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The risk levels in sterile compounding is assigned based on the likelihood of contamination of the product being contaminated with microorganisms, spores, endotoxins or any foreign physical or chemical material. The importance of risk reduction in sterile compounding cannot be underestimated as any contamination, errors of the amounts of the correct ingredients used or incorrect ingredients used could cause serious harm or death to the patient in question. This is especially true for aqueous based injections for the vascular or central nervous system. Very common sources of contamination include the raw materials, water, equipment, personnel and the environment. Some examples of these possible sources of contamination are particles from personnel and objects, non-sterile material used in the preparation before terminal sterilisation, unsuitable conditions of the compounding environment and an elongated pre-sterilisation process for aqueous preparations. Sterile compounding necessitates very clean facilities and equipment, very specific training and testing of personnel compounding the preparation, careful monitoring and maintaining the quality of air and a strong knowledge of the key features and practices of drug stability and product sterilisation.
The US pharmacopoeia has three main classes of risk associated with 'compounded sterile preparations (CSP)'. These are low risk, medium risk and high risk. These can be applied to health care institutions, pharmacies and all other facilities which compound, store and supply the sterile compounded preparations. They are intended to act as a guide to the licensed health care professional and are not binding. Instead, the final judgement is left up to the health care professional in question. These classifications are only applicable directly after the final aseptic manipulation or terminal sterilisation unless otherwise indicated by the properties of the final product e.g. for a lipid emulsion. Further risk may be introduced by subsequent shipping or storage of the compounded sterile preparation due to degradation of the product itself or perhaps due to contamination due to the interaction between the packaging and the preparation. All these addition factors must also be considered by the compounding personal when assigning the expiry date of the compounded sterile preparation. Any guides on the expiry dates and temperature limits provided apply only if there is an absence or lack of direct testing studies or other appropriate sources of information related to the compounded sterile preparation in question.
Compounded sterile preparations include products which according to the manufacturers label and subsequent manipulations expose the original preparation to possible microbial contamination and preparations which are composed of non-sterile ingredients or use non-sterile devices which are required to be sterilised before use. These can include biologics, drugs, nutrients and radiopharmaceuticals which have either of the above criteria.
The risk level is considered to be low if the compounded sterile preparation is compounded under the following conditions; the product is compounded with commercially available sterile components and/or drug products, the compounding itself involves simple manipulations over a short period of time and closed system transfers are undertaken in a suitable air quality (ISO class 5 specification, laminar flow workbench, hood or barrier isolator). Examples of these kinds of manipulations are sterile drugs products being transferred from vials, bags or ampoules into the final sterile container using a needle and syringe. The contents of the ampoules must undergo sterile filtration to remove any glass particles. Another example of a low-risk product is measuring and mixing not more than three commercially available components to produce compound drug mixtures and nutritional solutions. Certain quality assurance practices are recommended such regular disinfection of the compounding area and environment to minimise the risk of any possible bacterial surface contamination. In addition to this, air quality testing should also be frequently carried out to ensure that the air meets the specifications of ISO class 5. It should also be visually established that the operators are properly garbed with the correct and appropriate hair covers, face masks, gloves etc. A visual confirmation of the products should carried to validate the absence of any visible particulates in the solution, the lack of leaking in the containers or to check the accuracy of the labels attached to the containers in question. Finally, a check should be carried out to guarantee the identity and the quantities of ingredients were compounded. For these low risk compounded sterile preparations, without passing a sterility test, a expiry date of no more than 48 hours in a controlled temperature environment is given or not more than 14 days is given when stored at a cool temperature. Operators who are authorised to carry out these manipulations required for low risk sterile compounding are required to undertake media-fill tests at least once a year. The test must replicate most demanding and stressful conditions when carrying out these types of manipulations when compounding low risk products. An example of this media-test would be three sets of four 5mls Soybean-Casein Medium are transferred using a sterile 10ml syringe into separate vials. The manipulations are carried out in ISO class 5 air quality before the vials are then incubated under the appropriate conditions. Any observed growth results in a failing of this operator validation test.
The risk of contamination is considered to be medium when products compounded aseptically under low risk conditions have one or more of the following conditions associated with the compounded sterile product; there are numerous complex manipulations over a large period of time such as time required for dissolution or sufficient mixing to occur, many individual or small doses of sterile products are mixed together to prepare a product which is administered to either an individual patient on numerous occasions or multiple patients and the product in question does not contain many bacteriostatic agents and they are given over a few days. Without passing a sterility test, the compounded aseptic product should not be given an expiry date of more than thirty hours at a controlled environment or not more than seven days in a cold environment. Examples of some medium risk compounding are total parental solutions after seven days, injections that are used in a portable pump or reservoir, reconstituted antibiotic without the addition of preservatives and batch pre-filled syringes without preservative. To assure quality for medium risk compounding, the same practices as the lower risk compounding must be carried out (e.g. regular disinfection). In addition to these practices, operators must pass a more challenging media-fill test at least once a year. Under low and medium risk levels, operators allowed to compound these products are required to pass a media-fill test yearly. These media-fill tests are required to replicate most difficult and stress conditions during compounding of low and medium risk products respectively.
Products which are compounded that either are already contaminated or have a high probability of being contaminated with micro-organisms are classified as high-risk risk level compounded sterile products. The conditions that would be considered to be high risk are if non-sterile ingredients are used or a non-sterile device or instrument is used prior to terminal sterilisation. High-risk conditions also include when sterile ingredients, components, devices and mixtures are exposed to environment where the standard of air is below ISO class 5 specification i.e. laminar flow workbench, hood or barrier isolator and when the product is exposed for at least six hours before sterilisation takes place. The standard of ingredients is of sufficient purity and content so that the ingredients would meet their original specification whether in an opened or unopened package. The expiry date for high-risk compounding preparations without passing a sterility test is not more than 24 hours if stored in a controlled room temperature environment or not more than 3 days if stored at a cool temperature environment. All non-sterile instruments and devices are washed well with pyrogen free, sterile water before being thoroughly dried just before being used for the high risk compounding. Any compounded sterile product that is being terminally sterilised by steam sterilisation must be passed through a filter with a nominal porosity which is not greater than 1.2μm either before or during filling into the final container. Sterilisation of these high risk products is required to be carried in an environment where the air quality is of ISO class 5 standard or higher. Some examples of high-risk compounding are dissolving non-sterile drug powders or nutrient powders which will then be terminally sterilised or sterile nutritional solutions prepared from non-sterile ingredients with initial mixing and preparation in a non-sealed or non-sterile container or device. Mixing of the ingredients may take place in an air quality environment below that of the ISO class 5 standards (laminar flow workbench, hood or barrier isolator). To assure quality, the same methods that are carried out during preparation include all the low-risk level procedures for the compounding of sterile products. In addition to this, any personnel that are authorised to compound high-risk products are required to undertake media-fill test at least twice a year. The test is required to replicate the most challenging and demanding operating conditions during the compounding of high risk compounded sterile preparations. Furthermore, extra testing of the end product is a necessity as non-sterile starting materials are used in formulating this preparation.
In conclusion, the risk levels in sterile compounding can be broken down into three categories of low, medium and high risk. This categorisation gives recommended procedures when dealing with certain types of sterile compounding and, in addition to this, gives a guideline on the recommended expiry dates of the different categories in the absence of passing sterility tests. These are intended to act as a guide to the medical professional but are not prescriptive. Ultimately the final judgement on the risk assessment is up to the licenced health care professional who supervises the compounding of the sterile products to determine the appropriate risk level.