Isolators sterile products

Downstream processing involves employment of a purifying system that can isolate the product in as few steps as possible using the simplest purification technology that will achieve the required purity. While purity is a critical consideration for both small-molecule pharmaceuticals and biopharmaceuticals, the nature of biopharmaceutical administration (typically via injection) and the nature of biotechnology processes require that additional considerations be paid to the purity of biopharmaceuticals. The final product must meet regulatory purity and sterility standards and must be below the maximally acceptable cellular or microbial contamination (Ho and Gibaldi, 2003). 

Sweeney, M. Davenport, S. Edwards, L. Validation Issues for a Product Barrier/Isolator Sterile Liquid Filling System in a Controlled Environment, Proceedings of PDA/ISPE Conference on Advanced Barrier Technology, 1995. 

The principal industry drivers generating the interest in isolators in the last few years have been focused on improvements in process integrity. This includes operator protection from potent and hazardous materials and, in the case of sterile products manufacturing, to reduce the potential of contaminated non-sterile imits from being produced by a specific process. There are some circumstances in which reductions in occupied space and operational cost savings have been essential objectives. 

At present, the pharmaceutical industry regulatory requirements refer to isolators specifically in the context of the manufacture of sterile products. There is no reference to their role in broader areas of crosscontamination and operator safety control. Within Europe, the current EU GMP clearly states that isolators might produce improvements in sterility assurance of sterile products, and that aseptic processing manufacturing isolators should be placed in at least a Grade D surrounding environment. The Food and Drug Administration (FDA) requirements are less well defined, but it is likely that in equivalent circumstances, they would like to see an isolator located in a class 100,000 or M6.5 environment In Operation. ... 

Fig. 3 shows a pilot plant layout with restricted personnel access. This design would support the development and clinical manufacture of solid dosage forms, liquids, semisolids, aerosols, and sterile products. Multipurpose rooms are incorporated in each area to maximize the use of portable equipment, and scale factors similar to those shown in Table 1 are employed. Isolation suites are indicated in the manufacturing area their purpose and design are discussed in more detail later. The sterile area is isolated from the main corridor by the interior corridor design. At the far left, the main corridor provides access for future facility expansion, if necessary. 

A suitably sized solution preparation system similar to that mentioned under the previous sections can be used to provide material for bulk freeze drying. (Since product solutions can be sterile-filtered directly into the final container, microbial and particulate exposure will be minimized.) The sterile solution is subdivided into trays and placed into a sterilized freeze dryer. Aseptic transfer of sterile product in trays to the freeze dryer must be validated. After tray drying, the sterile product is aseptically transferred through a mill into suitably designed sterile containers. The preparation of sterile bulk material is usually reserved for those cases where the product cannot be isolated by more common and relatively less expensive crystallization methods. Due to recent advances in this field, a freeze drying process should be considered as a viable option. ... 

Once the radioactive fission products are isolated by one of the separation processes, the major problem in the nuclear chemical industry must be faced since radioactivity cannot be immediately destroyed (see Fig. 10-7c for curie level of fission-product isotopes versus elapsed time after removal from the neutron source). This source of radiation energy can be employed in the food-processing industries for sterilization and in the chemical industries for such processes as hydrogenation, chlorination, isomerization, and polymerization. Design of radiation facilities to economically employ spent reactor fuel elements, composite or individually isolated fission products such as cesium 137, is one of the problems facing the design engineer in the nuclear field. 

Clothing the operator completely in an impervious plastic suit represents the ultimate in personal protection and has the additional merit of isolating the product completely from operator and such suits have been used to maintain sterility during pharmaceutical manufacture. Isolator suits should not be used as the primary means of protecting the operator but must be used only in combination with effective techniques for safely dispensing, handling and freeze-drying hazardous products. 

An isolator is according to the description of EN-12469 a Class 111 safety cabinet, as said a complete physical barrier, see Fig. 28. Ig. The air inside the isolator is HEPA filtered, so inside the isolator a GMP Class A air quality is maintained. The gloves or full or half suits are the physical barrier between the sterile product inside the isolator and the operator standing outside and the integrity of this barrier requires very much attention. 

Sterile aqueous D-sorbitol solutions are fermented with y cetobacter subo >gichns in the presence of large amounts of air to complete the microbiological oxidation. The L-sorbose is isolated by crystallisation, filtration, and drying. Various methods for the fermentation of D-sorbitol have been reviewed (60). A.cetobacter suboyydans is the organism of choice as it gives L-sorbose in >90% yield (61). Large-scale fermentations can be carried out in either batch or continuous modes. In either case, stefihty is important to prevent contamination, with subsequent loss of product. 

Briefly stated, the production of chloramphenicol by the surface culture method involves inoculating a shallow layer, usually less than about 2 cm, of a sterile, aqueous nutrient medium with Streptomyces ver)ezuelae and incubating the mixture under aerobic conditions at a temperature between about 20° and 40°C, preferably at room temperature (about 25°C), for a period of about 10 to 15 days. The mycelium is then removed from the liquid and the culture liquid is then treated by methods described for Isolating therefrom tne desired chloramphenicol. 

The mold isolated by Alexander Fleming in early 1940s was Penicillium notatum, who noted that this species killed his culture of Staphylococcus aureus. The production of penicillin is now done by a better penicillin-producing mould species, Penicillium chryso-genum. Development of submerged culture techniques enhanced the cultivation of the mould in large-scale operation by using a sterile air supply. 

Ideally, when considering the level of treatment necessary to achieve sterility a knowledge of the type and total number of miciooiganisms present in a product, together with their likely response to the proposed treatment, is necessary. Without this information, however, it is usually assumed that organisms within the load are no more resistant than the reference spores or than specific resistant product isolates. In the latter case, it must be remembered that resistance may be altered or lost entirely by laboratory subculture and the resistance characteristics of the maintained strain must be regularly checked. 

Hydrolysis of parathion in a loessial semiarid soil was investigated by Nelson et al. (1982). They found that Arthrohacter sp. hydrolyzed parathion rapidly in sterilized, parathion-treated soil under aerobic conditions (20% w/w water content). This bacterium was isolated from a silty loam, sierozem soil of loessial semiarid origin (Gilat). It uses parathion or its hydrolysis product, p-nitrophenol, as the sole carbon source. However, when parathion hydrolysis causes the amount of p-nitrophenol to reach a concentration greater than 1 mM or if the concentration is greater than 1 mM in the case of a single application of p-nitrophenol, the hydrolysis product becomes noxious to the bacteria and their growth is inhibited. 

In Fig. 8 the vertical bars in the scheme on top of the diagram symbolize the respective isolated starting peak of the chromatogram below. The products of heat sterilizations are found on the horizontal lines below the chromatogram. The length of the bars indicates the relative peak areas obtained after sterilization. 

Nj = the load of microorganisms on the product to be sterilized Dg = D value of the most resistant isolate Nq = number of organisms on the biological indicator Dy = D value of biological indicator. 

FDA Guidance The critical operations that expose product or product contact surfaces to the environment (such as transfer of sterilized containers or closures to the aseptic filling areas) should be described. Any barrier or isolation systems should be described. 

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