Dr. Muqtader Mohammed Contact info: drmuqtaderx@gmail

1. STERILE PRODUCTS PHT 434 INTRODUCTIONTO STERILE DOSAGE FORMS Dr. Muqtader Mohammed Contact info: drmuqtaderx@gmail.com

2. objectives of the lecture • At the end of this lecture, you will be aware of: • What are Sterile dosage forms? • What are various types of Sterile dosage forms? • What are the applications and rationale of Sterile dosage forms? • What are advantages / disadvantages of Sterile dosage forms? • How Sterile dosage forms are prepared?

3. STERILE DOSAGE FORMS All preparations that are free of viable microorganisms. • Microrganism. • Spores. • Pathogens. • Sterile products are mostly injected, applied onto eye and administer intranasally. • Parenteral products, • Ophthalmic products, • Implants, • Intranasal & PulmonaryDrugDelivery systems, • Others • Solutionforirrigation • Radiopharmaceuticals • Surgical • Medicinal Devices

4. STERILIZATION • The term sterilization for pharmaceutical preparations, means the complete destruction of all living organisms and their spores or their complete removal from the preparation. • Five sterilization processes are described in the USP: • STEAM • DRY-HEAT • FILTRATION • GAS • RADIATION.

5. SELECTION OF THE STERILIZATION METHOD: • The selection of the sterilization method depend on: • The nature and amount of product. • Whether the product and container-closure system will have a predominately moist or dry environment during sterilization. • Both of these factors are of great importance in determining the conditions (time and temperature ) of any sterilization method chosen. • Type of microorganisms • A. Easy to kill with either dry or moist heat; • B. Susceptible to moist heat, but resistant to dry heat (Bacillus subtilis); • C. Resistant to moist heat but susceptible to dry heat (Clostridium sporogenes).

6. A. STEAM STERILIZATION (Autoclave) • Sterilization by saturated steam (moist heat) under pressure. • Autoclave: Chamber which is filled with hot steam under pressure. • Preferred method of sterilization, unless material is damaged by heat, moisture, or high pressure. • Temperature of steam reaches 121oC at 15 psig (2× atmospheric pressure). • Most effective when organisms contact steam directly or are contained in a small volume of liquid. • All organisms and endospores are killed within 15 minutes. • Require more time to reach center of solid or large volumes of liquid. • Mechanism: Denaturation and coagulation of some of the organism's essential protein. • ADVANTAGES OF STEAM STERLIZATION • Very efficient procedure, Quick and inexpensive. • Widely used treatment in the parenteral drug industry.

8. A. STEAM STERILIZATION (Autoclave).. • Application of pressure: • Note that the temperature, not the pressure is destructive to the microorganisms and that the application of pressure only for the purpose of increasing the temperature of the system, because it is not possible to raise the temperature of the steam above 100C. under atmospheric conditions. • b. Time of application: • The usual conditions (time/pressure/temperature), are as follow: • 10 pounds pressure (115.50C) for 30 minutes • 15 pounds pressure (121.50C) for 20 minutes • 20 pounds pressure (126.50C) for 15 minutes • As can seen, the greater the pressure applied, the higher the temperature obtainable and the less the time required for sterilization. • c.The penetration time of the moist heat • It depends on the nature of the load/product.

9. Applicable for pharmaceutical preparations and materials that can withstand the required temperature and are penetrated by, but not adversely affected by, moisture. • In sterilizing aqueous solutions, the moisture is already present, and all that is required is the elevation of the temperature of the solution for the prescribed period of time. Thus solutions packaged in sealed containers as ampules, are readily sterilized by this method. • Also applicable to bulk solutions, glassware and instruments. • AUTOCLAVE NOT APPLICABLE FOR: • The sterilization of oils, fats, oleaginous preparations. • Other preparations not penetrated by the moisture. • Sterilization of exposed powders that may be damaged by condensed moisture. APPLICATION OF AUTOCLAVE

10. B. DRY -HEAT STERILIZATION • Mechanism: Dry heat kill microorganisms primarily through oxidation. • Hot air sterilization: Two principal methods of dry-heat sterilization are infrared and convection hot air. (Infrared rays sterilize surfaces only.) • Dry heat sterilization is usually conducted at temperature of 160-1700C for 2 hours or 2600C for 45 min. • Note1: If a chemical agent melts or decomposed at 170 °C, but is unaffected at 140 °C, the lower temperature must be used and the exposure time would be increased. • Note2: Individual unit to be sterilized should be as small as possible, and the sterilizer should be loaded in such a manner as to permit free circulation of heated air throughout the chamber. • Direct Flaming: Used to sterilize inoculating loops and needles. Heat metal until it has a red glow. • Incineration: Effective way to sterilize disposable items (paper cups, dressings) and biological waste.

11. B. DRY -HEAT STERILIZATION..….. • Dry heat sterilization is generally employed for substances that are not effectively sterilized by moist heat such as: • Fixed oils, Glycerin, Various petroleum products such as petrolatum, liquid petrolatum (mineral oil). • Various heat-stable powders such as zinc oxide, kaolin and sulfur. • Dry heat transfers heat less effectively to a cool body, than moist heat. • Higher temperature and longer period of exposure are required.

12. C. GAS STERILIZATION (ETHYLENE OXIDE) • Some moisture-sensitive and heat-sensitive materials can be sterilized by exposure to ethylene oxide or propylene oxide gas. • Denature proteins by replacing functional groups with alkyl groups. • Several factors are important in determining whether ETO is effective as a sterilizing gas, such as • a. Gas concentration (500mL/L), • b. Temperature (50-600C), • c. Humidity (60%), • d. Exposure time (4-16 hrs) • These gases are highly flammable when mixed with air but can be employed safely when properly diluted with an inert gas such as carbon dioxide or a suitable fluorinated hydrocarbon.

13. C. GAS STERILIZATION (ETHYLENE OXIDE): APPLICATIONS • The great penetration qualities of ETO make it a useful sterilizing agent in special applications: • Sterilization of medical and surgical supplies such as catheters, needles, and plastic disposable syringes in their final plastic packaging. • Sterilize certain heat-labile enzyme preparations. • Certain antibiotics, and other drugs (with tests to assure of the absence of chemical reactions). • Most hospitals have ethylene oxide chambers to sterilize mattresses and large equipment.

14. D. STERILIZATION BY FILTRATION • Depends upon the physical removal of microorganisms by adsorption on the filter medium or by sieving mechanisms. • It Is used for sterilization of heat-sensitive solutions. • Millipore filters are thin plastic membranes of cellulosic esters with millions of pores/square inch of filter surface • The pores are extremely uniform in size and occupy approximately 80% of the filter membrane's volume. • They are available in pore size from 14-0.025μm where the smallest bacteria, about 0.2μm, and viruses about 0.025μm can be trapped.

15. D. STERILIZATION BY FILTRATION: ADVANTAGES • Its speed in the sterilization / filtration. • Its ability to sterilize thermo labile materials. • Inexpensive equipment required. • The complete removal of living and dead microorganism as well as other particulate matter from the solution. • DISADVANTAGES • The membrane is fragile thus it is essential to be sure that the membrane is not ruptured. • Filtration of large volumes of liquids would require more time (particularly if the liquids were viscous).

16. E. STERILIZATION BY RADIATION • Three types of radiation kill microbes: • Ionizing Radiation (X rays, GAMMA rays) • Dislodge electrons from atoms and form ions. • Cause mutations in DNA and produce peroxides. • Used to sterilize pharmaceuticals and disposable medical supplies. • Penetrates human tissues. May cause genetic mutations in humans. • Nonionizing Radiation (Ultraviolet light) • Damages DNA by producing thymine dimers, which cause mutations. • Used to disinfect operating rooms.

17. E. STERILIZATION BY RADIATION • Microwave Radiation. • Heat is absorbed by water molecules. • May kill vegetative cells in moist foods. • Bacterial endospores, which do not contain water, are not damaged by microwave radiation. • Solid foods are unevenly penetrated by microwaves.

18. E. STERILIZATION BY RADIATION

19. Testing of Sterilization Process Two types are performed to test the efficiency of sterilization: • Testing the sterility of the final product • Testing the sterilization process (by physical, chemical and biological methods) to confirm that the equipment is working satisfactory. • PHYSICAL TEST • Thermocouples test: is used to measure the temperature at selected sites in the chamber or within the load of a dry heat, steam or gas sterilizer. • In case of sterilization by radiation: A measurement of radiation dose i.e. the amount of energy absorbed by the material tested. • In case of sterilization by filtration: A bubble pressure test is used to determine the pore size of filters.

20. Testing of Sterilization Process: Chemical indicator tests Types that cannot indicate time of exposure: Klintex papers: • These are paper strips or stickers attach to each object to be sterilized. • The word (sterile) is written on the strip (colorless) but after exposure to the sterilizing agent as steam the word (sterile) will be cleared. • Klintex test tablets: • These contain 75% lactose, 24% starch and 1% magnesium trisilicate. • They are hard and white but after steam sterilization they become brown and gelatinous.

21. Testing of Sterilization Process: Chemical indicator tests C) Autoclave test tape (Bowie – Dick test): • This is a valuable test for confirming that the steam has displaced all the air from a porous load (i.e. air removal test). • The tape carries heat sensitive bars which become colored if steam has full penetrated the pack. • If air remains, the bars in the centre are lighter in color.

22. Testing of Sterilization Process: Chemical indicator tests Types that indicate time of exposure: Browne’ tubes: • Each tube consists of a sealed glass tube which contains a red fluid (an ester and acid - base indicator) that changes to yellow, brown and finally green on heating (the ester undergoes heat hydrolysis to form an acid + alcohol. The acid will change the color of the indicator). • Browne’s tube type I: Suitable for ordinary steam sterilizers • Browne’s tube type II: Suitable for high vacuum sterilizers • Browne’s tube type III: Suitable for hot air oven • Browne’s tube type IV: Suitable for I.R conveyer oven.

23. Testing of Sterilization Process: Biological indicator • Biological indicators consist of bacterial cultures which are usually used in the form of impregnated strips e.g. paper and metal foil and are placed in different sites in the sterilizer. • At the end of the process, the bacteria are transferred to a nutrient medium which is incubated and the presence or absence of growth is noted.

24. Testing of Sterilization Process: Biological indicator • The bacterial species to be used must be carefully selected, since it must possess high resistance to the particular process. • The following types of bacteria are commonly used in the different sterilization process. • Moist heat (autoclave): Standardized preparation of Bacillus strearothermophilus spores. • Hot air oven & Ethylene oxide sterilizer: Standardized preparation of Bacillus globigii spores. • Gamma radiation: Standardized preparation of Bacillus pumilus spores. • Filtration: Serratia marcescens is used.

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