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PARENTERAL PREPARATION
Prepared By:Roshni S. VoraPhD Research Scholar
Guided By:Dr. Yamini D. ShahAssociate Professor
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L. M. College Of Pharmacy-Ahmedabad
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Para-other than ; enteron-intestine
According to I.P "parenterals are injectable preparations, sterile products intended
for administration by injection, infusion or implantation in to the body."
Parenteral products are unique from any other type of pharmaceutical dosage
form for the following reasons:
Parenterals should be free of physical, chemical and biological contamination.
Parenteral preparations are sterile, pyrogen free liquids (solutions, emulsions,
or suspensions) or solid dosage forms packaged in either single-dose or multi
dose containers.
These preparations are administered through the skin or mucus membranes into
internal body compartments.
These includes any method of administration that does not involve passage
through the digestive tract.
Injectable solutions must be free from visible particulate matter. This includes
reconstituted sterile powders.
Products should be isotonic, although strictness of isotonicity depends on the
route of administration.
Ophthalmic products, although not parenteral, must also be isotonic. Products to
be administered by bolus injection by routes other than intravenous (IV) should
be isotonic, or at least very close to isotonicity. IV infusions must be isotonic.
All products must be stable, not only chemically and physically like all other
dosage forms, but also ‘stable’ microbiologically (i.e., sterility, freedom from
pyrogenic and visible particulate contamination must be maintained throughout
the shelf life of the product).
Products must be compatible, if applicable, with IV diluents, delivery systems,
and other drug products co administered.
a small-volume therapeutic injection (SVI), such as an antibiotic, to large-
volume injections (LVIs), such as 1000 mL of 0.9% sodium chloride solution, to
avoid the discomfort, for the patient, of a separate injection. 5
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During hospital pharmacy practice a pharmacist have been undertaken and more
information has been gained, it has been shown that knowledge of variable
factors, such as pH and the ionic character of the active constituents, aids
substantially in understanding and predicting potential incompatibilities.
Kinetic studies of reaction rates may be used to describe or predict the extent of
degradation.
a thorough study should be undertaken of each therapeutic agent in combination
with other drugs and IV fluids, not only of generic, but also of commercial
preparations, from the physical, chemical, and therapeutic aspects.
Types of Processes
Small scale dispensing - usually one unit at a time : Hospital Pharmacy
Large scale - manufacturing in which hundreds of thousands of units may
constitute one lot of product : In pharmaceutical Industry
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Parenteral products from non-sterile components in the highly technologically
advanced plants of the pharmaceutical industry, using cGMP principles includes
following
1. Ensuring that the personnel responsible for assigned duties are capable and
qualified to perform them.
2. Ensuring that ingredients used in compounding the product have the required
identity, quality, and purity.
3. Validating critical processes to be sure that the equipment used and the
processes followed ensure that the finished product has the qualities expected.
4. Maintaining a production environment suitable for performing the critical
processes required, addressing such matters as orderliness, cleanliness, asepsis,
and avoidance of cross contamination.
5. Confirming, through adequate quality-control procedures, that the finished
products have the required potency, purity, and quality.
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6. Establishing, through appropriate stability evaluation, that the drug products retain their
intended potency, purity, and quality, until the established expiration date.
7. Ensuring that processes are always carried out in accord with established, written
procedures.
8. Providing adequate conditions and procedures for the prevention of mix-ups.
9. Establishing adequate procedures, with supporting documentation, for investigating and
correcting failures or problems in production or quality control.
10. Providing adequate separation of quality-control responsibilities from those of production to
ensure independent decision making.
General Manufacturing Process The preparation of a parenteral product may encompass four general areas:
1. Procurement and accumulation of all components in a warehouse area, until released to
manufacturing;
2. Processing the dosage form in appropriately designed and operated facilities;
3. Packaging and labeling in a quarantine area, to ensure integrity and completion of the
product; and
4. Controlling the quality of the product throughout the process.
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Procurement:- selecting and testing according to specifications of the raw-material
ingredients and the containers and closures for the primary and secondary
packages
Processing :- cleaning containers and equipment to validated specifications,
compounding the solution (or other dosage form), filtering the solution, sanitizing
or sterilizing the containers and equipment, filling measured quantities of product
into the sterile containers, stoppering (either completely or partially for products to
be freeze-dried), freeze-drying, terminal sterilization (if possible), and final sealing
of the final primary container. Packaging normally consists of the labeling and
cartoning of filled and sealed primary containers.
Control of quality :- the incoming supplies, being sure that specifications are met.
Each step of the process involves checks and tests to ensure the required
specifications at the respective step are being met. The quality control unit is
responsible for reviewing the batch history and performing the release testing
required to clear the product for shipment to users.
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Typical water storage and distribution schematic
Water must be kept
circulating
Spray ballCartridge
filter 1 µm
Air breakto drain
Outlets
Hygienic pump
Optionalin-line filter
0,2 µm
UV light
Feed Water from
DI or RO
Heat ExchangerOzone Generator
Hydrophobic air filter& burst disc
Water for Pharmaceutical Use
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On site inspection:• Walk through the system, verifying the parts of the system as indicated in the drawing• Review procedures and "on site" records, logs, results• Verify components, sensors, instruments• Start with source water supply – follow whole system "loop“
Water treatment system inspection – Dead Legs– Filters – Pipes And Fittings– Ionic Beds– Storage Tanks– By-pass Lines– Pumps– UV Lights– Sample Points– Reverse Osmosis– Valves– Heat Exchangers
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Additional documentation to review• Qualification protocols and reports• Change control request (where applicable)• Requalification (where applicable)• QC and microbiology laboratory• SOP for sampling
Sampling• There must be a sampling procedure• Sample integrity must be assured• Sample point and Sample size
Testing• Chemical testing• Microbiological testing
– Test method– Types of media used– Incubation time and temperature– Objectionable and indicator organisms
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Suggested bacterial limits (CFU /mL)
Sampling location Target
Alert Action
Raw water 200 300 500
Post multimedia filter 100 300 500
Post softener 100 300 500
Post activated carbon filter 50 300 500
Feed to RO 20 200 500
RO permeate 10 50 100
Points of Use 1 10 100
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Water systems
Water systems (water used for product compounding or final rinsing of surfaces which will contact the product), are typically operated in the temperate ranges hot, ambient and cold:
• Hot systems are operated above 70 °C and Cold systems are
operated in the range between 2°C and 10°C
• Ambient systems are operated in the range of the environment in
which the system is located.
• Purified water systems can be operated at any temperature.
• WFI systems are preferably operated hot and with continuous
recirculation to control microbial growth. When WFI is stored and
distributed at cold or ambient temperatures, special precautions are
taken to prevent the ingress and proliferation of microbial
contaminants, as e.g. appropriate sanitization cycles which are
defined as part of the system qualification
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• Pharmaceutical water - used for product compounding or final
rinsing of surfaces - exists in different (compendia) qualities such as:
• Preparation of the different types of water must be performed according to
current USP and/or European Pharmacopoeia
• requirements and - if applicable - according to other pharmacopoeias (e.g.
Japanese) and local requirements.
http://www.nayagara.net/
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Monitoring – General Requirements
– Water systems undergo periodic monitoring of the specified required
characteristics.
– The monitoring program is based on the results of the qualification work
and/or according to the results of a risk assessment.
– Monitoring is performed according to written procedures, describing in
sufficient detail the responsibilities for sampling, the sampling sites,
and the sampling frequencies.
– Typical minimum sampling frequencies for process systems are described in
slide 11-12.
– Higher or lower sampling frequencies for specific processes or products are
justified according to the results of a risk assessment.
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Sampling
– Sampling sites must be selected based on a risk evaluation and / or as result of
the initial qualification.
– Samples have to be taken from representative locations within the distribution
and processing system.
– Selection of sampling sites must not compromise the quality (e.g.:
microbiological status) of the system being monitored.
– The sampling plan has to be dynamic allowing for adjustments to sampling
frequency and locations based on system performance trends.
– When routine monitoring points are reduced or increased, the reason for the
change has to be documented.
– Sampling practice must simulate the use of a process system during
manufacturing,
for example where water for manufacturing is delivered through a hose,
sampling has to be performed through this hose.
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Monitoring – Typical Minimum Sampling & Testing Frequencies 1
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Water For Injection (WFI) The source water contaminated with natural
suspended mineral and organic substances,
dissolved mineral salts, colloidal material, viable
bacteria, bacterial endotoxins, industrial or
agricultural chemicals, and other particulate
matter.
The degree of contamination varies with the
source and will be markedly different, whether
obtained from a well or from surface sources,
such as a stream or lake.
The source water must be pretreated by one or a
combination of the following treatments:
chemical softening, filtration, deionization,
reverse osmosis, purification.
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A conventional still consists of a boiler (evaporator), containing feed water
(distilland); a source of heat to vaporize the water in the evaporator; a
headspace above the level of distilland, with condensing surfaces for refluxing
the vapor, thereby returning nonvolatile impurities to the distilland; a means for
eliminating volatile impurities (demister/separation device) before the hot water
vapor is condensed; and a condenser for removing the heat of vaporization,
thereby converting the water vapor to a liquid distillate.
The specific construction features of a still and the process specifications have a
marked effect on the quality of distillate obtained from a still. Several factors
must be considered in selecting a still to produce WFI:
1. The quality of the feed water will affect the quality of the distillate. For
example, chlorine in water, especially, can cause or exacerbate corrosion in
distillation units, and silica causes scaling within. Controlling the quality of the
feed water is essential for meeting the required specifications for the distillate.
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2. The size of the evaporator will affect the efficiency. It should be large enough to provide a
low vapor velocity, thus, reducing the entrainment of the distilland either as a film on
vapor bubbles or as separate droplets.
3. The baffles (condensing surfaces) determine the effectiveness of refluxing. They should
be designed for efficient removal of the entrainment at optimal vapor velocity, collecting
and returning the heavier droplets contaminated with the distill and.
4. Redissolving volatile impurities in the distillate reduces its purity. Therefore, they should
be separated efficiently from the hot water vapor and eliminated by aspirating them to the
drain or venting them to the atmosphere.
5. Contamination of the vapor and distillate from the metal parts of the still can occur.
Present standards for high-purity stills are that all parts contacted by the vapor or distillate
should be constructed of metal coated with pure tin, 304 or 316 stainless-steel, or
chemically resistant glass.
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There are two basic types of WFI distillation units—the vapor compression still and
the multiple effect still.
Compression Distillation
The vapor-compression still, primarily designed for the production of large
volumes of high-purity distillate with low consumption of energy and water.
To start, the feed water is heated from an external source in the evaporator to
boiling. The vapor produced in the tubes is separated from the entrained
distilland in the separator and conveyed to a compressor that compresses the
vapor and raises its temperature to approximately 107°C.
It then flows to the steam chest, where it condenses on the outer surfaces of the
tubes containing the distilland; the vapor is, thus, condensed and drawn off as a
distillate, while giving up its heat to bring the distilland in the tubes to the boiling
point.
Vapor-compression stills are available in capacities from 50 to 2800 gal/hr.
24vapor-compression still
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Multiple-Effect Stills The multiple-effect still is also designed to conserve energy and water usage. In
principle, it is simply a series of single-effect stills or columns running at
differing pressures where phase changes of water take place.
A series of up to seven effects may be used, with the first effect operated at the
highest pressure and the last effect at atmospheric pressure. Steam from an
external source is used in the first effect to generate steam under pressure from
feed water; it is used as the power source to drive the second effect.
The steam used to drive the second effect condenses as it gives up its heat of
vaporization and forms a distillate.
This process continues until the last effect, when the steam is at atmospheric
pressure and must be condensed in a heat exchanger.
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The capacity of a multiple-effect still can be increased by adding effects. The quantity of
the distillate will also be affected by the inlet steam pressure; thus, a 600-gal/hr unit
designed to operate at 115 psig steam pressure could be run at approximately 55 psig and
would deliver about 400 gal/hr. These stills have no moving parts and operate quietly. They
are available in capacities from about 50 to 7000 gal/hr.
Multiple-Effect Stills
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Reverse Osmosis (RO) It is a natural process of selective permeation of molecules through a semi
permeable membrane separating two aqueous solutions of different
concentrations is Reverse osmosis.
Pressure, usually between 200 and 400 psig, is applied to overcome osmotic
pressure and force pure water to permeate through the membrane.
Membranes, usually composed of cellulose esters or polyamides, are selected to
provide an efficient rejection of contaminant molecules in raw water. The
molecules most difficult to remove are small inorganic molecules, such as sodium
chloride.
Passage through two membranes in series is sometimes used to increase the
efficiency of removal of these small molecules and decrease the risk of structural
failure of a membrane to remove other contaminants, such as bacteria and
pyrogens.
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Several WFI installations utilize both RO and distillation systems for generation of
the highest quality water. Since feedwater to distillation units can be heavily
contaminated and, thus, affect the operation of the still, water is first run through
RO units to eliminate contaminants.
Whichever system is used for the preparation of WFI, validation is required to be
sure that the system, consistently and reliably, produces the chemical, physical,
and microbiological quality of water required.
Such validation should start with the determined characteristics of the source
water and include the pretreatment, production, storage, and distribution systems.
Storage and Distribution
The rate of production of WFI is not sufficient to meet processing demands;
therefore, it is collected in a holding tank for subsequent use. In large operations,
the holding tanks may have a capacity of several thousand gallons and be a part
of a continuously operating system. In such instances, the USP requires that the
WFI be held at a temperature too high for microbial growth, normally a constant
80°C.
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Such a system requires frequent sanitization to minimize the risk of viable
microorganisms being present. The stainless-steel storage tanks in such systems
are usually connected to a welded stainless steel distribution loop, supplying the
various use sites with a continuously circulating water supply. The tank is
provided with a hydrophobic membrane vent filter capable of excluding bacteria
and nonviable particulate matter. Such a vent filter is necessary to permit changes
in pressure during filling and emptying.
The construction material for the tank and connecting lines is usually electro
polished 316L stainless steel with welded pipe. The tanks also may be lined with
glass or a coating of pure tin. Such systems are very carefully designed and
constructed and often constitute the most costly installation within the plant.
When the water cannot be used at 80°C, heat exchangers must be installed to
reduce the temperature at the point of use. Bacterial retentive filters should not be
installed in such systems, due to the risk of bacterial buildup on the filters and the
consequent release of pyrogenic substances.
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Purity Although certain purity requirements have been alluded to, the USP and EP
monographs provide the official standards of purity for WFI and Sterile Water
for Injection (SWFI).
The chemical and physical standards for WFI have changed in the past few
years. The only physical/chemical tests remaining are the new total organic
carbon (TOC), with a limit of 500 ppb (0.5 mg/L), and conductivity, with a limit
of 1.3 μS/cm at 25°C or 1.1 μS/cm at 20°C. The pH requirement of 5 to 7 in
previous revisions has been eliminated.
The SWFI requirements differ in that, since it is a final product, it must pass the
USP Sterility Test. WFI and SWFI may not contain added substances.
Bacteriostatic Water for Injection (BWFI) may contain one or more suitable
antimicrobial agents in containers of 30 mL or less.
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Sampling Point & Point of Use
PreparationVessel
point of use point of use= sampling point
sampling pointsampling point
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UVDisinfection
unit
Points of Use
Return
Storage Tank
Mixed ionexchange bed
Particle Filter
Pump
Ventilation Filter
Particle Filter
UVdisinfection
unit
Feed Water
Inflow
Monitoring – Typical Minimum Sampling & Testing Frequencies
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System-specific sampling points Depend on the construction and the technical conditions of the installation or system(e.g. Begin and end [=return] of the distribution system).
Relevant sampling points(API/potable water)
Evenly distributed throughout the plant (e.g. One sampling point per floor).
Critical points of use Depend on the individual manufacturingprocess: - For cleaning product contacting surfaces - During final crystallization of APIs - for final rinsing of product contacting- For aqueous granulation processes)
Selected sampling points Not directly relevant for the production(e.g. In cleaning/washing areas)
Selected sampling points for endotoxin testing
Where purified water is ultra-filtered to meet the endotoxin specification)
Monitoring – Typical Minimum Sampling & Testing Frequencies
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ReturnInflow
Monitoring – Typical Minimum Sampling & Testing Frequencies
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System-specific sampling points Depend on the construction and the technical conditions of the installation or system(e.g. Begin and end [=return] of the distribution system).
Relevant sampling points(API/potable water)
Evenly distributed throughout the plant (e.g. One sampling point per floor).
Critical points of use Depend on the individual manufacturingprocess: - For cleaning product contacting surfaces - During final crystallization of APIs - for final rinsing of product contacting- For aqueous granulation processes)
Selected sampling points Not directly relevant for the production(e.g. In cleaning/washing areas)
Selected sampling points for endotoxin testing
Where purified water is ultra-filtered to meet the endotoxin specification)
Monitoring – Typical Minimum Sampling & Testing Frequencies
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process-relevantbut not critical:organic coating
critical:aqueous coating
Monitoring – Typical Minimum Sampling & Testing Frequencies 8
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System-specific sampling points Depend on the construction and the technical conditions of the installation or system(e.g. Begin and end [=return] of the distribution system).
Relevant sampling points(API/potable water)
Evenly distributed throughout the plant (e.g. One sampling point per floor).
Critical points of use Depend on the individual manufacturingprocess: - For cleaning product contacting surfaces - During final crystallization of APIs - for final rinsing of product contacting- For aqueous granulation processes)
Selected sampling points Not directly relevant for the production(e.g. In cleaning/washing areas)
Selected sampling points for endotoxin testing
Where purified water is ultra-filtered to meet the endotoxin specification)
Monitoring – Typical Minimum Sampling & Testing Frequencies
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selected:washing/cleaning
Monitoring – Typical Minimum Sampling & Testing Frequencies 10
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Physical, Chemical and Microbiological Testing ParametersTEST MODULE SPECIFICATIONS REFERENCE
Appearance Clear, Colorless Liquid Ph. Eur. and USP
Conductivity < 1.1 µS / cm (20oC) or values as per Ph. Eur. Ph. Eur. and USP
Ammonium Not more intense in color than reference, corresponding to < 0.05 ppm
JP
Chlorides Complies to the test JP
Nitrates and Nitrites Not more intense in color than reference, corresponding to < 0.2 ppm
Ph. Eur. and JP
Total Organic Carbon (TOC) < 0.5 mg / L Ph. Eur. and USP
Oxidizable Substances Complies to the test JP
Acidity or Alkalinity Complies to the test JP
Heavy Metals Not more intense in color than reference, corresponding to < 0.1 ppm
Ph. Eur. and JP
Sulfates Complies to the test JP
Residue on Evaporation < 10 ppm JP
Microbial Contamination max. 10 cfu / 100 ml Ph. Eur. and USP
Bacterial Endotoxins < 0.25 EU / ml Ph. Eur. and JP
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Test Methods and Method Requirements
– All methods must be performed according to current USP and/or European Pharmacopoeia
and, if applicable other pharmacopoeia and/or local requirements (e.g. in case of potable
water).
– All methods or culture media have to be suitable to detect microorganisms that may be
present.
– The cultivation conditions, are selected to be appropriate for the specific growth
requirements of microorganisms to be detected, for example:
• Total aerobic count can be obtained by incubating at 30 to 35 °C for not less than three days
• Suitable culture media (low nutrient medium) is used for monitoring of water systems (30 to
35°C, at least 5 days).
– Testing of viable monitoring samples is performed under aerobic conditions unless there are
indications that the process is at risk for contamination with anaerobic microorganisms.
– It must be assured that cleaning or disinfection agents remaining on surfaces sampled does
not interfere with microbial recovery when methods using culture media are applied.
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Alert and Action Level in Microbiological Monitoring
– An Alert level in microbiological monitoring is that level of microorganisms that shows
significant differences from normal operating conditions.
– Alert levels are usually based upon historical information gained from the routine operation of the
process in a specific controlled environment.
– In a new facility, these levels are based on prior experience from similar facilities/ processes.
– Alert levels are re-examined and – if necessary – re-set at an established frequency. Trends that
show a deterioration of the environmental quality require respective CAPAs.
– An Action level is that specification level of microorganisms or particles that when exceeded
requires immediate follow-up and, if necessary, corrective action.
Common procedure of setting alter level based on a set of at least 12 months
data: 95% of all results < alert level AND 5 % of all results ≥ alert level
Typically, the initial alert level is set to… 50 % of the action level
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Procedures when an Alert level is exceeded
– Exceeding the Alert level does not necessarily require
a definitive corrective action, but it prompts at least
documented follow-up measures, as established in
a local procedure.
– These measures include but are not limited to the following:
o Comparison with results obtained concurrently with other related sampling
points.
o Comparison with historical data from the same sampling point.
o If possible re-sampling of the affected sampling point; routine sample(s) taken
from the affected point(s) within this period can be considered as resample.
no further Alert level => no additional action
again Alert level exceeding => repetition of re-sampling according to the procedure described above
consecutive Alert level exceeding => escalation of measures (e.g. following the procedures of exceeding an Action level)
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Procedures when an Action level is exceeded
– As soon as an Action level excursion is reported,
“immediate corrective actions” and an investigation have to be performed as
described in a local procedure.
– An evaluation of the potential impact this exceeding has on manufactured
products has to be made.
– When a definitive cause for the excursion can be determined immediately,
specific corrective actions are performed before re-sampling starts.
– Re-sampling of the affected points has to be performed immediately after the
implementation of “immediate / specific corrective actions”.
– Monitoring critical sampling points includes routine identification of
microorganisms to the species (or, where appropriate, genus) level at least
when Alert and Action Levels are exceeded.
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Documentation and Trending of Monitoring Data
All monitoring activities are documented properly (typically on form sheets
which are laid down in SOPs).
The results from critical sampling locations must be assignable to the respective
activity at the time of sampling (important in case of batch-related monitoring,
i.e. the environmental monitoring data must have a formal linkage to product
release as defined by procedures).
Monitoring data must be summarized on a periodic basis and issued to the
responsible senior management on a periodic basis (e.g. via Product Quality
Review).
Based on this summary, trends have to be evaluated and corrective action to be
defined, if appropriate.
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Q & A
Purified water systems have to be sampled (monitored) daily for microbiological
testing.
For chemical/physical testing of water systems, it is highly recommended to define
the last point of use (return) in the system as a routine sampling point.
Any Alert Level excursion initiates an immediate procedure.
Purified water with endotoxin limit is required for the final purification of a non-
sterile API to be used in a sterile parenteral Drug Product.
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Process Systems – General Qualification Provisions
Qualification is required for any process system (e.g. Water,
Nitrogen, Clean Steam, Compressed Air) …
• that is involved in the manufacture of APIs (beginning with
the regulatory starting materials), Drug Products or
intermediates
• that may affect testing results of an API, Drug Product or
intermediate, that is involved in final cleaning processes,
• where the utility supplied directly contacts an API, Drug
Product or intermediate,
• where the utility supplied comes in contact with surfaces
that have direct contact with APIs, Drug Products or
intermediates,
… and, therefore, could have an impact on the quality of the API,
Drug Product or intermediate.
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Before beginning the qualification of a process system, the following documentation has to be available:
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Test Items for Qualification of Process Systems
• Following table outlines parameters and aspects to be checked, evaluated and
tested within the qualification study of a process system, provided that these
are relevant for the particular qualification (see following slide).
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• Based on this table, the qualification team determines by means of a risk-based• approach … – the sampling points, e.g. by answering the following questions…
Which points of use are critical ? Which points of use are system-specific ? Is it necessary to realize a particular sampling point (due to the unattainability of
the point of use) ?
Usually, selected sampling
points include…
significant points of use
return loop
points prior to and after each
significant treatment step
storage tank
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Requalification of Process Systems• For-Cause Requalification• Generally, in case of changes or modifications, the same test items apply for requalification as for
initial qualification. However, based on a risk evaluation, the extent of a requalification may be reduced in comparison to the initial qualification.
• Periodic Requalification• The following periodic requalification
intervals apply:
• However, the regular evaluation of the• existing documentation such as…
– monitoring data,– quarterly reports,– change documentation,– logbooks,– maintenance/servicing documentation,– technical reports
• … equates to periodic requalification, provided that relevant• requalification item are appropriately covered.
“streamlined”requalificationapproach
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• In case of water systems, the qualification process entails a three-phase approach in order to satisfy the objective of demonstrating the reliability and robustness of the system in service over an extended period.
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• Phase 1:
– Initial phase, usually taking 2 to 4 weeks, serves to establish operating parameters and procedures,
– Does not end until the system operates stable and within the required ranges,
– Might be shortened in case of modifications to a water system already in use.
• Phase 2:
– Short-term control phase usually taking 2 to 4 weeks.
– Before water is permitted to be used for pharmaceutical purposes, an interim qualification report is
required, documenting the successful completion of Phase 2.
– However, water can also be used for pharmaceutical purposes during this phase, provided that the
respective batches are not released until the interim qualification report has been finalized.
• Phase 3:
– Long-term control phase usually taking 1 year, serves to demonstrate continuous and consistent
operation irrespectively of external and seasonal variations.
– Physico-chemical properties, microbial counts (as well as endotoxin where required) are
monitored and evaluated at close intervals, Where the season affects the quality of the feed water
(e.g. potable water), sampling should be increased.
– Phase 3 ends with the preparation of the final Qualification Report.
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Water-Miscible Vehicles These solvents are used to solubilize certain drugs in an aqueous vehicle and to
reduce hydrolysis. The most important solvents in this group are ethyl alcohol,
liquid polyethylene glycol, and propylene glycol.
Ethyl alcohol is used in the preparation of solutions of cardiac glycosides and
the glycols in solutions of barbiturates, certain alkaloids, and certain
antibiotics. Such preparations are given intramuscularly. There are limitations
with the amount of these co-solvents that can be administered, due to toxicity
concerns, greater potential for hemolysis, and potential for drug precipitation at
the site of injection.
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Non-Aqueous Vehicles The most important group of non-aqueous vehicles is the fixed oils. The
USP provides specifications for such vehicles, indicating that the fixed oils
must be of vegetable origin so they will metabolize, will be liquid at room
temperature, and will not become rancid readily. The USP also specifies
limits for the free fatty acid content, iodine value, and saponification value
(oil heated with alkali to produce soap, i.e., alcohol plus acid salt).
The oils most commonly used are corn oil, cottonseed oil, peanut oil, and
sesame oil. Fixed oils are used as vehicles for certain hormone (e.g.,
progesterone, testosterone, deoxycorticicosterone) and vitamin (e.g.,
Vitamin K, Vitamin E) preparations.
The label must state the name of the vehicle, so the user may beware in
case of known sensitivity or other reactions to it.
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Solutes
Care must be taken in selecting active pharmaceutical ingredients and
excipients to ensure their quality is suitable for parenteral administration.
A low microbial level will enhance the effectiveness of either the aseptic or
the terminal sterilization process used for the drug product.
It is now a common GMP procedure to establish microbial and endotoxin
limits on active pharmaceutical ingredients and most excipients.
Chemical impurities should be virtually nonexistent in active pharmaceutical
ingredients for parenterals, because impurities are not likely to be removed by
the processing of the product.
Depending on the chemical involved, even trace residues may be harmful to
the patient or cause stability problems in the product. Therefore,
manufacturers should use the best grade of chemicals obtainable and use its
analytical profile to determine that each lot of chemical used in the
formulation meets the required specifications.
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Reputable chemical manufacturers accept the stringent quality requirements for parenteral
products and, accordingly, apply good manufacturing practices to their chemical
manufacturing. Examples of critical bulk manufacturing precautions include:
1. Using dedicated equipment or properly validated cleaning to prevent cross-
contamination and transfer of impurities;
2. Using WFI for rinsing equipment;
3. Using closed systems, wherever possible, for bulk manufacturing steps not followed
by further purification; and
4. Adhering to specified endotoxin and bioburden testing limits for the substance.
Added Substances
The USP includes in this category all substances added to a preparation to improve or
safeguard its quality. An added substance may:
Increase and maintain drug solubility. Examples include complexing agents and surface
active agents. The most commonly used complexing agents are the cyclodextrins,
including Captisol. The most commonly used surface active agents are polyoxyethylene
sorbitan monolaurate (Tween 20) and polyoxyethylene sorbitan monooleate (Tween 80).
57
Provide patient comfort by reducing pain and tissue irritation, as do
substances added to make a solution isotonic or near physiological pH.
Common tonicity adjusters are sodium chloride, dextrose, and glycerin.
Enhance the chemical stability of a solution, as do antioxidants, inert gases,
chelating agents, and buffers.
Enhance the chemical and physical stability of a freezedried product, as do
cryoprotectants and lyoprotectants. Common protectants include sugars, such
as sucrose and trehalose, and amino acids, such as glycine.
Enhance the physical stability of proteins by minimizing self-aggregation or
interfacial induced aggregation. Surface active agents serve nicely in this
capacity.
Minimize protein interaction with inert surfaces, such as glass and rubber and
plastic. Competitive binders, such as albumin, and surface active agents are
the best examples.
58
Protect a preparation against the growth of microorganisms. The term ‘preservative’ is
sometimes applied only to those substances that prevent the growth of microorganisms
in a preparation. However, such limited use is inappropriate, being better used for all
substances that act to retard or prevent the chemical, physical, or biological
degradation of a preparation.
Although not covered in this chapter, other reasons for adding solutes to parenteral
formulations include sustaining and/or controlling drug release (polymers), maintaining
the drug in a suspension dosage form (suspending agents, usually polymers and surface
active agents), establishing emulsified dosage forms (emulsifying agents, usually
amphiphilic polymers and surface active agents), and preparation of liposomes
(hydrated phospholipids). Although added substances may prevent a certain reaction
from taking place, they may induce others. Not only may visible incompatibilities
occur, but hydrolysis, complexation, oxidation, and other invisible reactions may
decompose or otherwise inactivate the therapeutic agent or other added substances.
Therefore, added substances must be selected with due consideration and investigation
of their effect on the total formulation and the container-closure system.
59
Antimicrobial Agents The USP states that antimicrobial agents in bacteriostatic or fungistatic
concentrations must be added to preparations contained in multiple-dose
containers.
The European Pharmacopeia requires multiple-dose products to be bacteriocidal
and fungicidal. They must be present in adequate concentration at the time of use
to prevent the multiplication of microorganisms inadvertently introduced into the
preparation, while withdrawing a portion of the contents with a hypodermic needle
and syringe.
The USP provides a test for Antimicrobial Preservative Effectiveness to determine
that an antimicrobial substance or combination adequately inhibits the growth of
microorganisms in a parenteral product.
60
Large-volume, single-dose containers may not contain an added antimicrobial
preservative. Therefore, special care must be exercised in storing such products after the
containers have been opened to prepare an admixture, particularly those that support the
growth of microorganisms, such as total parenteral nutrition (TPN) solutions and
emulsions.
It should be noted that, although refrigeration slows the growth of most microorganisms,
it does not prevent their growth. Buffers are used to stabilize a solution against chemical
degradation or, especially for proteins, physical degradation (i.e., aggregation and
precipitation) which might occur if the pH changes appreciably.
Buffer systems should have as low a buffering capacity as feasible, so as not to
significantly disturb the body’s buffering systems when injected. In addition, the buffer
type and concentration on the activity of the active ingredient must be evaluated
carefully. Buffer components are known to catalyze degradation of drugs. The acid salts
most frequently employed as buffers are citrates, acetates, and phosphates. Amino acid
buffers, especially histidine, have become buffer systems of choice for controlling
solution pH of monoclonal antibody solutions.
61
Because antimicrobials may have inherent toxicity for the patient, the USP prescribes
maximum volume and concentration limits for those commonly used in parenteral
products (e.g., phenylmercuric nitrate and thimerosal 0.01%, benzethonium chloride
and benzalkonium chloride 0.01%, phenol or cresol 0.5%, and chlorobutanol 0.5%).
Benzyl alcohol, phenol, and the parabens are the most widely used antimicrobial
preservative agents used in injectable products. In oleaginous preparations, no
antibacterial agent commonly employed appears to be effective. However, it has been
reported that hexylresorcinol 0.5% and phenylmercuric benzoate 0.1% are moderately
bactericidal.
A physical reaction encountered is that bacteriostatic agents are sometimes removed
from solution by rubber closures. Protein pharmaceuticals, because of their cost and/or
frequency of use, are preferred to be available as multiple dose formulations (e.g.,
Human Insulin, Human Growth Hormone, Interferons, Vaccines, etc.).
Phenoxyethanol is the most frequently used preservative in vaccine products. Single-
dose containers and pharmacy bulk packs that do not contain antimicrobial agents are
expected to be used promptly after opening or discarded.
62
Anitoxidants are frequently required to preserve products, due to the ease with
which many drugs, including proteins with methionine or cysteine amino acids
conformationally exposed, are oxidized.
Sodium bisulfite and other sulfurous acid salts are used most frequently. Ascorbic acid
and its salts are also good antioxidants. The sodium salt of ethylenediaminetetraacetic
acid (EDTA) has been found to enhance the activity of antioxidants, in some cases, by
chelating metallic ions that would otherwise catalyze the oxidation reaction. Displacing
the air (oxygen) in and above the solution, by purging with an inert gas, such as nitrogen,
can also be used as a means to control oxidation of a sensitive drug.
Process control is required for assurance that every container is deaerated adequately and
uniformly. However, conventional processes for removing oxygen from liquids and
containers do not absolutely remove all oxygen. The only approach for completely
removing oxygen is to employ isolator technology, where the entire atmosphere can be
recirculating nitrogen or another non-oxygen gas. Tonicity Agents are used in many
parenteral and ophthalmic products to adjust the tonicity of the solution.
63
The water is contaminated as it passes through the valve
Bacteria can grow when the valve is closed
Stagnant water inside valve
Bio contamination control techniques There should be no dead legs
Water scours dead leg
If D=25mm & distance X isgreater than 50mm, we havea dead leg that is too long
Dead leg section
>1.5D
Flow direction arrows on pipes are important
Sanitary Valve
D
X
Ball valves are unacceptable
64
Bio contamination control techniques
• Pressure gauges separated from system membranes• Pipe work laid to fall (slope) – allows drainage• Maintain system at high temperature (above 70 degrees Celsius)• Use UV radiation
– Flow rate, life-cycle of the lamp• Suitable construction material• Periodic sanitization with hot water• Periodic sanitization with super-heated hot water or clean steam
– Reliable– Monitoring temperature during cycle
• Routine chemical sanitization using, e.g. ozone– Removal of agent before use of water important
65
Although it is the goal for every injectable product to be isotonic with physiologic
fluids, this is not an essential requirement for small volume injectables administered
intravenously. However, products administered by all other routes, especially into the
eye or spinal fluid, must be isotonic.
Injections into the subcutaneous tissue and muscles should also be isotonic to minimize
pain and tissue irritation. The agents most commonly used are electrolytes and mono-
or disaccharides.
Cryoprotectants and Lyoprotectants are additives that servem to protect
biopharmaceuticals from adverse effects, due tofreezing and/or drying of the product
during freeze-dry processing. Sugars (non-reducing), such as sucrose or trehalose,
amino acids, such as glycine or lysine, polymers, such as liquid polyethylene glycol or
dextran, and polyols, such as mannitol or sorbitol, all are possible cryo- or
lyoprotectants.
66
What do you need to know about Injection Sites?
Safety Considerations:
When preparing multiple injections, always label the
syringe immediately .
Keep the medication container with the syringe
Do not rely on memory to determine which solution is in
which syringe.
Carefully monitor the patient for any adverse effects for at
least 5 minutes after administration of any medication.
Handle multi-dose vials carefully and with aseptic
technique so that medicines are not wasted or contaminated.
67
Primary Parenteral Routes
Routes Usual volume (mL)
Needle commonly used
Formulationconstraints
Types of medication administered
SVP
Sub cutaneous 0.5-2 5/8 in. , 23 gauge
Need to be isotonic
Insulin, vaccines
Intra muscular 0.5-2 1.5 in. ,23 gauge
Can be solutions, emulsions, oils or suspensionsIsotonic preferably
Nearly all drug classes
Intra venous 1-100 Vein puncture1.5 in. , 20-22 gauge
Solutions, emulsions and liposomes
Nearly all drug classes
LVP 101 and larger(infusion unit)
Venoclysis 1.5 in. ,18-19 gauge
Solutions and some emulsions
Nearly all drug classes
68
No. ADVANTAGES DISVANTAGES1. Quick onset Wrong dose or over dose can be fatal
2. Vomiting and unconscious patients can take Pain at site3. Prolonged action by modified formulation Trained person required
4. Nutritive fluids can be given Expensive5. Drugs with poor absorption or instability from
GITNecessity Of Aseptic Conditions In Production, Compounding And Administration
When to Aspirate (IM & SC injection)
The reason for aspiration before injection a medication is to ensure that the needle is
not in a blood vessel. If blood appears in the syringe, withdraw the needle, discard the
syringe, and prepare a new injection.
When Not To Aspirate
When administering SC heparin/ insulin, it is recommended that you do NOT aspirate.
Because of the anticoagulant properties of heparin, aspiration could damage
surrounding tissue and cause bleeding and bursting.
69
Parenteral products: routes of administration
Intravenous (IV)Vein
Intramuscular (IM)
Muscle
Intradermal (ID)Into the kin
IntraarticularJoints
IntrasynovialJoint-fluid area
IntraosseousBones
Intraspinal Spinal column
IntracerebralBrain
Sublingual below tounge
Endotracheal Down the trachea
IntracardiacHeart
Intra-arterialArteries
IntrathecalSpinal fluid
Subcutaneous (SC)
Under the skin
Intramuscular Administration
Administered into a muscle or muscle group
Onset: variable
Volume: up to 4ml
Equipment:1-5 ml syringe, needle (18-23 g, ⅝ to 3 inch needle),
alcohol swab
Identify site and Cleanse site with alcohol
Pull skin taut and Hold needle like “dart”
Insert quickly at a 90° angle and Stabilize needle
Aspirate for blood, If no blood, instill medication slow and
steady and Quickly remove needle.
DO NOT RECAP. Activate safety feature. Place needle in
sharps container uncapped. Massage site with alcohol swab70
71
Injection Sites – Deltoid
Location: upper arm
Landmarks: Acromion Process, axillary fold
Muscle mass: triangle apex at axillary line and base of
triangle 2-3 finger breadths below acromion process.
Injection area: in the middle of the triangle / into belly of
the muscle mass. Avoid Brachial artery & Radial nerve
(BARN)
Should not be used in infants or children because of the
muscle’s small size.
Injection volume should not exceed 1ml in the adult
Use a 23-28 gauge, 5/8 to 1 inch needle
Rarely used for hospitalized patients. Primarily used for
immunizations.
72
Injection Sites – Ventrogluteal
Location: lateral (ventral) side of the hip
Landmarks: Iliac crest, anterosuperior illiac spine, greater trochanter of femur
Muscle mass: Gluteus medius and minimus
Injection area: opposing palm of hand over greater trochanter, middle finger
pointed toward the iliac crest, index finger toward anterosuperior iliac spine.
Inject into the triangle created by these fingers. No major vessels / nerves.
73
Injection Sites – Vastus Lateralis
Location: anterolateral aspect of the thigh
Landmarks: greater trochanter, lateral femoral
condyle
Muscle mass: vastus lateralis muscle
Injection area: between one handbreadth below the
greater trochanter and one handbreadth above the knee.
Width of area is from the midline on the anterior
surface of the thigh to midline on the lateral thigh.
Best to inject into outer middle third of the thigh.
No major vessels or nerves to avoid.
Identify the greater trochanter and the lateral femoral
condyle.
Select the site using the middle third and the anterior
lateral aspect of the thigh.
74
Injection Sites – Dorsal Gluteal
Location: Upper lateral aspect of the buttock
Landmarks: Posterior superior iliac spine,greater
trochanter
Muscle mass: Gluteus maximus muscle
Injection area: Draw an imaginary line between
the anatomic landmarks listed above. Administer
the injection lateral and slightly superior (2 inches)
to the midpoint of this line.
Avoid the sciatic nerve & superior gluteal artery
Most dangerous site because of sciatic nerve
location
75
Z – track
Seals the medication into the muscle tissue.
Minimizes subcutaneous tissue irritation from tracking of the medication as the
needle is withdrawn.
Used more frequently now to decrease discomfort and pain.
Used for irritating medications (Vistaril) and tissue staining meds (iron dextran –
Imferon).
Use in ventrogluteal or dorsogluteal sites
76
Intradermal Administration
Used for allergy and tuberculin
skin testing
Site: inner forearm (may use back
and upper chest)
Volume: 0.01-0.05 ml
Equipment: TB syringe (1ml, 25-
27g, ⅝ or ½ inch needle), alcohol
swab.
Administration angle: 10-15°
DO NOT massage. DO NOT
RECAP.
Subcutaneous Administration
Site: deep into tissue
Administration angle: 45-90 °
DO NOT ASPIRATE.
DO NOT RECAP.
Common drugs given SC:
1. Anticoagulants Lovenox
(enoxaparin sodium)
2. Insulin
3. Erythropoitic agents
4. Some Analgesics (-caine
type drugs)
77
Why there is requirement for Regulation for Pharmaceutical packaging
materials?? “A container closure system refers to the sum of packaging components
that together contain and protect the dosage form. This includes primary
packaging components and secondary packaging components, if the
latter are intended to provide additional protection to the drug product. A
packaging system is equivalent to a container closure system.” FDA 1999
“The primary packaging components (e.g. bottles, vials, closures, blisters)
are in direct physical contact with the product, whereas the secondary
components are not (e.g. aluminium caps, cardboard boxes).” WHO
guideline “Guidelines on packaging for pharmaceutical products, Annex 9”
Selecting types of packaging is a critical point because packaging
components are the major source of particulate matter; pyrogen and stability
problems.
78
Packaging Materials – Ideal Requirements
Protect the preparation from environmental conditions
Non-reactive with the product and so does not alter the identity of the product
Does not impart tastes or odors to the product
Nontoxic and Protect the dosage form from damage or breakage
Presentation & information
Packaging is essential source of information on medicinal product.
Information provided to patient may include:
Identification no. for dispensing records. Direction for use and Name and
address of dispensers.
Name, strength, quantity and Storage instructions.
Compliance
Design should be such that product can be easily administered in safer manner
to patient.
79
Packaging Components:
1. Primary components:
Syringes ,
Ampoules ,
Flexible Bags,
Bottles And
Closures
2. Secondary components:
Cartons and
Overlaps
3. Associated components:
Dosing Droppers And
Calibrated Spoon
80
ContainersGlass Plastic Rubber
Highly Resistant
Borosilicate Glass Treated Soda lime Glass Regular Soda Lime
Glass N.P (Non-parenteral)
Glass Type 4 is not used for
parenteral packaging,
others all are used for
parenteral packaging.
Plastic
containers are
used but they
face following
problems Permeation Sorption Leaching Softening
To provide closure for
multiple dose vials, IV
fluid bottles, plugs for
disposable syringes and
bulbs for ophthalmic
pipettes, rubber is the
material of choice. Problems associated
with rubber closures are Incompatibility Chemical instability Physical instability
81
Advantages
Economical
Superior protective
qualities
Readily available in a
wide variety of sizes &
shapes
Excellent barrier against every element
except light. Colored glass, especially
amber, can give protection against light
Disadvantages: Fragility
Heavy Weight
Glass Containers
82
Types Of Glass
Type I: Borosilicate Glass
Highly resistant glass.
Composed principally of silicone dioxide and boron oxide.
It is used to contain strong acids & alkalies as well as all types of solvents.
It is more chemically inert than the soda-lime glass.
Type II: Treated Soda-Lime Glass
When glassware is stored for several months, especially in a damp atmosphere or
with extreme temperature variations, the wetting of the surface by condensed
moisture (condensation) results in salts being dissolved out of the glass. This is called
“blooming” or “weathering” & it gives the appearance of fine crystals on the glass.
Type II containers are made of commercial soda-lime glass that has been treated with
sulfur dioxide or other dealkalizers to remove surface alkali. The de-alkalizing
process is known as “sulfur treatment” which increases the chemical resistant of the
glass.
83
Type III – Regular Soda-Lime Glass
Containers are untreated & made up of commercial soda-lime glass of
average or better-than-average chemical resistance.
Type NP – General Purpose Soda-Lime Glass
Containers made up of soda-lime glass are supplied for non-parenteral
products, those intended for oral or topical use.
84
QUALITY CONTROL TESTS FOR GLASSES
1) Chemical Resistant Of Glass Containers
A) Powdered Glass Test:
It is done to estimate the amount of alkali leached from the powdered glass
which usually happens at the elevated temperatures. When the glass is
powdered, leaching of alkali is enhanced, which can be titrated with 0.02N
sulphuric acid using methyl red as an indicator
Step-1: Preparation of glass specimen: Few containers are rinsed thoroughly
with purified water and dried with stream of clean air. Grind the containers in a
mortar to a fine powder and pass through sieve no.20 and 50.
Step-2: Washing the specimen: 10gm of the above specimen is taken into 250
ml conical flask and wash it with 30 ml acetone. Repeat the washing, decant the
acetone and dried after which it is used within 48hr.
85
Procedure: 10gm sample is added with 50ml of high purity water in a 250ml flask. Place
it in an autoclave at 121 C±2 C for 30min.Cool it under running water. ⁰ ⁰Decant the solution into another flask, wash again with 15ml high purity
water and again decant. Titrate immediately with 0.02N sulphuric acid using
methyl red as an indicator and record the volume.
B) Water Attack Test: Principle involved is whether the alkali leached or not from the surface of the
container.
Procedure: Fill each container to 90%of its overflow capacity with water and is
autoclaved at 121 C for 30min then it is cooled and the liquid is decanted ⁰which is titrated with 0.02N sulphuric acid using methyl red as an indicator.
The volume of sulfuric acid consumed is the measure of the amount of
alkaline oxides present in the glass containers.
86
3) Arsenic Test: This test is for glass containers intended for aqueous parenterals. Wash the inner and
outer surface of container with fresh distilled water for 5 min.
50ml.pipette out 10ml solution from combined contents of all ampoules to the flask.
Add 10ml of HNO3 to dryness on the water bath, dry the residue in an oven at
130 C for 30min cool and add 10ml hydrogen molybdate reagent.⁰ Swirl to dissolve and heat under water bath and reflux for 25min. Cool to room temp
and determine the absorbance at 840nm.Do the blank with 10ml hydrogen
molybdate.
The absorbance of the test solution should not exceed the absorbance obtained by
repeating the determination using 0.1ml of arsenic standard solution (10ppm) in
place of test soln.
87
4 ) Thermal Shock Test: Place the samples in upright position in a tray. Immerse the tray into a hot water
for a given time and transfers to cold water bath, temp of both are closely
controlled. Examine cracks or breaks before and after the test.
The amount of thermal shock a bottle can withstand depends on its size, design
and glass distribution. Small bottles withstand a temp differential of 60 to 80 C ⁰and 1 pint bottle 30 to 40 C.A typical test uses 45C temp difference between hot ⁰and cold water.
5) Internal Bursting Pressure Test: The test bottle is filled with water and placed inside the test chamber. A scaling
head is applied and the internal pressure automatically raised by a series of
increments each of which is held for a set of time. The bottle can be checked to a
preselected pressure level and the test continues until the container finally bursts.
88
TESTS CONTAINER
Powdered glass test Type I Type II Type III
Water attack test Type II(100ml or below) Type II(above 100ml)
6) Leakage Test: Drug filled container is placed in a container filled with coloured solution (due to the
addition of dye)which is at high pressure compared to the pressure inside the glass
container so that the coloured solution enters the container if any cracks or any
breakage is present.
89
GLASS PROPERTIES:
1. Chemical properties
Sodium/alkali leaching Alkali/Acid resistance
4. Optical properties Refractive index Dispersion Absorption Transmission Reflectivity
2. Electrical properties Volume resistivity Surface resistivity Dielectric constant
5. Thermal properties Coefficient of thermal expansion (CTE) Thermal conductivity Specific heat
3. Mechanical properties Stress Density Specific gravity
90
PLASTIC CONTAINERS
Advantage:
Ease of manufacturing
High quality
Extremely resistant to breakage
Limitations:
Permeation
Leaching and Sorption
Chemical reactivity
COMMONLY USED POLYMERS
LESS COMMONLY USED POLYMERS
PolyethylenePolypropylene
Polyvinyl chloride (PVC)
Polystyrene
Polymethyl methacrylatePolyethylene terephthalate
PolytrifluoroethyleneAminoformaldehydes
Polyamides
91
QUALITY CONTROL TESTS FOR PLASTICS
Leakage test for Injectable & Non-Injectable(IP 1996)
Fill the 10 containers with water and fit the closure.
Keep them inverted at RT for 24 hours.
No sign of leakage from any container.
92
Water vapor permeability test for injectable preparation(IP 1996)
Fill the 5 containers with nominal volume of water and seal.
Weigh the each container.
Allow to stand for 14 days at RH of 60 + 5% at 20 c to 25 c.
Reweigh the container.
Loss of the weight in each container should not be more than 0.2%.
93
Collapsibility test for Injectable and Non-Injectable preparation(IP 1996)
This test is applicable for those containers, which have to be squeezed for the
withdrawal of product.
A container by squeezing yields at least 90% of its nominal contents at require
flow rate at ambient temperature.
Measurement of diffusion coefficient through plastic
Stopcock A is first opened allowing evacuation of the system and this gives rise to a
barometric leg in the manometer .
As soon as A is closed, gas will diffuse through the membrane and mercury level
will increase.
The height of mercury level indicates diffusion of gas through the plastic.
94
Physicochemical tests
USP specifies the extracting medium; otherwise purified water is maintained
at 70 c. After the extraction following tests are performed:
Non-volatile residue which measures organic and inorganic residue soluble in
extracting medium.
Heavy metals: This detects the presence of metals such as lead, tin, zinc etc.
Buffering capacity: It measures the alkalinity/acidity of the extract.
Compatibility test
Compatibility components will not interact with the dosage form and may not
show leaching. Regular screening is done by liquid chromatography, mass
spectrometry, GC-MS etc.
Other changes like PH shift, precipitation, discoloration, which may cause the
degradation of the product should be evaluated.
95
Specific Types Of Closures:-
•Tamper-evident closures
• Child resistant closures
Closure
Characteristics of Good Pharmaceutical rubbers Good ageing qualities Satisfactory hardness and elasticity Resistance to sterilization conditions Impermeable to moisture and air
Examples Butyl Rubbers Natural Rubbers Neoprene Rubbers Polyisoprene rubbers Silicone Rubbers
96
Closures
Most vulnerable & critical component of a container..
Resistant & compatible with the product & the product/air space.
Should not lead to undesired interactions between contents and environment.
If closure is re-closable, it should be readily openable & effectively resealed.
Capable of high-speed application for automatic production by high speed
machines without loss of seal efficiency.
Offers additional functions: aid-pouring, metering, administration, child
resistance, tamper evidence, etc.
97
Available in various designs like…
Threaded screw cap
Crown cap
Roll on closures Pilferproof closures
Closures
98
CLOSURE
Closures are devices and techniques used to close or seal a bottle, jug, jar,
tube, can, etc
Closures can be a cap, cover, lid, plug, etc
The closure is normally the most vulnerable and critical component of a
container
An effective closure must prevent the contents from escaping and allow
no substance to enter the container
99
Function Of A Closure Provide a totally hermetic seal
Provide an effective seal which is acceptable to the products
Provide an effective microbiological seal
Characteristics Of Closure
It should be resistant and compatible with the product
If closure is of re closable type, it should be readily operable and should
be re-sealed effectively
It should be capable of high speed application
It should be decorative and of a shape that blends with the main
containers
100
Types Of Closures
Closures are available in five basic designs
1. Screw-on, threaded, or lug
2. Crimp-on (crowns)
3. Press-on (snap)
4. Roll-on
5. Friction.
Many variations of these basic types exist, including
1. Tamperproof
2. Child resistant
3. Dispenser applicators
101
THREADED SCREW CAP
The screw cap provides physical and chemical protection to content being
sealed.
The screw cap is commonly made of metal or plastics.
The metal is usually tinplate or aluminum, and in plastics, both
thermoplastic and thermosetting materials are used.
102
LUG CAP
The lug cap is similar to the threaded screw cap and operates on the same
principle
It is simply an interrupted thread on the glass finish, instead of a
continuous thread
Unlike the threaded closure, it requires only a quarter turn
The cap is widely used in the food industry
103
CROWN CAPS
This style of cap is commonly used as a crimped closure for beverage
bottles and has remained essentially unchanged for more than 50 years
104
ROLL-ON CLOSURES
The aluminum roll-on cap can be sealed securely, opened easily,
and resealed effectively
It finds wide application in the packaging of food, beverages,
chemicals, and pharmaceuticals
The roll-on closure requires a material that is easy to form, such as
aluminum or other light-gauge metal
105
PILFER PROOF CLOSURES
The pilfer proof closure is similar to the standard roll-on closure except
that it has a greater skirt length
When the pilfer proof closure is removed, the bridges break, and the bank
remains in place on the neck of the container
The torque is necessary to remove the cap.
106
TAMPER RESISTANT
Resistance to tampering is required for some types of products.
107
DISPENSING
• A wide variety of convenience dispensing features can be built in to
closures. Spray bottles and cans with aerosol spray have special closure
requirements.
108
CHILD-RESISTANT
• Child-resistant packaging or C-R packaging has special closures designed
to reduce the risk of children ingesting dangerous items Tamper-evident
109
CLOSURE LINES
A liner may be defined as any material that is inserted in a cap to effect a
seal between the closure and the container.
Liners are usually made of a resilient backing and a facing material. The
backing material must be soft enough to take up any irregularities in the
sealing surface and elastic enough to recover some of its original shape
when removed and replaced.
110
FACTORS IN SELECTING A LINER
The most important consideration is that the liner should be chemically inert with its
product.
Gas and vapor transmission rates are usually relative and depend chiefly on the
shelf life required for the product.
Homogenous Liner: These one piece liners are available as a disk or as a ring of
rubber and plastic.
– Expensive & Complicated to apply
– Widely used in pharmaceuticals
– Uniform properties
– Can withstand high-temperature sterilization
Heterogenous liner or composite liner: They are composed of layers of different
materials. It consists of two parts: a) facing and b) backing
111
PLASTIC CLOSURES
• The two basic types of plastic generally used for closures are
Thermosetting
Thermoplastic resins
Urea
phenols
112
RUBBER CLOSURES
Rubber is used in the pharmaceutical industry to make closures, cap liners
and bulbs for dropper assemblies.
The rubber stopper is used primarily for multiple dose vials and
disposable syringes.
Rubber closures for containers for aqueous parenteral
Preparations for powders and for freeze-dried powders
113
GLASS CLOSURE
114
METAL CLOSURE
115
Packaging Evaluation
An important step -- characterizing the materials and the chemicals that can
migrate or extract from packaging components to the drug product.
Figure shows the various types of chemicals that can migrate from polymeric
materials.
antioxidant
stabilizer plasticizermonomer
lubricantcontaminant
A number of tests can be used to establish initial qualification of the container
closure system, and a quality control plan can help ensure compatibility and safety.
116
Test on Rubber closures
1. Closure efficiency
Placing a desiccant in a packed stored under high RH.
Putting liquid in side pack, storing at high temperature and low RH,
detecting any moisture loss as reduction in weight.
Checking of cap removal torque.
Checking on compression ring seal in cap liner when a system contains
a liners.
Putting liquid in pack, inverting and applying a vaccum. A poor seal is
detected by liquid seeping.
117
2. Fragmentation test
Place a volume of water corresponding to nominal volume minus 4 ml in each of 12 clean vials.
Close the vial with closure and secure caps for 16 hours.
Pierce the closures with 21 SWG hypodermic needle (bevel angle of 10 to 14) and inject 1 ml
water and remove 1 ml air.
Repeat the above operation 4 times for each closure (use new needle for each closure).
Count the number of the fragments visible to the naked eye.
Total numbers of the fragments should not be more than 10 except butyl rubber where the
fragments should not exceed 15.
118
3. Self – sealability
• This test is applicable to closures intended to be used with water
close the vials
with the
‘Prepared’
closures
For each closure, use a
new hypodermic needle
with an external
diameter of 0.8 mm &
pierce the closure 10
times, each time at a
different site.
Immerse the vials
upright in a 0.1% w/v
solution of methylene
blue & reduce the
external pressure by
27KPa for 10 min.
Restore the atmospheric
pressure and leave the
vials immersed for 30
minutes. Rinse the outside
of the vials.
None of the vials
contains any trace
of coloured
solution.
119
4) PH OF AQUEOUS EXTRACT:
20ml of solution A is added with 0.1ml bromothymol blue when it is added with a
small amount of 0.01M NaOH which changes the colour from blue to yellow. The
volume of NaOH required is NMT 0.3ml .
5) LIGHT ABSORPTION TEST:
Solution is filtered through 0.5μ filter and its absorbance is measured at 220 to
360nm. Blank is done without closures and absorbance is NMT 2.0.
6) REDUCING SUBSTANCES:
20ml of solution A is added with 1ml of 1M H2SO4 and 20ml of 0.002M KMnO4
and boil for 3min then cool and add 1gm of potassium iodide which is titrated
with sodium thio-sulphate using starch as an indicator. The difference between
titration volumes is NMT 0.7ml.
7) RESIDUE ON EVAPORATION:
50ml of solution A is evaporated to dryness at 105 C.Then weigh the residue ⁰NMT 4mg.
120
Evaluations
To establish suitability , evaluation of four attributes is required : protection,
compatibility, safety, and performance/ drug delivery .
Suitability refers to the tests used for the initial qualification of the container
closure system with regard to its intended use.
Which tests…….???
Suitability testing should be able to establish the following criteria:
Materials of construction of container and closure components are safe for
their intended use.
Container components are compatible with the dosage form
The container and closure system adequately protects the dosage form
The entire system functions in the manner in which it is intended.
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Dosage Form Condition Route Of Delivery Possible Package Form
Solids Aseptic Inhalation -Dry-Powder Inhaler
Liquids Sterile Parenteral,Ophthalmic
-Glass Ampoules-Glass Or Plastic Vial With Stopper-Glass Or Plastic Vials With Applicators-Pre-Filled Syringe-Bag-Pre-Filled Form-Fill-Seal Plastic Container
Ointments Sterile Ophthalmic
-Collapsible Tube-Glass Or Plastic Bottle And Cap-Form-Fill-Seal Plastic Bottle-Glass Of Plastic Jar-Soft Gelatin Capsules
Dosage forms and package forms
122
OVERVIEW OF MANUFACTURING PROCESS OF PARENTERALS
documentationPlanning & scheduling
Material management-Raw material & API-Packaging material
Warehousing
Equipment & facility Manufacturing
requirement
personal
Finishing
Manufacturing
Bulk analysis
Sterilization
Q.C. Testing
Aseptic filling
Visual inspection
Labeling & packing
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FLOW OF MATERIALS:-
Ingredients vehicle solute
Processing equipment
Container component
Compounding of product
Cleaning
Cleaning
Filtration of solutes
Sterilization
Sterilization
Filling PackagingSealing Product storage
Diagram of flow of materials through the production department
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[QUALITATIVE LAYOUT OF PARENTERAL MANUFACTURING]
Function Area
Square meter Percentage
Production 11,094 45.1
Warehouse 7,606 30.9
Utility 1,716 4.1
Quality control 1,716 7.0
Administration 1,018 4.1
Maintenance 1,014 4.5
Employee services 1,014 4.1
Security 39 0.9
Total 24,607 100.0
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1.AREA PLANING AND ENVIRONMENTAL CONTROL:- Area planning may be addressed by functionalgroups ground this critical area with particular attention given to maintaining
cleanliness.Functional groupings:-Warehousing:- 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.
Finished product and certain raw materials need special environmental storage conditions, such as, temperature and humidity control.
Administrative areas :- Administrative area planning requires careful analysis of the direct and indirect
administrative requirements of a particular plant. Successively higher levels of supervision are usually provided successively larger
office areas. Some offices are individual, while some are grouped in an “open area concept”,
126
ZONES AS PER GAZZETE OF INDIA:
1st.zones as per gazette of India
• White zone:- final step (filling of parenteral)• Grey zone:- weighing, dissolution & filtration.• Black zone:- storage, worst area from contamination view point.
BLACK
GRAY
WHITE
127
ENVIRONMENTAL CONTROL ZONE GROUPING :-
1st.zones as per the c GMP:-
• 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
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Zone 7:- filling line:- The walls of the filling area are the last physical barrier to the ingress of
contamination, but within the filling area a technique of contamination control known as laminar flow may be considered as the barrier to contamination.
For aseptic filling process
Sterilization and Depyrogenation of containers
before filling, normally hot air oven or autoclave.
Provision must be made for
Filling requires
An aseptic environment with the attendant support roomsInspection and packaging
129
Zone 6:- filling area:- Zone 6 is a distinct zone of the controlled environment area for an aseptic filling
process but may not be distinct zone for non-aseptic filling process.Zone 5:- weighing, mixing, and transfer area:- Zone 5 encompasses activities of “weighing, mixing, filling or transfer
operations” addressed by c GMP section 212.81 which are not handled as zone 6 but which require a controlled environment.
Zone 4:- clean area:- Activities in this may include washing and preparations of equipment or
accumulation and sampling of filled product. Zone 3:- general production and administration area:- The third zone of environmental controls is formed by the periphery of the general
production area.Only essential materials-handling equipment and personnel.Zone 2:- plant exterior:- It is a base point from which to work in determining the requirements for the
various control barriers.Control zone 1 might include the maintenance of sterile areas around the facility.
130
2. WALL & FLOOR TREATMENT:
The design of filling areas or more generally, controlled environment areas
involves attention to many seemingly minor details. The basic cleanlability
requirement includes smooth, celanable walls, floors, ceilings, fixtures, and
partition exposed columns, wall studs, bracing, pipes, and so on are unacceptable.
The need for cleanability also eliminates the open floor system commonly used in
the microelectronics industry for laminar airflow rooms.
The goal of the designer, when creating the details for the architectural finishes
and joining methods, is to eliminate all edges or surfaces within the room where
dirt may accumulate.
All inside walls must be finished;
Example: common methods of finish are block, plaster, or gypsum board.
131
3. 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.
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.
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.
132
Clothing dispenser hand dryer hand wash
Exit Glove dispenser Change bench entrance
Change room
133
5. 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.
Discontinuous and crowed flow patterns can decrease production efficiency, increase security problems, and increase the problem of maintaining a clean environment.
x Design \/ Design
31
4 2
1 2
4 3
134
6. 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. 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.
135
7.Engineering and maintenance :- From an engineering stand point, even a location outside the plant can serve well if
access to the production area by engineers for field work is not too difficult often particularly in small or less complex plants, maintenance or other plant service functions such as utilities or combined with engineering, making an in-plant location desirable.
Maintenance responsibilities cover all areas of the plant and can generally be grouped into two categories: plant maintenance and production maintenance.
production maintenance is a direct production support function and all the routine and recurring operating maintenance work. Production maintenance facilities are usually minimal, often only a place to store a tool box, and seldom have more than a small workbench.
plant maintenance operations, in contrast, are more diverse. They vary from heavy maintenance on production equipment to cosmetic work on the building exterior and often include plant service functions such as sanitation, ground sweeping, or waste disposal.
136
LIST OF EQUIPMENTS (as per schedule-M):The following equipments is recommended: a)Manufacturing area :-1. Storage equipment for ampoules, vials bottles and closures.2. Washing and drying equipment.3. Dust proof storage cabinet.4. Water still.5. Mixing and preparation tanks or other containers.6. Mixing equipment where necessary.7. Filtering equipment.8. Hot air sterilizer.b) Aseptic filling and sealing room:-9. Benches for filling and sealing.10. Bacteriological filters.11. Filling and sealing unit under laminar flow work station.C) General room:-12. Inspection table 13. Leak testing table.14. Labeling and packing benches.15. Storage of equipment including cold storage and refrigerators if necessary.
137
Production facilities of parenterals• The production area where the parenteral preparation are manufactured can be divided into
five sections: Clean-up area:
All the parenteral products must be free from foreign particles & microorganism. Clean-up area should be withstand moisture, dust & detergent. This area should be kept clean so that contaminants may not be carried out into aseptic
area. Preparation area:
In this area the ingredients of the parenteral preparation are mixed & preparation is made for filling operation.
It is not essentially aseptic area but strict precautions are required to prevent any contamination from outside.
138
Aseptic area:
The parenteral preparations are filtered, filled into final container & sealed
should be in aseptic area.
The entry of personnel into aseptic area should be limited & through an
air lock.
Ceiling, wall & floor of that area should be sealed & painted.
The air in the aseptic area should be free from fibers, dust and
microorganism.
The High efficiency particulate air filters (HEPA) is used for air.
UV lamps are fitted in order to maintain sterility.
139
Quarantine area:
After filling, sealing & sterilization the parenteral product are held up in
quarantine area.
Randomly samples were kept for evaluation.
The batch or product pass the evaluation tests are transfer in to finishing or
packaging area.
Finishing & packaging area:
Parenteral products are properly labelled and packed.
Properly packing is essential to provide protection against physical damage.
The labelled container should be packed in cardboard or plastic container.
Ampoules should be packed in partitioned boxes
140
Aseptic Processing
• Certain pharmaceutical products must be sterile
– injections, ophthalmic preparations, irrigations solutions, haemodialysis
solutions
• 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
• Objective is to maintain the sterility of a product, assembled from sterile
components
• Operating conditions so as to prevent microbial contamination
• To review specific issues relating to the manufacture of aseptically prepared
products
141
WHO GMP US 209E US Customary ISO/TC (209) ISO 14644
EEC GMP
Grade A M 3.5 Class 100 ISO 5 Grade A Grade B M 3.5 Class 100 ISO 5 Grade B Grade C M 5.5 Class 10 000 ISO 7 Grade C Grade D M 6.5 Class 100 000 ISO 8 Grade D
Manufacturing Environment
Classification of Clean Areas
Grade At rest In operation
maximum permitted number of particles/m3 0.5 - 5.0 µm > 5 µm 0.5 - 5.0 µm > 5 µ
A 3 500 0 3 500 0
B 3 500 0 350 000 2 000
C 350 000 2 000 3 500 000 20 000
D 3 500 000 20 000 not defined not defined
“At rest” - production equipment installed and operating
“In operation” - Installed equipment functioning in defined operating mode and specified number of personnel present
142
• Grade D (equivalent to Class 100,000, ISO 8):
Clean area for carrying out less critical stages in manufacture of aseptically
prepared products eg. handling of components after washing.
• Grade C (equivalent to Class 10,000, ISO 7):
Clean area for carrying out less critical stages in manufacture of aseptically
prepared products eg. preparation of solutions to be filtered.
• Grade B (equivalent to Class 100, ISO 5):
Background environment for Grade A zone, eg. cleanroom in which laminar flow
workstation is housed.
• Grade A (equivalent to Class 100 (US Federal Standard 209E), ISO 5
Local zone for high risk operations eg. product filling, stopper bowls, open vials,
handling sterile materials, aseptic connections, transfer of partially stoppered
containers to be lyophilized. Conditions usually provided by laminar air flow
workstation.
• Each grade of cleanroom has specifications for viable and non-viable particles
– Non-viable particles are defined by the air classification
143
Limits for viable particles (microbiological contamination)
Grade Air sample (CFU/m3)
Settle plates (90mm diameter)
(CFU/4hours)
Contact plates (55mm
diameter) (CFU/plate)
Glove print (5 fingers)
(CFU/glove)
A < 3 < 3 < 3 < 3 B 10 5 5 5 C 100 50 25 - D 200 100 50 -
These are average values Individual settle plates may be exposed for less than 4 hours• Values are for guidance only - not intended to represent specifications• Levels (limits) of detection of microbiological contamination should be established for alert and action purposes and for monitoring trends of air quality in the facility
144
Environmental Monitoring - Physical
• Particulate matter
– Particles significant because they can contaminate and also carry organisms
– Critical environment should be measured not more than 30cm from worksite, within
airflow and during filling/closing operations
– Preferably a remote probe that monitors continuously
– Difficulties when process itself generates particles (e.g. powder filling)
– Appropriate alert and action limits should be set and corrective actions defined if limits
exceeded
• Differential pressures
– Positive pressure differential of 10-15 Pascals should be maintained between adjacent
rooms of different classification (with door closed)
– Most critical area should have the highest pressure
– Pressures should be continuously monitored and frequently recorded.
– Alarms should sound if pressures deviate
145
• Air Changes/Airflow patterns
– Air flow over critical areas should be uni-directional (laminar flow) at a velocity
sufficient to sweep particles away from filling/closing area
– for B, C and D rooms at least 20 changes per hour are ususally required
• Clean up time/recovery
– Particulate levels for the Grade A “at rest” state should be achieved after a short
“clean-up” period of 20 minutes after completion of operations (guidance value)
– Particle counts for Grade A “in operation” state should be maintained whenever
product or open container is exposed
• Temperature and Relative Humidity
– Ambient temperature and humidity should not be uncomfortably high (could cause
operators to generate particles) (18°C)
• Airflow velocity
– Laminar airflow workstation air speed of approx 0.45m/s ± 20% at working position
(guidance value)
146
Personnel
• Minimum number of personnel in clean areas especially during aseptic processing
• Inspections and controls from outside
• Training to all including cleaning and maintenance staff
– initial and regular
– manufacturing, hygiene, microbiology
– should be formally validated and authorized to enter aseptic area
• Special cases
– supervision in case of outside staff
– decontamination procedures (e.g. staff who worked with animal tissue
materials)
• High standards of hygiene and cleanliness
– should not enter clean rooms if ill or with open wounds
147
• Periodic health checks
• No shedding of particles, movement slow and controlled
• No introduction of microbiological hazards
• No outdoor clothing brought into clean areas, should be clad in factory clothing
• Changing and washing procedure
• No watches, jewellery and cosmetics
• Eye checks if involved in visual inspection
• Clothing of appropriate quality:
– Grade D
• hair, beard, moustache covered
• protective clothing and shoes
– Grade C
• hair, beard, moustache covered
• single or 2-piece suit (covering wrists, high neck), shoes/overshoes
148
– Grade A and B
• headgear, beard and moustache covered, masks, gloves
• not shedding fibres, and retain particles shed by operators
• Outdoor clothing not in change rooms leading to Grade B and C rooms
• Change at every working session, or once a day (if supportive data)
• Change gloves and masks at every working session
• Frequent disinfection of gloves during operations
• Washing of garments – separate laundry facility
– No damage, and according to validated procedures (washing and
sterilization)
• Regular microbiological monitoring of operators
149
Aseptic Processing
• In aseptic processing, each component is individually sterilised, or several
components are combined with the resulting mixture sterilized.
– Most common is preparation of a solution which is filtered through a sterilizing
filter then filled into sterile containers (e.g active and excipients dissolved in
Water for Injection)
– May involve aseptic compounding of previously sterilized components which
is filled into sterile containers
– May involve filling of previously sterilized powder
• sterilized by dry heat/irradiation
• produced from a sterile filtered solution which is then aseptically
crystallized and precipitated
– requires more handling and manipulation with higher potential for
contamination during processing
150
Preparation and Filtration of Solutions
• Solutions to be sterile filtered prepared in a Grade C environment
• If not to be filtered, preparation should be prepared in a Grade A environment with Grade B
background (e.g. ointments, creams, suspensions and emulsions)
• Prepared solutions filtered through a sterile 0.22μm (or less) membrane filter into a
previously sterilized container
– filters remove bacteria and moulds
– do not remove all viruses or mycoplasmas
• filtration should be carried out under positive pressure
• consideration should be given to complementing filtration process with some form of heat
treatment
• Double filter or second filter at point of fill advisable
• Same filter should not be used for more than one day unless validated
• If bulk product is stored in sealed vessels, pressure release outlets should have hydrophobic
microbial retentive air filters
151
Preparation and Filtration of Solutions
• Time limits should be established for each phase of processing, e.g.
– maximum period between start of bulk product compounding and sterilization
(filtration)
– maximum permitted holding time of bulk if held after filtration prior to filling
– product exposure on processing line
– storage of sterilized containers/components
– total time for product filtration to prevent organisms from penetrating filter
– maximum time for upstream filters used for clarification or particle removal (can
support microbial attachment)
• Filling of solution may be followed by lyophilization (freeze drying)
– stoppers partially seated, product transferred to lyophilizer (Grade A/B conditions)
– Release of air/nitrogen into lyophilizer chamber at completion of process should be
through sterilizing filter
152
Prefiltration Bioburden (natural microbial load)
• Limits should be stated and testing should be carried out on each batch
• Frequency may be reduced after satisfactory history is established
– and biobuden testing performed on components
• Should include action and alert limits (usually differ by a factor of 10) and action
taken if limits are exceeded
• Limits should reasonably reflect bioburden routinely achieved
• No defined “maximum” limit but the limit should not exceed the validated
retention capability of the filter
• Bioburden controls should also be included in “in-process” controls
– particularly when product supports microbial growth and/or manufacturing
process involves use of culture media
• Excessive bioburden can have adverse effect on the quality of the product and
cause excessive levels of endotoxins/pyrogens
153
Filter integrity
• Filters of 0.22μm or less should be used for filtration of liquids and gasses (if applicable)
– filters for gasses that may be used for purging or overlaying of filled containers or to
release vacuum in lyphilization chamber
• filter intergrity shoud be verified before filtration and confirmed after filtration
– bubble point
– pressure hold
– forward flow
• methods are defined by filter manufacturers and limits determined during filter validation
Filter validation
• Filter must be validated to demonstrate ability to remove bacteria
– most common method is to show that filter can retain a microbiological challenge of
107 CFU of Brevundimonas diminuta per cm2 of the filter surface
– a bioburden isolate may be more appropriate for filter retention studies than
Brevundimonas diminuta
154
– Challenge concentration is intended to provide a margin of safety well beyond
what would be expected in production
– preferably the microbial challenge is added to the fully formulated product
which is then passed through the filter
– if the product is bactericidal, product should be passed through the filter first
followed by modified product containing the microbial challenge (after
removing any bactericidal activity remaining on the filter)
– filter validation should be carried out under worst case conditions e.g.
maximum allowed filtration time and maximum pressure
– integrity testing specification for routine filtration should correlate with that
identified during filter validation
155
Equipment/container preparation and sterilization
• All equipment (including lyophilizers) and product containers/closures should be sterilized
using validated cycles
– same requirements apply for equipment sterilization that apply to terminally sterilized
product
– particular attention to stoppers - should not be tightly packed as may clump together and
affect air removal during vacuum stage of sterilization process
– equipment wrapped and loaded to facilitate air removal
– particular attention to filters, housings and tubing
• heat tunnels often used for sterilization/depyrogenation of glass vials/bottles
– usually high temperature for short period of time
– need to consider speed of conveyor
– validation of depyrogenation (3 logs endotoxin units)
• worst case locations: tunnel supplied with HEPA filtered air
156
• equipment should be designed to be easily assembled and disassembled, cleaned,
sanitised and/or sterilized
– equipment should be appropriately cleaned - O-rings and gaskets should be
removed to prevent build up of dirt or residues
• rinse water should be WFI grade
• equipment should be left dry unless sterilized immediately after cleaning (to
prevent build up of pyrogens)
• washing of glass containers and rubber stoppers should be validated for endotoxin
removal
• should be defined storage period between sterilization and use (period should be
justified)
157
Process Validation
• Not possible to define a sterility assurance level for aseptic processing
• Process is validated by simulating the manufacturing process using
microbiological growth medium (media fill)
– Process simulation includes formulation (compounding), filtration and filling
with suitable media using the same processes involved in manufacture of the
product
– modifications must be made for different dosage formats e.g. lyophilized
products, ointments, sterile bulks, eye drops filled into
semi-transparent/opaque containers, biological products
• Media fill program should include worst case activities
– Factors associated with longest permitted run (e.g. operator fatigue)
158
– Representative number, type, and complexity of normal interventions, non-routine
interventions and events (e.g. maintenance, stoppages, etc)
– Lyophilisation
– Aseptic equipment assembly
• Worst case activities (cont)
– No of personnel and their activities, shift changes, breaks, gown changes
– Representative number of aseptic additions (e.g. charging containers, closures, sterile
ingredients) or transfers
– Aseptic equipment connections/disconnections
– Aseptic sample collections
– Line speed and configuration
– Weight checks
– Container closure systems
• Written batch record documenting conditions and activities Should not be used to justify
risky practices
159
Duration
– Depends on type of operation
– BFS, Isolator processes - sufficient time to include manipulations and
interventions
– For conventional operations should include the total filling time
Size
– 5000 - 10000 generally acceptable or batch size if <5000
– For manually intensive processes larger numbers should be filled
– Lower numbers can be filled for isolators
Frequency and Number
– Three initial, consecutive per shift
– Subsequently semi-annual per shift and process
– All personnel should participate at least annually, consistent with routine duties
– Changes should be assessed and revalidation carried out as required
160
Line Speed: Speed depends on type of process
Environmental conditions
– Representative of actual production conditions (no. of personnel, activity levels etc) -
no special precautions (not including adjustment of HVAC), if nitrogen used for
overlaying/purging need to substitute with air
Media
– Anaerobic media should be considered under certain circumstances, should be tested
for growth promoting properties (including factory isolates)
Incubation, Examination
– In the range 20-35ºC.
– All integral units should be incubated. Should be justification for any units not
incubated.
– Units removed (and not incubated) should be consistent with routine practices
(although incubation would give information regarding risk of intervention)
– Batch reconciliation
161
• Interpretation of Results
– When filling fewer than 5000 units:
• no contaminated units should be detected
• One (1) contaminated unit is considered cause for revalidation, following an
investigation
– When filling from 5000-10000 units
• One (1) contaminated unit should result in an investigation, including
consideration of a repeat media fill
• Two (2) contaminated units are considered cause for revalidation, following
investigation
– When filling more than 10000 units
• One (1) contaminated unit should result in an investigation
• Two (2) contaminated units are considered cause for revalidation, following
investigation
162
• Interpretation of Results
– Media fills should be observed by QC and contaminated units reconcilable with time and
activity being simulated (Video may help)
– Ideally - no contamination. Any contamination should be investigated.
– Any organisms isolated should be identified to species level (genotypic identification)
– Invalidation of a media fill run should be rare
• Batch Record Review
· In-process and laboratory control results
· Environmental and personnel monitoring data
· Output from support systems(HEPA/HVAC, WFI, steam generator)
· Equipment function (batch alarm reports, filter integrity)
· Interventions, Deviations, Stoppages - duration and associated time
· Written instructions regarding need for line clearances
· Disruptions to power supply
163
• Isolators
– Decontamination process requires a 4-6 log reduction of appropriate Biological
Indicator (BI)
– Minimum 6 log reduction of BI if surface is to be free of viable organisms
– Significant focus on glove integrity - daily checks, second pair of gloves inside
isolator glove
– Traditional aseptic vigilance should be maintained
• Blow-Fill-Seal (BFS)
– Located in a Grade D environment
– Critial zone should meet Grade A (microbiological) requirements (particle count
requirements may be difficult to meet in operation)
– Operators meet Grade C garment requirements
– Validation of extrusion process should demonstrate destruction of endotoxin and
spore challenges in the polymeric material
– Final inspection should be capable of detecting leakers
164
• Issues relating to Aseptic Bulk Processing
Applies to products which can not be filtered at point of fill and require aseptic
processing throughout entire manufacturing process.
Entire aseptic process should be subject to process simulation studies under worst case
conditions (maximum duration of "open" operations, maximum no of operators)
Process simulations should incorporate storage and transport of bulk.
Multiple uses of the same bulk with storage in between should also be included in process
simulations
Assurance of bulk vessel integrity for specified holding times.
Process simulation for formulation stage should be performed at least twice per year.
Cellular therapies, cell derived products etc
•products released before results of sterility tests known
•should be manufactured in a closed system
•sterility testing of intermediates, microscopic examination (e.g. gram stain)
•endotoxin testing
165
Formulation:Methods of Sterilization Steam(autoclave): Steam sterilization is conducted in an autoclave and employs
steam under pressure.The usual temperature and the approximate length of time
required is 121°C for 15 to 30 minutes, depending on the penetration time of moist
heat into the load.
Dry heat: The transfer of energy from dry air to the object that is sterilized. The
transfer occurs through conduction, convection and radiation, higher temperature
and longer time are required(250°C for two hours).
Filtration: Sterilization by filtration depends on the physical removal of
microorganisms by adsorption on the filter medium or by a sieving mechanism, for
heat-sensitive solutions, membrane filters(0.22 μm).
Membrane filters are used exclusively for parenteral solutions, due to their
particle-retention effectiveness, non-shedding property, non-reactivity, and
disposable characteristics.
166
Formulation:Methods of Sterilization
Filtration: The most common membranes are composed of Cellulose
esters, Nylon, Polysulfone, Polycarbonate, PVDF,
Polyethersulfone(PES) or Polytetrafluoroethylene(Teflon). The
integrity of the filters has to be proven. If the drug formulation content
benzyl alcohol, it is recommended to use nylon filter instead of PES
filter due to the incompatibility issue.
Ionizing radiation:High-energy photons are emitted from an isotope
source (Cobalt 60) producing ionization throughout a product. It can be
applied under safe, well-defined, and controlled operating parameters,
and is not a heat- or moisture generating process. Most importantly,
there is no residual radioactivity after irradiation (Gamma Radiation).
167
168
EVALUATION OF PARENTERAL PREPARATIONS
The finished parenteral products are subjected to the following tests, in order
to maintain quality control:
A) Sterility test
B) Clarity test
C) Leakage test
D) Pyrogen test
E) Assay
METHOD A: Membrane filtration
METHOD B: Direct inoculation
TEST FOR STERILITY
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Sterility is defines as freedom from the presence of viable microorganism
170
Media to be used in the sterility test
Fluid Thioglycolate Medium
Soyabean-casein digest Medium
171
MINIMUM QUANTITY TO BE USED FOR EACH MEDIUM
Quantity per container Minimum quantity to be used for each medium
Liquids
1. less than 1 ml The whole contents of each container
2. 1-40 ml Half the contents of each container but not less than 1 ml
3.Greater than 40 ml and not greater than 100 ml
20 ml
4. Greater than 100 ml 10 per cent of the contents of the container but not less than 20 ml
Antibiotic liquids 1 ml
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Membrane filtration method (METHOD 1):
Membrane filtration Appropriate for : (advantage)
– Filterable aqueous preparations
– Alcoholic preparations
– Oily preparations
– Preparations miscible with or soluble in aqueous or oily (solvents with
no antimicrobial effect)
All steps of this procedure are performed aseptically in a Class 100
Laminar Flow Hood
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Membrane filter 0.45μ porosity
Filter the test solution
After filtration remove the filter
Cut the filter in to two halves
First halves (For Bacteria) Second halves (For Fungi)
Transfer in 100 ml culture media(Fluid Thioglycollate medium)
Incubate at 30-350 C for not less then 7 days
Transfer in 100 ml culture media(Soyabeans-Casein Digest medium)
Incubate at 20-250 C for not less then 7 days
Observe the growth in the media Observe the growth in the media
174
Direct inoculation method (METHOD 2):
Suitable for samples with small volumes
volume of the product is not more than 10% of the volume of the medium
suitable method for aqueous solutions, oily liquids, ointments and creams
Direct inoculation of the culture medium suitable quantity of the
preparation to be examined is transferred directly into the appropriate
culture medium & incubate for not less than 14 days.
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INTERPRETATION OF RESULTS
• If the material being tested renders the medium turbid so that the presence
or absence of microbial growth cannot be easily determined by visual
inspection,14 days after the beginning of incubation , transfer portion (<
1 ml) of the medium to fresh vessels of the same medium and then
incubate original and transfer vessel for not less than 4 days.
• If No evidence of microbial growth is found- complies with test for
sterility.
• If evidence of microbial growth is found- does not complies with test for
sterility.
176
B) Clarity test
• Particulate matter is defined as unwanted mobile insoluble matter other
than gas bubble present in the product.
• If the particle size of foreign matter is larger than the size of R.B.C.. It can
block the blood vessel.
• The permit limits of particulate matter as per I.P. are follows:
177
Methods for monitoring particulate matter contamination:
1) Visual method
2) Coulter counter method
3) Filtration method
4) Light blockage method
178
C) LEAKAGE TEST
Leakage test is employed to test the package integrity.
Package integrity reflects its ability to keep the product in and to keep
potential contamination out.
Which is the flow of matter through the barrier itself.
Leakage tests are 4 types
1. Visual inspection
2. Bubble test
3.Dye tests
4.Vacuum ionization test
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leakage test
The sealed ampoules are subjected to small cracks which occur due to rapid temperature changes or due to mechanical shocks.
Filled & sealed ampoules
Dipped in 1% Methylene blue solutionUnder negative pressure in vacuum chamber
Vacuum released colored solution enter into the ampoule
Defective sealing
Vials & bottles are not suitable for this test because the sealing material used is not rigid
180
Leakage test apparatus
High voltage leak detection
181
D) Pyrogen test
Pyrogen = “Pyro” (Greek = Fire) + “gen” (Greek = beginning).
Fever producing, metabolic by-products of microbial growth and death.
Bacterial pyrogens are called “Endotoxins”. Gram negative bacteria produce more
potent endotoxins than gram + bacteria and fungi.
Endotoxins are heat stable lipopolysaccharides (LPS) present in bacterial cell walls, not
present in cell-free bacterial filtrates
• TEST FOR PYROGEN
The test involves measurement of the rise in body temperature of rabbits following the
IV injection of a sterile solution into ear vein of rabbit.
Dose not exceeding 10 ml per kg injected intravenously within a period of not more
than 10 min
Test animals: Use healthy, adult rabbits of either sex, preferably of the same variety.
Recording of temperature: Clinical thermometer
182
PRELIMINARY TEST(SHAM TEST)
If animals are used for the first time in a pyrogen test or have not been used during
the 2 previous weeks condition them 1 to 3 days before testing the substance by
injecting IV 10ml per kg pyrogen free saline solution warmed to about 38.5°
Record the temperature of the animals beginning at least 90 min before injection
and continuing for 3 hours after injection. Any animal showing a temperature
variation of 0.6° or more must not be used in main test
MAIN TEST
Carry out the test using a group of 3 rabbits.
Dissolve the substance in or dilute with pyrogen free saline solution . Warm the
liquid to approximately 38.5° before injection. Inject the solution under
examination slowly into the marginal veins of the ear of each rabbit over a
period not exceeding 4 min.
Record the temperature of each animal at half-hourly intervals for 3 hours after
injection. The highest temperature recorded for a rabbit is taken to be its
response.
183
INTERPRETATION OF RESULT
184
E) Assay• Assay is performed according to method given In the monograph of that
parental preparation in the pharmacopoeia • Assay is done to check the quantity of medicament present in the
parenteral preparation
UNIFORMITY OF WEIGHT
Remove the labels& wash the container & dry
Weigh the container along with content
Empty the container completely
Rinse with water & ethanol,dry at 100°C to a constant weight
Cool& weigh
Net weight shout be calculated
185
UNIFORMITY OF CONTENT
30 sterile units are selected from each batch. The weight of 10 individual sterile
units is noted and the content is removed from them and empty individual sterile
unit is weighed accurately again.
Then net weight is calculated by subtracting empty sterile unit weight from gross
weight.
The dose uniformity is met if the amount of active ingredient is within the range of
85-115.0% of label claim. Relative standard deviation is equal to or less than 6.0%.
If one unit is outside the range of 85-115.0%, and none of the sterile unit is outside
the range of 75-125.0% or if the relative standard deviation of the resultant is
greater than 6.0% ,or if both condition prevail, an additional 20 sterile unit should
be tested.
The sterile units meet the requirements if not more than one unit is out side the
range of 85-115%, no unit is outside the range of 75-125.0% and the calculated
relative standard deviation is 7.8%.
186
PARTICULATE MATTER TEST
Particulate matter refers to the extraneous, mobile, undissolved particles, other
than gas bubbles, unintentionally present in the solutions.
Two methods are used:
1. Light obstruction Particle Count Test
2. Microscopic particle count test
LIGHT OBSTRACTION PARTICLE COUNT TEST
Use a suitable apparatus based on the principle of light blockage which allows an
automatic determination of the size of particles and the number of particles
according to size.
187
Sample Particle size in μm Maximum no. of particles.
LVP ≥ 100 ml 1025
Average in the units tested25 per ml3 per ml
SVP – 100 ml and less than 100 ml
1025
6000 per container600 per container
Limits
188
MICROSCOPIC PARTICLE COUNT TEST
• Wet the inside of the filter holder fitted with the membrane filter with several
milliliter of particle-free water .
• Transfer the total volume of a solution pool or of a single unit to the filtration
funnel, and apply vacuum.
• Place the filter in a Petri dish and allow the filter to air-dry.
• After the filter has been dried, place the Petri dish on the stage of the microscope,
scan the entire membrane filter under the reflected light from the illuminating
device, and count the number of particles
Sample Particle size in μm Maximum no. of particles.
LVP ≥ 100 ml 1025
Average in the units tested12 per ml2 per ml
SVP – 100 ml and less than 100 ml
1025
3000 per container300 per container
Limits :
189
TEST FOR BACTERIAL ENDOTOXIN
Measures the concenration of bacterial endotoxin
Test is using lysate derived from hemolymph cells or amoebocytes
of horse shoe crab
Endotoxin limit calculated by K/M
K maximum no.of endotoxin which receive the patient without
suffering toxic reaction
M maximum dose administered to a patient/kg/hr
Procedure
Equal volume of LAL reagent and test solution (usually 0.1 ml of
each) are mixed in a depyrogenated test-tube
Incubation at 37oC, for1 hour
Remove the tube – invert in one smooth motion (180o)
Observe the result
190
Mechanism of LAL Test
The test is based on the primitive blood-clotting mechanism of the horseshoe
crabLimulus amebocyte lysate [LAL] test
LAL reagent
Bleeding adult crabs blood into an anticlotting solution
Washing and centrifuging to collect the amoebocytes
Lysing in 3% NaCl
Lysate is washed and lyophilized for storage
191
Different Techniques
Three different techniques:
The gel-clot technique – gel formation
The turbidimetric technique – the development of turbidity after cleavage
of an endogenous substrate
The chromogenic technique – the development of color after cleavage of a
synthetic peptide – chromogen complex
Chromogenic Technique
This is based on the measurement of color change which is caused by the
release of the chromogenic chemical
p-nitroanilide
The quantity of the p-nitroanilide produced is directly proportional to the
endotoxin concentration
192
Gel Clot Technique
A solid gel is formed in the presence of endotoxins
This technique requires positive and negative controls
Positive controls – a known concentration of endotoxin added to the lysate
solution
Negative controls – water, free from endotoxins, added to the lysate solution
Turbidimetric Technique
The test is based on the measurement of opacity change due to the formation
of insoluble coagulin
Opacity is directly proportional to the endotoxin concentration
This technique is used for water systems and simple pharmaceutical
products
193
References
1. Donald C. Liebe, Packaging of Pharmaceutical Dosage Form, Modern Pharmaceutics by
G.S.Banker, Marcel Dekker, p 681-725.
2. C.P.Croce, A.Fischer & R.L.Thomas, Packaging material Science, The theory & Practice of
Industrial Pharmacy by Leon Lachman, Third edition, p 711-732
3. Plastic Packaging , Remington: The Science and Practice of Pharmacy, 19th edition, Volume
II, p 1487
4. Indian Pharmacopoeia, 2007, Government of Indian ministry of health and family welfare,
The Indian pharmacopoeia commission, Ghaziabad, volume-1, 599-609.
5. Dean D. A., Evans E. R. and Hall I. H.: Pharmaceutical Packaging Technology, Taylor and
Francis, London and New York, First Indian reprint, 2006, 5 and 73.
6. Carter S.J., “Packaging”; Cooper and Gunn’s Tutorial Pharmacy, sixth edition, CBS
publicashers and distributors, New Delhi, 2005, 133-136 and 139-140.
7. Pharmaceutical Dosage Forms. Vol. 3 : Parenteral Medications, Pub Informa Healthcare,
Edi. Avis, Kenneth E, Vol I, pg173-180
8. Encyclopedia of pharmaceutical technology by James Swarbrick pg.no.1266-1299
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