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Sterile compounding is the compounding of products that will ultimately be free from all viable forms of life. This can be done by aseptic compounding or by a process of terminal sterilization. The criteria for sterile compounding is much more vigorous than for non sterile compounding in that the facilities need to be cleaner, the personnel need to be trained in the aseptic technique, the room in which compounding takes place needs to have a controlled, clean air supply, sterilization needs to be effectively carried out and stability on storage needs to be assessed. A compounded sterile preparation is known as a CSP. The most commonly used CSPs are probably aqueous parenterals and if these preparations aren't sterile, pose a serious threat to patients' health and safety. The main objectives of sterile compounding are to prevent microbial contamination, prevent the presence of bacterial endotoxins which could lead to pyrogens, to insure the correct excipients and active ingredients are present in the preparation and to prevent any significant content errors in the correct excipients. If any of these properties were compromised, fatality to patients would probably result.
Like any process, there is risk levels associated with sterile compounding. Risk levels vary with the individual product, and need to be appropriately assigned to each preparation in order to achieve the appropriate sterility. There are three levels, designated low, medium and high. They are appointed depending on the probability that a CSP will become contaminated microbially (by spores, endotoxins, microbial organisms), physically or chemically. The latter may arise due to foreign chemicals or physical matter. There are many potential sources of this contamination including contamination from the personnel conducting the compounding, ineffective processing environments and the incorporation of non-sterile dosage forms into the CSP. The purpose of the three levels is to give an indication of the depth of care that needs to be abided by during compounding of the preparations. The most significant factor in determining the risk level is sound professional judgement of the licensed health care professional which is based on an in depth knowledge of the aseptic technique. It is their responsibility to determine the appropriate procedure and environment for the risk level that they designate. Usually, these risk levels apply to the preparation directly after the sterilization process or after the final aseptic mixing or filling. The personnel must also take into consideration the extra risk that contamination may occur during shipping or storage due to chemical degradation of excipients. This is taken into account when assigning the expiry dates.
The assignment of risk levels depends on the conditions of the compounding as well as the product being prepared.
The conditions for low risk levels are that procedures, such as mixing, measuring or transferring, are carried out using closed or sealed packages and that they are carried out efficiently and quickly; procedures are limited to transferring sterile solutions in sterile syringes to sterile devices for administration, aseptically opening ampoules and inserting sterile needles into vials via sterile stoppers; that the CSPs are stored for no longer than 48 hours at a controlled room temperature, no more than 14 days at a cold temperature and for 45 days in freezing conditions. A low risk level process would be a single transfer of sterile dosage form from a vial (or other sterile container) using a sterile needle to another sterile device. Glass ampoules would need additional sterile filtration to insure that there are no glass particles present in the sample.
The quality of the process also needs to be validated and some practices include examining the quality of air and disinfecting the air that encompasses the process' environment to prevent any microbial contamination of surfaces; to insure that personnel are wearing the correct protective garbing; to insure the correct amounts of the correct excipients are being incorporated into the product and to visually analyse the CSP to qualify the absence of any particulate matter; to check the label and ensure quality of the packaging. A media fill test is also undertaken every year by each person involved in the compounding of these products to insure their standard is maintained. The conditions of the test are quite vigorous and would probably represent the most challenging conditions that would arise during the compounding of these products.
Medium risk levels arise when products are being made under low risk conditions and extra conditions arise. Such conditions may include that small doses are combined in order to obtain a CSP that will ultimately be used by multiple patients or to a single patient more than once; that a complicated aseptic technique is required rather than a single volume transfer; that the process is longer than usual or that the product is given over a period of time, maybe implanted into the patient. Also for a medium- risk preparation, the storage times in the absence of a sterility test differ to those for low-risk preparations. They may be stored not exceeding 30 hours at a controlled room temperature, no more than 7 days at a cold temperature and for 45 days in freezing conditions. Specific examples of medium-risk level processes would be the reconstitution of several vials of drug powder with a specific volume of sterile diluents, and if the solution was then subsequently transferred to several SVP mini-bags or LVP bags. Another example would be the aseptic filling of an injection device with drugs where air must be extruded prior to dispensing of the injection. The quality of the process is validated via the same procedures as for low-risk level products. However a more difficult media filled test is taken annually by the personnel. They may also need to pass more frequently than for the low-risk products.
When a CSP is already contaminated or where there is a high probability that it will become contaminated, it is known as a high-level risk product. It may be elevated from a medium risk level preparation if the location of compounding is altered. For example, a product that is prepared in a fume hood within a pharmacy may be of medium risk, but when the location of preparation is changed to a nursing station or a patient's bedside, the product would be deemed a high-risk level preparation. This is because the new location lacks the controlled environment of the pharmacy and contamination is much more likely. A preparation would be of a high- risk level if the excipients and active ingredients are non sterile or if the administration device is not sterile prior to sterilization. It would also be of a high- level if the sterile preparation has been exposed to air whose quality is inferior to the quality of air that would exist in a fume hood (ISO class 5). Another condition would be if a nonsterile preparation is jeoparidized by being exposed for 6 hours prior to sterilization. If a high-risk level CSP has not yet passed a sterility test, certain storage requirements apply as with the other two levels. Prior to administration, the preparation cannot be exposed and is adequately stored for not more than 24 hours at a controlled room temperature, no longer than 3 days at a cold temperature and for 45 days in freezing conditions (-20°C or less). Prior to use for high- risk level compounding, the equipment that is to be used is rinsed with sterile water and drained or dried directly before the compounding commences. For a solution of high-risk level that is to be terminally sterilized by steam, it is necessary to pass the solution through a filter whose pores are no greater than 1.2µm in size immediately prior or during the transferring of the solution into its final container. If a high-risk level CSP is sterilized by filtration, the process must take place with an ISO Class 5 or greater quality air environment. Examples of high-risk level compounding are the preparation of a CSP from a bulk, non-sterile drug powder form e.g. morphine by dissolving in order to prepare a solution that will ultimately be sterilized or weighing sterile drugs, blending and mixing components in non sterile equipment prior to sterilization. Validation of process quality involves the quality procedures required for low-risk and medium- risk level CSP. On top of this, a media fill test which corresponds to the preparation of high-risk level products is undertaken twice a year by the personnel involved in the compounding. Like the other tests, it represents the most intense conditions that would be met during high-risk level compounding.
It is vital that the personnel involved in sterile compounding are sufficiently trained in operating under an aseptic environment. This includes following the most up to date standard operating procedures(SOPs) on hand washing, garbing into protective clothing, working in a laminar air flow unit, cleaning the laminar airflow unit prior to compounding and suitable disposal of waste materials. They must operate efficiently in a cleanroom i.e. an environment where the particulate contamination and bacterial contamination are limited to prescribed levels. They must have sufficient knowledge of the suitable quality of ingredients that are incorporated into CSPs and how they should be stored. The personnel's' technique must be assessed in accordance with the risk level of the compound they are preparing. This is essential in order to maintain quality and to ensure patient safety. They must pass written and practical assessments, as previously discussed, on their aseptic technique. In the case of microbial growth in the practical component, or a fail in the written, the person in question must be re-instructed and examined once again by an expert in order to correct the fault in the process. Personnel involved in high-risk level compounding are evaluated more regularly, usually twice a year, than those involved in low and medium risk level CSPs.
Critical site exposure is also a risk factor during the preparation of the product. The degree of exposure is affected by the length of time it is exposed, the size of the site and the characteristics of the critical site. When the site is opened, there is an increased chance that contamination from the environment will enter the sterile product. The increase is directly proportional to the length of time exposed. The size also affects the risk. There is less chance of the tip of a needle becoming contaminated than the tip of an open bottle or vial. In order to decrease the risk of the critical site becoming contaminated, the operator must work quickly and must be organised to keep exposure time to a minimum.
Sterile compounding is an exact and tightly regulated process. The risk levels that are assigned are vital in order to designate the appropriate standard to the compounding of the product. This ensures patient safety is maintained as the priority of the process.