Freeze drying facility

De Luca, P. P. and Trappier, Ed. Design and operational requirements of freeze-drying facilities for pharmaceuticals. The American type culture election and the Merieux Foundation. A compact freeze-drying course on the fundamental aspects on the preservation of sensitive biologicals. Washington DC. April 2-4, 1990... 

Urea-formaldehyde resins are generally prepared by condensation in aqueous basic medium. Depending on the intended application, a 50-100% excess of formaldehyde is used. All bases are suitable as catalysts provided they are partially soluble in water. The most commonly used catalysts are the alkali hydroxides. The pH value of the alkaline solution should not exceed 8-9, on account of the possible Cannizzaro reaction of formaldehyde. Since the alkalinity of the solution drops in the course of the reaction, it is necessary either to use a buffer solution or to keep the pH constant by repeated additions of aqueous alkali hydroxide. Under these conditions the reaction time is about 10-20 min at 50-60 C. The course of the condensation can be monitored by titration of the unused formaldehyde with sodium hydrogen sulfite or hydroxylamine hydrochloride. These determinations must, however, be carried out quickly and at as low temperature as possible (10-15 °C), otherwise elimination of formaldehyde from the hydroxymethyl compounds already formed can falsify the analysis. The isolation of the soluble condensation products is not possible without special precautions, on account of the facile back-reaction it can be done by pumping off the water in vacuum below 60 °C imder weakly alkaline conditions, or better by careful freeze-drying. However, the further condensation to crosslinked products is nearly always performed with the original aqueous solution. 

Figure 3.29. Photographic representation of a blow-fill-seal machine, which can be particularly useful in the aseptic filling of liquid products (refer to text for details). While used fairly extensively in facilities manufacturing some traditional parenteral products, this system has not yet found application in biopharmaceutical manufacture. This is due mainly to the fact that many biopharmaceutical preparations are sold not in liquid, but in freeze-dried format. Also, some proteins display a tendancy to adsorb onto plastic surfaces. Photo courtesy of Rommelag a.g., Switzerland...

Because products rich in desirable NPs command a high price, it becomes economic to build storage facilities that reduce NP loss and to invest in improved packaging—look at foil wrapped tea or vacumn wrapped coffee. Freeze drying, controlled atmosphere packaging and optimum harvesting also help deliver the best NP-rich products to the consumer. 

Freeze-drying is another unit operation that has been interrogated with in situ NIR spectroscopy. A group in AstraZeneca R D has demonstrated how the process insight provided by NIR was complementary to and corroborated by the information obtained from temperature monitoring.60 Their work was demonstrated in a pilot-scale facility and involved the construction of special equipment to ensure a representative sample. 

The harvest is a very complex mixture of bacterial cells, metabolic products and exhausted medium. In the case of a live attenuated vaccine it should be innocuous, and all that is necessary is for the bacteria to be separated and resuspended under aseptic conditions in an appropriate diluent, possibly for freeze-drying. In a vaccine made from a virulent strain of pathogen the harvest may be intensely dangerous and great care is necessary in the subsequent processing. Adequate containment will be required and for class 3 pathogens such as Salmonella typhi or Yersinia pestis or bulk production of bacterial toxins, dedicated facilities that will provide complete protection for the operators and the environment are essential. 

Work using STEMl at Brookhaven began with a careful study of the first premise of the facility, namely that single heavy atoms could serve as specific labels for biological specimens. It was determined that these predictions were overly optimistic and that a dose of at least 1000 electrons/A was needed for an adequate signal-to-noise ratio (Wall, 1978), whereas dose-response measurements for mass loss and loss of resolution on freeze-dried specimens set a useful imaging limit at 10-100 electrons/A with the specimen cooled to — 140°C. Furthermore, the heavy atoms were found to move significantly from one scan to the next (Hainfeld and Wall, 1978 Wall et al, 1978). 

Lyophilization (freeze drying) can be used to preserve nonvolatile analytes in liquid samples. The homogenized sample is frozen and the water content is removed over 12-24 h. This is very good for stabilizing some analytes that would be susceptible to enzymic degradation in biological samples and the specimen can then be stored at room temperature without the need for expensive freezer facilities. Analytes that are heat labile can be freeze-dried and then stored as a powder in a freezer. Lyophilization is... 

Biological standards and reference materials are stored at the appropriate temperature in controlled, calibrated, monitored, and alarmed storage facilities. The freeze-dried materials are normally stored at —20°C to maintain stability over the period of the materials availability, which may be a decade or more. Freeze-dried materials should be sufficiently stable to withstand short-term shipping at ambient temperatures without deterioration to their intended use. 

The key factors in determining successful freeze-drying are long-term stability, preservation of sufficient activity, and rapid facile reconstitution. The product residual moisture content and atmospheric composition (in terms of oxygen content) are adjuncts to this. In the WHO guidelines, there are no set limits for minimal moisture level. We have an in-house limit of <1% to reduce the likelihood of water catalyzed hydrolytic and other degradative processes. However, in practice the level of residual moisture is usually well below this for most of our materials. 

Breaking points are the availability of the raw materials and primary containers of reliable suppliers, the feasibility of analysis of the drug substance and the preparation and the availability of equipment. As an example, preparation processes such as tableting, freeze-drying or aseptic production are accessible in a few pharmacies. The preparation of oral solids with controlled release is not possible in pharmacies mainly to lacking equipment (fluidised-bed techniques and instrumental analysis, etc). Working with radiopharmaceuticals also requires very specific facilities, as is the case with preparation of solid dosage forms with hazardous substances. 

Blood Neutron activation analysis was used to determine the level of uranium in samples of blood, urine, and hair of exposed people (woikers in uranium production facilities in Slovenia) and unexposed population (Byrne and Benedik 1991). Blood samples were collected by venipuncture from the arm. The samples were freeze-dried and powdered and well mixed before encapsulation in polythene vials that were heat-sealed. The samples were irradiated with a 4 10 n cm s neutron flux for up to 30 min and rapidly ashed with 50 mg of uranium that served as a carrier. The uranium was then extracted with TBP in toluene and after cleaning the organic phase by acid washing the samples were counted with a HPGe gamma detector for 20 min. The 74.7 keV peak formed by neutron irradiation and the 185.7 keV peak (from the... 

No new laboratory facilities are required for - H NMR spectroscopy beyond those necessary for the conduct of work with tritiated compounds. Tritiated compounds recovered from tracer and other experiments are usually in very dilute solution and then will need to be concentrated by freeze-drying and redissolution in a small volume of NMR solvent containing internal H reference (i.e., tetramethylsilane or sodium 4,4-dimethyl-4-silapentanesulphonate). This solution, having sufficient total... 

Irradiations and Dosimetry. Dilatometers are irradiated in one of several dry cobalt-60 y-ray facilities, which are viewed through periscopes. Temperature control is maintained by using either appropriate freezing mixtures or externally controlled constant temperature baths, from which the fluid is circulated into and out of the bath in the irradiation cell. 

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