IPQC FOR PARENTRALS AND OPTHALMIC PRODUCTS

S
IPQC FOR PARENTRALS
AND OPTHALMIC
PRODUCTS
Guided by:
Dr. (Mrs.)S. P. Mahaparale.
Presented by:
Ms. Sai Shrikant Bapat.
M.Pharm Quality Assurance
 IPQC - In Process Quality Control
 IPQC means controlling the procedures involved in manufacturing of dosage forms
starting from raw material purchase to dispatch of the quality product in ideal
packaging.
 IPQC gives an assurance to the manufacturer that the finished pharmaceutical
product fulfills all the quality requirements.
IMPORTANCE:
 To minimize human errors.
 Provide accurate, specific and definite description of procedure to be employed.
 Its planned system to identify materials, equipments processed and operations.
 Inspection of raw material, equipment, environment, process, testing with respect
to specification, packing and so on.
STEPS INVOLVED IN IPQC-:
1) Identify types of formulations manufacturing or going to manufacture,
e.g. Parentrals, ointments.
2) Identify which are the critical steps in the manufacturing of product,
where it will be necessary to check certain parameters to confirm that
the process is in control.
3) Identify specification of parameters which will confirm parameters are
within control.
4) Define frequency of checking of parameters.
5) Create monitoring and control records for all IPQC process.
6) Keep provision for modification of process if required.
7) The entire process is described and explained to IPQC workers and
supervisors before implementing. Records of such IPQC training may be
kept.
IPQC FOR PARENTRALS AND OPTHALMICS
 Leakage test
 Sterility test
 Pyrogen test
 Clarity test
 Content uniformity and weight
Leakage Test-:
It is employed to check pakage 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.
Visual inspection-:
It is easiest leak test to perform and use for evaluation of large volume parentrals.
To increase the sensitivity of method the visual inspection of the sample container
may be coupled with the application of vaccum to make leakage more readily
observable.
This method is simple and inexpensive.
Dye Bath Test –: For parentrals
1. The test container immersed in vaccum chamber consisting of 1%
methylene blue solution.
2. A vacuum of about 27” inches Hg is created for 15-30 mins.
3. This causes the solution to enter the container with defective sealing.
4. The vacuum is released and ampoules are observed.
5. If a leakage is present , solution in container appear blue in colour.
The test is qualitative, destructive and slow. It is used for
ampoules and vials.
This test is widely accepted in industry and is approved
in drug use.
1) Select 10 tubes of the ointment with seals applied when specified.
2) Thoroughly clean and dry the exterior surfaces of each tube with an
absorbent cloth.
3) Place the tubes in horizontal position on a sheet of absorbent blotting
paper in an oven maintained at temperature of 60 for 8 hours.
4) No significant leakage occurs during or at the completion of test.
5)If leakage is observed from one, but more than one of the tubes repeat the
test with additional 20 tubes of ointments.
6)The requirement is met if no leakage is observed from the first 10 tubes
tested or if leakage is observed from not more than one of 30 tubes tested.
Leaker test -: For ophthalmic
Opthalmic Preparations
 Opthalmic products are the sterile products meant to instillation in
to the eye in the space between eye lid and the eye ball.
 These products must be sterile and are prepared under the same
condition and by the same methods as other parentral
preparations.
 Opthalmic products includes-:
 Eye drops
 Eye lotions
 Eye ointment
 Eye suspension
 Contact lens solution
Sterility Test-:
The test for sterility are intended for detecting the presence of viable
micro-organism in sterile preparation.
It is based on principle that if micro-organism are placed in a medium
that provide optimum condition of nutrition, moisture, pH, aeration,
temperature, they can grow and their presence will be indicated by
presence of turbidity in clear medium.
It is done by two methods-
1. Membrane filtration method
2. Direct inoculation method
Membrane Filtration Method –
Use membrane filters having a nominal pore size not greater than 0.4μm whose
effectiveness to retain microorganisms has been established.
Cellulose nitrate filters, are used for aqueous, oily, and weakly alcoholic solutions;
and cellulose acetate filters, are used for strongly alcoholic solutions.
Specially adapted filters may be needed for certain products (e.g., for antibiotics).
The technique described below assumes that membranes about 50 mm in diameter
will be used.
If filters of a different diameter are used, the volumes of the dilutions and the
washings should be adjusted accordingly. The filtration apparatus and membrane
are sterilized by appropriate means.
The apparatus is designed so that the solution to be examined can be introduced
and filtered under aseptic conditions: it permits the aseptic removal of the
membrane for transfer to the culture medium, or it is suitable for carrying out the
incubation after adding the medium to the apparatus itself.
After filtration the preparation membrane is cut into two halves. One halve is
transferred in to 100ml of culture medium meant for the growth of the bacteria
and incubated at 30 to 35°C for not less than 7 days. The another halve is
transferred to 100 ml of culture medium meant for fungi and incubated at 20 -
25 o C for not less than 7 days.
Detection of contamination used two culture media-:
A) Soyabean-Casein digest medium -: incubate at 20-25 degree C
B) Fluid thioglycollate medium -: incubated at 30- 35 degree
C on 7 days.
 Direct Inoculation Method –
Although international pharmacopoeias recommend using standard membrane
filtration for sterility testing, there are certain products that are not filterable or
deformable.
These products are normally tested using direct inoculation.
In this method, the test sample is added directly into the required media, ensuring
that the amount of sample is below 10%.
To comply with your different direct inoculation method requirements, sterility
test media in various volumes, from 9mL tubes up to 75 mL bottles are available.
In this method an aliquot quantity of the material being tested is drawn
aseptically from the container and transferred to a vessel containing a measured
quantity of a suitable culture medium.
The culture is incubated at appropriate temperature for not less than 14 days.
The culture medium is observed at periodic intervals during the incubation period
and at the end to detect presence of any microbial growth.
Membrane Filtration Direct Inoculation
It requires the membrane filter unit. Does not require membrane filter
unit.
Sample is not directly inoculated into
media.
Samples are directly inoculated
into media.
Passes through a 0.45 mm
membrane filter
-
Product to be analyzed should be
aqueous solution, soluble solid, oil
or oily solutions, semisolids.
Product to be analyzed should be
oily liquids, semisolids,
 Pyrogen test-:
Pyrogens are products of metabolism in microorganism gram –ve bacteria
produces most potent pyrogens.
When these pyrogens are introduced into a body they produce a mark response of
fever with body ache and vasoconstriction within onset of 1 hour. Basically these test
performed to detect presence of pyrogens in sterile parentral products.
LAL Test
Rabbit Test
Limulus Amebocyte Lysate (LAL) Test-
The LAL Assay is an in vitro assay used to detect the presence and
concentration of bacterial endotoxins in drugs and biological products.
This test is based upon the gelling property of an enzyme, the limulus
amebocyte lysate extracted from the horse shoe crab, limulus polyphormus.
The enzyme gels in the presence of bacterial endotoxin and the degree of
gelling is related to the amount of endotoxin present.
A no. of instrument is available for measuring the degree of gelling of
enzyme. The test can be used for quantifying the amount bacterial
endotoxin present and provide a better information regarding the quality of
a product than rabbit pyrogen test which is more of a qualitative test.
Rabbit Test-:
 Preliminary Test (SHAM test)-
If animals are used for the first time in a pyrogen test or have not been used
during the two previous weeks, condition them one to three days before
testing the substance being examined, by injecting I.V. 10 mL of pyrogen-free
saline solution per kilogram of body weight.
Carry out the test in a room with no risk of disturbing or exciting the animals,
and a room temperature that is within 3 degrees of the area where the
animals are housed, or in which the animals have been maintained for at least
18 hours before the test.
Food and drink should be withheld from the animals overnight and until the
test is completed.
Record the temperature of the animals beginning at least 90 min. before
injection and for 3 hours following injection of the solution under
investigation.
Any animal showing a temp. In the main test, any change of 0.6 or greater
must be avoided.
 Main Test-
Inject the solution under examination slowly into the marginal vein of the ear
of each rabbit over a period not exceeding 4 minutes, unless otherwise
prescribed in the monograph.
Record the temperature of each animal at half-hourly intervals for 3 hours
after the injection.
The difference between the “starting temperature” and the “maximum
temperature,” which is the greatest temperature a rabbit has ever been
measured at, is considered its response.
 Interpretation of results -
If the sum of the responses of the group of three rabbits does not exceed
1.4°C and if the response of individual rabbits is less than 0.6°C, the
preparation under examination passes the test.
If it exceeds, repeat the test with five more rabbits.
 Clarity Test-:
It is carried out to check the particulate matter in the sample.
It’s practically impossible that every unit of lost is perfectly free from visible
particulate matter.
There are 2 methods-
1) Visual inspection by naked eye
2) Instrumental method
USP limit for LVP-
Particle size Particle limit
10mm or larger/ml 50
25mm or larger/ml 5
 Visual inspection by naked eyes-:
Each injectable is inspected visually against white and black backgrounds.
The white background aids in detection of dark coloured particles.
The light or reflective particles will appear against the black background.
 Instrumentation method-:
This is also called As the particle count method.
Particle counting may be based on any on eof the following principles;
change in
• Electrical resistance
• Light absorption
• Light scattering
 Metal particles in ophthalmic ointment-:
 Extrude as completely as practicable the content of 10 tubes individually into
separate, clear, flat-bottom, 60 mm petridishes that are free from scratches.
 Cover the dishes and heat at 85 degree C for 2 hours, increasing the
temperature slightly if necessary to ensure that a fully fluid state is obtained.
 Taking precautions against disturbing the melted sample, allow each to cool to
room temperature and to solidify.
 Remove the covers and invert each petridish on the stage of suitable
microscope adjusted to furnish 30 times magnification and equipped with an
eye pieces mm disk that has been calibrated at the magnification being used.
 Examine the entire bottom of petridish for metal particles.
 Count number of metals particles that are 50um on larger in any dimension.
The requirements are met if total no. of particles in all 10 tubes does not
exceeds 50 an dif not more than 1 tube is found to contain more than 8 such
particles.
 If these results are not obtained, repeat the test on 20 additional tubes.
 Content Uniformity & Weight
Determine the content of the active ingredient of each of 10 containers taken at
random. The preparation under examination complies with the test if the
individual values thus obtained are all between 85 and 115 percent of the
average value.
The preparation under the examination fails to comply with the test if more than
one individual value is outside the limits 85 to 115 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.
 Limits for uniformity of weight is given in Table –
Pharmaceutical
Formulation
Average Mass Percentage
Deviation (%)
Powders for
parenteral use
More than 40 mg 10
Powders for eye drops Less than 300mg 10
Powders for eye
lotions
300mg or more 7.5
THANK YOU
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IPQC FOR PARENTRALS AND OPTHALMIC PRODUCTS

  • 1. IPQC FOR PARENTRALS AND OPTHALMIC PRODUCTS Guided by: Dr. (Mrs.)S. P. Mahaparale. Presented by: Ms. Sai Shrikant Bapat. M.Pharm Quality Assurance
  • 2.  IPQC - In Process Quality Control  IPQC means controlling the procedures involved in manufacturing of dosage forms starting from raw material purchase to dispatch of the quality product in ideal packaging.  IPQC gives an assurance to the manufacturer that the finished pharmaceutical product fulfills all the quality requirements. IMPORTANCE:  To minimize human errors.  Provide accurate, specific and definite description of procedure to be employed.  Its planned system to identify materials, equipments processed and operations.  Inspection of raw material, equipment, environment, process, testing with respect to specification, packing and so on.
  • 3. STEPS INVOLVED IN IPQC-: 1) Identify types of formulations manufacturing or going to manufacture, e.g. Parentrals, ointments. 2) Identify which are the critical steps in the manufacturing of product, where it will be necessary to check certain parameters to confirm that the process is in control. 3) Identify specification of parameters which will confirm parameters are within control. 4) Define frequency of checking of parameters. 5) Create monitoring and control records for all IPQC process. 6) Keep provision for modification of process if required. 7) The entire process is described and explained to IPQC workers and supervisors before implementing. Records of such IPQC training may be kept.
  • 4. IPQC FOR PARENTRALS AND OPTHALMICS  Leakage test  Sterility test  Pyrogen test  Clarity test  Content uniformity and weight
  • 5. Leakage Test-: It is employed to check pakage 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. Visual inspection-: It is easiest leak test to perform and use for evaluation of large volume parentrals. To increase the sensitivity of method the visual inspection of the sample container may be coupled with the application of vaccum to make leakage more readily observable. This method is simple and inexpensive.
  • 6. Dye Bath Test –: For parentrals 1. The test container immersed in vaccum chamber consisting of 1% methylene blue solution. 2. A vacuum of about 27” inches Hg is created for 15-30 mins. 3. This causes the solution to enter the container with defective sealing. 4. The vacuum is released and ampoules are observed. 5. If a leakage is present , solution in container appear blue in colour. The test is qualitative, destructive and slow. It is used for ampoules and vials. This test is widely accepted in industry and is approved in drug use.
  • 7. 1) Select 10 tubes of the ointment with seals applied when specified. 2) Thoroughly clean and dry the exterior surfaces of each tube with an absorbent cloth. 3) Place the tubes in horizontal position on a sheet of absorbent blotting paper in an oven maintained at temperature of 60 for 8 hours. 4) No significant leakage occurs during or at the completion of test. 5)If leakage is observed from one, but more than one of the tubes repeat the test with additional 20 tubes of ointments. 6)The requirement is met if no leakage is observed from the first 10 tubes tested or if leakage is observed from not more than one of 30 tubes tested. Leaker test -: For ophthalmic
  • 8. Opthalmic Preparations  Opthalmic products are the sterile products meant to instillation in to the eye in the space between eye lid and the eye ball.  These products must be sterile and are prepared under the same condition and by the same methods as other parentral preparations.  Opthalmic products includes-:  Eye drops  Eye lotions  Eye ointment  Eye suspension  Contact lens solution
  • 9. Sterility Test-: The test for sterility are intended for detecting the presence of viable micro-organism in sterile preparation. It is based on principle that if micro-organism are placed in a medium that provide optimum condition of nutrition, moisture, pH, aeration, temperature, they can grow and their presence will be indicated by presence of turbidity in clear medium. It is done by two methods- 1. Membrane filtration method 2. Direct inoculation method
  • 10. Membrane Filtration Method – Use membrane filters having a nominal pore size not greater than 0.4μm whose effectiveness to retain microorganisms has been established. Cellulose nitrate filters, are used for aqueous, oily, and weakly alcoholic solutions; and cellulose acetate filters, are used for strongly alcoholic solutions. Specially adapted filters may be needed for certain products (e.g., for antibiotics). The technique described below assumes that membranes about 50 mm in diameter will be used. If filters of a different diameter are used, the volumes of the dilutions and the washings should be adjusted accordingly. The filtration apparatus and membrane are sterilized by appropriate means. The apparatus is designed so that the solution to be examined can be introduced and filtered under aseptic conditions: it permits the aseptic removal of the membrane for transfer to the culture medium, or it is suitable for carrying out the incubation after adding the medium to the apparatus itself.
  • 11. After filtration the preparation membrane is cut into two halves. One halve is transferred in to 100ml of culture medium meant for the growth of the bacteria and incubated at 30 to 35°C for not less than 7 days. The another halve is transferred to 100 ml of culture medium meant for fungi and incubated at 20 - 25 o C for not less than 7 days. Detection of contamination used two culture media-: A) Soyabean-Casein digest medium -: incubate at 20-25 degree C B) Fluid thioglycollate medium -: incubated at 30- 35 degree C on 7 days.
  • 12.  Direct Inoculation Method – Although international pharmacopoeias recommend using standard membrane filtration for sterility testing, there are certain products that are not filterable or deformable. These products are normally tested using direct inoculation. In this method, the test sample is added directly into the required media, ensuring that the amount of sample is below 10%. To comply with your different direct inoculation method requirements, sterility test media in various volumes, from 9mL tubes up to 75 mL bottles are available. In this method an aliquot quantity of the material being tested is drawn aseptically from the container and transferred to a vessel containing a measured quantity of a suitable culture medium. The culture is incubated at appropriate temperature for not less than 14 days. The culture medium is observed at periodic intervals during the incubation period and at the end to detect presence of any microbial growth.
  • 13. Membrane Filtration Direct Inoculation It requires the membrane filter unit. Does not require membrane filter unit. Sample is not directly inoculated into media. Samples are directly inoculated into media. Passes through a 0.45 mm membrane filter - Product to be analyzed should be aqueous solution, soluble solid, oil or oily solutions, semisolids. Product to be analyzed should be oily liquids, semisolids,
  • 14.  Pyrogen test-: Pyrogens are products of metabolism in microorganism gram –ve bacteria produces most potent pyrogens. When these pyrogens are introduced into a body they produce a mark response of fever with body ache and vasoconstriction within onset of 1 hour. Basically these test performed to detect presence of pyrogens in sterile parentral products. LAL Test Rabbit Test
  • 15. Limulus Amebocyte Lysate (LAL) Test- The LAL Assay is an in vitro assay used to detect the presence and concentration of bacterial endotoxins in drugs and biological products. This test is based upon the gelling property of an enzyme, the limulus amebocyte lysate extracted from the horse shoe crab, limulus polyphormus. The enzyme gels in the presence of bacterial endotoxin and the degree of gelling is related to the amount of endotoxin present. A no. of instrument is available for measuring the degree of gelling of enzyme. The test can be used for quantifying the amount bacterial endotoxin present and provide a better information regarding the quality of a product than rabbit pyrogen test which is more of a qualitative test.
  • 16. Rabbit Test-:  Preliminary Test (SHAM test)- If animals are used for the first time in a pyrogen test or have not been used during the two previous weeks, condition them one to three days before testing the substance being examined, by injecting I.V. 10 mL of pyrogen-free saline solution per kilogram of body weight. Carry out the test in a room with no risk of disturbing or exciting the animals, and a room temperature that is within 3 degrees of the area where the animals are housed, or in which the animals have been maintained for at least 18 hours before the test. Food and drink should be withheld from the animals overnight and until the test is completed. Record the temperature of the animals beginning at least 90 min. before injection and for 3 hours following injection of the solution under investigation. Any animal showing a temp. In the main test, any change of 0.6 or greater must be avoided.
  • 17.  Main Test- Inject the solution under examination slowly into the marginal vein of the ear of each rabbit over a period not exceeding 4 minutes, unless otherwise prescribed in the monograph. Record the temperature of each animal at half-hourly intervals for 3 hours after the injection. The difference between the “starting temperature” and the “maximum temperature,” which is the greatest temperature a rabbit has ever been measured at, is considered its response.  Interpretation of results - If the sum of the responses of the group of three rabbits does not exceed 1.4°C and if the response of individual rabbits is less than 0.6°C, the preparation under examination passes the test. If it exceeds, repeat the test with five more rabbits.
  • 18.  Clarity Test-: It is carried out to check the particulate matter in the sample. It’s practically impossible that every unit of lost is perfectly free from visible particulate matter. There are 2 methods- 1) Visual inspection by naked eye 2) Instrumental method USP limit for LVP- Particle size Particle limit 10mm or larger/ml 50 25mm or larger/ml 5
  • 19.  Visual inspection by naked eyes-: Each injectable is inspected visually against white and black backgrounds. The white background aids in detection of dark coloured particles. The light or reflective particles will appear against the black background.  Instrumentation method-: This is also called As the particle count method. Particle counting may be based on any on eof the following principles; change in • Electrical resistance • Light absorption • Light scattering
  • 20.  Metal particles in ophthalmic ointment-:  Extrude as completely as practicable the content of 10 tubes individually into separate, clear, flat-bottom, 60 mm petridishes that are free from scratches.  Cover the dishes and heat at 85 degree C for 2 hours, increasing the temperature slightly if necessary to ensure that a fully fluid state is obtained.  Taking precautions against disturbing the melted sample, allow each to cool to room temperature and to solidify.  Remove the covers and invert each petridish on the stage of suitable microscope adjusted to furnish 30 times magnification and equipped with an eye pieces mm disk that has been calibrated at the magnification being used.  Examine the entire bottom of petridish for metal particles.  Count number of metals particles that are 50um on larger in any dimension. The requirements are met if total no. of particles in all 10 tubes does not exceeds 50 an dif not more than 1 tube is found to contain more than 8 such particles.  If these results are not obtained, repeat the test on 20 additional tubes.
  • 21.  Content Uniformity & Weight Determine the content of the active ingredient of each of 10 containers taken at random. The preparation under examination complies with the test if the individual values thus obtained are all between 85 and 115 percent of the average value. The preparation under the examination fails to comply with the test if more than one individual value is outside the limits 85 to 115 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.
  • 22.  Limits for uniformity of weight is given in Table – Pharmaceutical Formulation Average Mass Percentage Deviation (%) Powders for parenteral use More than 40 mg 10 Powders for eye drops Less than 300mg 10 Powders for eye lotions 300mg or more 7.5