STERILIZATION OF PARENTERALS

1. STERILIZATION OF PARENTERALS N.SANTHI PRIYA,Mpharm ASSISTANT PROFESSOR CHALAPATHI INSTITUTE OF PHARMACEUTICAL SCIENCES

2. PARENTERAL The term parenteral • Derived from the Greek words: para (outside) and enteron (intestine) • Denotes routes of administration other than oral route.

3. Parenteral Routes of Administration 1. Intra-articular –joints 2. Intraspinal –spinal cord 3. Intra-arterial –arteries 4. Intravenous –veins 5. Intradermal –skin 6. Intrasynovial –joint fluid 7. Intrathecal –spinal fluid 8. Intracardiac –heart 9. Intramuscular –muscles 10. Subcutaneous –under the skin

5. Development of manufacturing process

6. sterilization

7. Terminology • Aseptic: areas / practices where the product is to be sterile • Aseptic processing: those operations performed between the sterilization of preparation and final sealing of its package • Bacteriocide:any agent that destroys the microorganism

8. Terminology • Bacteriostat: any agent that arrests or retard the growth of microorganism • Bioburden: the number of viable microorganism present prior to sterilization usually expressed in colony forming units • Disinfection: a process that decreases the probability of infection by destroying vegetative microorganisms,but not ordinary bacterial spores • Sanitization: a process that reduces the level of bioburden to a safe level Terminology

9. Sterile: absolute absence of viable microorganism. • Sterility assurance level: an estimate of the effectiveness of sterilization process . It is usually expresses interms of negative power of 10 { 1 in million = 10-6 } • Terminal sterilization: a process used to render products sterile to a preferred SAL • Validation:the act of verifying that a procedure is capable of producing the intended result under prescribed circumstances and challenges to predefined specifications

10. sterilization The term sterilization ,is a process by which all viable microorganisms are removed or destroyed, based on the probability function

11. Sterilization methods • Steam sterilization • Dry heat sterilization • Filtration sterilization • Gas sterilization • Sterilization by Ionizing radiation

12. Physical Processes of Sterilization Thermal Method Microorganisms are killed by heat by coagulation of the protein of a living cell. The lethal effectiveness of heat is dependent on: 1. The degree of heat 2. The exposure period 3. The moisture present

13. Steam sterilization Steam is an effective sterilant for two reasons: • saturated steam is an extremely effective “carrier” of thermal energy. It is many times more effective in conveying this type of energy to the item than is hot (dry) air. • steam is an effective sterilant because any resistant, protective outer layer of the microorganisms can be softened by the steam, allowing coagulation of the sensitive inner portions of the microorganism

14. Steam sterilization requires four conditions: • Adequate contact • Sufficiently high temperature • Time • Sufficient moisture

15. Heat resistances

16. condition for an accurate sterilization • It is a perfect and total air release from the sterilization chamber. • The air needs to be totally replaced by steam to create a 100% steam atmosphere. • Only this ensures an efficient steam sterilization and a homogenous temperature distribution. • Remaining air in the chamber results even at sterilization temperature in a few folds less sterilization efficiency

17. The usual steam pressures, the temperatures obtainable under these pressures, and the approximate length of time required after the system reaches the indicated temperatures are as follows: 1. 10 pounds pressure (115°C), for 30 min. 2. 15 pounds pressure (121°C), for 20 min. 3. 20 pounds pressure (126°C), for 15 min

19. General arrangement of a direct operating, self-acting pressure reducing station

21. DRY HEAT STERILIZATION • Usually carried out in ovens and are generally thermostatically controlled • Due to the high temperatures required for dry heat sterilization can only be used for thermostable, moisture sensitive or moisture impermeable pharmaceutical and medicinal. • These include products like; • Dry powdered drugs • Oily injections, implants, ophthalmic ointments, ointment base

22. DRY HEAT STERILIZATION • The Dry-Heat sterilization process is accomplished by conduction; that is where heat is absorbed by the exterior surface of an item and then passed inward to the next layer. • Eventually, the entire item reaches the proper temperature needed to achieve sterilization. • proper time and temperature for Dry-Heat sterilization is 160°C (320°F) for 2 hours or 170°C (340°F) for 1 hour • Dry-heat destroys microorganisms by causing coagulation of proteins.

23. There are two types of Hot-Air convection (Convection refers to the circulation of heated air within the chamber of the oven) sterilizers: • Natural convection • Mechanical convection

24. Natural convection process • As air is heated, it expands and possesses less density (weight per unit volume) than cooler air. • Therefore, the heated air rises and displaces the cooler air (the cooler air descends). • The method of Dry-heat gravity convection produces inconsistent temperatures within the chamber and has a very slow turn over.

25. Mechanical convection process • A mechanical convection oven contains a blower that actively forces heated air throughout all areas of the chamber. • The flow created by the blower ensures uniform temperatures and the equal transfer of heat throughout the load. • For this reason, the mechanical convection oven is the more efficient of the two processes.

26. Natual convection Forced convection

27. Sterilization by filtration Reduces microbial population or sterilizes solutions of heat-sensitive materials by removing microorganisms Depth filters – thick fibrous or granular filters that remove microorganisms by physical screening, entrapment, and/or adsorption Membrane filters – porous membranes with defined pore sizes that remove microorganisms primarily by physical screening

28. Filtration process does not destroy but removes the microorganisms. It is used for both the clarification and sterilization of liquids and gases as it is capable of preventing the passage of both viable and non viable particles. The major mechanisms of filtration are • sieving • adsorption • trapping within the matrix of the filter material Sterilizing grade filters are used in the treatment of heat sensitive injections and ophthalmic solutions, biological products .

29. Application of filtration for sterilization • HEPA (High efficiency particulate air) filters can remove up to 99.97% of particles >0.3 micrometer in diameter. • Air is first passed through prefilters to remove larger particles and then passed through HEPA filters. • The performance of HEPA filter is monitored by pressure differential and airflow rate measurements

31. gas sterilization • Some heat sensitive and moisture sensitive materials can be sterilized much better by exposure gases like ethylene oxide or propylene dioxide • 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 flourinated hydrocarbon

32. Ethylene oxide • It is used to sterilize heat-sensitive materials, microbicidal and sporicidal • Boiling point 10.7°C, Very good penetration • Used with CO2, argon etc. to avoid explosions, > 3% ethylene oxide in air is explosive. Mechanism: ethylene oxide alkylates hydroxyl, carbonyl and sulfhydryl amino groups of enzymes • Effect depends on • gas pressure • exposure time • temperature • type of microorganism or spore • moisture content (optimum 28-33%)

33. The great penetrating qualities of EtO makes it useful in sterilization of medical and surgical appliances such as : • Catherters • Needles • Plastic disposable syringes • In their final plastic packaging just prior to shipment

36. Sterilization by radiation • Both, X rays and Gamma rays have wavelength shorter than the wavelength of ultraviolet light. X rays, which have wavelength of 0.1 to 40 nm, and gamma rays, which have even shorter wavelength, are forms of radiation, so named because it can dislodge electrons from atoms, creating ions • These forms of radiation kill microorganisms by damaging DNA and produces peroxides, which act as powerful oxidizing agents in cells.

37.  High-energy gamma irradiation is used mainly in the healthcare industries to sterilize disposable medical devices. • Pharmaceutical companies now radiation sterilize drugs such as ophthalmic preparations, topical ointments, veterinary products, and parenterals. • Regulatory pressure to adopt terminal-sterilization processes has promoted radiation sterilization.

38. Radiation Sterilization

39. List of Injectable Materials Sterilized by different Methods

40. List of Non injectable sterile fluids Sterilized

41. Evaluation and In Process Monitoring of Sterilization Procedures

42. sterilization monitoring • Sterilization is a process designed to kill all microbes. • Because we can't actually test whether all microbes are killed during the sterilization process. • the next best thing is to determine whether the process kills the most resistant microbe. If so, we may assume all others have been killed as well.

43. Demonstrating the death of bacterial spores provides the main guarantee of sterilization, because it assess the process directly using live resistant microorganisms. • Using bacterial spores to monitor the sterilization process is referred to as biologic monitoring (or spore-testing) and the bacterial spores used for monitoring the sterilization process are referred to as biologic indicators (BIs). 

44. Types of Biological indicators • BIs contain the bacterial spores used for monitoring. • The spores used are Geobacillusstearothermophilus (for testing steam or chemical vapor sterilization) or Bacillus subtilis (for testing dry-heat or ethylene oxide gas sterilization). • Currently, no BIs are available for routine testing of liquid chemical sterilants or disinfectants.

45. Spore strips • The medium that in turn is incubated for two to seven days at • 55°C/131°F (for G.stearothermophilus) or at 37°C/98.6°F (for B. subtilis). • If live bacterial spores still are present, they will grow and produce cloudiness and/or change the color of the growth medium, indicating sterilization failure. • Spore strip BIs can be used to monitor all forms of heat sterilization. 

46. Self-contained vial • This comprises both a spore strip or disk and an ampule filled with growth medium, contained in a plastic vial with a vented cap to permit entrance of the sterilizing agent into the vial • After processing through the sterilizer, either the vial is squeezed or the cap is pushed down to break the internal ampule, which mixes the growth medium with the spores. • The vial is then incubated at 55°C/131°F, and if live bacterial spores still are present, they will grow and change the color of the growth medium, indicating sterilization failure. 

47. SPORE STRIP SELF CONTAINED VIAL

48. chemical indicators Chemical indicators change color or form when exposed to specific high temperatures or to the sterilizing conditions within a sterilizer. This is referred to as chemical monitoring (or process monitoring).

49. Mechanical monitoring • Mechanical monitoring involves observing and recording the physical aspects • e.g., • temperature, • pressure, • time of the cycle when the sterilizer is being operated. 

50. Sterility assurance level • Sterility assurance level (SAL) is a term used to describe the probability of a single unit being non-sterile after it has been subjected to the sterilization process • SAL is also used to describe the killing efficacy of a sterilization process, where a very effective sterilization process has a very low SAL.