Transcript large scale producti..

LARGE SCALE PRODUCTION
OF STERILE DOSAGE FORMS
Manufacture of parenteral formulations
• In general, sterile products used for parenterals,
must be:
• 1- Free from chemical and physical
contaminants
• 2- Accurately and correctly compounded
• 3- Pharmaceutically elegant
• 4- Pyrogen-free
• 5- Stable for their intended shelf-life.
• 6- They must be packaged in a manner that will
assure maintenance of their quality until used.
• *Two essential requirements of parenteral formulations
are sterility and the absence of pyrogens. These two
requirements directly influence the methods by which
parenteral formulations are manufactured.
• Two categories of sterile products are presents:
• Those that can be sterilized in final container (terminally
sterilize
• Those that cannot be terminally sterilized and must be
aseptically prepared.
• *There are basic differences between the production of
sterile drug products using aseptic processing and
production using terminal sterilization.
• *Terminal sterilization 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 inprocess product and to help ensure that the subsequent
sterilization process is successful.
• In most cases, the product, container, and closure have low
bioburden, but they are not sterile. The product in its final
container is then subjected to a sterilization process such as
heat or irradiation.
• NB: Bioburden is normally defined as the number of bacteria
living on a surface that has not been sterilized.
• *In an aseptic process, the drug product, container, and closure are first
subjected to sterilization methods separately, as appropriate, and then
brought together.
• Before aseptic assembly into a final product, the individual parts of the
final product are generally subjected to various sterilization processes.
• For example, glass containers are subjected to dry heat; rubber closures are
subjected to moist heat; and liquid dosage forms are subjected to filtration.
• Each of these manufacturing processes requires validation and control.
• Each process could introduce an error that ultimately could lead to the
distribution of a contaminated product.
• 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.
• A terminally sterilized drug product, on the other hand, undergoes final
sterilization in a sealed container, thus limiting the possibility of error.
Source of contamination
• 1- The air supply:
• Heating ventilation and Air conditioning
(HVAC)
• (Treated with Laminar air flow – HEPA filter).
• 2- People (most common):
• Touch contamination.
• Generation of particulates from shedding cells
or hair.
• -The skin: (nail should be scrubbed- hands and
for-arms should be washed thoroughly with
detergent solution)
• -The breath: (use masks)
• -Clothing: always wear sterile gown over
normal clothing
• -The hair : long hair should be tied back and
wear a cotton cap
• 3- The working surfaces: clean the working surfaces with
bactericidal solution or ethyl alcohol.
• 4- Equipment: Inappropriate materials of construction
• 5- Packaging: Improper closure preparation processes ,
compromised container closure integrity, degradation of
closures and leaching of compounds from the closures
• 6- Infiltration
– Particles from adjacent spaces (e.g. anteroom)
• 7- Internal design
– Walls, floors, ceilings.
GMP REQUIREMENTS FOR
MANUFACTURING OF PARENTERALS
• 1- The flow of components, drug product containers,
closures, labeling, in-process materials, and drug products
through the building or buildings shall be designed to
prevent contamination.
• 2- Operations shall be performed within specifically
defined areas of adequate size. There shall be separate or
defined areas or such other control systems for the firm’s
operations as are necessary to prevent contamination or
mix-ups during the course Aseptic processing, which
includes as appropriate:
• (i) Floors, walls, and ceilings of smooth, hard surfaces that
are easily cleanable
• (ii) Temperature and humidity controls
• (iii) An air supply filtered through high-efficiency
particulate air filters under positive pressure, regardless
of whether flow is laminar or non-laminar
• (iv) A system for monitoring environmental conditions
• (v) A system for cleaning and disinfecting the room
and equipment to produce aseptic conditions
• (vi) A system for maintaining any equipment used to
control the aseptic conditions.
• 3- Equipment for adequate control over air pressure,
micro-organisms, dust, humidity, and temperature shall
be provided when appropriate for the manufacture,
processing, packing, or holding of a drug product.”
• 4- Air filtration systems, including prefilters and particulate
matter air filters, shall be used when appropriate on air
supplies to production areas.
• 5- Equipment used in the manufacture, processing, packing,
or holding of a drug product shall be of appropriate design,
adequate size, and suitably located to facilitate operations for
its intended use and for its cleaning and maintenance.”
• 6- Equipment shall be constructed so that surfaces that
contact components, in-process materials, or drug products
shall not be reactive, additive, or absorptive so as to alter the
safety, identity, strength, quality, or purity of the drug product
beyond the official or other established requirements.”
• 8-Equipment and utensils shall be cleaned, maintained, and
sanitized at appropriate intervals to prevent malfunctions or
contamination that would alter the safety, identity, strength,
quality, or purity of the drug product beyond the official or
other established requirements.
• 9-Appropriate written procedures, designed to prevent
microbiological contamination of drug products purporting to
be sterile, shall be established and followed. Such procedures
shall include validation of any sterilization
• 10-Operators within the manufacturing area must wear special
(sterile) work clothing, ensuring that there is no operator
contamination of the product and environment process.
Objectives of Aseptic Processing
• Aseptic processes are designed:
• 1- To minimize exposure of sterile articles to the potential
contamination hazards of the manufacturing operation.
• 2- To Limit the duration of exposure of sterile product
elements
• 3- To provide the highest possible environmental control
• 4- To optimize process flow
• 5- To design equipment appropriately.
• 6- To prevent entrainment of lower quality air into the
Class 100 (ISO 5) clean area are essential to achieving high
assurance of sterility.
Key factors contributing to the
preparation of sterile products
• For convenience, the key factors contributing
to the preparation of sterile products of high
quality can be divided into four categories:
• 1- Components (raw materials)
• 2- Facilities
• 3- Environmental control
• 4- Operators
Requirements for the manufacture
of aseptically prepared products
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Manufacturing environment
Clean areas
Personnel
Preparation and filtration of solutions
Pre-filtration bioburden
Filter integrity/validation
Equipment/container preparation and sterilization
Filling Process
Validation of aseptic processes
Specific issues relating to Isolators, BFS and Bulk
Manufacturing Environment
• Clean room or area:
• Definition of clean room:
• A clean room or area is a room or area with environmental control
of particulate contamination, temperature and humidity, constructed
and used in such away as to minimize the introduction, generation
and retention of the particles inside the room.
• Clean rooms or areas are needed to reduce contamination levels in
the product or services performed.
• 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.
• The various operations of component preparation
(such as containers and closures), product
preparation, filling and sterilization should be
carried out in separate areas within a clean area.
• Clean areas should be maintained to an
appropriate standard of cleanliness and supplied
with air that has passed through filters of an
appropriate efficiency.
Classification of Manufacturing
Areas by Air Cleanliness
• Facilities for processing sterile pharmaceutical products
comprise clean areas controlled based on predefined airborne
particle and microbiological standards.
• The areas are classified as critical, direct support, and indirect
support areas depending on the nature of the operation to be
conducted.
• Generally, the cleanliness of air in processing areas is defined
by the number of airborne particles ≥ 0.5 μm in diameter per
unit volume of air. The number of particles ≥ 5 μm in diameter
may serve as a reliable parameter for early detection of
environmental deterioration, if regularly monitored and
evaluated by linear trend analysis
*The ISO class designation in parenthesis refers to the count during operation.
**There are cases where maximum allowable number may not be specified
Table 1: Categories of clean areas
Air
Air
cleanliness*
Maximum allowable number of airborne particles
(/m3)
Count under nonCount under operating
operating conditions
conditions
≥ 0.5 μm
≥ 0.5 μm
≥ 5.0 μm
3,520
20
3,520 29
3,52000
2,900
3,52000 2,900
3,520000
29,000
3,520
Aseptic
processing
area
Critical
area
Direct
support
area
≥ 5.0 μm
20
Grade A (ISO 5)
Grade B (ISO 7)
Grade C (ISO 8)
Indirect support area
3,520.000 29,000
Grade D
Dependent on process
attributes **
• By federal standards:
• Clean room have been classified into four groups. This
classification is based on the particle count. The maximum
allowance of particles permissible is 0.5 μm and larger or
5.0 μm and larger.
(1) Class 100,000: -Particle count not to exceed a total
100,000 particles per cubic foot of a size 0.5µ and larger
700 particles per cubic foot of size 5.0µ and larger.
• (2) Class 10,000:- Particle count not to exceed a total
10,000 particles per cubic foot of a size 0.5µ and larger
65-70 particles per cubic foot of a size 5.0µ and larger.
of
or
or
or
• (3) Class 1,000: - Particles count not to
exceed a total of 1000 particles per cubic foot
of a size 0.5µ and larger or 10 particles per
cubic foot of a size 5.0µ and larger.
• (4) Class 100: - Particles count not to exceed a
total of 100 particles per cubic foot of a size
0.5µ and larger
Critical Area (Grade A)
• 1-The critical area is a processing area where sterilized products and
materials as well as their surfaces are directly exposed to the environment.
The environmental conditions should be specified to be suitable for the
virtual elimination of contamination risks and preservation of the sterility
of products. The following processes are conducted in this area:
sterilization activities (e.g. sterile connections, addition of sterile materials)
prior to filling, sterile filling, and sterile closure.
• 2-The per-cubic-meter content of particles ≥ 0.5 μm in diameter in the
critical area should be controlled to be below 3,520 under both operating
(in operation) and non-operating conditions (At rest). This level of air
cleanliness is designated as Grade A, Class 100, or ISO-5 according to
domestic and international standards on air quality.
• 3-The intervention of personnel into the critical area should always
be kept to a minimum.
• 4- The count of airborne particles and microorganisms should be
regularly monitored by appropriate procedures at sites which are
critical for ensuring sterility of pharmaceutical products.
• -It is recommended that airborne particles be continuously counted
throughout aseptic processing, including during critical preparatory
steps such as assembly of sterile parts that may contact
pharmaceutical products. The location of monitoring should
preferably be as close (≤ 30 cm) as the working place.
• -The frequency and method of microbiological monitoring should be
carefully selected in order not to break sterility of products by the
monitoring
• 5- Powder filling operations may generate
higher counts of airborne particles than the
specifications. If such a deviation occurs, the
count of airborne particles should be obtained
by, for example, sampling air at different
locations or monitoring the count in the same
room while no powder filling operation is
going, and causes of the deviation should be
identified to maintain air quality in the room at
a required level.
Direct Support Area (Grade B)
• 1. The direct support area is defined as a background area
of the critical area when aseptic processing is conducted
using an open clean booth or restricted access barrier
system (RABS).
• The direct support area is a working area for personnel
who operate machines installed in the critical area and
for those who supervise the operation of machines.
• The direct support area also serves as a route for the transfer
of sterilized products, materials, and equipment to the
critical area or for moving sterilized products from the
critical area. In the latter case, appropriate measures need to
be implemented to protect sterilized products or materials
from direct exposure to the environment
Cont.
• 2. The per-cubic-meter count of particles
(diameter: ≥ 0.5 μm) in the direct support area
should be controlled below 352,000 and 3,520
under operating and non-operating conditions,
respectively. These levels of air cleanliness are
designated as Grade B, Class 10,000, or ISO-7
(under
standard
operating
conditions)
according to domestic and international
standards on air quality.
Cont.
• 3. The count of airborne particles and
microorganisms should be regularly monitored
by appropriate procedures in the direct support
area. The frequency and method of monitoring
should be carefully selected based on
evaluation results of product contamination
risks in the critical area.
Indirect Support Areas (Grade C or D):
• 1. The indirect support area is an area used for processing
materials and products prior to sterilization processes and
hence materials and products are directly exposed to the
environment. Example indirect support areas include an
area for preparing drug solution prior to sterilization and an
area for washing and cleaning sterilization equipment and
apparatuses.
• 2. The cleanliness of the indirect support area needs to be
controlled by establishing specifications for acceptable
airborne particle count by taking into account the required
level of contamination control and type of works performed
in the area.
• 3. Air cleanliness of the indirect support area may be
either of the following two grades.
• - One of the grades specifies that the per-cubic-meter
particle content (diameter: ≥ 0.5 μm) should not exceed
3,520,000 and 352,000 under operating and nonoperating conditions, respectively. These levels of
cleanliness are designated as Grade C, Class 100,000,
or ISO-8 (standard under operating conditions)
according to domestic and international standards on air
quality. The other grade specifies that the per-cubicmeter particle content (diameter: ≥ 0.5 μm) should not
exceed 3,520,000 under non-operating conditions. This
level of cleanliness is designated as Grade D.
• 4. Weighing and preparation processes should
preferably be conducted in Grade C or cleaner
areas. If powder handling might elevate the
airborne particle count above the specification, air
quality should be maintained below the
specification by accurately determining the
particle count that may cause contamination in the
area, and for the determination, air should be
sampled, for example, at multiple locations and/or
under powder-free conditions.
Heating, Ventilating and Air
Conditioning System
• -Air in clean areas needs to be maintained at
appropriate levels by designing, instituting, and
managing a suitable heating, ventilation, and air
conditioning (HVAC) system.
• The integrity of the system should be ensured with
respect to not only temporal variations due to
operational activities, such as door opening and closing
and facility equipment operation, but also sustained
variations due to non-operational activities, such as
seasonal changes in outdoor conditions or deterioration
of equipment and apparatuses over time
• The HVAC system and its management
program are comprised of the following basic
elements:
• temperature, relative humidity, air flow
volume, air exchange rate, unidirection of air
flow, pressure difference relative to adjacent
rooms, integrity of HEPA filter, airborne
particles count, and microbacterial count.
Temperature and Relative Humidity
• Temperature and relative humidity have a
direct impact on the comfort of personnel and
potential for microbial contamination in
processing
areas;
therefore,
these
environmental
parameters
should
be
appropriately defined, controlled, monitored,
and maintained at appropriate levels
throughout processing.
Air -Flow
• It is critical to secure constant airflow from an
area of higher cleanliness level to an area of
lower cleanliness level in order to maintain
required environmental conditions of clean
areas.
• 1. Pressure difference between the APA and
indirect support areas should be adequately
defined, monitored, and controlled
Cont.
• 2. Air locks should be established between the APA and
indirect support areas and pressure difference between
these areas should be maintained at a level sufficient to
prevent the reversal of defined pressure difference or
airflow. (+ve pressure inside the critical room)
• For example, a desired pressure difference between
areas, when both closed, should be at least 10 to 15 Pa.
The air lock design should meet requirements.
• An appropriate pressure difference should be
established and maintained between indirect support
areas of different cleanliness levels.
• 3. Airflow in the critical area (Grade A) should be
unidirectional and supplied at velocity and uniformity
sufficient to swiftly remove airborne particles away from
the critical area.
• Airflow should also be supplied with sufficient care so as
not to create reverse currents from adjacent areas (direct
support areas, Grade B) into the critical area to prevent
contamination. When conventional clean benches and
RABS are used, the recommended mean flow rate is 0.45
m/sec ± 20%. Lower flow rate may be necessary depending
on the type or usage of isolator system. Proper design and
control should prevent turbulence or stagnant air in the
aseptic processing line or clean area.
• 4. Wherever pressure difference is an essential part of
sterility assurance, it is recommended to continuously
monitor pressure difference between areas and install
an alarm system to enable prompt detection of
abnormal pressure differences.
• 5.The airflow requirements should be verified by
appropriate method of validation by smoke test or other
qualification tests at the installation of airflow
equipment. Similar validation is also necessary when
airflow patterns are changed or suspected of being
changed.
• 6. An appropriate air change rate should be established by
evaluating the potential of product contamination for
individual processing areas and gowning rooms in the APA to
maintain air cleanliness at specified levels. The generally
recommended air change rate is 30 times per hour in the direct
support area and 20 times per hour in Grade C work rooms
among indirect support areas. These change rates should be
monitored at regular intervals to verify that the rates are
continuously maintained as specified.
• Air current should be controlled not to ascend to prevent
deterioration of work environment due to dust and bacteria
stirred up from the floor. The most common method of
securing downward current is to install supply vents close to
the ceiling and exhaust vents close to the floor.
• 7. Changes in flow velocity can alter flow
direction when airflow is specified to be
unidirectional. The velocity should be confirmed
to be constant at a predetermined level by
monitoring the velocity of airflow from HEPA
filters at time intervals specified in the program.
8. The cleanliness of the work room must be
promptly returned to the non-operating level after
completion of processing and workers leave the
room. In the direct support area, airborne particle
count should preferably be returned to the nonoperating count in 15 to 20 minutes
• 9. Intended differential pressure and airflow
patterns during processing should be specified
and documented and then validated to be suitable
and appropriate for commercial manufacture. The
impact of turbulence created by the movement of
personnel on the cleanliness of the manufacturing
environment should be evaluated, and evaluation
results should be reflected in relevant SOPs.
• 10. It is necessary that the critical area be cleaned
most often with the best cleaning ability without
introducing contamination.
PERSONNEL
• - minimum number of personnel
• - initial and regular training (hygiene ,
microbiology)
• - the processing of animal-tissue materials or
of cultures of microorganisms.
• - high standards of personal hygiene and
cleanliness are essential.
• - periodic health checks
• - Outdoor clothing should not be brought into clean areas
• Wrist-watches and jewellery
• The clothing required for each grade is as follows:
• • Grade D. The hair and, where relevant, beard and
moustache should be covered. Protective clothing and
appropriate shoes or overshoes should be worn.
Appropriate measures should be taken to avoid any
contamination from outside the clean area.
•
• Grade C. The hair and, where relevant, beard
and moustache should be covered. A single or
two-piece trouser suit, gathered at the wrists
and with a high neck, and appropriate shoes
or overshoes should be worn. The clothing
should shed virtually no fibres or particulate
matter.
•
• Grades A/B.
• Headgear should totally enclose the hair and, where relevant,
beard and moustache.
• A single or two-piece trouser suit, gathered at the wrists and with a
high neck, should be worn.
• The headgear should be tucked into the neck of the suit.
• A face mask should be worn to prevent the shedding of droplets.
• Appropriate, sterilized, non-powdered rubber or plastic gloves and
sterilized or disinfected footwear should be worn.
• Trouser-bottoms should be tucked inside the footwear and
garment sleeves into the gloves. The protective clothing should
shed virtually no fibers or particulate matter and should retain
particles shed by the body.
•
• Outdoor clothing should not be brought into changing
rooms leading to grade B and C rooms.
• For every worker in a grade A/B room, clean sterilized
or adequately sanitized protective garments should be
provided at each work session, or at least once a day if
monitoring results justify this.
• Gloves should be regularly disinfected during
operations.
• Masks and gloves should be changed at least at every
working session.
• The use of disposable clothing may be necessary.
• Clothing used in clean areas should be laundered
or cleaned in such a way that it does not gather
additional particulate contaminants that can later
be shed.
• Separate laundry facilities for such clothing are
desirable. If fibers are damaged by inappropriate
cleaning or sterilization, there may be an
increased risk of shedding particles.
• Washing and sterilization operations should
follow standard operating procedures.
Premises
• All premises should as far as possible be designed to
avoid the unnecessary entry of personnel. Grade B
areas should be designed such that the operations are
visible from outside.
• In clean areas, all exposed surfaces should be smooth,
impervious and unbroken in order to minimize the
shedding or accumulation of particles or
microorganisms and to permit the repeated application
of cleaning agents and disinfectants where used.
•
• To reduce the accumulation of dust and to facilitate
cleaning, there should be no uncleanable recesses and
a minimum of projecting ledges, shelves, cupboards
and equipment. Doors should be carefully designed to
avoid uncleanable recesses; sliding doors are
undesirable for this reason.
• False ceilings should be sealed to
contamination from the space above them.
prevent
• Pipes and ducts should be installed so that they do not
create recesses which are difficult to clean.
• Sinks and drains should be avoided wherever possible
and should be excluded from areas where aseptic
operations are carried out.
• Where installed they should be designed, located, and
maintained so as to minimize the risks of microbial
contamination; they should be fitted with effective,
easily cleanable traps with air breaks to prevent backflow.
• Any floor channel should be open, easily cleanable and
be connected to drains outside the area in a manner
which prevents entry of microbial contaminants.
• Changing rooms should be designed as airlocks
and used to provide separation of the different
stages of changing, so minimizing microbial and
particulate contamination of protective clothing.
• They should be effectively flushed with filtered
air. The use of separate changing rooms for
entering and leaving clean areas is sometimes
desirable.
• Hand-washing facilities should be provided only
in the changing rooms, not in areas where aseptic
work is done.
• Airlock doors should not be opened simultaneously. An interlocking
system and a visual and/or audible warning system should be
operated to prevent the opening of more than one door at a time.
• The utilization of absolute-barrier technology and automated
systems to minimize human interventions in processing areas can
produce significant advantages in ensuring the sterility of
manufactured products.
• When such techniques are used, the recommendations in this
section, particularly those relating to air quality and monitoring, still
apply, with appropriate interpretation of the terms "work station"
and "environment".
•
Equipment
• 1- A filtered air supply should maintain a positive
pressure relative to surrounding areas under all
operational conditions and flush the area
effectively
• 2- air flow patterns do not present a
contamination risk, e.g. care should be taken to
ensure that air flows do not distribute particles
from persons, operations, or machines to zones of
higher product risk.
•
• warning system should be included to indicate
failure in the air supply
• restricting unnecessary access to critical filling
areas, e.g. grade A filling zones, by the use of a
physical barrier.
• A conveyor belt should not pass through a
partition between a clean area B and a processing
area of lower air cleanliness, unless the belt itself
is continuously sterilized (e.g., in a sterilizing
tunnel).
• Equipment used for processing sterile products should be
chosen so that it can be effectively sterilized by steam or
dry heat or other methods.
•
• Equipment fittings and services should be designed and
installed so that operations, maintenance and repairs can be
carried out outside the clean area.
• If the equipment has to be sterilized, it should be
resterilized after complete reassembly.
•
•
• When equipment maintenance is carried out
within the clean area, clean instruments and
tools should be used,
• The area should be cleaned and disinfected
where
appropriate
before
processing
recommences, if the required standards of
cleanliness and/or asepsis have not been
maintained during the maintenance work.
• Water treatment plants should be designed,
constructed and maintained so as to ensure the
reliable production of water of an appropriate
quality.
• They should not be operated beyond their
designed capacity.
• Water should be produced, stored and
distributed in a manner which prevents
microbial growth.
Filtration of Pharmaceutical Products which Cannot be
Sterilized in Their Final Container
• Certain solutions and liquids that cannot be sterilized in the
final container can be filtered through a sterile filter of
nominal pore size 0.22 micron (or less), or with at least
equivalent microorganism retaining properties, into a
previously sterilized container.
• Such filters can remove bacteria and moulds, but not all
viruses or mycoplasmas.
• Consideration should then be given to complementing the
filtration process with some degree of heat treatment.
•
• Due to the potential additional risks of the
filtration method as compared with other
sterilization processes, a double filter layer or
second filtration via a further sterilized
microorganism-retaining filter immediately
prior to filling may be advisable.
• The final sterile filtration should be carried out
as close as possible to the filling point.
•
• Fiber-shedding filters should not be used. The use of asbestoscontaining filters should be absolutely excluded.
•
• The integrity of the filter should be checked by an appropriate
method such as a bubble point test immediately after each use (it
may also be useful to test the filter in this way before use).
• The time taken to filter a known volume of bulk solution and the
pressure difference to be used across the filter should be determined
during validation and any significant differences from this should be
noted and investigated.
• Results of these checks should be recorded in the batch record.
•
• The same filter should not be used for more
than one working day unless such use has been
validated.
• The filter should not affect the product by
removal of ingredients from it or by release of
substances into it.
Finishing of sterile products
• 1 Containers should be closed by
appropriately validated methods. Samples
should be checked for integrity according to
appropriate procedures.
• 2 Containers sealed under vacuum should
be sampled and the samples tested, after an
appropriate predetermined period, to
ensure that the vacuum has been
maintained.
• Filled containers of parenteral products should be
inspected individually.
• When inspection is done visually, it should be done under
suitable and controlled conditions of illumination and
background.
• Operators doing the inspection should pass regular
eyesight checks, with spectacles if worn, and be allowed
frequent breaks from inspection.
• Where other methods of inspection are used, the process
should be validated and the performance of the
equipment checked at intervals.
• The results should be recorded.
•