Lecture 4 Sterilization Quality Control and Clinical Hazards PDF

Modern Pharmaceutics Parenteral Products 595 STERILIZATION METHODS Five sterilization processes are described in the USP: steam, dry heat, filtration, gas, and ionizing radiation. All are commonly used for parenteral products, exc...

Modern Pharmaceutics Parenteral Products 595 STERILIZATION METHODS Five sterilization processes are described in the USP: steam, dry heat, filtration, gas, and ionizing radiation. All are commonly used for parenteral products, except gas and ionizing radiation, which are widely used for devices and surgical materials. To assist in the selection of the sterilization method, certain basic information and data must be gathered. This includes determining (i) the nature and amount of product bioburden and (ii) whether the product and container-closure system will have a predominantly moist or dry environment during sterilization. Sterilization by Steam When drug solutions and containers can withstand autoclaving conditions, this method is preferred to other sterilization methods because moist heat sterilizes quickly and inexpensively. However, judgment must be exercised, and experiments run to ensure that the solution and container are permeable to steam. Oils, dry powders and tightly closed containers, are not normally sterilizable by steam. Aqueous thermostable formulations normally sterilizable by steam. Moist heat sterilization kills microorganisms by coagulating and denaturing their enzymes and structural protein. Sterilization by Dry Heat Dry heat is widely used to sterilize thermostable glassware, metal instruments; it is also used for anhydrous fats, oils, powders and equipment parts in manufacturing areas for parenteral products. Dry Heat is not as corrosive as steam. However, heat-up time is slow, necessitating long sterilization periods at high temperatures. Dry heat kills microorganisms by destructive oxidation of essential cell constituents as well as inactivating the most resistant spores. The two principal methods of dry-heat sterilization are infrared and convection hot air. Infrared rays will sterilize only surfaces. Sterilization of interior portions must rely on convection hot air. 596 Boylan and Nail Figure 9 Autoclave. Parenteral Products 597 Sterilization by Ethylene Oxide/Gas Sterilization Ethylene oxide (ETO), a colorless gas, is widely used as a sterilant in hospitals and industry for items that cannot be sterilized by steam. It is often diluted with carbon dioxide, or sometimes fluorocarbons, to overcome its flammable and explosive nature. The mechanism by which ETO kills microorganisms is by alkylation of various reactive groups in the spore or vegetative cell. Several factors are important in determining whether ETO is effective as a sterilizing gas: gas concentration, temperature, humidity, and pressure. ETO should be present at a concentration of about 500 mL/L for maximum effectiveness. ETO sterilization is mainly used to sterilize plastic and rubber materials. ETO sterilization can be used to sterilize thermolabile dry powder drugs. Unlike other methods, it is necessary to post treat the product, either through vacuum purging or by allowing the product to remain at ambient conditions for a time, to allow removal of residual ETO. 598 Boylan and Nail Figure 10 ETO sterilization cycle. Abbreviation: ETO, Ethylene Oxide. Sterilization by Filtration Only in the past 30 years filters have become sufficiently reliable to use them on a wide scale to sterilize injectable solutions. Even now it is prudent to use filtration to sterilize only those products that cannot be terminally sterilized as well as thermolabile solutions. In addition, it is used to sterilize air in aseptic area. Filters are of two basic types: depth and membrane. Depth filters rely on a combination of tortuous pathway and adsorption to retain particles or microorganisms. Membrane filters rely on sieving and, to a lesser degree, absorption to prevent particles from passing. Pores in a membrane filter used for sterilization must not exceed 0.2µm. Ionizing Radiation It is a cold sterilization method that involves the use of either gamma radiation or electron beam radiation. Ionizing radiation is generally used to sterilize thermolabile materials. The effective dose of sterilization is 2.5 megarads (Mrad). Parenteral Products 599 CLINICAL CONSIDERATIONS IN PARENTERAL PRODUCT DESIGN Sterility, freedom from pyrogens, and acceptably low level of extraneous particulate matter are critical quality attributes of all injectable products. Additional critical quality attributes depend on the clinical use of the product. For example, for IV, IM, and SC routes, isotonicity and physiological pH (7.4) are always desirable to minimize potential irritation upon injection. Other factors may preclude this, however. If the required dose of drug must be administered in a small volume, it may not be feasible to formulate an isotonic solution. Likewise, solubility or stability considerations may preclude formula - tion at physiological pH. This explains why formulation pH for injectable drugs varies from about pH 3 to about pH 10. However, for certain routes of injection, such as intrathecal, intraocular, or into any part of the brain, isotonicity and physiological pH are critical to minimize potential nerve damage. Absence of preservatives is also critical for these routes of administration for the same reason. Parenteral Products 605 Quality Control Testing and Evaluation Quality control testing and evaluation is involved primarily with incoming raw materials, the manufacturing process, and the final product. Testing of incoming raw materials includes routine testing on all drugs, chemicals, and packaging materials. Process controls include daily testing of WFI (USP), conformation of fill doses and yields, checking and approving intermediate production tickets, and checking label identity and count. Finished product control includes all the tests necessary to ensure the potency, purity, and identity of the product. Parenteral products require additional tests, which include those for sterility, pyrogens, clarity, and particulate analysis, and for glass - sealed ampoules, leaker testing. Sterility Testing The purpose of a sterility test is to determine the probable sterility of a specific batch. The USP lists the procedural details for sterility testing and the sample sizes required (1). The USP official tests are the direct or (culture) tube inoculation method and the membrane filtration method. The culture medium (Growth promotion medium) is a crucial aspect in the success of the sterility testing. Hence, the USP demands the use of the following media: Fluid thioglycollate medium (FTM) which promotes the growth of anaerobic microorganisms. Soybean casein digest medium (SCD): promotes the growth of both aerobic microorganisms and fungi. As mentioned above that the culture media is a crucial aspect also the type of method equally important. Membrane filtration method is used with formulations that will interfere with the sterility test results. These formulations either contain antimicrobial agents (preservatives) and/or oils as well as powders (suspensions). All sterilizing equipment must be validated to ensure that the proper temperatures are obtaine d for the necessary time period. These validations are obtained by the use of thermocouples, chemical and biological indicators, sealed ampoules containing culture medium with a suspension of heat-resistant spores, and detailed sterility testing. Pyrogen Testing Pyrogenic substances are primarily lipid polysaccharide products of the metabolism of microorganisms; they may be soluble, insoluble, or colloidal. Pyrogens produced by gram-negative bacilli are generally the most potent. Minute amounts of pyrogens produce a wide variety of reactions in both animals and humans, including fever, leukopenia, and alterations in blood coagulation. Large doses can induce shock and eventually death. Pyrogens readily contaminate biological materials because of their ability to withstand autoclaving as well as to pass through many filters. Several techniques are used to remove them from injectable products. The ideal situation is one in which no pyrogens are present in the starting materials. This is achieved by strict control of the cleanliness of equipment and containers, distillation of water, and limited processing times. In general, pyrogens may be destroyed by being subjected to prolonged heating. Other pyrogen- removal techniques, which are generally less effective or applicable, include ultrafiltration, absorption or adsorption, chemical (oxidation), aging, or a combination of these. 606 Boylan and Nail One pyrogen test is a qualitative biological test based on the fever response of rabbits. If a pyrogenic substance is injected into the vein of a rabbit, a temperature elevation will occur within three hours. Many imitative medical agents will also cause a fever. A preferred method for the detection of pyrogens is the limulus amebocyte lysate (LAL) test. A test sample is incubated with amebocyte lysate from the blood of the horseshoe crab, Limulus polyphemus. A pyrogenic substance will cause a gel to form. This is a result of the clottable protein from the amebocyte cells reacting with the endotoxins. This test is more sensitive, more rapid, and easier to perform than the rabbit test. Leaker Testing and Sealing Verification Ampoules that have been sealed by fusion must be tested to ensure that a hermetic seal was obtained. The leaker test is performed by immersing the ampoules in a dye solution, such as 1% methylene blue, and applying at least 25 in. (64 cm) of vacuum for a minimum of 15 minutes. The vacuum on the tank is then released as rapidly as possible to put maximum stress on weak seals. Next, the ampoules are washed. Defective ampoules will contain blue solution. Another means of testing for leakers is a high-frequency spark test system developed by the Nikka Densok Company of Japan, which detects pinholes in ampoules. Some advantages of this system include higher inspection accuracy, higher processing speed, and eliminating the possibility of product contamination. Bottles and vials are not subjected to such a vacuum test because of the flexibility of the rubber closure. However, bottles that are sealed under vacuum may be tested for vacuum by striking the base of the bottle sharply with the heel of the hand to produ ce a “water hammer” sound. Another test is the spark test, in which a probe is applied outside the bottle. When it reaches the air space of the bottle, a spark discharge occurs if the headspace is evacuated. The microbiological integrity of various packages, such as vials and stoppers, disposable syringes, and plastic containers, should be determined. A microbiological challenge test is performed by filling the package with a sterile medium, and then exposing the sealed container to one of the following tests that is appropriate for the package system: (i) static-aerosol challenge, (ii) static-immersion challenge, (iii) static-ambient challenge, or (iv) dynamic-immersion challenge. The static-immersion challenge test is used commonly with new package combinations. The sealed containers are periodically challenged by immersion into a suspension of challenge organisms. Storing the containers at 5°C or 40°C to 50°C, or both, before immersion provides additional stress. Clarity Testing and Particulate Analysis Clarity is defined as the state or quality of being clear or transparent to the eye. Clarity is a relative term subject to the visual acuity, training, and experience of the sorter. Clarity Parenteral Products 607 specifications are not given in the USP, other than to state that all injections be subjected to visual inspection. Clarity testing is done visually as follows: All products containing clear solutions should be inspected against a black and a white background using a special light source. Although manual visual inspection is the most common means of inspection, electronic particle detection equipment and computer-controlled electrooptic systems are replacing manual inspection and using a light source or camera, or both, positioned behind, above, or below the units being inspected. Instruments that measure scattered light, such as the Photo -Nephelometer (Coleman Instruments, Oak Brook, Illinois, U.S.), are used to evaluate and set clarity standards for parenteral preparations. It is not possible to establish an overall standard value for all products (e.g., 30 nephelos) because the value itself is relative and influenced by many factors, including concentration, aging, stopper extracts, and the solubility characteristics of the raw materials. Nephelometer readings are insensitive to contamination by large (visible) particulates. Particulate matter is defined in the USP as extraneous, mobile, undissolved substances, other than gas bubbles, unintentionally present in parenteral solutions. Test methods and limits for particulates are stated in the USP for large-volume injections and small-volume injections. The development of sorting standards is the responsibility of the manufacturer. Parenteral solutions are sorted for foreign particles, such as glass, fibers, precipitate, and floaters. The significance of particulate contamination in all parenteral preparations and devices has received much attention. Although it has not been established that particles can cause toxic effects, the pharmaceutical industry, the medical profession, hospital pharmacists, and the FDA all realize the importance of reducing particulate levels in all parenteral products and devices. Sources of particulate matter include the raw materials, processing and filling equipment, the container, and environmental contamination. Several methods have been developed for identifying the source of particulates in a product so that they may be eliminated or reduced. The most effective method is that of collecting the particulates on a membrane filter and identifying and counting them microscopically. However, this method is time consuming and not adaptable to in-line inspection. Several video image projection methods for in-line detection of particles have been developed that provide potential for mechanizing inspection. Electronic particulate counters have been applied to parenterals because of the rapidity at which they do particulate analysis. Their main disadvantages are the lack of differentiation of various types of particulates, including liquids such as silicones, and the fact that particle size is measured differently from microscopic analysis. The USP tests for particulate matter in injections utilize both the microscopic and light obscuration methods. Volume and content unifomaty This test is done to ensure the stated volumes labeled on the containers. Earlier this test was done by pouring the content of selected number of containers in measuring devices. However, nowadays this test is done mechanically by using inspection machines that measure the height of fluids. This has the advantage of inspecting the entire patch in less time plus preserving all the patch containers. 32 Clinical hazards of injectable drug administration Any route of drug administration has certain risks or hazards. Injecting drug products directly into blood or tissue offers greater risks and hazards compared with any other route of adminis- tration. All injectable routes of administration have risks and hazards, but the intravenous (IV) and, especially, the intraarterial (IA) routes are most hazardous. The most common injectable hazards will be presented in alphabetical order with all hazards listed in Table 32-1 (1).1 Although not strictly classified as a clinical hazard, pain upon injection and the fear of receiving an injection are the most common concerns of injectable drug administration. Science continues to investigate ways to reduce both physiological and psychological adverse reactions to pain upon injection as well as to develop better methods for predicting pain and/or irritation upon injection (2). AIR EMBOLI Air emboli result principally from IV infusions, particularly if infusions administration uses pumps that do not have active air alarms. If air enters the bloodstream it can occlude cerebral or coronary arteries, resulting in major strokes and potential death. Air can cause blood vessels of the lung to constrict that, in turn, causes pressure in the right side of the heart to rise. Air can then move on to the brain or coronary arteries. Small amounts of air are not harmful, but 10 mL or more air injected into the blood- stream could be fatal. To minimize or eliminate air from entering the bloodstream, great care should be exerted to purge all air bubbles from the syringe or IV line prior to starting an injection or infusion and ensure that the system used remains airtight throughout their use. Perhaps the greatest advantage of using plastic bags composed of polyvinylchloride (PVC) for IV infusions is the great characteristic of PVC to collapse upon itself as the internal fluid is administered so that when all the fluid is gone, the collapsed bag will not have any air to release into the IV line. 1. BLEEDING Bleeding usually occurs in patients given injections who either have platelet deficiency or hemophilia. If bleeding tendency in a patient is known, the IV route may be safer than the intramuscular (IM) route because bleeding may be better controlled. Those patients with hemophilia or with vitamin K or platelet deficiencies should be given antihemophilic glob- ulin, Factor VIII, vitamin K, and/or platelet transfusions prior to administration of parenteral products. 1 Visual examples of clinical hazards of injectable administration of drugs may be found at the follow- ing websites: http://www.sciencephoto.com/, http://www.photoresearchers.com/main.html, http://catalog.nucleusinc.com, or simply use key words on a search engine site. 482 STERILE DRUG PRODUCTS: FORMULATION, PACKAGING, MANUFACTURING, AND QUALITY Table 32-1 Alphabetical Listing of Potential Hazards of Injectable Drug Administration. Air emboli. Bleeding. Fever. Hypersensitivity. Incompatibilities. Infiltration and extravasation. Overdosage. Pain and irritation. Particulate matter. Phlebitis. Sepsis. Thrombosis. Thrombophlebitis. Toxemia INCOMPATIBILITIES Incompatibilities are unfortunately a frequent problem occurring in parenteral therapy. The concern about incompatibilities resulted in texts published by Baxter, Abbott, and Trissel (4) that inform the pharmacist and other health care professionals what combinations of drugs potentially are incompatible. Incompatibilities cause drug precipitation in the container or in the administration set and, worse, could cause adverse side effects such as platelet aggregation, anaphylactoid reactions resulting in shock, and/or pulmonary infarctions. INFILTRATION AND EXTRAVASATION These hazards are caused by faulty needle injection technique. Infiltration is one of the most common problems that can occur when fluid infuses into the tissues surrounding the venipuncture site. Extravasation occurs when there is accidental infiltration of a vesicant or chemotherapeutic drug into the surrounding IV site. This cause infection, phlebitis, thrombosis, or necrosis of the infiltrated tissue. PHLEBITIS Phlebitis is a local inflammatory reaction usually associated with IV injection or infusion. Symptoms of phlebitis include redness (erythema) of the skin where the injection/infusion occurred, pain along the vein, edema, and hardness of the vein. Phlebitis caused by infusion can usually be reduced simply by slowing down the infusion rate. SEPSIS AND TOXEMIA Sepsis results from. microorganisms contaminating the product or delivery system that are subsequently injected; or. microorganisms from the skin surface that are carried into the body when the product is injected, or. microorganisms that migrate from the skin into the vein along a sleeve of an IV line (catheter) if present. In fact, any indwelling device like a catheter or needle may serve as an attractive residence for circulating microorganisms where they will eventually depart from the foreign device and reseed the bloodstream. Sepsis may be localized forming an abscess and/or may be systemic producing septicemia and metastatic infections. Sepsis, not surprisingly, is the most dangerous of all potential hazards possible when administering drug products by the parenteral route.  CLINICAL HAZARDS OF INJECTABLE DRUG ADMINISTRATION 483 With respect to endotoxins, the condition called toxemia results from a c c i d e n t a l infusion or injection of a biological toxin such as endotoxin. Endotoxins cause fever, leucopenia, circulatory collapse, capillary hemorrhages, necrosis of tumors, and other cascades of problems that can lead to death if the amount of endotoxin is high.