Sterilization three phases

The sterilization process consists of three phases, as shown in Fig. 2.46 ... 

Validation is described as proof that the system performs as stated. As an engineering control, the LAF system must demonstrably support the intended aseptic or controlled process. Validation of the aseptic manufacturing process and the LAF systems that support terminal sterilization in pharmaceutical manufacturing applications should be carried out in accordance with industry standards. Such validation should be accomplished in three phases, consisting of installation qualification (IQ), operational qualification (OQ), and process qualification (PQ), with full and detailed documentation of all activities and... 

ISO 11607 addr ses the package system validation in three phases, or clauses. Clause 4 specifies the basic attributes required for a wide range of materials as they combine and interact with various medical devices, packaging designs, sterilization methods, and distribution modes. Clause 5 defiites the framework of activities to qualify the processes used to make and assemble the final package... 

Rebif is produced via recombinant DNA technology in a CHO cell line. It displays an identical amino acid sequence to that of native human IFN-P-la and, like the native product, is glycosylated. After cell culture the interferon is purified using a series of chromatographic steps (affinity, ion-exchange, gel-filtration and reverse-phase liquid chromatography). It is formulated as a sterile solution in pre-filled syringes and contains mannitol, HSA, sodium acetate, acetic acid and sodium hydroxide as excipients. It is administered subcutaneously three times weekly. 

Figure 9.1 Inverse partial melting problem in the three-dimensional space of elements 1, 2, 3 when the source is known. Projection of the source onto the sample subspace provides the mass-fraction of each phase of the molten source. If one phase is at the origin (sterile phase), every representative point can be shifted by a constant vector.

Incorporated in printing inks, phase-stabilized a-Copper Phthalocyanine Blue, like nonstabilized types, is too reddish to be employed as a process color for three and four color printing. It is used, however, to a considerable extent in all types of printing inks for special and packaging purposes. The prints are stable to common organic solvents and exhibit perfect fastness properties in special application (Sec. 1.6.2.3). Metal deco prints withstand up to 200°C for 10 minutes or 170 to 180°C for 30 minutes. They may safely be sterilized. 

The hydrolysis half-life in three different natural waters was approximately 48 d at 25 °C (Macalady and Wolfe, 1985). At 25 °C, the hydrolysis half-lives were 120 d at pH 6.1 and 53 d at pH 7.4. At pH 7.4 and 37.5 °C, the hydrolysis half-life was 13 d (Freed et al, 1979). At 25 °C and a pH range of 1-7, the hydrolysis half-life was about 78 d (Macalady and Wolfe, 1983). However, the alkaline hydrolysis rate of chlorpyrifos in the sediment-sorbed phase were found to be considerably slower (Macalady and Wolfe, 1985). In the pH range of 9-13, 3,5,6-trichloro-2-pyridinol and 0,0-diethyl phosphorothioic acid formed as major hydrolysis products (Macalady and Wolfe, 1983). The hydrolysis half-lives of chlorpyrifos in a sterile 1% ethanoFwater solution at 25 °C and pH values of 4.5, 5.0, 6.0, 7.0, and 8.0 were 11, 11, 7.0, 4.2, and 2.7 wk, respectively (Chapman and Cole, 1982). 

Fermentation processes, except for sterilization, have in common many of the familiar chemical engineering unit operations. For example, aerobic fermentations involve the mixing of three heterogeneous phases microorganisms, medium, and air. Other unit operations include mass transfer of oxygen from the air to the organisms and heat transfer from the fermentation medium. 

The final phase is formulation, wherein a diluent is chosen for the protein, incorporating the best mix of fluids, buffers, stabilizers, and minerals to achieve optimal protein stability, maximal shelf life, and patient acceptability. Sterile water, normal saline, and dextrose 5% in water are three common diluents. Variables to deal with include protein traits and patient-disease factors. Formulation of proteins is confounded by the general delicate nature of proteins and the many degrading processes that can occur with them (Table 2). 

The performance qualification (PQ) phase of validation follows the development of the sterilization specifications and of the sterilizer parameters which will deliver them. The purpose of PQ in steam sterilization of pharmaceutical products, equipment, laboratory media, and SIP systems is to confirm that the sterilization specification consistently achieves its intended purpose. The process is run using the parameters derived from process development on (usually) three separate occasions and tested for compliance with a variety of predetermined acceptance criteria. As a subset of PQ, the purpose of bio-validation is to confirm that the lethality expected from the process does not significantly deviate from what is expected. Biovalidation is a test of consistency. If the acceptance criteria are not achieved, there may be need for more process development. 

SLN might be produced aseptically with or without a final sterilization step [40,41], If no sterilization follows the aseptic production, the addition of a preservative is required because the aqueous continuous phase is susceptible to microbial contamination. For biological stabilization of SLN, thiomersal has been used so far [4]. To determine whether the addition of thiomersal to SLN induces cytotoxicity, three different SLN formulations were stabilized with 0.002% (w/w) thiomersal and tested in different concentrations for their tolerability on murine peritoneal macrophages. The same formulations without thiomersal were taken as control. In comparison to the SLN without thiomersal, no increase in cytotoxicity could be detected. 

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