Ophthalmic preparations

Definition
Ophthalmic preparations (eye preparations) are sterile, liquid, semi-solid, or solid
preparations that may contain one or more active pharmaceutical ingredient( s) intended for
application to the conjunctiva (intraocular), the conjunctival sac (periocular) or the eyelids
(topical).
The choice of base and any excipients used for the preparation of ophthalmic preparations
must be proven through product development studies not to affect adversely either the
stability of the final product or the availability of the active ingredients at the site of action.
The addition of colouring agents is not recommended.
Unless the active ingredient itself has antimicrobial activity, ophthalmic preparations supplied
as multidose preparations may include a suitable antimicrobial agent. The antimicrobial
activity should remain effective throughout the entire period of use.
The different categories of ophthalmic preparations include drops consisting of emulsions,
solutions or suspensions, and ointments.
Factors affecting drug absorption in the eyey:
- Rapid solution drainage by gravity, induced lachrymation, blinking reflex, and normal tear
turnover:
- The normal volume of tears = 7 ul, the blinking eye can accommodate a volume of up to 30
ul without spillage, the drop volume = 50 ul
Manufacture
The manufacturing processes should meet the requirements of Good Manufacturing
Practices, especially with regard to cross contamination. The following information is
intended to provide very broad guidelines concerning the main steps to be followed during
production, indicating those that are the most important.
 BFS Technology
• It refers to the technology and related equipment and procedures in which the
formation of the container, its filling with liquid pharmaceutical material, and
subsequent formation and application of a seal for container are achieved aseptically
in an uninterrupted sequence of operations without exposure to nonsterile
environments between operations.
It involves following steps
1. Extrusion
• An endless sterile plastic tube (made from Low density polyethylene (LDPE) resin) is
continuously extruded from the melted granulate in the filling cavity of the mould.
2. Blowing
• Final container is produced by sterile air pressure from Blow and Fill nozzle.
3. Filling
• After the container is formed inside the mould, sterile liquid product is introduced into
the container.
4. Sealing
• Final container is sealed in place by closing of the seal-mould form onto the container
top.
5. Mould opening
• Upon completion of filling and sealing steps, the mould is separated, producing the
sterile filled and sealed container.
ADVANTAGE OVER CONVECTIONAL ASEPTIC FILLING
 • There is no need to purchase and stock a range of pre-fabricated container and
closures.
• Cleaning and sterilizing pre-fabricated container and closures are not required. A
clean sterile container is made with in the BFS machine.
• The cost of material transport, storage and inventory control is reduced.
• Validation requirement are reduced.
• There is a large choice of neck and opening device shapes.
• Saving floor space.
• Less labour intensive than conventional one.
• The code number and variables can be moulded into container it-self.
• With blow-fill-seal, you produce a one-piece, aseptically filled container with a built-
in safety seal.
• The blow-fill-seal process is suitable for heat-sensitive products.
Throughout manufacturing, certain procedures should be validated and monitored by carrying
out appropriate in-process controls. These should be designed to guarantee the effectiveness
of each stage of production. In-process controls during production of ophthalmic preparations
should include monitoring environmental conditions (especially with respect to particulate
and microbial contamination), pyrogens (use of a limulus amoebocyte lysate (LAL) test may
be advantageous), pH and clarity of solution, and integrity of container (absence of leakage,
etc.). Appropriate limits should be set for the particle size of the active ingredient(s). It is
essential that ophthalmic preparations are sterile. An aseptic manufacturing process is usually
employed when the dosage form does not allow routine sterilization methods to be used.
Packaging must be adequate to protect ophthalmic preparations from light, moisture,
microbial contamination, and damage due to handling and transportation.
Containers
The materials for containers and closures should not adversely affect the quality of the
preparation or allow diffusion of any kind into or across the material of the container into the
preparation. The container should be fitted with a closure that minimizes microbial
contamination and a device that reveals whether the container has ever been opened. A
special plastic ophthalmic package made of polypropylene is introduced. The bottle is filled
then sterilized by steam under pressure at 121°C.
Labelling
Every pharmaceutical preparation must comply with the labelling requirements established
by Good Manufacturing Practices.
The label should include:
(1) the name of the pharmaceutical product;
(2) the name(s) of the active ingredient(s); International Nonproprietary Names (INN) should
be used wherever possible;
(3) the concentration(s) of the active ingredient(s) and the amount or the volume of
preparation in the container;
(4) the batch (lot) number assigned by the manufacturer;
(5) the expiry date, the utilization period, and, when required, the date of manufacture;
(6) any special storage conditions or handling precautions that may be necessary;
(7) if applicable, the period of use after opening the container;
(8) directions for use, warnings and precautions that may be necessary;
(9) the name and address of the manufacturer or the person responsible for placing the
product on the market;
(10) if applicable, the name(s) and concentration(s) of antimicrobial agent(s) and/or
antioxidant(s) incorporated in the preparation; and
(11) the statement "This preparation is sterile".
Storage
Ophthalmic preparations should maintain their integrity throughout their shelf-life when
stored at the temperature indicated on the label. Special storage recommendations or
limitations are indicated in individual monographs.
REQUIREMENTS FOR SPECIFIC TYPES OF OPHTHALMIC PREPARATIONS
Ophthalmic drops
Definition: Ophthalmic drops (eye drops) are sterile aqueous or oily solutions, suspensions,
or emulsions intended for instillation into the conjunctival sac.
Ophthalmic drops should be clear and practically free from particles when examined under
suitable conditions of visibility. "Water for injections" should be used in the manufacture of
aqueous ophthalmic drops. Examples of topical eye drops: Atropine sulphate eye drops,
Pilocarpine eye drops, Silver nitrate eye drops and Zinc sulphate eye drops.
Manufacturing: The preparation of aqueous ophthalmic drops requires careful consideration
of the need for isotonicity, a certain buffering capacity, the desired pH, the addition of
antimicrobial agents and/or antioxidants, the use of viscosity-increasing agents, and the
choice of appropriate packaging. Manufactured by dissolution of the active ingredients and a
portion of the excipients into all portion of water. The sterilization of this solution done by
heat or by sterilizing Filtration through sterile depth or membrane filter media Into a sterile
receptacle. This sterile solution is then mixed with the additional required Sterile components
such as viscosity –imparting agents, Preservatives and so and the solution is brought to final
Volume with additional sterile water.
Ophthalmic drops are considered isotonic when the tonicity is equal to that of a 0.9% solution
of sodium chloride. The eye can usually tolerate solutions equivalent to 0.5-1.8% of sodium
chloride.
Ideally, the pH of ophthalmic drops should be equivalent to that of tear fluid, which is 7.4.
However, the decision to add a buffering agent should be based on stability considerations.
The pH selected should be the optimum for both stability of the active pharmaceutical
ingredient and physiological tolerance. If a buffer system is used, it must not cause
precipitation or deterioration of the active ingredient. The influence on the lachrymal flow
should also be taken into account.
Visual inspection
Evidence of physical instability is demonstrated by the cloudiness of aqueous solutions, due
to the formation of a precipitate.
Containers
Ophthalmic drops are normally supplied in suitable multidose containers that allow
successive drops of the preparation to be administered. The container should be fitted with a
tamper-evident device. The maximum volume of the preparation in such a container should
be no more than 10 mL, unless otherwise specified and authorized. Multidose ophthalmic
drop preparations may be used for up to 4 weeks after the container is initially opened.
Droppers supplied separately should also comply with Test for sterility.
Ophthalmic drops may also be provided in suitable single-dose containers that will maintain
the sterility of the contents and the applicator up to the time of use.
It is recommended that single-dose containers for surgical use should not include any
antimicrobial agents.
Ophthalmic ointments
Definition: Ophthalmic ointments are sterile, homogeneous, semi-solid preparations intended
for application to the conjunctiva or the eyelids.
They are usually prepared from non-aqueous bases, e.g. soft paraffin (Vaseline), liquid
paraffin, and wool fat. They may contain suitable additives, such as antimicrobial agents,
antioxidants, and stabilizing agents. The ointment vehicles used in ophthalmology is mixture
of Mineral oil and petrolatum base. The mineral oil is used to modify melting point and
modify consistency. Petrolatum vehicle used as a ocular lubricate to treat dry Eye syndromes.
They are mostly used as adjunctive night time therapy, while eye drops administered during
the day
It is suitable for moisture sensitive drugs and has longer Contact time than drops.
Chlorobutanol and methyl- and propylparaben are the most commonly used preservatives in
ophthalmic ointments.
Disadvantage:
Their are greasy nature, blurring of vision.
Manufacturing: The ointment base is sterilized by heat and appropriately filtered while
molten to remove foreign particulate matter. It is then placed into a sterile steam jacket kettle
to maintain the ointment in a molten state under aseptic conditions, and the previously
sterilized active ingredient (s) and excipients are added aseptically. The entire ointment may
be passed through a previously sterilized colloid mill for adequate dispersion of the insoluble
components. After the product is compounded in an aseptic manner, it is filled into a
previously sterilized container.
Organoleptic inspection
Evidence of physical instability is demonstrated by:
- a noticeable change in consistency, such as excessive "bleeding" (separation of excessive
amounts of liquid) or formation of agglomerates or grittiness;
- discoloration;
- emulsion breakdown;
- crystal growth;
- shrinking due to evaporation of water; or
- evidence of microbial growth.
Uniform consistency
Ophthalmic ointments should be of uniform consistency. When a sample is rubbed on the
back of the hand, no solid components should be noticed.
Containers
Ophthalmic ointments are normally supplied in small, sterilized, collapsible tubes fitted with
a tamper-evident applicator. The containers or the nozzles of the tubes are shaped so that the
ointment can be applied without contaminating what remains in the tube. The content of such
a container is limited to not more than 5 g of the preparation. Suitable single-dose containers
may also be used.
Ophthalmic ointment are packaged in :
1. Small collapsible tin tube usually holding 3.5g of product. the pure tin tube is compatible
with a wide range of drugs in petrolatum-based ointments.
2. Aluminum tubes have been used because of their lower cost and as an alternative should
the supply of tin.
3. Plastic tubes made from flexible LDPE resins have also been considered as an alternative
material.
Filled tubes may be tested for leakers. The screw cap is made of polyethylene or
polypropylene. The tube can be a source of metal particles and must be cleaned carefully
before sterilization (by autoclaving or ethylene oxide).
Evaluation test for Metal Particles
This test is required only for ophthalmic ointments. The presence of metal particles will
irritate the corneal or conjunctival surfaces of the eye.
It is performed using 10 ointment tubes.
The content from each tube is completely removed onto a clean 60 - mm - diameter Petri dish
which possesses a flat bottom. The lid is closed and the product is heated at 85 ° C for 2 h.
Once the product is melted and distributed uniformly, it is cooled to room temperature.
The lid is removed after solidification.
The bottom surface is then viewed through an optical microscope at 30× magnification.
The viewing surface is illuminated using an external light source positioned at 45 ° on the
top.
The entire bottom surface of the ointment is examined, And the number of particles 50 μm or
above are counted using a calibrated eyepiece micrometer.
The USP recommends that the number of such particles in 10 tubes should not exceed 50,
with not more than 8 particles in any individual tube. limits are not met, the test is repeated
with an additional 20 tubes.
In this case, the total number of particles in 30 tubes should not exceed 150, and not more
than 3 tubes are allowed to contain more than 8 particles.
Leakage test
This test is mandatory for ophthalmic ointments, which evaluates the intactness of the
ointment tube and its seal.
Ten sealed containers are selected, and their exterior surfaces are cleaned.
They are horizontally placed over absorbent blotting paper.
Maintained at 60±3 ° C for 8 h.
The test passes if leakage is not observed from any tube.
If leakage is observed, the test is repeated with an additional 20 tubes.
The test passes if not more than 1 tube shows leakage out of 30 tubes.
Ophthalmic semisolids should be free from anaerobic and aerobic bacteria and fungi.
Sterility tests are therefore performed by the:
1. Membrane filtration technique .
2. Direct - inoculation techniques.

In the Membrane filtration method :

A solution of test product (1%) is prepared in isopropyl myristate and allowed to penetrate
through cellulose nitrate filter with pore size less than 0.45 μ m.
If necessary, gradual suction or pressure is applied to aid filtration.
The membrane is then washed three times with 100 – mL quantities of sterile diluting and
rinsing fluid and transferred aseptically into fluid thioglycolate (FTG) and
soybean – casein digest medium (SBCD) .
The membrane is finally incubated for 14 days.
Growth on FTG medium indicates the presence of anaerobic and aerobic bacteria.
Soybean casein digest medium indicates fungi and aerobic bacteria
Absence of any growth in both these media establishes the sterility of the product.
In the Direct - inoculation technique :
1 part of the product is diluted with 10 parts of sterile diluting and rinsing fluid with the help
of an emulsifying agent
Incubated in Fluid thioglycolate (FTG) and soybean –casein digest medium (SBCD) media
for 14 days .
In both techniques, the number of test articles is based on the batch size of the product.
If the batch size is less than 200 the containers, either 5% of the containers or 2 containers
(whichever is greater) are used.
If the batch size is more than 200, 10 containers are used for sterility testing .
Test for Bacterial Endotoxins:
The addition of a solution containing endotoxins to a solution of the lysate produces turbidity,
precipitation or gelation of the mixture. However, addition of a chromogenic substrate to a
solution of the lysate results in development of color due to release of chromophore from the
substrate upon activation by the endotoxin present in the solution. The rate of reaction
depends on the concentration of endotoxin, the pH and the temperature. The reaction requires
the presence of certain bivalent cations, a clotting cascade enzyme system and clottable
protein, all of which are provided by the lysate
According to BP, There are 3 techniques for this test: the gel- clot technique, which is based
on gel formation; the turbidimetric technique, based on the development of turbidity after
cleavage of an endogenous substrate; and the chromogenic technique, based on the
development of color after cleavage of a synthetic peptide-chromogen complex