IPQC: Definition:
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Checks performed during production in order to
monitor and, if necessary, to adjust the process to
ensure that the product conforms to its
specifications. The control of the environment or
equipment may also be regarded as a part of
inprocess control.
In-process controls are usually performed within
the production area. The performance of such inprocess controls should not have any negative
effect on the quality of the product or another
product.
IPQC:
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In-process inspection and testing should be
performed by monitoring the process or by actual
sample analysis at defined locations and times.
The results should conform to established process
parameters or acceptable tolerances.
Work instructions should delineate the procedure
to follow and how to use the inspection and test
data to control the process.
Introduction:
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IPQC is concerned with providing accurate, specific,
and definite description of procedures to be
employed from the receipt of raw materials to the
release of finished dosage forms.
It is a planned system to identify the materials,
equipment, process, and operations.
In general the in process control procedures are
usually rapid and simple tests or inspections that
are performed when the manufacturing of a
product batch is in progress.
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It is an imp function of IPQA programme to ensure that
the finished dosage forms have uniformity, purity, and
quality within batch and between batch.
Is accomplished by identifying critical steps in
manufacturing and controlling them within defined
limits.
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IPQC aims to increase the assurance of batch
uniformity.
There must be written procedure describing the
control and test or examination to be conducted.
In process specification/controls must be rational
and consistence with the finished product
specification.
They derived from previous validated process
variations.
OBJECTIVE
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To minimize the human errors.
Provides accurate, specific, and definite description
of the procedure to be employed.
To detect the errors if and when it does occur.
Corrective action instituted by people.
To pin point the responsibility to the personnel
involved in the operation of the entire process.
To enforce the flow of manufacturing and packing
operations according to established routes and
practice.
Rigidly followed.
Should detect any abnormality immediately and at
the same time indicate the kind of action needed to
correct the problem.
DIFFERENT TYPES OF IN-PROCESS CONTROL
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Environmental control
Building and equipment control
Control of records
Manufacturing control
Packaging control
Labeling control
Warehousing control
Finished product control
IPQC ON STERILE PRODUCT, PARENTERAL
PREPARATION AND STERILE OPHTHALMIC
PREPARATIONS.
General: Sterile products being very critical and sensitive in
nature, a very high degree of precaution, prevention
and preparation are needed.
 Dampness, dirt, and darkness are to be avoided to
ensure aseptic condition.
Environmental Monitoring and Environmental control: The recommended frequencies of periodic
monitoring shall be as follows:
 Particulate monitoring in air - 6 Monthly
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HEPA filter integrity testing(smoke testing) -Yearly.
Air changes rates - 6 Monthly
Air pressure differentials - Daily.
Temperature and humidity - Daily.
Microbiological monitoring by settle plate and/or
swabs in aseptic areas – daily, and at decreased
frequency in other areas.
There shall be written environmental monitoring
programme and microbiological results shall be
recorded.
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Recommended limits for microbiological monitoring
of clean areas “in operation” are as given in the
table below:
Grade
Air sample
Cfu/m3
Settle plates
(dia.90 mm)
Cfu/2 hrs.
Contact plates
(dia.55 mm)
Cfu/plate
Glove points
(five fingers)
cfu/gloves
A
<1
<1
<1
<1
B
10
5
5
5
C
100
50
25
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D
500
100
50
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Appropriate action shall be taken immediately if the
result of particulate and microbiological monitoring
indicates that the counts exceeds the limits.
 The SOP shall contain corrective action.
Sanitation: There shall be written procedure for the sanitation of
sterile processing facilities.
 Employees carrying out sanitation of aseptic areas
shall be trained specially for this purpose.
 Different sanitation agents shall be used in rotation
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Equipment: SOP shall be available for each equipment for its
calibration and operation and cleaning.
 Gauges and other measuring devices attached to
equipment shall be calibrated at suitable interval
against a written programme.
Water and steam systems:Potable water - meeting microbiological specification of
not more than 500 cfu/ml and indicating absence of
individual pathogenic micro-organism.
Purified water – prepared by demineralization shall
meet the microbiological specification of not more
than 100 cfu/ml and indicates absence of
pathogenic micro-organism in 100 ml.
Water for injection – shall be prepared from potable
water or purified water meeting the above
specification by distillation.
 WFI shall meet microbiological specification of not
more than 10 cfu/100 ml.
 Bulk solution of liquid parenteral shall be made in
WFI.
 It also meets IP specification for WFI.
Water for non injectable sterile products –
 Like eye drops shall meet IP specification for purified
water.
 In addition microbiological specification of not more
than 10 cfu/100ml and absence of pseudomonas
aeruginosa and e. coli in 100 ml shall also meet.
Steam coming in contact with the product, primary
containers and other products.
 Contact surface shall be sterile and Pyrogen free.
 The steam condensate shall meet microbiological
specification of not more than 10 cfu/100ml.
Manufacturing process: Bulk raw material shall be monitored for bio-burden
periodically.
 Bio-burden of bulk solution prior to membrane
filtration shall be monitored and a limit of not more
than 100 cfu/ml is recommended.
 Gases coming in contact with the sterile product
shall be filtered through two 0.22 μ filters
connected in series.
 These filter shall be tested for integrity.
Sterilization (autoclaving): Sterilization process shall be validated appropriately.
 The validity of the process shall be verified at regular
interval, but at least annually.
 Whenever significant modification have been made to
the equipment and product, records shall be
maintained thereof.
 The use of biological indicator shall be considered as
an additional method for monitoring the sterilization.
Sterilization ( By Dry Heat ): Each heat sterilization cycle shall be recorded on a
time/temperature chart of a suitable size by
appropriate equipment of the required accuracy and
precision.
 The position of temperature probes used for
controlling and/or recording shall be determined
during the validation.
Sterilization ( By Moist Heat ): Both the temp and pressure shall be used to
monitoring the process.
Control instrumentation shall normally be
independent of monitoring instrumentation and
recording charts.
 System and cycle fault shall be registered by the
system and observed by the operator.
 Frequent leak test done on the chamber during the
vacuum phase of the cycle.
Product container and closures: All container and closures intended for use shall
comply with the pharmacopoeia and other
specified requirement.
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Suitable sample sizes, specification, test methods,
cleaning procedures,& sterilization procedures,
shall be used to assure that container and closures
& other components part of drug packages are
suitable & are not reactive, additive, absorptive, or
leachable.
Finished product control: Checking the bulk solution before filling, pH, color
and completeness of solution.
 Checking the filled volume of liquid or filled weight
of sterile powder for injection in the final container
at the predetermined interval during filling
operation.
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Testing for the leakage of flame sealed ampoules.
 Subjecting the product to physical examination, for
appearance, clarity, & particulate contamination.
Sterility testing procedure:- determines
 Physical condition of testing room.
 Laboratory procedure for handling sterile samples.
 Use of UV lights.
 No. of units tested per batch.
 Procedure for identifying test media with specific
batches.
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Pyrogen testing procedure.
 Determine if animal involved in positive Pyrogen test
are withdrawn from use for the required period.
Indicators
 Determine type of indicator used to assure sterility,
such as lag thermometer, peak control, test cultures,
biological indicators.
 If biological indicators are used, review the current
USP on sterilization and biological indicators.
 In some cases testing biological indicators may
become all or part of the sterility testing.
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Particulate matter testing: Particulate matter consist of extraneous, mobile,
undissolved substance, other than gas bubbles,
unintentionally present in parenteral solution.
 Cleanliness specification or levels of non-viable
particulate contamination must be established.
 The levels of particulate contamination in sterile
powder are generally greater than in LVP.
 LVP solution are filtered during the filling operation.
IPQC ON ORAL LIQUIDS
Building and equipment: Manufacturing area shall have entry through
double door air lock facility.
 It shall be made by fly proof by use of ‘fly catcher
and/or air curtain’.
 Tank, container, pipe work and pumps shall be
designed and installed so that they can be easily
cleaned and sanitized.
Purified water: The chemical and microbiological quality of purified
water used shall be specified and monitored
routinely.
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The microbiological evaluation include testing for
absence of pathogens and shall not exceeds 100
cfu/ml.
There shall be written procedure for operation and
maintenance of the purified water system.
Care shall be taken to avoid the risk of microbial
proliferation with appropriate methods like
recirculation, use of UV treatment, treatment with
heat and sanitizing agent.
Manufacturing: Care shall be taken to maintain the homogeneity of
emulsion by use of of appropriate stirrer during
filling.
 Mixing and filling processes shall be specified and
monitored.
 The primary packaging area shall have an air
supply, which is filtered through 5 micron filters.
 The temp of the area shall not exceed 30 ⁰.C
Finished product protocol: Checking the bulk solution before filling, pH, color,
sedimentation volume, viscosity & completeness of
solution.
 Use of water for cleaning shall be restricted &
controlled.
 Routinely used disinfectants are suitable for
sanitizing the different areas.
Equipments: Suitable check weights, spray testing machines, &
labeling machines shall be provided in the
equipment.
All the equipment shall be suitably calibrated and their
performance validated on receipt and thereafter
periodically.
Manufacture: There shall be an approved master formula records for
the manufacture of metered dose inhalers.
 All propellants, liquids & gases shall be filtered
through 2 µ filters to remove particle.
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IPQC ON ACTIVE PHARMACEUTICAL
INGREDIENTS.
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In process controls for chemical reaction may
includes the following:
Reaction time or reaction completion
Reaction mass appearance, clarity, completeness
or pH solution.
Reaction temperature.
Concentration of the Reactant.
Assay or purity of the product.
Process completion check by TLC/any other
means.
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In process controls for physical operation may
includes the following:
Appearance and color.
Uniformity of the blend.
Temperature of a process.
Concentration of a solution.
Processing rate or time.
Particle size analysis.
bulk / tap density.
pH determination.
Moisture content.
IPQC ON METERED DOSE INHALERS.
General: Manufacture shall be done under condition which
shall ensure minimum microbial and particulate
contamination.
 Assurance of the quality of components and the bulk
products is very important, where medicament are in
suspended state, uniformity of suspension shall be
established.
 Building and civil work: The manufacturing area shall be segregated into
change rooms for personnel, container preparation
area, bulk preparation & filling area, quarantine area,
and spray testing & packing area.
Environmental condition: The requirements of temperature and humidity in the
manufacturing area shall be decided depending on
the type of product and propellant handled in the
facility.
 There shall be difference in room pressure between
the manufacturing area and the supported areas that
is not less than 15 Pascal.
 Written scheduled for monitoring temp, humidity.
Sanitation: Written procedures for the sanitation of the MDI
manufacturing facility.
 Care taken to handle residues and rinses of
propellants.