Sterilization procedure

Pasteurization, the heating of certain fluids, frequentiy milk or dairy products (see Milk and milk products), destroys potentially harmful organisms such as mycobacteria, M. tuberculosis M. bovis or M. avium. Pasteurization, carried out at 62°C for 30 min or at 72°C for 15 s, is not a sterilization procedure. 

Such sterilization procedures (see also Chapter 20) may include heat treatment, filtration, irradiation, recrystallization flxm a bactericidal solvent such as an aleohol, or for dry products where eompatible, ethylene oxide gas. If the raw material is only a minor constituent and the final product is adequately preserved either by lack of chemically... 

For gaseous sterilization procedures, elevated temperatures are monitored for each sterilization cycle by temperature probes, and routine leak tests are performed to ensure gas-tight seals. Pressure and humidity measurements are recorded. Gas concentration is measured independently of pressure rise, often by reference to weight of gas used. 

The information on the container and the development pharmaceutics is to cover the qualitative composition (polymeric and other), closure type and method of operation, tightness of the closure, dosing device information, tamper evidence and child resistance, stability of the product in the container, the method of administration of the medicinal product, any sterilization procedures, the ability of the container to protect the contents from external factors,... 

Water system Cleaning practices Computer validation Process validation Test methods validation Sterilization procedures Stability evaluation... 

Media are prepared per manufacturer instruction. Adjust the pH. The sterilization procedure is conducted per related MFM (manufacturing formula and method) for media fill mn. 

Even when impurities and degradation profiles of a drug substance have been established and containers comply with guidelines, some unexpected drug-container interactions can occur during the sterilization procedure or shelf life. 

These considerations have been extensively explored by producers of canned foods and some simplified kinetics have been derived to allow better control of sterilization procedures. For example, the overall death process in a mixed culture can be described by an exponential decay curve. The equation will follow the form... 

Bearing in mind the previous discussion, there are basic official or unofficial sterilization procedures, all of which are overkills, designed to kill or get rid of the very last and most resistant organism in the system being treated. Filtration is, of course, designed to physically remove all bacteria present. It does not usually remove viruses or mycoplasms and, as noted above, some of the assumptions made during a filtration process need to be very carefully evaluated by the operator. 

The basic sterilization procedures involve the application of dry or moist heat, the use of sterilizing radiation or, more recently, the use of intense bright light. A valuable source of information is the section on Sterilization and Sterility Assurance of Compendial Articles in the General Information Chapter (<1211>) of the United States Pharmacopeia, now in its 28th revision. Since it is now revised on an annual basis the interested reader is referred to the latest edition for up-to-date information. 

From a number of pilot applications Fig. 1.4-8 shows the quasi-continuous train for the sterilization of fruit juices with pulp contents. The high pressure sterilization offers valuable advantages with respect to the quality of the final product compared to other sterilization procedures, especially if natural fractions of fruit pulp are desired by the consumers. 

Sterilization procedures, Air and water quality are covered in appropriate subparts of Table 1. 

Validation of the lyophilizer cleaning and sterilization processes should be accomplished. Particular care should be taken to verify that there is no back-migration of contaminants, whether from adjuvant fluids integral to the equipment of by cross-contamination from previous product. Typically, an overkill approach using a sufficient number of thermocouples and biological indicators is the method of choice. Finally, fill testing to verify the adequacy of the sterilization procedure and the aseptic manipulations involved with product filling, transfers, and lyophilization needs to be performed. 

The completion of a successful OQ should allow finalization of calibration, operating, cleaning and sterilization procedures, operator training and preventative maintenance requirements. It should permit a formal >release< of the systems and equipment. 

Validation of systems is obligatory in the production of biopharmaceuticals and, thus, the bioreactors must be validatable. In the case of stirred-tank bioreactors, apart from the functional validation, the cleaning and sterilization procedures have to be validated, since these are repeated use equipment. These requirements pose additional challenges to the process engineers. 

The plastic bag is disposable and is provided sterile by the manufacturer. This makes it a very attractive bioreactor type for production purposes, especially if the production scale is not very large. Since it is not sterilized in-house, there is no need for validation of the sterilization procedure. The validation of bag sterilization is the responsibility of its manufacturer. Since it is not reused, there is no need for cleaning and validation of cleaning procedures. Figure 9.6 (see color section) shows a photograph and a schematic representation of a wave bioreactor. 

The concept of validation came up in the 1970s in association with sterilization procedures and was extended to all steps of pharmaceutical manufacturing procedures. Validation means proving that any and all procedures, processes, equipment, material, operations, and systems comply with the expected performance. Well-planned and well-conducted validation studies constitute GMP principles once they guarantee a consistently safe and efficacious final product. Validation is important for companies, first for QA, and also for cost reduction, decreasing failures, rejection, reworks, recalls, and complaints. The positive aspect of validation is an increase in productivity, as a consequence of a well-controlled process. Validation is required by the regulatory agencies of many countries. 

When the dispersed phase, usually but not necessarily the cells, is of interest, no separation of phases need take place during sampling. The system must be opened in such a way that no infections can enter the reaction space either during sampling or between the sampling events. This requires the use of nonreturn valves and probably some repetitive sterilization procedure of the valve and exit line(s), as depicted in Fig. 18. 

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