Pharmaceutical Manufacturing Laboratory (MIDTERMS)

MEDICATED APPLICATIONS: SEMISOLIDS

They are generally referred to as therapeutic ointments, creams, pastes and other forms of viscous consistency intended for external application onto the skin.

1. As vehicles for topically applied drugs.

2. As emollients - provides soothing or softening effect on the surface tissues.

3. As protective or occlusive dressing on the skin

USES OF MEDICATED APPLICATIONS (3)

partition coefficient, moisture and temperature in the environment of the skin, pathological injury to the skin, type of vehicle used (bases)

Factors influencing absorption of drugs through the skin

Petrolatum and mineral oil

are the MOST WIDELY USED substances in semisolids, next to water

PETROLATUM

A complex mixture of semisolids containing hydrocarbon aliphatic, cyclic, saturated, unsaturated, branched and unbranched substances in varying proportions.

MINERAL OIL

Derived from petroleum acid. It is less tacky and with lower viscosity.

Hydrocarbon waxes

Help increase the viscosity of hydrocarbons such as petrolatum and mineral oil Prevent separation of hydrocarbons from the ointment

Hydrocarbon waxes

Examples: paraffin, beeswax, ceresin wax (mixture of paraffin and ozokerite)

OLEAGINOUS SUBSTANCES

Vegetable fixed oils which contain glycerides of mixtures of saturated and unsaturated fatty acids (MCT's and FA's) These are employed for its EMOLLIENT and SKIN-LUBRICATING effects

OLEAGINOUS SUBSTANCES

Examples: Fixed oils of peanut, olive, sesame, cottonseed, coconut, corn

FATTY ACIDS AND ALCOHOLS

Functions as; ➢ Auxiliary emulsifiers ➢ Viscosity-builders

Stearic acid

emulsifiers in water- removable creams

Stearyl/Cetyl Alcohols

emollients, provides the necessary firmness/softness in consistency of creams

EMULSIFIERS

➢ Prevent coalescence

➢ Act as product stabilizers

Emulsifiers

Examples: Triethanolamine stearate, SPANS, TWEENS, CARBOWAX™

POLYOLS

Used as humectants, prevents dehydration and "crusting" on top of creams and ointments in jars

POLYOLS

Examples: Glycerin, PG, Sorbitol 70%, PEG (lower MW)

INSOLUBLE POWDERS

These must be uniformly dispersed throughout the semisolid vehicle to assure product, homogeneity.

74

These solids must be impalpable to the touch Particles less than__ microns (equivalent to 200 mesh) is said to be (equivalent to 200 mesh) is said to be impalpable to most people

1. Nature of the skin lesion

2. Skin type

3. Solubility of the formulation components

4. Stability of the API’s

FACTORS INFLUENCING THE CHOICE OF SEMISOLID VEHICLES (4)

HYDROCARBON BASES

Typically lipophilic, Spreads easily onto the skin, Difficult to remove/wash-off, Act as occlusive dressings, since the normal evaporation of insensible perspiration is inhibited

HYDROCARBON BASES

Examples: White petrolatum, Mineral oil, White/Yellow Ointment, USP

ABSORPTION/EMULSIFIABLE BASES

These are hydrophilic mixtures formed by the addition of substances that possess polar groupings (sulfates, carboxyl, hydroxyl or ether linkages) to a Hydrocarbon Base.

Lanolin, cholesterol, sorbitan monostearate/ monooleate

are added to hydrocarbon bases to make it hydrophilic

w/o

Absorption bases are of ____ type

WATER-REMOVABLE / WASHABLE BASES

These are o/w emulsions referred to as Creams. Upon application, there is little or no evidence of its presence onto the skin Best for moist skin lesions, since its o/w character tend to adsorb serous discharges

➢ Petroleum jelly ➢ Absorption base (Lanolin or Lanolin Alcohol) ➢ Water-soluble base

Semisolid ophthalmic vehicles frequently contain any of the following bases that have been sterilized;

PRESERVATIVES

Are added to prevent contamination, deterioration, and spoilage by bacteria and molds

BORIC ACID

may be used in ophthalmic ointments against bacterial/ fungal contamination

ANTIOXIDANTS

Are added to semi-solids whenever oxidative. deterioration is anticipated.

FUSION METHOD

ANHYDROUS OINTMENTS are manufactured by this process, which is made by dissolving the API's in the previously melted fats and waxes. The melted mass must be mixed while cooling to ensure the homogenous distribution of the ingredients.

BLOW FILL SEAL METHOD (BFS) SEQUENCE in ONE EASY OPERATION

1. Fabrication of containers 2. Filling the product 3. Sealing

FORM FILL SEAL METHOD (FFS)

The conventional method of filling ophthalmic ointments.

Well-closed

Opaque or light resistant

Keep in cool place (8-15 deg C)

PACKAGING, STORAGE AND LABELING OF MEDICATED APPLICATIONS

➢ Staphylococcus aureus

➢ Pseudomonas aeruginosa

MICROBIAL SCREENING (Microbial Limit Tests) FOR SEMI SOLIDS

90% , 95%

SEMISOLIDS

Product weighing 60 g or mL - NLT ___ of the labeled amount.

Product weighing 60 g or mL to 150 g or mL - NLT ___ of the labeled amount.

1. Membrane Filtration Technique

2. Test Tube Inoculation Method

STERILITY TESTS FOR SEMI SOLIDS

TAPE STRIPPING

IN VIVO DERMATOPHARMACOKINETIC STUDIES

NMT 0.5% water content for Ointments containing:

1. Bacitracin

2. Chlortetracycline HCI

3. Nystatin

Specification for water content

NMT 1% water content for ointments, creams or gels

1. Erythromycin

2. Gentamycin sulfate

3. Neomycin sulfate

4. Tetracycline HCI

Specifications for water content

Metal Particle Detection Test

Mandatory for ophthalmic ointments only, 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.

LEAKER TEST

Mandatory for ophthalmic ointments filled in collapsible tubes. By Classical Blotting Paper Method

10, 1

Requirements are met in leaker test if :

Out of the first ___ tubes tested, NO LEAK is observed.

NMT ___ tube out of the 30 tubes should leak.

STERILE PRODUCT

Is an important pharmaceutical dosage form that has a common characteristic of being prepared as a "sterile" that is free from contaminating microorganisms

INJECTIONS/INJECTABLES

They are broadly defined as sterile, pyrogen-free preparations intended to be administered parenterally

"pyrogens"

are fever producing organic substances arising from microbial contamination and are responsible for many of the febrile reactions, which occur in patients following intravenous injections

SMALL VOLUME PARENTERALS

These injectables are packaged in small ampules or vials, with fill volumes of as little as 0.5mL to a maximum of 50mL.

Caffeine and Sodium benzoate injection

cardiac and respiratory stimulants. (SVP)

Procaine hydrochloride injection

local anesthetic parenteral (SVP)

Insulin

a SVP intended for diabetes

LARGE VOLUME PARENTERALS

These injectables are packaged in collapsible bags or 1 liter size vials

100-1,000

Large volume parenteral are administered in volumes of ___________mL amounts and more per day, by small IV drip sets with or without controlled rate infusion system

Maintenance Therapy

For patients entering or recovering from surgery or for patients who are unconscious and unable to obtain fluids, electrolytes or nutrition orally.

Replacement Therapy

For patients who have suffered a great loss of fluids and electrolytes, as in severe diarrhea and vomiting or in the replenishment of blood.

Minimal injection, USP

diuretic LVP

Lactated Ringer's injection, USP

systemic alkalanizer LVP

Dextrose and Sodium chloride injection, USP

fluid, nutrient, electrolyte replenisher LVP

Sodium chloride injection, USP

isotonic vehicle. LVP

Sterility

is of utmost importance, since it is introduced or directly placed in direct contact with the internal body fluids or tissues, where infections can easily arise

sterile

means free from contaminating microorganisms

Aqueous vehicle

The most frequently used vehicle is water, since it is the vehicle for all natural body fluids The superior quality requirements is described under water for injection, USP (WFI)

Non-Aqueous

USP Specifications for Fixed Oils as Parenteral Vehicles Must be of vegetable origin for faster metabolism. Must remain liquid at room temp. (contain esters of unsaturated fatty acids). Must not become rancid rapidly (antioxidants may be added to retard oxidation).

water, equipment, solutes, manufacturing methods

sources of pyrogen

Autoclaving

Sterilization Process that will not destroy pyrogen

dry heating

pyrogens can be destroyed by _________ heating

➢ Antimicrobial agents

➢ Buffers

➢ Tonicity agents

➢ Anti-oxidants

The USP includes in this category all substances added to a parenteral preparation, to improve or safeguard the quality of the product. It includes; (4)

Borosilicate glass (I)

glass container Generally suitable for all parenteral

Treated Soda Lime Glass (II)

Treated with Sulfur dioxide. Suitable for parenteral solutions which are buffered, with pH below 7, and not reactive with glass.

Soda Lime Glass (III)

glass container suitable for anhydrous parenteral liquids or dry substances.

Type NP

glass container Not for parenteral use. Suitable only for extractives.

LD PET, PVC, and Polyolefins

3 plastic conteiners for sterile preparations

FREEZE-DRIED / LYOPHILIZED PARENTERAL PRODUCTS

Process involves removal of water from the parenteral solution, by sublimation, after it is frozen. This process is only applicable to thermo-labile or unstable drugs in aqueous, liquid form.

ISOTONICITY

It is important for the comfort of the patient, especially for the intraspinal injection, where the CSF is slow and disturbances of the osmotic pressure will cause headache and vomiting

AIRLOCK AREA

Access by personnel to aseptic corridors, compounding area and filling rooms only through the ____________

LAMINAR FLOW ENCLOSURES

This equipment has been developed, to allow for the draft-free flow of clean, filtered air over the work area.

HEPA - High Efficiency Particulate AiR

Thus, providing circulation of clean, sterile air inside the Laminar Flow Hood / Enclosure

ULTRAVIOLET (UV) IRRADIATION

Controls air-borne microorganisms by installing installation of UV / mercury vapor lamps in the clean-up area, aseptic area and compounding area

Deflectors

The personnel must be protected from direct exposure of UV irradiation by installing ____________

AIR SAMPLING TECHNIQUES

Collection of particulate matter by drawing air sample through a clean, sterile membrane filter. Collection of air sample into a measured volume of NUTRIENT BROTH, in an impinger Drawing a measured volume of air through a slit sampler, which causes air to impinge on the surface of a slowly rotating AGAR PLATE

EXPOSURE OF NUTRIENT AGAR PLATES TO THE SETTLING OF MICROORGANISMS FROM THE AIR

Applicable for the detection of pathogenic microorganisms, provided that Blood Agar Plates are used.

TOTAL STERILITY TESTS

The best indication of the efficiency of an aseptic filling process (machine and its operator) Done by filling and sealing sterile fluids such as (a) Fluid Thioglycollate Medium (FTM) and (b) Trypticase soy broth (TSB) in sterile containers, under the same conditions used for the aseptic fill of the product

INSTRUMENTAL SCANNERS

Obtain particle counts from a measured volume of air, as a means of indicating the level of particle contamination in the environment. It operates on the principle of the measurement of light-scattered from particles passed through the optical system.

FOR CLARIFICATION PURPOSES

Also termed as "POLISHING," which require the removal of particulate matter down to at least 3 to 5 microns in size

Filtration

Removal of approximately 0.2 to 0.45 microns of viable microorganisms and spores. This is employed for heat-labile parenteral solutions only.

CELLULOSE ESTER MEMBRANE

It requires no pre-treatment and may be sterilized by autoclaving or gas. Its disadvantage is SURFACE CLOGGING

gravity

For large volume parenterals, filling is done by _______, a pressure pump filling machine or vacuum filling machine.

AUGER or FILLING WHEEL

In filling sterile solids (antibiotics), the rate of flow is slow and irregular. This can be remedied by using a filling machine equipped with an

TIP SEALING / BEAD SEALING METHOD

Ampules are sealed by melting enough glass at the tip of the ampule neck, to form a bead and close the opening, Tip-sealing equipment for ampules. Flame-seals using propane and tech grade oxygen at 10 to 20 psi

PULL SEALING METHOD

Ampules are sealed by heating the neck (below the tip) of the ampule, leaving enough of the tip for grasping with forceps or other mechanical pulling device.

slower

Pull seal method is ________, but seals much more sure than the Tip seal method

Pull-sealing method.

Sterile powders filled in funnel-topped ampules are sealed by___________

the Tip-seal method.

Sterile liquids filled in standard ampules are sealed by__________

LEAKER

An improperly or insufficiently sealed ampule is called a _________

MEMBRANE FILTRATION METHOD

is the official method recommended by FDA for sterility test in parenterals. The parenteral liquid is filtered, retaining microorganisms (if any) on the filter, washed and transferred in a culture media.

TEST TUBE INOCULATION METHOD

is another official method, wherein turbidity is the measure of growth of microorganisms.

QUALITATIVE FEVER RESPONSE IN RABBITS

This in vivo testing method show physiologic response (to fever) similar to the human body. ➢ Brewer's Yeast - used to induce fever in rabbits. ➢ NSS used as negative control

LIMULUS AMOEBOCYTE LYSATE (LAL) METHOD

An in vitro, pass-fail test for pyrogens based on; ➢ Gelling (gel-clot formation) ➢ Color development of a pyrogen contaminated injection, in the presence of lysate on the horseshoe crab (Limulus polyphemus)

● Bacterial endotoxin test (BET)

● Monocyte activation test (MAT)

ALTERNATIVES TO LAL METHOD

CLARITY TEST

USP does not provide specifications for this test.The USP contains only a statement that CGMP requires that each final container of an injection be subjected individually to a visual inspection.

LEAKER TEST

Ampules that have been sealed by fusion MUST BE subjected to this test, to determine whether or not a passageway remains open outside. Vials or BR bottles are not subjected to this test, because the rubber stoppers are not rigid. Therefore, results from this test will be meaningless.