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Parenteral Preparations
Parenteral is derived from two words ‘‘para’’
and ‘‘enteron’’ meaning to avoid the intestine.
Parenteral articles are defined according to the
USP 24/NF19 ‘‘as those preparations intended
for injection through the skin or other external
boundary tissue, rather than through the
alimentary canal, so that the active substances
they contain are administered using gravity or
force directly into a blood vessel, organ, tissue,
or lesion.
Parenteral products are prepared scrupulously by
methods designed to ensure that they meet
pharmacopeial requirements for sterility,
pyrogens, particulate matter, and other
contaminants, and, where appropriate, contain
inhibitors of growth of microorganisms. The first
historical references to the parenteral
administration of a compound was in the late
15th century when a blood transfusion from
three young boys was given to Pope Innocent
VIII, resulting in the death of all four
individuals.
It was not until the 17th century that studies on the
parenteral administration of compounds was first
studied in animals. The development of the
hypodermic needle and the use of parenterally
injected drugs in humans is first reported in the
mid-19th century. By the end of this century, there
was an increased interest in the use of intravenous
administration of glucose and normal saline
solutions. Baxter produced the first commercially
prepared intravenous solutions in 1931. However,
parenteral products and their administration became
acceptable and a mainstay in the treatment of
patients in the mid 20th century.
Advantages
1. Useful for patients who cannot take drugs orally
2. Useful for drugs that require a rapid onset of action (primarily
intravenous administration)
3. Useful for emergency situations
4. Useful for providing sustained drug delivery (implants,
intramuscular depot injections)
5. Can be used for self-delivery of drugs (subcutaneous)
6. Useful for drugs that are inactivated in the gastrointestinal
tract or susceptible to first-pass metabolism by the liver
7. Useful for injection of drugs directly into a tissue (targeted
drug delivery)
8. Useful for delivering fluids, electrolytes, or nutrients (total
parenteral nutrition to patients)
9. Useful for providing precise drug delivery by intravenous
injection or infusion utilizing pharmacokinetic techniques
10.Can be done in hospitals, ambulatory infusion centers, and
in home health care
Disadvantages
1. More expensive and costly to produce
2. Potential for infection at site of injection
3. Potential for sepsis
4. Potential for thrombophlebitis
5. Potential for fluid overload
6. Potential for air embolism
7. Potential for extravasation
8. Psychological distress by the patient
9. Require specialized equipment, devices, and techniques to
prepare and administer drugs
10.Potential for pain upon injection
11.Potential for tissue damage upon injection
12.Risk of needle stick injuries and exposure to blood-borne
pathogens by health care worker
13.Increased morbidity associated with long-term vascular
access devices Disposal of needles, syringes, and other
infusion devices requires special consideration
The most commonly used routes of administration for parenteral products:
(A) intraperitoneal; (B) intravenous; (C) intramuscular; (D) subcutaneous;
(E) intradermal.
Other Routes
•
•
•
•
•
•
•
•
•
•
•
Intra-abdominal
Intra-arterial,
Intraarticular,
Intracardiac,
Intracisternal,
Intradermal,
intraocular,
Intrapleural,
Intrathecal,
Intrauterine,
Intraventricular
TYPES OF PARENTERAL PRODUCTS
Parenteral products can be divided into two general classes according to the
volume of the product.
1. Small-volume parenterals (SVP) or injections are 100 ml or less and can be
provided as a single- or multidose product.
2. Large-volume parenterals (LVP) are intended to be used intravenously as a singledose injection and contain more than 100 ml of solution.
SVPs and LVPs are often combined during the extemporaneous preparation of
intravenous admixtures.
On the Basis of Number of doses
1. Single Dose
2. Multiple Dose
On the basis of Dosage Form
1. Wet Injections:
1. Sterile Solution for Injection
2. Sterile Suspension for Injection
3. Sterile Emulsion for Injection
2.
Dry Injections:
• Sterile Powder for Solution
• Sterile powder for Suspension
Parenterals Products must be sterile and free from pyrogens
and foreign particulate matter. These three major
characteristics distinguish sterile dosage forms from any other
pharmaceutical product.
Sterility
Sterility is a state of absolute freedom from microbial
contamination. Interestingly, the word sterile on the label of a
sterile product has had a historic meaning that a sample of the
product lot passed the compendial test for sterility. Today, to
claim that a product is sterile involves much more than passing
a sterility test. Achievement of sterility involves the combination
and coordination of a wide range of activities and processes
such as:
1.Cleaning and sanitization of all facilities and equipment
2.Cleaning and sterilization of equipment, packaging, and all
other items to be in contact with the sterile product
3. Installation and certification of laminar air flow areas where
sterile air is provide via high-efficiency particulate air (HEPA)
filters
4. Environmental monitoring of the facility, equipment, water,
and personnel for strict microbiological and particulate
control
5. Appropriate gowning and training of personnel in aseptic
techniques
6. Validation of sterilization processes
7. Validation of the filter system
8. Integrity testing of the filter system before and after filtration
9. Integrity testing of the container-closure system to maintain
sterility of the product
10.Conductance of the sterility test initially for all lots and at the
end of the shelf-life expiration dating period for the product
lot under stability testing
Freedom from Pyrogens
Pyrogens are metabolic byproducts of microbial growth.
Injected in sufficient amounts in humans (infact, in any
mammal), pyrogens can react with the hypothalamus of the
brain to raise the body temperature. In addition, they can cause
a number of other adverse physiological effects, including
death.
The serious problems with sepsis are a result of high levels of
endotoxins, endotoxins being a major type of pyrogen.
Pyrogens are very small, water-soluble, heat-resistant
lipopolysaccharides that cannot be destroyed by typical
steam-sterilization cycles or removed by 0.2 µ membrane
filters. Prevention rather than elimination is the key for pyrogen
removal. The primary source of pyrogenic contamination in
parenteral products is water.
Fortunately, pyrogens are destroyed by distillation. Water used
to clean containers and closures can also be a source of
pyrogens. However, glass is sterilized by dry heat at
temperatures hot enough (usually >250C to destroy pyrogens).
Rubber closures are steam-sterilized, which does not destroy
pyrogens. Closures are depyrogenated by the cleaning and
rinsing process using pyrogen free water. If the parenteral
product is contaminated with pyrogens, there is no practical
way to remove or destroy them.
Pyrogenic contamination is detected using two tests. In the
older method, rabbits are injected with product samples, and
rectal temperature is measured.
The newer method involves a relatively simple in vitro
technique called the Limulus Amebocyte Lysate (LAL) test. It is
based on the high sensitivity of amebocytes of the horseshoe
crab (Limulus) to the lipopolysaccharide component of
endotoxins.
Freedom from Particulate Matter
Particulate matter is viewed as unacceptable contamination in
parenteral solutions. It is recognized that subvisible particulate
matter will exist in certain amounts, but the USP now has limits for
acceptable levels of particulate matter for Parenteral (no more than
6000 particles per container >0.5µ, no more than 600 particles per
container >25 µ). Parenteral solutions with visible particulate
matter should not be used.
Stability
Drugs in Parenteral are generally unstable. Many drugs are so
unstable that they cannot be marketed as ready to use solutions.
Drugs with sufficient solution stability will still require certain
formulation, packaging, and storage conditions to maintain stability
during shelf life storage and use. The primary pathways of drug
degradation involves oxidation (reaction with molecular oxygen
catalyzed by various factors including high temperature, high pH
level, heavy metals, light, and peroxide contaminants) and
hydrolysis (reaction with water catalyzed by high temperature and
extremes in pH).
For protein pharmaceuticals, aggregation of the protein,
resulting in a loss of potency, can be a major degradation
pathway. Drugs can also react with packaging and formulation
components, resulting in physical and chemical degradation.
Many SVP products are packaged in light protective packaging,
require storage at controlled room or lower (refrigeration)
temperatures, are formulated at low pH, contain antioxidants
and/or metal chelating agents, and are processed in ‘‘oxygen
free’’ conditions where water is saturated with an inert gas, and,
before to sealing the container, the product is overlayed with an
inert gas to remove oxygen from the headspace of the
container.
Many drugs in liquid Parenteral will react with water and form
hydrolytic degradation products. Hydrolysis and decomposition
occur as solution pH may change and are catalyzed by resulting
hydrogen and/or hydroxyl ions.
Buffers play an important role in certain injectable products to
achieve tight control of solution pH. Hydrolysis of solid-state
injectables can occur with moisture from the headspace in the
container, moisture remaining in the solid product, and/or moisture
originating from or through the rubber closure. Control of residual
moisture during and after processing and the use of effective
container-closure systems to minimize moisture ingress are very
important to protect dried powders from hydrolytic degradation.
Isotonicity
Parenteral should be isotonic with blood, tears, spinal fluid, and
other biological fluids into which the product is injected or instilled.
This means that the injected or instilled solution contains the same
‘‘number’’ of solute ‘‘particles’’ in solution as is contained in the
biological cell. Isotonicity means that the ‘‘tone’’ of the cell will not
be disturbed, either by the ingress of water from the injected
solution (if the solution is hypotonic) or egress of water from the
cell (if the solution is hypertonic). Solution tonicity can be
ascertained by measurement of a colligative property such as
osmotic pressure or freezing-point depression.
FORMULATION INGREDIENTS
Parenteral are simple formulations compared with other
pharmaceutical dosage forms. Solution Parenteral contain
water, the active ingredient, and a minimal number of inactive
added ingredients. Solid Parenteral contain the active
ingredient and usually one or two added ingredients.
Solvent
The most widely used solvent for Parenteral is water for
injection (WFI), USP. As a solvent, WFI is used in preparing
the bulk solution (compounding) and as a final
rinse for equipment and packaging preparation. WFI is
prepared by distillation or reverse osmosis (200 to 400 psi),
although only distillation is permitted for sterile water for
injection,
USP. Sterile water for injection is used as a vehicle for
reconstitution of sterile solid products before administration and
is terminally sterilized by autoclaving. Bacteriostatic water for
injection, USP, is commercially available as a reconstitution
vehicle for solid products intended for multiple-dose use.
Benzyl alcohol is a common antimicrobial preservative used in
bacteriostatic water for injection.
Sesame oil, cottonseed oil, fractionated coconut oil, arachis oil
and other vegetable oils are used as vehicles for water
insoluble drugs such as corticosteroids and oil-soluble
vitamins. Oily solutions can be administered only by
intramuscular injection.
Solubilizers
Solubilizers are used to enhance and maintain the aqueous
solubility of poorly water soluble drugs. Examples of
solubilizing agents used in sterile products
include:
1. Liquid co solvents: glycerin, polyethylene glycol (300, 400,
3350), propylene alcohol, and ethanol, Cremophor EL, sorbitol.
2. Surface active agents: polysorbate 80 (polyoxyethylene
sorbitan monooleate), polysorbate 20, Pluronic 68, lecithin.
3.Complexing
agents:
b-Cyclodextrins,
Captisol,
polyvinylpyrrolidone, carboxymethylcellulose sodium.
Liquid solubilizers act by reducing the dielectric constant
properties of the solvent system, thereby reducing the
electrical conductance capabilities of the solvent and
increasing the solubility of hydrophobic or non-polar drugs.
Surface active agents increase the dispersability and water
solubility of poorly soluble drugs owing to their unique
chemical properties of possessing both hydrophilic and
hydrophobic functional groups in the same molecule (the same
is true of b-cyclodextrins, addressed below). The hydrophobic
groups adsorb to surface molecules of the drug, whereas the
hydrophilic groups interact with the water-solvent molecules.
Therefore, the drug molecules locate within the hydrophobic
core of the surface active agent (sometimes called a micelle)
while the polar molecules of the surface active agent are
oriented with water, and the drug is solubilized within the
surface active agent dissolved in water.
Complexing agents act by forming soluble inclusion complexes
in aqueous solution. These molecules, as with surface active
agents, are amphiphilic.
Antimicrobial Preservative Agents
Antimicrobial preservatives serve to maintain the sterility of the
product during its shelf life and use. They are required in
preparations intended for multiple dosing
from the same container because of the finite probability of
accidental contamination during repeated use. They also are
included, although this is quite controversial,
in some single-dose products that are aseptically manufactured
to provide additional assurance of product sterility. The
combination of antimicrobial preservative agents and
adjunctive heat treatment (usually temperatures below 110 oC)
also is used to
increase assurance of sterility for products that cannot be
terminally sterilized. Very few antimicrobial preservative agents
are acceptable. Most substances with antimicrobial activity are
irritating and toxic at relatively low concentrations and usually
have stability limitations.
They can be incompatible with the drug and formulation
ingredients and can interact adversely with packaging
components. Most commonly used parenteral antimicrobial
preservatives are alcoholic or phenolic chemicals.
Antimicrobial preservative agents in small-volume
parenterals
Agent
Phenol
m-Cresol
Methylparaben
Propylparaben
Chlorobutanol
Benzyl alcohol
Benzalkonium chloride
Thimerosal
Concentration range (%)
0.065–0.5
0.16–0.3
0.05–0.18
0.011–0.035
0.5–0.55
0.75–2.0
0.01–0.025
0.0075–0.01
Buffers
Buffers are used to maintain the pH level of a solution in the range
that provides either maximum stability of the drug against hydrolytic
degradation or maximum or optimal solubility of the drug in
solution. The appropriate choice of buffer depends on the pH range
in which the drug in question is most stable (or most soluble) that
matches the pKa (dissociation constant) of the buffer species. For
example, if a pH of 4.5 is most desirable, the correct choice of
buffer would be an acetate buffer because the pKa of acetic acid is
4.76. At pH 4.76, acetic acid exists 50% as the acid (un-ionized
form) and 50% as the salt (ionized form).
Common buffer systems used in small-volume parenteral
products
pH
Buffer system
Concentration (%)
3.5–5.7
Acetic acid–acetate
1–2
2.5–6.0
Citric acid–citrate
1–5
6.0–8.2
Phosphoric acid–phosphate
0.8–2
8.2–10.2
Glutamic acid–glutamate
1–2
Antioxidants
Antioxidants function by reacting preferentially with molecular
oxygen and minimizing or terminating the free radical autooxidation reaction. Many drugs are sensitive to the presence of
oxygen and will degrade very rapidly in the absence of protection.
In addition to the use of antioxidants, other precautions must be
taken. These include protection from light, heat, heavy metal and
peroxide contamination, and excessive exposure to air.
Formulating the product at low pH is preferable if the product is
stable and soluble at low pH.
The most widely used agent is sodium bisulfite because its
oxidation-reduction potential lies in the range at which it does not
preferentially oxidize too slowly or too rapidly. Other sulfurous acid
salts also are effective antioxidants, as are ascorbic acid and
sodium ascorbate. Sometimes, combinations of antioxidants
strengthen oxidative drug protection as well as the combination of
an antioxidant and a chelating agent. The most common chelating
agent used in parenterals is disodium ethylenediaminetetraacetic
acid (DSEDTA).
Antioxidants commonly used in small-volume parenterals
Antioxidant
Water soluble
Sulfurous acid salts
Sodium bisulfite
Sodium sulfite
Sodium metabisulfite
Sodium thiosulfate
Sodium formaldehyde sulfoxylate
Ascorbic acid isomers
L- and D-Ascorbic acid
Thiol derivatives
Acetylcysteine
Cysteine
Thioglycerol
Thioglycolic acid, Thiolactic acid,Thiourea
Oil soluble
Propyl gallate
Butylated hydroxyanisole
Butylated hydroxytoluene
Ascorbyl palmitate
Nordihydroguaiaretic acid
a-Tocopherol
Concentration range (%)
0.05–1.0
0.01–0.2
0.025–0.1
0.1–0.5
0.005–0.15
0.02–1.0
0.1–0.5
0.1–0.5
0.1–0.5
0.001–0.05
0.05–0.1
0.005–0.02
0.005–0.02
0.01–0.02
0.01–0.05
9 0.05–0.075
Tonicity Adjusters
A variety of agents are used in sterile products to adjust tonicity.
Most common are simple electrolytes such as sodium chloride or
other sodium salts and non-electrolytes such as glycerin and
lactose. Tonicity adjusters are usually the last ingredient added to
the formulation after other ingredients in the formulation are
established and the osmolality of the formulation measured. If the
formulation is still hypotonic (i.e.<280 mOsm/kg as measured by a
commonly used osmometer instrument), tonicity adjusting agents
are added until the formulation is isotonic. If the formulation is
hypertonic, the degree of hypertonicity and the intended route of
drug administration need to be considered. For intravenous
administration, hypertonicity values up to approximately 360
mOsm/kg are not considered harmful. However, for other routes of
administration, efforts should be made to make the final product
isotonic before administration. This can be accomplished either by
reducing concentrations of ingredients, if acceptable, or by diluting
the product before administration.
Other Ingredients
Bulking agents are used in freeze-dried preparations to increase
the solid content of the ‘‘plug’’ in the container after the sublimation
process during the freeze drying cycle. Bulking agents not only
serve to enhance the elegance of the product but also can serve as
stabilizers in adsorbing excess moisture during shelf life.
Suspending agents keep the drug suspended in the solvent after
shaking and allow homogeneous dosing of the suspended drug
from the container. Emulsifying agents lower the interfacial tension
of an oil and water interface to allow the two immiscible solvents to
mix and form a stable emulsion dosage form. Examples of these
different additives are:
1.Bulking agents: mannitol, lactose, sucrose, dextran.
2.Suspending agents: carboxymethylcellulose, methylcellulose,
gelatin, sorbitol.
3. Emulsifying agents: lecithin, polysorbate 80.
STERILE PRODUCT MANUFACTURING
The manufacture of sterile products is universally acknowledged to
be the most difficult of all pharmaceutical production activities to
execute. The production of sterile products requires fastidious
design, operation, and maintenance of facilities and equipment. It
also requires attention to detail in process development and
validation to ensure success.
FACILITY DESIGN
To have microbial, pyrogen, and particles controls over the
production environment are essential. The facility concerns
encompass the entire building, but the most relevant components are
those in which production materials are exposed to the environment.
Ware House
Environmental protection of materials commences upon receipt
where samples for release are taken from the bulk containers.
Protection of the bulk materials is accomplished by the use of ISO 7
classified environments for sampling. All samples should be taken
aseptically (sterile material).
Preparation Area
The materials utilized for production of sterile processes move toward
the filling area through a series of progressively cleaner
environments. Typically, the first step is transfer into an ISO 8
[Class 100,000, European Union (EU) Grade D] environment
in which the pre-sterilization preparation steps are performed.
Wooden pallets and corrugated materials should always be
excluded from this zone. Preparation areas provide protection
to materials and components for a variety of activities:
component washing (glass, rubber, and other package
components),
cleaning
of
equipment
and
preassembly/wrapping.
The preparations area typically includes storage areas where clean
and wrapped change parts, components, and vessels can be held
until required for use in the fill or compounding areas. The
preparations area is ordinarily located between the warehouse and
the filling/compounding areas and connected to each of those by air
locks.
Preparation areas are supplied with high - efficiency particulate air
(HEPA) filters. The common design requirement is more than 20 air
changes per hour, turbulent airflow and temperature and relative
humidity controlled for personnel comfort. As in any clean room area
designed for total particulate control, the air returns should be low
mounted.
Wall and ceiling surfaces should be smooth, easily cleaned, and
tolerant of localized high humidity. Floors should be typically
monolithic with integral drains to prevent standing water. Common
utilities are water for injection, deionized water, compressed air, and
clean/plant steam.
Ordinarily, present within the preparation area are localized areas
of ISO 5 unidirectional airflow (Class 100) utilized to protect
washed components prior to sterilization and/or de-pyrogenation.
They are designed to reduce/eliminate the potential for particle
contamination of unwrapped washed materials.
Operators in the preparations area are typically garbed in low
particle uniforms with shoe, hair, and beard covers. The use of
latex or other gloves is required when contacting washed
components. Equipment within the preparations area can include
manual or ultrasonic wash/rinse sinks, single or double door
automated parts washers, batch or continuous glass washers,
stopper washers for closure components, equipment wrap areas
and staging areas for incoming (pre-wash) components, dirty
equipment, and cleaned components/equipment. The preparations
area may include the loading areas for both sterilizers and ovens.
Compounding Area
The manufacture of parenteral solutions is ordinarily performed in
ISO 7 (Class 10,000, EU Grade C) controlled environments in
which localized ISO 5 unidirectional flow hoods are utilized to
provide greater environmental control during material addition.
These areas are designed to minimize the microbial, pyrogen, and
particle contributions to the formulation prior to sterilization.
Depending upon the scale of manufacture, the vessels can range
from small containers (up to 50 L) to portable tanks (up to 600 L)
to large fixed vessel (10,000 L or more have been used) in which
the ingredients are formulated using mixing, heating, cooling, or
other unit operations.
Compounding areas often include equipment for measuring mass
and volume of liquid and solid materials including, for example,
graduated cylinders, and scales of various ranges, transfer and
metering pumps, homogenizers, pre-filters, and a variety of other
liquid/powder handling equipment.
Because parenteral formulations can include aqueous and nonaqueous vehicles, suspensions, emulsions, and other liquids, the
capabilities of the compounding area may vary. Agitators can be
propeller, turbine, high shear. Walls and ceiling materials are selected
to be impervious to liquids and chemical spills and are easy to clean.
Floors in these areas are monolithic and should be sloped to drains
with appropriate design elements and control procedures to eliminate
backflow potential. Compounding areas are supplied with HEPA filters
(ceiling - mounted terminal HEPAs are more common). The common
design requirement is more than 50 – 60 air changes per hour,
turbulent airflow, with temperature and relative humidity for personnel
comfort. Air returns may be at or near floor level, with localized
extraction provided as necessary to minimize dusting of powder
materials.
Common utilities are water for injection, de-ionized water, nitrogen,
compressed air, clean/plant steam, and heating and cooling media for
the fixed and portable tanks. Cleaning of the fixed vessels and
portable tanks is accomplished using either manual sequenced
cleaning procedures or more commonly with a CIP system.
Personnel working in the compounding area typically wear a coverall
(which may be sterilized for contamination control as required), with
head/beard covers, as well as dust masks and sterile gloves.
Additional personnel protective equipment may be necessary for
some of the materials being processed. A fresh gown should be
donned upon each entry into the compounding area. Separate
gowning/de-gowning rooms should be provided to minimize cross contamination potential for personnel working with different
materials.
Aseptic Filling Rooms and Aseptic Processing Area
The filling of aseptic formulations (and many terminally sterilized
products as well, by reason of their lesser number) is performed in
an ISO 5 (Class 100) environment, which is accessed from an ISO
6/7 background environment in which personnel are present. Some
measure of physical separation is provided between the ISO 5 and
ISO 6/7 environments as a means of environmental protection as
well as a reminder to personnel to restrict their exposure to ISO 5.
aseptic processing areas (APAs) are built to the same design
standards: smooth, impervious ceilings, walls and floors, flush mounted windows, clean room door designs, coved corners, finishes
capable of withstanding the aggressive chemicals utilized for
cleaning and sanitization. Air returns throughout the APA are located
at or near floor level.
Unidirectional airflow is provided over all exposed sterile materials,
that is, fill zone, sterilizer/oven/tunnel unload areas, and anywhere
else sterile materials are exposed to the environment. Air changes in
these ISO 5 environments can approach 600 per hour, though lesser
values have proven successful. Air changes in the background
environment vary from 60 to 120 per hour.
Non-sterilized items should not be allowed to enter the ISO 5 portion
of the fill zone, and sanitization is essential for all non-product
surfaces in the fill zone, as well as the surrounding background
environment.
Discharge of sealed containers can be accomplished via a exit port
or “ mouse hole ” that allows for the passage of the containers from
the APA to the surrounding environment. Proper design of the mouse
hole system ensures protection of the
classified fill area from contamination fl owing against the flow of the
containers. In many instances the discharge is into a non-classified
inspection area that may lead directly to the secondary
labeling/packaging area.Personnel working in aseptic compounding
wear full aseptic garb i.e. sterile gown, hood, face mask, goggles,
foot covers, and gloves.
Capping and Crimp Sealing Areas
The application of aluminum seals over rubber stoppers is essential
to secure them properly. In many older facilities this was
accomplished outside the aseptic processing area in an unclassified
environment. Current practice requires that air supplied to this
activity meet ISO 5 under static conditions. crimps should be applied
in a separate crimping room accessible from the filling room
maintained at a negative pressure differential relative to the filling
environment.
Sterilizer Unload (Cool-down) Rooms
Sterilizers/ovens are unloaded and items staged prior to
transfer to the individual fill rooms. ISO 5 air is provided over
the discharge area of ovens (and autoclaves if items are
sterilized unwrapped) to provide protection until the items are
ready for transfer.
Air Locks and Pass - Throughs
Air locks serve as transition points between one environment
and another. Ordinarily, they are designed to separate
environments of different classification i.e. ISO 6 from ISO 7.
When this is the case, they are designed to achieve the higher of
the two air quality levels in operation. If they are utilized for
decontamination purposes for materials/equipment that cannot be
sterilized, but must be introduced into the higher air quality
environment, they may be fitted with ultraviolet (UV) lights,
spray systems, vapor phase hydrogen peroxide generators, or
other devices that may be effectively utilized for decontamination
of materials. The doors at each end can be automatically
interlocked or managed by standard operating procedure. In some
instances a demarcation line is used to delineate the extent to
which individuals from one side should access the air lock.
A smaller scale system with comparable capabilities is the pass through. This differs from the air lock primarily in dimension, as items
are typically placed into the pass - through by personnel, whereas the
air lock is customary for pallet, portable tanks, and larger items In
general pass - throughs should be supplied with HEPA filters and
should be designed to meet the air quality level of the higher air
quality classification room served.
Air locks and pass - throughs are bidirectional and can be used for
movement in either direction.
Gowning Rooms
The gowning area used for personnel entry/exit presents some unique
problems. Gowning facilities must be designed to the standards of the
aseptic processing area, yet personnel upon entry are certainly not
gowned. Because un-gowned staff will release higher concentrations
of contaminants into the environment, gown rooms must be designed
with sufficient air exchange so that this contamination is effectively
and promptly removed.
In general, the contamination load within a gowning environment
will require air exchange rates. Gowning areas are separated into well
defined zones where personnel can progress through the various
stages of the gowning process.
The most common approach in industry is a three - stage gowning
area design in which three linked rooms with increasing air quality
levels are utilized to efficiently and safely affect clothing change.
Staff should enter the first state of the gowning room wearing plant
uniforms. No articles of outerwear worn outside the facility should be
worn to the gowning area. Therefore, a pre-gowning room equipped
with lockers is required so that operators can change into dedicated
plant clothing prior to moving to the gowning area. Generally, the pregowning locker area is not classified, although entry is controlled and
temperature and humidity are maintained at 20 – 24 ° C and 50% +
10%.
The pre-gown area should have extensive hand washing facilities
equipped with antibacterial soap, warm water, and brushes for
cleaning finger nails. Soap and water dispensing should be automatic
and hands should be air rather than towel dried.
Upon entry into the first stage gowning room, which is generally
designed to an ISO 7 air quality level, the operators put off the plant
uniform and shoes. Upon entry to the 2nd stage operator don a hair
cover, body cover, surgical mask, sterilized shoes and shoe covers
and then sterilized gloves.
In the second and third stages of the gowning area room classification
is typically ISO 6 or ISO 6 followed by ISO 5 at the exit point. A dry
glove decontamination point utilizing disinfectant foam is generally
provided prior to exiting the gowning area. In some facilities air
showers, which provide a high intensity blast of HEPA air for a
predetermined length of time, are employed after gowning is
completed. Side by side gowning of personnel should be avoided to
preclude adventitious contamination. Similarly, personnel exiting the
aseptic area should use a separate de-gowning area.
Inspection, Labeling, and Packaging
These activities are performed on finished product containers in
unclassified environments. The primary design requirements are
straightforward i.e. separation of products to prevent mix up,
adequate lighting for the processes, and control over labeling
materials.
UTILITY REQUIREMENTS
Water for injection (WFI)
The most important utility in sterile manufacturing is WFI. Not only is it a
major component in many formulations, it is also utilized as a final rinse of
process equipment, product contact parts, utensils, and components.
The WFI may be produced by either distillation (multiple effect or vapor
compression) or reverse osmosis (generally in conjunction with
deionization) and is ordinarily stored and recirculated at an elevated
temperature greater than 70 ° C to prevent microbial growth.
Clean (Pure) Steam
Sterilizers and SIP systems in the facility are supplied with steam which
upon condensation meets WFI quality requirements. It is generally produced
by boilers or steam generators.
Process Gases
Air or nitrogen used in product contact is often supplied in stainless
steel piping and ordinarily equipped with point of use filters.
Compressed air is typically provided by oil free compressors to
minimize potential contaminants and is often treated with a drier to
obviate the possibility of condensation within the lines which could
be a source of contamination. Nitrogen is supplied as a bulk cryogenic
liquid. Argon and carbon dioxide have also been utilized as inert
gases, while propane or natural gas may be needed for sealing of
ampoules.
Clean Room
(a) Federal Standard 209 Definition
"A Clean Room is an enclosed area employing control over the
particulate matter in air with temperature, humidity and pressure control
as required. To meet the requirements of a 'Clean Room' as defined by
this standard, all Clean Rooms must not exceed a particulate count as
specified in the air cleanliness class."
(b) BS 5295 Definition
"A Clean Room is a room with environmental control of particulate
contamination, temperature and humidity, constructed and used in such
a way as to minimize the introduction, generation and retention of
particles inside the room."
Federal Standard 209D Class Limits
Federal Standard 209E Airborne Particulate Cleanliness Classes
BR 525 Environmental Cleanliness Classes
Selected ISO 209 airborne particulate cleanliness classes for clean rooms and clean zones.
EU
HEPA Filter Components
HEPA Filter Media - Typically a micro fine fiberglass media, synthetic fibers,
expanded film such as Polytetrafluorethylene (PTFE) that can be pleated back and
forth to form a compact element. Close pleating is necessary to fit all the required
media into the desired space, because the paper has a high resistance to airflow
and the media velocity is usually in the range of 6 feet per minute.
HEPA Filter Separators - These devices support the HEPA media pleats, and
provide channels through which the air can flow to reach the media in a laminar
flow pattern.
HEPA Filter Pack - This is the term used to describe the combined HEPA media
and separator unit.
HEPA Filter Sealant - This is an adhesive, commonly urethane or silicone, used to
create a leak-proof seal between the HEPA filter pack and its supporting frame.
Sealant may also be used to patch any small leaks that are found in the HEPA filter
during in-situ leak testing.
HEPA Filter Seal - This is the seal on a HEPA filter frame that prevents air bypass
around the filter. In most instances it is either a closed cell neoprene gasket
attached to the face of the filter frame, or a groove in the frame to allow a knifeedge to penetrate a non-Newtonian gel (a gel that will not be influenced to fall out
due to the forces of gravity)
Dry Injection Lay Out
Wet Injection Lay Out