BULK FREEZE DRYING

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.  

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Nearly all pharmaceutical products must be processed under strict aseptic conditions and be protected from outside contamination. In addition, as is the case for an-timinotic drugs used in cancer therapy, some products are toxic, such as cytostatica, and should not be released into the environment. Bulk freeze-drying is best done within a controlled, confined container that in turn does not hinder processing. 

Liquid can be dispensed into plastic or metal trays for bulk freeze-drying. For single-dose applications, freeze-drying in ampoules or vials is more appropriate. 

Development of a New Concept for Bulk Freeze-Drying LYOGUARD Freeze-Dry Packaging... 

Unveils innovations currently advancing the field, including LYOGUARD packaging for bulk freeze-drying and the irradiation of pharmaceutical and biological products. 

In the first example, procaine penicillin, an aqueous vehicle containing the soluble components (such as lecithin, sodium citrate, povidone, and polyoxyethylene sorbitan monooleate) is filtered through a 0.22 pm membrane filter, heat sterilized, and transferred into a presterilized mixing-filling tank. The sterile antibiotic powder, which has previously been produced by freeze-drying, sterile crystallization, or spray-drying, is aseptically added to the sterile solution while mixing. After all tests have been completed on the bulk formulation, it is aseptically filled. 

Several polyols (i.e. molecules displaying multiple hydroxyl groups) have found application as polypeptide stabilizing agents. Polyols include substances such as glycerol, mannitol, sorbitol and PEG, as well as inositol (Table 6.9 and Figure 6.22). A subset of polyols is the carbohydrates, which are listed separately (and thus somewhat artificially) from polyols in Table 6.9. Various polyols have been found to stabilize proteins in solution directly, and carbohydrates in particular are also often added to biopharmaceutical products prior to freeze-drying in order to provide physical bulk to the freeze-dried cake. 

Fig. 4.6. Distribution of grain size as a function of bulk density of freeze dried coffee extract, which has been gassed with different pressures of C02 before freezing.

Another concern with freeze-drying LEH is the instability of liposome structure upon lyophilization. Vesicle formation occurs in the presence of bulk water and when water is removed, loss of structural integrity is inevitable. Fusion, crystal formation, and phase transition are observed, resulting... 

If the crude moist sulfonyl chloride is to be preserved, it must be thoroughly and reasonably rapidly dried. The checker found it very convenient to use a freeze-drying apparatus to remove the bulk of the moisture. 

Trehalose is a relatively new bulk sweetener with potential for use in soft drinks. It is a di-glucose sugar and it occurs in nature in shellfish and mushrooms, where it confers a degree of protection to plant and animal cells in conditions causing dehydration. This led to its use as a cryoprotectant in freeze-drying systems in the pharmaceutical industry. In food markets, its potential use is as a bulk sweetener. It is manufactured using the Hayashibara patented process using starch as a raw material. The process involves enzymatic conversion and crystallisation to the trehalose dehydrate crystal (LFRA, 2001). 

Herman BD, Sinclair BD, Milton N, Nail SL. The effect of bulking agent on the solid-state stability of freeze-dried methylprednisolone sodium succinate. Pharm Res 1994 11 1467-1473. 

Fakes et al. [1.152] evaluated the moisture sorption behavior of mannitol, anhydrous lactose, sucrose, D-(+)-trehalose, dextran 40 and povidine (PVP K24) as bulking agents. Mannitol was found to be crystalline and non-hygroscopic before and after freeze-drying with RM 0.1-0.3% w/w at 25 °C and 10-60% RH. Anhydrous lactose, sucrose and trehalose were crystalline and relatively non-hygroscopic with RM 0.86, 0.15 and 9.2% respectively. After freeze-drying they where amorphous with RM 1.6, 2.5 and 1.2%, respectively, and adsorbed moisture in an increasing RH atmosphere. Lactose adsorbed 10% water and formed its crystalline hydrate at 55% RH. 

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