Injections freeze-dried products

Bashir, J. A., Avis, K. E. Evaluation of excipients in freeze-dried products for injection. Bull Parenter Drug Assoc. 

Freeze-Dried Products. Freeze drying was first carried out in 1890 by Altman but became well known through the industrial development of the process. The process is used in the food industry, e.g., for the production of instant coffee, tea, and other products. In the field of pharmaceutical technology, it was for a long time restricted to only few formulations for injection containing the active ingredient in the freeze-dried state in an ampoule to be dissolved just before application. With the increasing interest in protein and peptide formulations, freeze-dried products became more important. These are discussed under section Microparticles for Injection. ... 

Lyophilized products are characterized by prolonged shelf-life, and chemical bacteria or enzymatic changes do not easily occur. The sterility is more guaranteed and solubility assured. In addition, transportation is easier. Finally, certain compounds or radiopharmaceutical kits exist only as lyophilized products. However, freeze-dried products suffer from certain disadvantages. The reentry of moisture may destroy the products. Direct optical control of lyophilized products cannot be performed. Therefore, the risk of particle contamination of the final product is high. Bacterial contamination can only be avoided by using the proper installations (clean rooms) for manufacturing injectable lyophilized products. 

Spray-freeze-dried products can be delivered to the human body by various routes of administration. Pulmonary, nasal and ophthalmic delivery, needle-free injection and sustained release injectables have been described in literature for SFD products [2]. For each route of delivery, different particle characteristics are essential. 

Dry powders for reconstitution as an injectable product may be produced by several methods filling the product into vials as a liquid and freeze-drying, aseptic crystallization followed by powder filling, and spray-drying followed by powder filling. A brief discussion of each follows. 

Neumega is the tradename given to the IL-ll-based product approved for the prevention of thrombocytopenia. The product is produced in engineered E. coli cells and is presented as a purified product in freeze-dried format. Excipients include phosphate buffer salts and glycine. It is reconstituted (with water for injections) to a concentration of 5 mg ml-1 before s.c. administration. 

Enbrel is a product now approved for medical use that is based upon this strategy. The product is an engineered hybrid protein consisting of the extracellular domain of the TNF p75 receptor fused directly to the Fc (constant) region of human IgG (see Box 13.2 for a discussion of antibody structure) The product is expressed in a CHO cell line from which it is excreted as a dimeric soluble protein of approximately 150 kDa. After purification and excipient addition (mannitol, sucrose and trometamol), the product is freeze-dried. It is indicated for the treatment of rheumatoid arthritis and is usually administered as a twice-weekly s.c. injection of 25 mg product reconstituted in WFI. Enbrel functions as a competitive inhibitor of TNF, a major pro-inflammatory cytokine. Binding of TNF to Enbrel prevents it from binding to its true cell surface receptors. The antibody Fc component of the hybrid protein confers an extended serum half-life on the product, increasing it by fivefold relative to the soluble TNF receptor portion alone. 

J.A. Jones, I.R. Last, B.R MacDonald and K.A. Prebble, Development and transferability of near-infrared methods for determination of moisture in a freeze-dried injection product, J. Pharm. Biomed. Anal. 11, 1227-1231 (1993). 

Two of the more recent such approvals are that of Ovitrelle and Luveris. Ovitrelle is the trade name given by Serono to its recombinant hCG-based product. The producer is an engineered CHO cell line that has been co-transfected with the genes coding for both the hCG a- and P-subunits. Downstream processing entails a combination of several chromatographic and ultrafiltration steps and the final product is presented in freeze-dried form. Each vial of product contains 285 fig of active substance (hCG) and the product has been assigned a 2 year shelf-life. It is reconstituted with water for injections (WFI) immediately before use. 

Last and Prebble [51 ] developed a near-infrared reflectance (NIR) method for the determination of moisture in an experimental freeze-dried injection product. NIR spectra were collected through the bases of unopened product vials using a horizontal instrument accessory. The samples in these vials were then used for Karl Fischer analysis to generate a standard curve for the analysis. The NIR data must be correlated with an accepted residual moisture technique in order to yield a meaningful result. This article states that NIR accuracy and precision in this application are not consistent with allowing the use of the current method in anything but a screening role. 

Figure 1 Typical freeze-drying program for injectable drug product.

Figure 23 Manufacturing process flow of FMOX injectable product after freeze-drying.

Most freeze-dried pharmaceuticals—and, of course, all injectable products—need to be sterile. Until now, the usual rule to achieve that goal has been to start with a sterile solution and, from there on, to carry out an entirely sterile process. Indeed, the time is over when the manufacturers could add a 1/10,000 merthiolate to get rid of an accidental contamination. Today all freeze-dryers have their cabinets opening within a sterile room while the machinery is sitting behind the wall in the engine room. Moreover, the drying chambers are all equipped with clean-in-place (CIP) systems and can be sterilized by pressure steam before each operation. Finally, those products that are prepared in vials are sealed directly within the chamber thanks to moving pressure plates that drive the stoppers tight into the neck of the vials. 

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