Quality Control Tests for Ophthalmics

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Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 1
A Seminar as a part of curricular requirement
for I year M.Pharm I Semester
Presented by
Ms. T.Jayasree (20L81S0709)
Pharmaceutical analysis
Under the guidance/Mentorship of
Dr.K.Vinod Kumar., M.Pharm.,Ph.D
Professor of pharmaceutical analysis.
Head of department- pharmaceutical analysis.
Quality control tests for ophthalmics

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• Introduction
• Universal tests
• Quality control test
• References
Contents

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• Ophthalmic preparation (eye preparations) are sterile,liquid,semi-soild, or
solid preparations that may contain one or more active pharmaceutical
ingredient(s) intended for application to the conjuctiva,the conjuctival sac or
the eyelids.
• The manufacturing processes should meet the requirements of GMP,
especially with regard to cross-contamination.
• The dosage forms intended to be administered into the external surface of
the eye, inside or adjacent to the eye or those used in combination with
ocular appliances.
Introduction

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Based on the site of administration
• Topical preparation(external surface of the eye)
• Intraocular preparation(inside the eye)
• Periocular preparation(adjacent to the eye)
Several categories of eye preparations may be distinguished as:
• Eye drops & Eye ointments & Eye solutions.
• Semi-solid eye preparations.
• Ophthalmic inserts
• Powders for eye drops or eye lotions
Classification of Ophthalmic preparations

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Description
• This test is often called appearance on a specification and is a qualitative
description of the ophthalmic pharmaceuticals.
• For example, the description of ophthalmic preparations on a specification may
read: transparent/opaque preparation, proper labeling, imprinted with ‘‘Rx”.
Identification
• The purpose of an identification or identity test is to verify the identity of the
active pharmaceutical ingredient (API) in the ophthalmic pharmaceuticals.
• This test should be able to discriminate between compounds of closely related
structures that are likely to be present.
UNIVERSAL TESTS

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 Assay
• This test determines the strength or content of the API in the ophthalmic
pharmaceuticals and is sometimes called a content test.
 Impurities
• This test determines the presence of any component that is not the API or
an excipient ophthalmic pharmaceuticals.
• The most common type of impurities that are measured is related
substances, which are processed impurities from the new drug substance
synthesis, degradation products of the API, or both.

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Quality control Tests:

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• Where only 1 or 2 drops of a solution containing them are added to the eye,
the buffering action of the tears is usually adequate to raise the pH and
prevent marked discomfort.
• In some cases pH may vary between 3.5 and 8.5.
• Some drugs, notably pilocarpine hydrochloride and epinephrine bitartrate, are
more acid and overtax the buffer capacity of the lacrimal fluid.
• Ideally, an ophthalmic solution should have the same pH, as well as the same
isotonicity value, as lacrimal fluid. This is not usually possible since, at pH 7.4,
many drugs are not appreciably soluble in water

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• Most alkaloidal salts precipitate as the free alkaloid at this pH.
Additionally, many drugs are chemically unstable at pH levels
approaching 7.4.
• This instability is more marked at the high temperatures employed in
heat sterilization.
• For this reason, the buffer system should be selected that is nearest
to the physiological pH of 7.4 and does not cause precipitation of the
drug or its rapid deterioration

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• The final pH of the solution is often a compromise, because many
ophthalmic drugs have limited solubility and stability at the desired pH of
7.4.
• Buffers or pH adjusting agents or vehicles can be added to adjust and
stabilize the pH at a desired level.
• Ophthalmic solutions are ordinarily buffered at the pH of maximum
stability of the drugs they contain.
• The buffers are included to minimize any change in pH during the storage
life of the drug.

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Isotonicity:
• The term isotonic, meaning equal tone .
• A solution is said to be isotonic when its effective osmole
concentration is the same as that of another solution.
• Solutions that are isotonic with tears are preferred.
• An amount equivalent to 0.9% sodium chloride (NaCl) is ideal for
comfort and should be used when possible.

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• The eye can tolerate tonicities within the equivalent range of 0.6 to 2%
NaCl without discomfort.
• There are times when hypertonic ophthalmic solutions are necessary
therapeutically, or when the addition of an auxiliary agent required for
reasons of stability supersedes the need for isotonicity.
• A hypotonic ophthalmic solution will require the addition of a
substance (tonicity adjusting agent) to attain the proper tonicity range.

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• when an ophthalmic solution without a buffer is desired, any
compatible salt or non-electrolyte that is approved for ophthalmic
products may be used.
• Sodium chloride, sodium nitrate, sodium sulfate, and dextrose are
common neutral tonicity adjustors.

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Viscosity:
• Viscosity enhancers are used in ophthalmic solutions to increase
their viscosity.
• This enables the formulation to remain in the eye longer and gives
more time for the drug to exert its therapeutic activity or undergo
absorption.
• Commonly used viscosity enhancers and their maximum
concentrations .

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• Typical concentrations of viscosity-enhancing agents approved for
use in ophthalmic liquids:
Viscosity enhancer Maximum
concentration (%)
Hydroxyethylcellulose 0.8
Hydroxypropylmethylcellulose 1.0
Methylcellulose 2.0
Polyvinyl alcohol 1.4
Polyvinylpyrrolidone 1.7

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• The most common viscosity desired in an ophthalmic solution is
between 25 and 50 cps.
• The actual concentration of the enhancer required to produce that
viscosity will depend on the grade of the enhancer.
• For example, if methylcelluse 25 cps is used, a 1% solution will
create a viscosity of 25 cps.
• If methylcellulose 4000 cps is used, a 0.25% solution provides the
desired viscosity.

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Therapeutic Efficacy:
• The active ingredient(s) should be present in the most therapeutically
effective form.
• This goal must often be compromised for reasons of solubility or
stability of the active ingredient or patient comfort.
• For example, while many drugs are most active in their undissociated
form, they are least soluble in this form.
• They may also be less stable at pH values that favor the undissociated
form.

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Compatibility with the Eye:
• Ophthalmic solutions should be free of chemicals or agents that cause
allergy or toxicity to the sensitive membranes and tissues of the eye.
• Auxiliary agents, such as preservatives and antioxidants, should be
added with care because many patients are sensitive to these
substances.
• Before adding an auxiliary agent, check with the patient about allergies
and sensitivities.

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Clarity:
• Ophthalmic solutions must be free from foreign particles, and this is
generally accomplished by filtration.
• The filtration process also helps to achieve clarity of the solution.
• These agents are surfactants that improve aqueous drug solubility
and are compatible with vehicles used to prepare ophthalmic liquids.
• Clarifying agents used in ophthalmic preparations:
clarifying agent Usual concentration [%]
Polysorbate 20 1.0
Polysorbate 80 1.0

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Particulate Matter:
• Particulate matter consists of particles that will not dissolve in solution
other than gas bubbles that are unintentionally present on the product.
• Particulate matter can come from many sources in the processing.
• Ophthalmic solutions should be essentially free from particles that can be
observed on visual inspection.
• USP suggested light obscuration particle count (LOPC) and microscopic
particle count (MPC) tests for the determination of particulate matter in
ophthalmic solutions.

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 Light obscuration particle count test:
• This method analyzes the products using a light obscuration particulate analyzer.
• This test applies to ophthalmic solutions, including solutions constituted from sterile
solids, for which a test for Particulate matter is specified in the individual monograph.
• The test counts suspended particles that are solid or liquid
• The ophthalmic solution meets the requirements of the test if the average number of
particles present in the units tested does not exceed the appropriate value .
• If the average number of particles exceeds the limit, test the article by the Microscopic
Particle Count Test.

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• USP limits for particulate matters determined by LOPC test
Microscopic particle count test :
• This method filters the products through a 0.8 µm grey gridded filter.
The filter is then counted microscopically at 100X to determine the
number of particles.
Nominal value Diameter
≥10µm ≥25µm
Number of particles 50 per mL 5 per mL

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• The microscopic particle count test enumerates subvisible, essentially
solid, particulate matter in ophthalmic solutions, after collection on a
microporous membrane filter.
• Some ophthalmic solutions, such as solutions that do not filter readily
because of their high viscosity, may be exempted from analysis using
the microscopic test.
• The ophthalmic solution meets the requirements of the test if the
average number of particles present in the units tested does not exceed
the appropriate value.

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• USP limits for particulate matters determined by MPC test:
Uniformity of Volume
• Consistent with IP this test is appropriate for eye drops.
• For this test pour completely the contents of ophthalmic preparation of
each container into calibrated volume measures of the appropriate size
and determine the volume of contents of containers.
Nominal value Diameter
≥10µm ≥25µm ≥50µm
Number of particles 50 per mL 5 per mL 2 per mL

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• According to IP the average net volume of the contents of the 10 containers is not
less than the labeled amount.
• the net volume of the contents of any single container is not less than 91% and
not more than 109% of the labeled amount where the labeled amount is 50 ml or
less;
• It is not less than 95.5% and not more than 104.5% of the labeled amount. where
the labeled amount is more than 50 ml but not more than 200 ml;
• It is not less than 97% and not more than 103% of the labeled amount where the
labeled amount is more than 200 ml but not more than 300 ml.

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• IP limits for uniformity of volume
 Particle Size:
• According to BP, This test is suitable for eye drops semisolid eye prepration.
• Introduce a suitable quantity of the suspension into a counting cell or with a micropipette onto a slide,
as appropriate, and scan under a microscope an area corresponding to 10 µg of the solid phase.
Volume Percentage
deviation
≤50mL ±9%
50-200 mL ±4.5%
200-300 mL ±3%

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• For practical reasons, it is recommended that the whole sample is first
scanned at low magnification (e.g. × 50) and particles greater than 25 µm
are identified.
• These larger particles can then be measured at a larger magnification (e.g.
× 200 to × 500).
• For each 10 µg of solid active substance, not more than 20 particles have a
maximum dimension greater than 25µm and not more than 2 of these
particles having maximum dimensions greater than 50µm .None of the
particles has a maximum dimension greater than 90µm.

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• According to IP, this test is suitable for eye drops and eye ointment.
• Introduce a suitable volume of the sample into a counting cell or onto a
microscope slide.
• Scan under a microscope an area corresponding to 10 µg of the solid phase.
Scan at least 50 representative fields.
• Not more than 20 particles have a maximum dimension greater than 25 µm,
not more than 10 particles have a maximum dimension greater than 50 µm
and none has a maximum dimension greater than100 µm.

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Uniformity of Mass:
• According to BP single-dose powders for eye drops and eye lotions
comply with the test.
• if the test for uniformity of content is prescribed for all the active
substances, the test for uniformity of mass is not required.
• Consistent with BP, weigh individually 20 units taken at random or, for
single-dose preparations presented in individual containers, the
contents of 20 units, and determine the average mass.

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• Not more than 2 of the individual masses deviate from the average
mass by more than the percentage deviation and none deviates by
more than twice that percentage
• BP limits for uniformity of Mass
Dosage form Average Mass Percentage deviation
Powder for eye
drops
Less than 300 mg 10
and eye lotions 300 mg or more 7.5

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Leakage test:
• Select 10 tubes of ointments, with seals applied when specified.
• Thoroughly clean and dry the exterior surfaces of each tube with an absorbent cloth.
• Place the tubes in a horizontal position on a sheet of absorbent blotting paper in an oven maintained at
a temperature of 60 ± 3°C for 8 hrs.
• No significant leakage occurs during or at completion of the test (disregards traces of ointment
presumed to originate externally from within the crimp of the tube or from the thread of the cap).
• If the leakage is observed from one but not more than one, of the tubes, repeat the test with 20
additional tubes of the ointment.
• The requirement is met if no leakage is observed from the first ten tubes tested or if the leakage is
observed from not more than one of the 30 tubes tested.

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Uniformity of content:
• The test for uniformity of content of single dose preparation is based
on the assay of the individual contents of active substance of a
number of single dose units
• To determine whether the individual contents are within the limits
set with reference to the average contents of the sample.
• To determine the individual contents of the active substances of
10dosage units taken at random.

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• The preparation complies with the test if each individual content is between 85% and
115% of the average content.
• The preparation fails to comply with the test if more than one individual content is
outside the limits of 75% to 125% of the average content.
• If one individual content is outside the limits of 85% to 115% but within the limits of
75% to 125%, determine the individual contents of another 20 dosage units taken at
random.
• The preparation complies with the test if not more than one of the individual contents
of the 30units is outside 85% to 115% of the average content and none is outside the
limits of 75% to 125% of the average content.

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Uniformity of Weight:
• According to IP this test is used for eye ointments.
• Select a sample of 10 filled containers and remove any labeling that might be altered in
weight while removing the contents of the containers.
• Clean and dry the outer surfaces of the containers and weigh each container.
• Remove quantitatively the contents from each container.
• If necessary, cut open the container and wash each empty container with a suitable solvent,
taking care to ensure that the closure and other parts of the container are retained.
• Dry and again weigh each empty container together with its parts which may have been removed.

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• The difference between the two weights is the net weight of the contents of
the container.
• In line with IP, the average net weight of the contents of the 10 containers is
not less than the labeled amount
• The net weight of the contents of any single containers is not less than 91
percent and not more than 109 percent of the labeled amount where the
labeled amount is 50 g or less.
• It is not less than 95.5 percent and not more than 104.5 percent of the
labeled amount where the labeled is more than 50 g but not more than 100 g.

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Sterility Test:
• Sterility is defined as the absence of viable microbial contamination. Sterility is an absolute
requirement of all ophthalmic formulations.
• Contaminated ophthalmic formulations may result in eye infections that could ultimately
cause blindness, especially if the Pseudomonas aeruginosa microbe is involved.
• Therefore, ophthalmic formulations must be prepared in a laminar flow hood using aseptic
techniques just the same as intravenous formulations.
• The sterile formulations must be packaged in sterile containers .
• As stated by USP and BP the sterility test may be carried out using the technique of
membrane filtration or by direct inoculation of the culture media with the product.

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• Two basic methods for sterility testing:
• I) Direct inoculation method:
• It involves the direct introduction of product test samples into the culture
media.
• II) Membrane filtration method:
• It involves filtering test sample through the membrane filter,washing the
filter with fluid to remove inhibitory property and transferring the
membrane aspetically to appropriate culture media.

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• Detection of contamination used to culture media:
• A) Soyabean-casen digest medium: Incubated at 20 to 25°C
• B) Fluid thioglycolate medium: Incubatedat 30 to 35°c on 7 days.

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1. Sandle T. Sterile ophthalmic preparations and contamination control. J GXP Compliance.
2014;18(3):1-5.
2. Trattler WB, Kaiser PK, Friedman NJ. Review of ophthalmology. 2nd Edition, New York: Elsevier;
2012.
3. Jr LVA. Remington: Introduction to pharmacy. 1st ed. UK: Pharmaceutical Press; 2013.
4. Uddin MS. Quality control tests for pharmaceutical aerosols. In: Advances in Natural and Life
Sciences, Volume II, USA: United Scholars Publications; 2016.
5. Uddin MS. Quality control of pharmaceuticals: Compendial standards and specifications. Germany:
Scholars’ Press; 2017.
6. McCormick K. Quality. New York: Butterworth-Heinemann; 2002.34. United States Pharmacopoeial
Convention. United States Pharmacopoeia 39-NationalFormulary 34. USA: Stationery Office; 2016.
References

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7.McCormick K. Quality. New York: Butterworth-Heinemann; 2002.34. United
States Pharmacopoeial Convention. United States Pharmacopoeia 39-
NationalFormulary 34. USA: Stationery Office; 2016.
8.Pramar Y. Compounding ophthalmic liquids. (Accessed: 28 May 2017)
9. Ritter JM. Drug regulation & therapeutic efficacy. British J Clinical Pharma.
2008; 65(6):801-802.
10. Gennaro AR. Remington: the science and practice of pharmacy. 19th Editon,
New York: Lippincott Williams & Wilkins; 2000.

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11.World Health Organization. International Pharmacopoeial 4th
Edition. Switzerland: WHO; 2015.
12.Society of Japanese Pharmacopoeia. Japanese Pharmacopoeia. 17th
Edition, Japan: Pharmaceuticals and Medical Devices Agency; 2016.
13.British Pharmacopoeia Commission. British Pharmacopoeia. Great
Britain: Stationery Office; 2016.
14.Indian Pharmacopoeia Commission. Indian Pharmacopoeia.
Ghaziabad: Indian Pharmacopoeia Commission; 2014.

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Quality Control Tests for Ophthalmics

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