Manufacturing and quality control of ointment

1. Aseptic Process Technology
Manufacturing of Sterile Ointment
Prepared by
Dr. Kandekar Ujjwala Y.
Assistant Professor
JSPM’s Rajarshi Shahu College of Pharmacy and Research, Tathwade, Pune

2. Ointment:
These are semisolid greasy preparations for
application to the skin, rectum and mucosa. The base
is anhydrous and contains medicament in solution or
suspension.

3. Ophthalmic Ointment:
• Sterile preparation applied inside the lower eyelid.
• Only unhydrous bases are used in their preparation.
• The ointment is applied as a narrow band 0.25-0.5 inch.
• When applied to the eyes, they reside in the conjunctival
sac for prolonged periods compared to solutions and
suspensions and improve the fraction of drug absorbed
across ocular tissues.
• Ophthalmic ointments are preferred for nighttime
applications as they spread over the entire corneal and
conjunctival surface and cause blurred vision.

4. Formulation Consideration:
• Must be sterile
• Contains suitable antimicrobial preservative, antioxidant and stabilizer
• e.g. Preservative: According to USP- Cholorpobutol, Methyl and Propyl
paraben
• Must be free from particulate matter
• Particle size must be less than 25microns
• Ointment base must be non-irritant to eye
• Ointment base should melt near to body temperature so as to permit
diffusion of the drug through the lacrimal secretion of the eye.
• Ointment base is a mixture of mineral oil (modify consistency and
melting point)and petrolatum base (Lubricant).

5. Manufacturing of Ointment
Ingredients:
1. Active Ingredients: e. g. Sulphur, Antibiotics like
betamethasone, benzoic acid etc.
2. Ointment Bases:
A. Hydrocarbon Bases
B. Absorption bases
C. Water miscible bases
D. Water soluble bases

6. Hydrocarbon Base
• Hydrocarbon bases are made of oleaginous materials.
• They provide emollient and protective properties and remain in the skin for
prolonged periods.
• They are not absorbed by the skin
• Sticky
• It is difficult to incorporate aqueous phases into hydrocarbon bases. However,
powders can be incorporated into these bases with the aid of liquid petrolatum.
• Removal of hydrocarbon bases from the skin is difficult due to their oily nature.
• Almost inert: saturated hydrocarbons, hence less incompatible and little
tendency to rancidify.
• Readily available and cheap
• E.g. Soft Paraffin, Hard Paraffin, Liquid Paraffin. Vegetable oil

7. B. Absorption bases:
• Contain small amounts of water.
• They provide relatively less emollient properties than hydrocarbon bases. Similar to
hydrocarbon bases.
• Absorption bases are also difficult to remove from the skin due to their hydrophobic
nature
Types:
• Non-Emulsified Bases:
• Absorb water and aq. Solution and produce w/o emulsion.
• They assist oil soluble medicament to penetrate the skin
• Easier to spread
• e.g. Wool fat- absorb about 50% of its of water and too sticky, widely used.
• Used in eye ointment as several medicament are alkaloid salts such as atropine
sulphate.
• Other examples: Wool alcohol, Bees Wax, cholesterol.

8. B. Water in oil Emulsion:
e.g. Hydrous wool fat (Lanolin)
C. Water Miscible bases:
• These are oil - in - water emulsions.
• Unlike hydrocarbon and absorption bases, a large proportion of aqueous phase can
be incorporated into water .
• It is easy to remove these bases from the skin due to their hydrophilic nature.
• Miscibility with exudate from the skin.
• Less interference with skin function
• Good contact with skin due to surfactant content
• High cosmetic acceptability
• Ease of removal from hair.
• e.g. emulsifying oinment

9. D. Water soluble bases:
• Do not contain any oily or oleaginous phase.
• Solids can be easily incorporated into these bases.
• They may be completely removed from the skin due to their water solubility.
• e.g. Macrogols (mixture of polycondensation product of ethylene oxide and water.
• Vary in consistency from viscous liquid to waxy solid, product with ointment
consistency can be prepared by mixing liquid and waxy forms.
• Non-toxic and non-irritant to skin
• Sterilized by dry heat and autoclave
• Good absorption by the skin
• Good solvent property
• Free from greasiness
• Satisfying aging property (do not hydrolase, rancidify or support microbial
growth)

10. Disadvantages:
1. Limited uptake of water
2. Less bland than paraffin's
3. Reduction in activity of certain antibacterial agents
4. Solvent action on polythene and bakelite

11. Preparation of eye ointment:
Melt wool fat , soft paraffin, on a water bath. Add liquid paraffin filter through coarse
filter placed in a heated funnel. It is sterilized by dry heat method. (160 for 2 hrs).
It is then placed into sterile steam jacket kettle to maintain the ointment in molten
state under aseptic condition.
Previously sterilized active ingredients are added aseptically. The entire ointment
may be passed through a previously sterilized colloidal mill for adequate dispersion
of insoluble components. After the product is compounded in aseptic manner, it is
filled into previously sterilized container, label and evaluate.

12. Step:1 Water Phase: Fill D.M. water in water phase vessel , heat with stirring.
Step:2 Wax Phase: Fill wax in wax phase vessel, heat with stirring
Step:3 Melted wax and heated water will be transfer to in the Ointment
Manufacturing Vessel and mixed in the vessel. Then add drugs and ingredient
with Heating and stirring by speed homogenizer.
Step:4 The material will be store in the storage tank and this tank having facility
for heating and trolley wheel for move to filling area.
Step:5 The storage tank carry to filling machine by manually and the material will
be heated by hot water circulation for easy transferring high viscous material to
the hopper of filling machine.
Step:6 The Ointment/ Cream will be fill and seal by filling machine and packed by
packing line machinery.

13. SPECIFIC REQUIREMENTS FOR MANUFACTURE OF TOPICAL PRODUCTS i.e.
EXTERNAL PREPARATIONS (CREAMS, OINTMENTS, PASTES, EMULSIONS, LOTIONS,
SOLUTIONS, DUSTING POWDERS AND IDENTICAL PRODUCTS).
1. The entrance to the area where topical products are manufactured shall be
through a suitable airlock. Outside the airlock, insectocutors shall be installed.
2. The air to this manufacturing area shall be filtered through at least 20 µ air filters
and shall be air-conditioned.
3. The area shall be fitted with an exhaust system of suitable capacity to effectively
remove vapors, fumes, smoke or floating dust particles.
4. The equipment used shall be designed and maintained to prevent the product
from being accidentally contaminated with any foreign matter or lubricant.
5. Suitable cleaning equipment and material shall be used in the process of cleaning
or drying the process equipment or accessories used.

14. 6. Water used in compounding shall be Purified Water IP.
7. Powders, whenever used, shall be suitably sieved before use.
8. Heating vehicles and a base like petroleum jelly shall be done in a separate mixing
area in suitable stainless steel vessels, using steam, gas, electricity, solar energy etc.
9. A separate packing section may be provided for primary packaging of the products

15. Evaluation of sterile OINTMENT:
1.Impurities
2. pH
3. Identification tests for drug: Chromtography, NMR
4. Assay of drug
5. Dissolution
6. BET
7. Metal particles in ophthalmic Ointment
8. Container and closure
9. Leakage

16. Impurities:
Process impurities, synthetic by-products, and other inorganic and organic impurities
may be present in the drug substance and excipients used in the manufacture of the drug
product.
These impurities are controlled by the drug substance and excipients compendial
monographs.
Organic impurities arising from the degradation of the drug substance in the drug
product and those arising during the manufacturing process of the drug product should
be monitored.

17. 1.Sterility Test:
Use the contents of each container to provide not less than 200 mg. Ointments in a
fatty base and emulsions of the water-in-oil type may be diluted to 1 percent in
isopropyl myristate as described above, by heating, if necessary, to not more than 40
°C. . In exceptional cases it may be necessary to heat to not more than 44°C. Filter as
rapidly as possible.
Direct inoculation of the culture medium:
Transfer the quantity of the preparation to be examined directly into the culture
medium (neutral solution of meat or casein peptone) so that the volume of the
product is not more than 10 percent of the volume of the medium, unless otherwise
prescribed. If the product to be examined has antimicrobial activity, carry out the test
after neutralising this with a suitable neutralising substance or by dilution in a
sufficient quantity of culture medium. When it is necessary to use a large volume of
the product it may be preferable to use a concentrated culture medium prepared in
such a way that it takes account of the subsequent dilution. Where appropriate, the
concentrated medium may be added directly to the product in its container.

18. Incubate the inoculated media for not less than 14 days. Observe the cultures
several times during the incubation period. Shake cultures containing oily
products gently each day.
When fluid thioglycollate medium is used for the detection of anaerobic
microorganisms keep shaking or mixing to a minimum in order to maintain
anaerobic conditions .

19. If no evidence of microbial growth is found, the product to be examined complies with
the test for sterility.
If evidence of microbial growth is found the product to be examined does not comply
with the test for sterility, unless it can be clearly demonstrated that the test was invalid
The test may be considered invalid. only if one or more of the following conditions are
fulfilled
□ The data of the microbiological monitoring of the sterility testing facility show a fault
□ A review of the testing procedure used during the test in question reveals a fault
□ Microbial growth is found in the negative controls
□ After determination of the identity of the micro-organisms isolated from the test, the
growth of this species or these species may be recognized clearly to faults with respect
to the material and or the technique used in conducting the sterility test procedure.
If the test is declared to be invalid it is repeated with the same number of units as in the
original test. If no evidence of microbial growth is found in the repeat test the product
examined complies with the test for sterility. If microbial growth is found in the repeat
test the product examined does not comply with the test for sterility .

20. Metal particles in ophthalmic Ointment:
Extrude, as completely as practicable, the contents of 10 tubes individually into
separate, clear, flat-bottom, 60-mm Petri dishes that are free from scratches.
Cover the dishes, and heat at 85 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 Petri dish on the stage of a suitable microscope
adjusted to furnish 30 times magnification and equipped with an eye-piece micrometer
disk that has been calibrated at the magnification being used.

21. In addition to the usual source of light, direct an illuminator from above the ointment
at a 45 angle.
Examine the entire bottom of the Petri dish for metal particles. Varying the intensity
of the illuminator from above allows such metal particles to be recognized by their
characteristic reflection of light.
Count the number of metal particles that are 50 µm or larger in any dimension: the
requirements are met if the total number of such particles in all 10 tubes does not
exceed 50, and if 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: the
requirements are met if the total number of metal particles that are 50 µm or larger
in any dimension does not exceed 150 in all 30 tubes tested, and if not more than 3 of
the tubes are found to contain more than 8 such particles each.

22. Containers
Containers, including the closures, for ophthalmic ointments do not interact
physically or chemically with the preparation in any manner to alter the strength,
quality, or purity beyond the official requirements under the ordinary or customary
conditions of handling, shipment, storage, sale, and use.

23. Leakage:
Select 10 tubes of the Ointment, 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 for 8 hours.
No significant leakage occurs during or at the completion of the test (disregard traces
of ointment presumed to originate externally from within the crimp of the tube or
from the thread of the cap).
If 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 10 tubes tested, or if
leakage is observed from not more than 1 of 30 tubes tested.

24. References:
1. Pharmaceutical dosage forms(parenteral preparation) by Kennith E. Avis,
Leon Lachman, Vol 1.
2. Pharmaceutical dosage forms(parenteral preparation) by Kennith E. Avis,
Leon Lachman, Vol 2.
3. Dispensing for pharmaceutical students, 10th edition, S.J. Carter.
4. The theory and practice of industrial Pharmacy, 3rd edition, Leon Lachman.
5. www.pharmaguidelines.com