In Process Quality Control Tests (IPQC) For Parenteral or Sterile Dosage Forms
In Process Quality Control Tests (IPQC) For Parenteral or Sterile Dosage Forms
In Process Quality Control Tests (IPQC) For Parenteral or Sterile Dosage Forms
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In Process Quality Control Tests (IPQC) For Parenteral or Sterile Dosage Forms
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IPQC for Parenterals or Sterile Dosage Forms | Mr. Sagar Kishor Savale
Parenteral Route
It is a route of administration other than the oral route, this route of administration
bypasses the alimentary canal.
It includes, I.V., I. M., Subcutaneous route for parenteral administration.
Types of Parenteral
1. Based on types of packaging
a) Single dose units: ampoules, infusions and prefilled disposable syringes.
b) Multiple dose units: multiple dose vials.
Quality Control: The procedure or set of procedures intended to ensure that a manufactured
product or performed service adheres to a defined set of quality criteria or meets the
requirements of the client or customer.
IPQC
IPQC means controlling the procedures involved in manufacturing of the dosage forms
starting from raw materials purchase to dispatch of the quality product in ideal packaging.
It monitors all the features of the product that may affect its quality and prevents errors
during processing.
These are the tests performed between QA and QC and provides for the authorization of
approved raw materials for manufacturing based on actual laboratory testing generally
called as IPQC such as physical, chemical, microbiologic and biologic tests.
IPQC is concerned with providing accurate, specific & definite descriptions of the
procedures to be employed, from, the receipt of raw materials to the release of the finished
dosage forms.
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IPQC for Parenterals or Sterile Dosage Forms | Mr. Sagar Kishor Savale
1. Leakage Test (visual inspection, bubble test, dye tests and vacuum ionization 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”. It is because leakage occurs when
a discontinuity exists in the wall of a package that can allow the passage of gas under pressure
or concentration differential existing across the wall. Leakage test can be done by dye bath test.
Dye Bath Test
The test container is immersed in a dye bath. Vacuum and pressure is applied for some time.
The container is removed from the dye bath and washed. The container is then inspected for
the presence of dye either visually or by means of UV spectroscopy. The dye used may be of
blue, green, yellowish-green color. The dye test can be optimized by use of a surfactant and or
a low viscosity fluid in the dye solution to increase the capillary migration through the pores.
The dye test is widely accepted in industry and is approved in drug use. The test is inexpensive
and is requires no special equipment required for visual dye detection. However, the test is
qualitative, destructive and slow. The test is used for ampoules and vials.
2. Clarity Test
Clarity testing is carried out to check the particulate matter in the sample. In this test transparent
particles or white particles observed against the black background and the black or dark
particles observed against the white background.
3. pH
Checking the bulk solution, before filling for drug content, pH, color, clarity and completeness
of solution.
The pH of a formulation must be considered from following standpoint:
The effect on the body when the solution is administered
The effect on stability of the product
The effect on container-closure system
pH measurement
pH is measured by using a pH meter .
pH meter is initially calibrated with respective buffer capsule then the pH of the
preparation is measured.
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IPQC for Parenterals or Sterile Dosage Forms | Mr. Sagar Kishor Savale
5. Sterility Test
Sterility can be defined as the freedom from the presence of viable microorganisms.
It is done for detecting the presence of viable forms of bacteria, fungi and yeast in
parenteral products.
The test for Sterility must be carried out under strict aseptic conditions in order to avoid
accidental contamination of the product during test.
All glassware's required for the test must be Sterile.
Sterility testing attempts to reveal the presence or absence of viable microorganisms in
a sample number of containers taken from batch of product.
Based on results obtained from testing the sample a decision is made as to the sterility
of the batch.
Environmental conditions:
Environmental conditions avoid accidental contamination of the product during the test.
The test is carried out under aseptic conditions regular microbiological monitoring
should be carried out.
Culture conditions:
Appropriate conditions for the growth of any surviving organism should be provided
by the culture media selection.
Factors affecting growth of bacteria:
Nutrition
Moisture
Air
Temperature
pH
Light
Osmotic pressure
Growth inhibitors
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IPQC for Parenterals or Sterile Dosage Forms | Mr. Sagar Kishor Savale
Specific role of some ingredients primarily intended for the culture of anaerobic
bacteria.
Incubation of the media: 14 days at 30 -35°C
The entire contents can be tested providing an advantage in the sterility testing of
LVP and increasing the ability to detect contamination.
The antimicrobial agent and antimicrobial solutes in the product sample can be
eliminated by rinsing prior transferring the filter into test tubes of media
Thereby minimizing the incidence of false-negative test results.
Organisms present in an oleaginous product can be separated from the product during
filtration and cultured in a more desirable aqueous medium.
Disadvantages
This method cannot differentiate the extent of contamination between units if present
because all product contents are combined and filtered through a single filter and
cultured in single test tube.
There exists a higher probability of inadvertent contamination in manual operations.
Required quantities of liquid is removed from the test containers with a sterile pipette /
sterile syringe.
Aseptically transfer the specified volume of the material from each container to vessel
of culture medium
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IPQC for Parenterals or Sterile Dosage Forms | Mr. Sagar Kishor Savale
Interpretation of results
At the end of the incubation period the following observations are possible:
No evidence of growth; hence the preparation being examined passes the test for
sterility.
If there is evidence of growth, retesting is performed using the same number of samples,
volumes to be tested and the media as in the original test. If no evidence of microbial
growth is then found, the preparation being examined passes the test for sterility.
If there is again evidence of the microbial growth then isolate and identify the
organisms. If they are not readily distinguishable from those growing in the containers
of the first test then the preparation being examined fails the test for sterility.
If they are distinguishable from the organisms of the first test then again do the test
using twice the number of samples. The preparation being examined passes the test for
sterility in case there is no evidence of microbial growth. In case there is evidence of
growth of any microorganisms in second re –test, the preparation being examined fails
the tests for sterility.
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IPQC for Parenterals or Sterile Dosage Forms | Mr. Sagar Kishor Savale
Cool the flask, decant the water from the flask into a clean vessel, and wash the
residual powdered glass with high purity water, add 5 drops methyl red solution,
titrate immediately with 0.02 N sulphuric acid.
Record the volume of 0.02N Sulphuric acid used to neutralize the extract from 10 g of
the prepared specimen of glass.
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IPQC for Parenterals or Sterile Dosage Forms | Mr. Sagar Kishor Savale
Fragmentation
Self sealability
Clarity and color
6. 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.
Stable to at least 175ºC; steam sterilization ineffective.
Water soluble; monomer unit of LPS can be 10,000 Daltons (1.8 nm) so endotoxins can
easily pass through 0.22μm filters.
Sources: Water (main), raw materials, equipment, process environment, people, and
protein expression systems if using gram negative bacteria.
Other Source: Equipment, Containers (Glass, plastic, metal), Solvent and Solute.
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IPQC for Parenterals or Sterile Dosage Forms | Mr. Sagar Kishor Savale
Elimination of pyrogens
1. Dry heat sterilization: For glass wares, metal equipments, powders, waxes, oils, heat stable
drugs.
650 o C temp - 1 min
250 o C temp - 30 min
180 o C temp - 240 min
2. Ultra filtration
3. Reverse osmosis: RO membrane is composed of cellulose acetate phthalate/ polyamide
4. Distillation
5. Adsorption method
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percent of the average value or if any one individual value is outside the limits 75 to 125 percent
of the average value. If one individual value is outside the limits 85 to 115 percent but within
the limits 75 to 125 percent of the average value, repeat the determination using another 20
containers taken at random. The preparation under examination complies with the test if in the
total sample of 30 containers not more than one individual value is outside the limits 85 to 115
percent and none is outside the limits 75 to 125 percent of the average value.
Table 3: Limits for Uniformity of Weight
Pharmaceutical Average Percentage
Formulation Mass Deviation (%)
Powders for More than 40 10
parenteral use mg
Powders for eye Less than 300 10
drops mg
Powders for eye 300 mg or 7.5
lotions more
8. Extractable Volume
a) Single Dose Containers
Method I: Where the nominal volume does not exceed 5ml. Use 6 containers, 5 for the tests
and 1 for rinsing the syringe used. Using a syringe with appropriate capacity, rinse the syringe
and withdraw as much as possible the contents of one of the containers reserved for the test
and transfer, without emptying the needle, to a dry graduated cylinder of such capacity that the
total combined volume to be measured occupies not less than 40% of the nominal volume of
the cylinder. Repeat the procedure until the contents of the 5 containers have been transferred
and measure the volume. The average content of the 5 containers is not less than the nominal
volume and not more than 115% of the nominal volume. Alternatively the volume of contents
in milliliter can be calculated as mass in grams divided by the density.
Method II: Where the nominal volume is more than 5ml. Transfer the contents of not less than
3 containers separately to dry graduated cylinders such that the volume to be measured
occupies not less than 40% of the nominal volume of the cylinder and measure the volume
transferred. The contents of each container are not less than the nominal volume and not more
than 110% of the nominal volume.
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IPQC for Parenterals or Sterile Dosage Forms | Mr. Sagar Kishor Savale
9. Volume Filled
Volume in container
An injection container is filled with a volume in slight excess of the labelled size Physical and
chemical tests.
Test Apparatus
pH pH Meter
Viscosity Ostwald viscometers
Osmolality Osmometer (count of the number of particles in a fluid sample)
Conductivity Conductometer (conductivity of vehicle used in sterile
preparation) (Pure Water 0.55mS/cm)
Temperature For Heat Thermometer, Digital Thermometer (To maintain the constant
Sterilization temperature during heat sterilization of product)
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IPQC for Parenterals or Sterile Dosage Forms | Mr. Sagar Kishor Savale
Surface disinfection: Must be inherently neat, orderly, reliable and alert. Should be in good
health.
Air control (HEPA filters): It is composed of glass fibers and filters. It is 99.97% efficient
removes particles of 0.3 um size and larger. (Velocity is 100+/- 20 ft/min).
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IPQC for Parenterals or Sterile Dosage Forms | Mr. Sagar Kishor Savale
Aseptic Techniques:
Aseptic area: the area which are used to kill the pathogenic microorganisms.
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IPQC for Parenterals or Sterile Dosage Forms | Mr. Sagar Kishor Savale
Instrumental Methods
This is also called as the particle count method particle counting may be based on any one
of the following principles; change in
Electrical resistance
Light absorption
Light scattering
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IPQC for Parenterals or Sterile Dosage Forms | Mr. Sagar Kishor Savale
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IPQC for Parenterals or Sterile Dosage Forms | Mr. Sagar Kishor Savale
Cleaning of
Sealing the
containers and Sterilization
container
Equipment
Preparation of
Labeling &
parenteral Filtration
packaging
products
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IPQC for Parenterals or Sterile Dosage Forms | Mr. Sagar Kishor Savale
Sterile Products
Injections
Injections are sterile solutions, emulsions or suspensions prepared by dissolving emulsifying
or suspending the active ingredients and other additives in water for injection or other suitable
non-aqueous vehicle or in mixture of two, if they are miscible.
Intravenous Infusion
These are sterile aqueous solutions or emulsions with water as continuous phase. When a drug
is infused intravenously at a constant rate, a plateau concentration will be reached progressively
in the most frequently most of the cases follows first order kinetics. On starting the infusion,
there is no drug in the body and therefore, no elimination. The amount of drug in the body then
rises, but as the drug concentration increases, so does the rate of elimination. Thus, the rate of
elimination will keep rising until it matches the rate of infusion. The amount of drug in the
body is then constant and is said to have reached a steady state or plateau.
Implants
Implants are sterile solid preparations of size and shape for implantation into body tissues so
as to release active ingredient over an extended period of time. An implant is a medical device
manufactured to replace a missing biological structure, support a damaged biological structure,
or enhance an existing biological structure. Medical implants are man-made devices, in contrast
to a transplant, which is a transplanted biomedical tissue. The surface of implants that contact
the body might be made of a biomedical material such as titanium, silicone or apatite depending
on what is the most functional. In some cases implants contain electronics e.g. artificial
pacemaker and cochlear implants. Some implants are bioactive, such as subcutaneous drug
delivery devices in the form of implantable pills or drug-eluting stents.
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IPQC for Parenterals or Sterile Dosage Forms | Mr. Sagar Kishor Savale
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Contact
Mr. Sagar Kishor Savale,
M. Pharm (Pharmaceutics),
Mobile No.: +91 9960885333,
Email: savalesagar484@gmail.com
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