Thermal sterilization

Co-administration of ofloxacin and chitosan in eyedrops increased the bioavailabUity of the antibiotic [290]. Trimethyl chitosan was more effective because of its solubility (plain chitosan precipitates at the pH of the tear fluid). On the other hand, N-carboxymethyl chitosan did not enhance the corneal permeability nevertheless it mediated zero-order ofloxacin absorption, leading to a time-constant effective antibiotic concentration [291]. Also W,0-carboxymethyl chitosan is suitable as an excipient in ophthalmic formulations to improve the retention and the bioavailability of drugs such as pilocarpine, timolol maleate, neomycin sulfate, and ephedrine. Most of the drugs are sensitive to pH, and the composition should have an acidic pH, to enhance stability of the drug. The delivery should be made through an anion exchange resin that adjusts the pH at around 7 [292]. Chitosan solutions do not lend themselves to thermal sterilization. A chitosan suspension, however. 

Death kinetics are obviously important in chemical or thermal sterilization. The spores formed by some bacteria are the hardest to kill. Problem 12.3 gives data for a representative case. 

Wang et al. report the death kinetics of Bacillus stearothermophilus spores using wet, thermal sterilization. Twenty minutes at 110°C reduces the viable count by a factor of lO". The activation temperature, E/Rg, is 34,200 K. How long will it take to deactivate by a factor of lO ... 

The existence and possible presence of bacterial spores determines the parameters, i.e. time and temperature relationships, of thermal sterilization processes which are used extensively by the food and pharmaceutical industry. These are defined below (see also Chapters 20 and 23). 

In sterile product manufacturing, five major steps are involved in approaching the validation of a sterile process. These are outlined below using thermal sterilization as the example process. 

Dicofol or l,l-bis(p-chlorophenyl)-2,2,2-trichloroethanol is a polychlorinated aromatic alcohol. It has an empirical formula of C14H9C150 and a molecular weight of 370.51. The technical material contains at least 70% of the p,p isomer and about 18% of the o,p isomer. A contaminant has been identified (1) in which the hydroxyl group has been replaced by a chlorine atom. Dicofol is insoluble in water but very soluble in aromatic and aliphatic solvents. It is incompatible with highly alkaline materials. On exposure to UV radiation at 2537 A, it breaks down into the corresponding phenone, and it is also degraded by thermal sterilization. 

Seals, o-rings, and valve membranes must be manufactured out of polymers that are resistant to thermal sterilization and to the bases and acids used in the biopharmaceutical industry. When in contact with the product, the elastomers employed must additionally present the following safety characteristics the rates of release of polymer components must be low and remain below well-established threshold levels the components released must be innocuous to human health, according to rules previously established. 

The kinetics of the hydroxide ion-catalyzed epimerization of pilocarpine to isopilocarpine and of its hydrolysis to pilocarpic acid have been studied (56). Both forms of degradation lead to loss of pharmacological activity. The importance of possible inactivation by epimerization during thermal sterilization of ophthalmic preparations of pilocarpine was pointed out. It was also considered that some epimerization would always occur during the extraction of pilocarpine from Jaborandi leaves, and that isopilocarpine might, therefore, be an artifact and not a genuine plant alkaloid (55). 

The separative process of filtration is widely used within the biopharmaceutical industry to remove contaminants from liquids, air, and gases, such as particulate matter but especially microorganisms. Microorganism removal is either required to achieve a sterile filtrate or, if the pharmaceutical product is thermally sterilized, to reduce the bioburden and, therefore, avoid elevated levels of endotoxins—the debris of gram-negative organisms. ... 

Another possibility, proposed by Rodriguez et considers the concept of accumulated lethality (Fo), used for thermal sterilization, but applied to optimization of EtO sterilization technology. A mathematical model of the inactivation of biological indicators spores by EtO was developed, along with two formulas a response equation for calculating the number of survivors of a sterilization cycle, and a formula for determining the accumulated lethality of exposure to EtO. Experiments verified that the equations are applicable to processes with relative humidity values between 15% and 90%, enabling users to compare the lethality of dissimilar EtO cycles. 

The change in colour of a 20% solution of povidone K 17 (Kollidon 17 PF) in water was from a slight yellow tint (Yellow 7 according to Ph.Eur.) to stronger yellow (Yellow 4) after thermal sterilization at 120-121 °C for 20 min. The addition of 0.2% of sodium bisulfite provided excellent colour stabilization. Ascorbic acid cannot be used as an antioxidant as it undergoes hydrolysis itself, giving rise to an even darker yellow-brown colour. 

Stability of the molecular weight in liquid dosage forms after thermal sterilization and storage... 

First of all, thermal sterilization, which includes the use of steam or dry heat, is the earliest method used. Steam sterilization is up to now the most widely employed sterilization process. It is carried out in a chamber called autoclave. A typical autoclave cycle corresponds to a period of 15 minutes at 121 °C. In the case of dry-heat, the process is undertaken in an oven with heated and filtered air, distributed uniformly. The cycle is of two hours at 160 °C. 

Both methods enable reaching the recommended SAL value of at least 10 . They are considered as the techniques of reference. However, a major limitation is that they are unapplicable to heat-labile substances (and packaging when used as a terminal process). The number of drugs, which cannot withstand high temperatures, is increasing especially with the new generation of treatments based on the use of proteins. Alternatives to thermal sterilization are therefore necessary. 

The major disadvantage of radio-sterilization is the peculiarity of the radiation chemistry induced simultaneously to sterilization, which requires a special study the irradiated drug is thus considered as a "new" drug. While micro organisms are killed, various products of degradation of the main compounds may appear in traces amounts though they are often the same as in thermal sterilization. 

All these recommendations are summarized in the Decision trees for the selection of sterilization methods, edited by the EMEA [23] (Fig. 1).Two cases are considered on one hand, the aqueous products and on the other hand, the non-aqueous liquid, semi-solid and dry powder products. Figure 1 shows the order of preference of the sterilization methods for the second group. The terminal ones are ranked in the first place. Among them, thermal sterilization is still referred as the best choice, radio-sterilization ranking right after. Since gas sterilization is excluded and non-terminal methods are listed as the last choice, radiosterilization now precedes all these methods. It is deemed as the recommended alternative method to thermal sterilization. 

Leadley, C., Tucker, G., and Eryer, P.A. 2008. Comparative study of high pressure sterilization and conventional thermal sterilization Quality effects in green beans. Innovative Food Science and Emerging Technologies 9 70-79. 

Ethylene oxide sterilization is suitable for both small-scale and large-scale applications. It is primarily a method of cold sterilization and has so many associated complications that it is never used in preference to thermal sterilization for heat-stable materials. Sterilization by gamma radiation is more reliable than ethylene oxide for cold sterilization, and it is simpler to control. It is, however, limited by suitability of materials and only operates on a large scale. 

Chamber temperature should be controllable and monitored throughout all cycles. The temperature obtained in a load is a function of the initial product temperature and Its specific heat, the amount of steam injected, and the effectiveness of the insulation or the jacket at preventing heat loss. Temperature during the exposure phase of ethylene oxide sterilization cycles is not controlled by steam injection into the chamber as occurs in thermal sterilization. Loss of temperature may be compensated for by steam Injection into the jacket. The control probe is usually located within the chamber rather than within the jacket, and control of temperature is a good deal less fine than ini steam sterilizers because of the slower response through the jacket. Ethylene oxide sterilizers should be equipped with both jacket and chamber temperature indicators, and with chamber temperature recorders. Sterilizers should be specified with access... 

The emphasis for routine control of irradiation sterilization and thermal sterilization has been toward tight control of the physical parameters that lead to microbial inactivation rather than toward control through biological testing. At one time there would have been an emphasis on biological methods for controlling... 

---