to evaluate actual quality achieved by
the product.
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 PRODUCTION STEPS
1. Formula ingredients, container components &
processing equipment released for use are
drawn from respective storage areas.
2. Ingredients compounded according to master
formula in environment maintained at high level
of cleanliness.
3. Solution is filtered during transfer to aseptic
filling room.
4. Equipment & container components cleaned
according to specifications & assembled in clean
environment, usually sterilized &
depyrogenated before use. 8
5. All equipment & supplies sent into filling area
should be sterile & enter through double-ended
sterilizers.
6. Otherwise passed through openings of
minimum size that can be reclosed quickly
under aseptic conditions.
7. Outer wrapping of packages loosened &
contents received by personnel by grasping the
inner wrappings.
8. Otherwise, outer surfaces of boxes, packages or
equipments be wiped with disinfectant solution
and transferred to aseptic room.
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9. Transfer be made in such a manner that aseptic
condition of the room is maintained and any
chance of introduction of contaminant into product
eliminated.
10.Sealing of product in final container is done in
aseptic room, then transferred to packaging area
(clean).
11.Stored in quarantine until all tests have been
completed and then released for distribution.

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 Air locks
 Small room generally composed of interlocked
doors, constructed to maintain air pressure
control between adjoining rooms.
 Intent of an aseptic processing airlock is to
preclude ingress of particulate matter and
microorganism contamination from a lesser
controlled area.
 Air balance for the bio-safety of facility should be
established and maintained to ensure that
airflow is from areas of least to greater
contamination.
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 Functions of Airlocks
1. Airlock helps to protect classified area from men
& material movement.
2. “Air lock system” in pharmaceutical manufacturing
is to avoid chances of cross contamination & to
separate different process areas.
3. Airlocks are closed room having two or more
doors between two different controlled areas
having different cleanliness level as Class B & C,
Class B & D & Class C & D areas.
4. These airlocks prevent direct air flow between
these areas during entry of material or personnel.

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 Types of Air Locks
 Airlocks are called PAL (Personnel Air Lock) when
used for personnel and MAL (Material Air Lock)
when used for transferring the material.
 There are three basic airlock designs that can be
combined or used individually to protect the clean
room and/or prevent cross contamination between
two adjacent areas of different process operations
served by two different HVAC systems.
 These three airlocks are:
1. Cascade Airlock
2. Bubble Airlock
3. Sink Airlock
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 1- Cascade Airlock
 These airlocks are very common having higher
pressure on one side & lower pressure on
another side.
 In this system positive air pressure flows from higher
pressure internal zone to airlock and from the
airlock to the lesser or lower pressure grade area.
 Prevents entry of dust and contamination from
outside to airlock and from airlock to inner side.
Application
 Any manufacturing facilities where product requires
protection from particulate but people outside
the clean-room do not need protection from
product in the clean room. 16
 2- Bubble Airlock
 These types of airlocks have higher pressure
inside the airlock and lower pressure on both
outsides.
 It creates a barrier where contaminants within either
area pushed back into their own respective areas.
Application
 Areas where product needs protection and people
external to cleanrooms require protection from
product, to reduce possibility of viable particulate
from entering the lesser pressure clean-room.
 Area such as higher potency, compounding areas
where terminal sterilization is not an option.
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 3- Sink Airlock
 Airlocks having lower pressure inside airlock and
higher pressure on both sides of the airlock.
 Airlock pulls air from both adjacent areas creating a
low pressure barrier and reduces the opportunity of
contaminations passing to the internal zone.
Application
 In many research facilities, substance that are
experimented on are highly dangerous, and it is
essential to keep them from being exposed.
 During a few type of production processes in a
clean-room, air from a contaminated area has to be
contained in one place.
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General airlock concept by classification

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 Importance & Features of Airlocks
 Proper URS(User Requirement Specification)& subject
matter expertise is need of hour to design, qualify &
operate such clean room facilities with good airlocks.
 Air Locks are ventricles of heart, if they fail the whole
system collapses.
 Air change rate is another important clean room
design parameter.
 For Class 100,000 (ISO 8) supporting rooms, airflow
sufficient to achieve at least 20 air changes per hour is
typically acceptable.”
 Design requires hard numbers, so there is temptation
for design team to use this statement as a final Quality
position—“that 20 air changes is acceptable in a
Grade C area.” 24
 Adjacent rooms of different grades should have
pressure differential of 10-15 pa (guidance values) &
12.5 Pa between a classified & non-classified room.
 Doors of airlocks should be open to higher pressure
side which help to close the door.
 Interlocking system should be provided to prevent
the opening of both doors at a time.
 An alarm should be provided to indicate that one
door is opened, it helps to prevent entry of
contamination through the airlocks.
 Higher air changes per hour rate should be
maintained in airlock, it should be minimum 20 air
changes per hour.
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 It helps to remove the contaminants entered
from the outside easily.
 Airlocks should be kept empty, material such as
garments, shoes covers etc. should not kept in the
airlocks.
 In Pharmaceutical, Bio-Pharmaceutical and sterile
manufacturing, the Clean room environment is
the major prerequisite for all manufacturing
activity.
 Without a proper movement mechanism &
background environment, no medicine can be
produced for patient consumption.
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 Air Cleanliness Level
 A quality which indicates the condition of cleanliness
of a monitored item, expressed as number of
particles larger than 0.5 μm permitted per m3. Is
classified in grades A, B, C, and D according to the
required particulate number in the air.
 Heating ventilation air condition (HVAC) system
An air handling system including Heating,
Ventilation, & Air Conditioning.
 High Efficiency Particulate Air (HEPA) filter
 Filters designed to retain particulates of larger than
a certain size with defined efficiency.
 The filter retains particles of ≥ 0.3 μm size with a
minimum efficiency of 99.97%.
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 Facilities
 Maintain cleanliness for each step.
 Buffer areas be present around aseptic rooms in
which level of cleanliness is slightly lower.
 Be of suitable size, construction & location to
facilitate suitable cleaning, maintenance and
appropriate operation.
 Have adequate space for placement of
equipment as well as production & packaging
materials.
 Consider sequence of operation during design
phase; paying particular attention to the location
of equipment & removal of unnecessary traffic.
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 Have adequate internal temperature,
ventilation & lighting.
 Have smooth surfaces (no cracks, crevices
or shedding), which are easily cleaned.
 Have adequate segregation of materials
products and components to further reduce the
risk of cross contamination.

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Specific floor plan of a sterile dosage form manufacturing facility
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 Measures Necessary for proper design
 To achieve exceptional design & standards of
construction – knowledge of purpose of facility, best
material and design.
i. Ceiling, walls and floors – easy to clean and non
porous to prevent accumulation of debris and
moisture.
ii. Spray on tile – ceramic epoxy finish applied to form
a smooth & continuous seal coating on ceiling and
walls.
iii. Ceramic-plastic cement for floors as thick coat to
form a sealed surface.
iv. Moveable metal partitions are problematic.
v. Glass partition – supervisory view, pleasant, lighted
and less confining environment.
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v. Lighting fixture recessed, exposed piping or
similar dirt collecting surfaces intolerable.
vi. Furniture – nonporous and hard surface (Steel).
vii. Components of equipment difficult to sterilize be
kept out of aseptic area or continuously disinfected.
viii.Careful planning for electrical, Gas, water, air
ventilation & other lines to prevent interruption &
contamination.
ix. Use of HEPA filtered laminar flow added to clean
room to achieve better control in a specific area.

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 Environment Control
 Both Physical and 1. Aseptic manufacturing
Biological. should be done under
 Flexible for variations most rigid control.
in control associated 2. For products to be
with seasonal terminally sterilized, less
conditions. rigid biologic control of
 Standards of the compounding and filling
environmental control areas but rigid standards
vary according to area of cleanliness required.
& product. 3. High standards of
 Clean-up cleanliness, excluding
 Packaging disinfecting procedures for
clean-up and packaging
 Compounding
areas are required.
 Filling 38
 Traffic Control
1. Environmental control easy to maintain in static
conditions but much difficult in working conditions.
2. Minimize traffic in and out of aseptic area.
3. No direct access from outside.
4. Personnel access to aseptic corridor, compounding and
filling rooms through air locks.
5. Pass-through openings and double-ended
sterilizers for controlled passage of supplies.
6. Entry of personnel only after following prescribed
rigid procedures.
7. After entry not allowed to move in & out without
regowning.
8. Even personnel working in cleaning and packaging
areas not allowed to enter.
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 Housekeeping
 Cleaning personnel should follow the approach that not
even one particle of debris is acceptable.
 Many of contaminating particles are of very small size.
 Cleaning of equipment & working area at end of the
day/process.
 Ceiling, walls and structures cleaned with appropriate
frequency (laminar airflow).
 Cleaning equipment be effective, lint-free and specified
for aseptic use only.
 Surface Disinfection
 After cleaning, surfaces are disinfected usually by a liquid
disinfectant.
 U V rays are also used to irradiate different surfaces.
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 AIR CONTROL
 Air must be exchanged at intervals & filtered, fresh or
recycled air introduced free from contaminants.
 Spun glass, cloth or shredded polyethylene filter used
as prefilter (single/multiple).
 To remove finer particles of debris & microorganisms in
submicron range, HEPA filters are used.
 Defined as at least 99.97% efficient in removing
particles of 0.3µm or larger.
 Composed of glass fibers & fillers or electrostatic
precipitators & provide air virtually free from foreign
matter.
 Air cleaning systems wash air with a disinfectant & at
the same time controls humidity.
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 HVAC System
1. HVAC systems assists in ensuring manufacture
of quality products and also result in operator
comfort.
2. HVAC systems design influences architectural
layouts, with regard to items such as airlock
positions, doorways and lobbies.
3. Prevention of contamination and cross-
contamination is an essential design
consideration of the HVAC system.
4. The design of the HVAC system should be
considered at the concept design stage.

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Fundamental rules for cleanrooms
1. Contaminants must not be introduced into the
controlled environment from the outside.
2. The apparatus or equipment within the
controlled environment must not generate or
otherwise give rise to contaminants (for
example as a result of friction, chemical reactions,
or biological processes).
3. Contaminants must not be allowed to
accumulate in the controlled environment.
4. Existing contaminants must be eliminated to the
greatest extent possible, and as rapidly as
possible.
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 AHS
 Air handling system is regarded as HVAC or
“aitch-vak” systems which are mechanical
arrangements that treat outside air to produce
cleaned (from dust & microbes) and conditioned air
(temp. & Humidity) for use in controlled and critical
areas within the Pharmaceutical manufacturing
space.
 The systems normally consist of filtration, heating,
cooling, dehumidification & humidification steps.
 It is the technology of indoor environmental control
and/or comfort.
 Acronym HVAC means: H= Heating, V=
Ventilation; A= Air; C= Conditioning
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 APPLICATIONS OF AIR HANDLING SYSTEM
Ideal cGMP (HVAC system) should provide:
1. Product protection From contamination, cross-
contamination, contamination by operatives, correct
conditions of humidity and temperature.
2. Personnel protection Prevent contact with dust,
prevent contact with fumes, good comfort condition.
3. Environment protection No dust discharge, no
fumes discharge, no effluent discharge
4. Preservation of materials & equipment Handling,
holding and storage.
5. Maintenance of animals and equipment.
 The GMP environment is only possible with an Air
Handling System 45
 HVAC systems basic functions
DEF: Simultaneous control of various components
& parameters of air to specific limit as required for
manufacturing of quality medicine is known as air
conditioning.
1. Control airborne particles, dust & micro-organisms
– Through air filtration using high efficiency
particulate air (HEPA) filters.
2. Maintain room pressure (delta P) – Areas that
must remain “cleaner” than surrounding areas must
be kept under a “positive” pressurization, meaning
that air flow must be from “cleaner” area towards the
adjoining space (through doors or other openings) to
reduce chance of airborne contamination.
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3. Maintain space moisture (RH) – Humidity is
controlled by cooling air to dew point
temperatures or by using desiccant
dehumidifiers. Humidity can affect the efficacy
and stability of drugs.
4. Maintain space temperature - Temperature can
affect production directly or indirectly by fostering
the growth of microbial contaminants on workers.
 Each of above parameter is controlled and
evaluated in light of its potential to impact product
quality.
a) Product quality depends on air quality
b) Products can only be as pure as environments in
which they are produced 47
LIMITATIONS
1. HVAC can not
clean up the
surfaces of a
contaminated
surface, room
or equipment.
2. HVAC can not
compensate
for workers
who do not
follow
procedures

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Factors that contribute to quality products
 Factors that contribute to quality products:
1) Starting materials and packaging materials
2) Validated processes
3) Personnel
4) Procedures
5) Equipment
6) Design and quality of premises
7) Manufacturing environment (Related to
HVAC System)

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 Direct Effect of Environment
 Some environmental factors have a direct influence on a
product:
1. Light, for light sensitive products (photo-degradation)
2. Temperature, for temperature sensitive products (many
injectables, vaccines)
3. Humidity, often for capsules and always for
effervescent tablets
4. Air movement, affecting contamination and cross-
contamination
5. Microbial contamination can lead to destruction of
product & grave accidents in case of injectables or
sterile products.
6. Particulate contamination is critical in injectable forms
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1- Harmful effects of temperature

 Thermal degradation of Drugs

A. Chemical Change: Thermo labile drugs are
decomposed if they are stored in higher
temperature.
B. Physical Change: Temperature may change
the color, odor and taste of drugs

 Microbial Growth

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2-

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 3- Harmful Effects of Moisture
 Hydrolysis of drugs
 Oxidation of drugs
 Physical changes due to chemical
decomposition
i. Color Change
ii. Odor Change
iii. Taste Change
iv. Production of Toxic Chemicals
 Microbial Growth

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 AHS/HVAC COMPONENTS
 HVAC system comprises of Air Handling Unit
(AHU) connected to a ductwork ventilation
system that distributes the conditioned air through
the building and returns it to the air handler(AHU).
 Air Handling Unit (AHU) is a device used to
condition and circulate air as a part of HVAC.
 It is usually a large metal box containing a blower,
heating or cooling elements, filter racks or
chambers, sound attenuators and dampers.

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 AHS/HVAC COMPONENTS
1) Ducting (For delivery of controlled air)
2) Fan component
3) Vibration isolator (Flex joint)
4) Heating and /or coiling coil
5) Filter compartment (Houses pre and post filters)
6) HEPA Filter
7) Mixed (Re-circulated + outside ) air duct
8) Louvers (Weather)
9) Damper (Fixed adjustment of volume of air)
10)Dehumidifiers
11) Flow rate controller
12)Humidity, Temperature, Pressure sensors, alarms and
audit log system
13)Dust extractors
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 Level of Protection Concept
1. Defines environmental
requirements
2. Helps prevent
contamination and
cross-contamination
3. Allows production
under optimal hygiene
conditions
4. Takes into account
a) Product sensitivity to
contamination
b) Therapeutic risk
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Levels of Protection
 Parameters to be defined:
1. Air cleanliness
requirements (filters type
and position, air changes, air
flow patterns, pressure
differentials, contamination
levels by particulate matter
and micro-organisms)
2. Personnel and material
transfer methods
3. Permitted operations
4. Building design and
finishes
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 Based on cleanroom class requirements, various
Levels of Protection have to be created, including:
1. Correlation between process operations and
cleanroom classes
2. Type of operation permitted in each Level of
Protection
3. Definition of cleanroom class (parameters,
building materials, room requirements, HVAC
systems)
4. Requirements for personnel and material in the
different classes (clothing, training, type of
materials, etc.)
5. Requirements on entry conditions for
personnel and material (change procedures) 61
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 Parameters influencing Levels of
Protection
1. Number of particles in the air
2. Number of micro-organisms in the air or on
surfaces
3. Number of air changes for each room
4. Air velocity
5. Air flow pattern
6. Filters ( type, position )
7. Air pressure differentials between rooms
8. Temperature, humidity

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Clean Rooms: Airflows and Air Change Rates
Air changes per hour (ACPH)
 Volume of air supplied to a room, in m³/hr, divided by
the room volume, in m³
 Air changes per unit of time are related to the volume
of the room and are many times greater in
Unidirectional flow design than those supplied to a
Turbulent airflow clean room
 Minimum air change rate for Class 100,000 clean
rooms: 20 ACPH
 There is no clear criteria for minimum air change
rates for Class 1,000, 10,000 or Class 100

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 Length, height and width of process room are 12 ft,
8 ft and 10 ft respectively.
 Volume of air of that room
 Volume of air = Volume of Room
= Length x height x width = 12 x 8 x 10 =960
ft3.
 Weight of dry air of that room
 Volume of air = Volume of Room
 = Length, x height x width = 12 x 8 x 10= 960 ft3.
 Weight of air = Volume x Density
= 960 ft3 x 0.0807 lb/ ft3.
= 83.52 lb.
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Sub-systems

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AIR TYPES

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