Lyophilised products

As indicated above, the properties of certain plastics may be temporarily modified by the combination effects of moisture and temperature during the autoclaving cycle. In general, the physical properties of rubber formulations are not affected by the moist heat sterilisation other than the fact that closure systems may absorb moisture (depending on the rubber formulation/ materials employed) during the autoclave cycle. This can be an issue for lyophilised products or aseptically filled dry powders where long drying cycles for the rubber closures are sometimes employed to prevent desorption of moisture from the closure into the product. 

A haze was found to form on reconstitution of the stored lyophilised product. The haze was identified as containing paraffin, silicone oil and zinc. Despite screening of fifty different rubber formulations, the only viable solution at that time was to use the West Company s Teflon coated injection stopper. With the development of so-called Tow extract rubber formulations, MSD has been able to approve non-Teflon faced closures for this application. These Tow extract rubber formulations are normally vulcanised using unconventional cross-linking systems and so avoid the problems of sulphur and organic accelerators. 

Steam sterilisation (autoclave) Ethylene oxide (ETO) sterilisation Gamma irradiation Preferred method, established effectiveness No closure moisture level increase No closure moisture level increase Increased closure moisture level giving potential problems in lyophilised products Ethylene oxide sorbs into closures Not suitable for all rubber formulations... 

Blister trays are particularly useful where several items are involved in the medication, i.e. lyophilised product plus water for injection. 

LOEL lowest-observed-effect level LOQ limit of quantification lyophilisate product of freeze drying lysosome cell organelle containing hydrolases (hydrolytic enzymes) it is active in phagocytosis, i.e. in intracellular digestion and destruction accompanied by release of the cell contents... 

Pikal, M. (., 1999b. Impact of polymorphism on the quality of lyophilised products, in Polymorphism in Pharmaceutical solids (ed. H. G. Brittazin). Marcel Dekker,... 

Initially fermentation broth has to be characterised on the viscosity of the fluid. If the presence of the biomass or cells causes trouble, they have to be removed. Tire product is stored inside the cells, the cells must be ruptured and the product must be freed. Intracellular protein can easily be precipitated, settled or filtered. In fact the product in diluted broth may not be economical enough for efficient recovery. Enrichment of the product from the bioreactor effluents for increasing product concentration may reduce the cost of product recovery. There are several economical methods for pure product recovery, such as crystallisation of the product from the concentrated broth or liquid phase. Even small amounts of cellular proteins can be lyophilised or dried from crude solution of biological products such as hormone or enzymes.2,3... 

Willemer, H. Influence of product temperature and gas composition on the lyophilisation process. International Congress, p. 63-77, Basel 1994, Copyright 1994 PDA, Inc., Bethesda, Maryland, USA... 

Figure 2.89 illustrates a commercially available Quickfit lyophiliser (Bibby Science Products) accommodating a single flask of such a size that the volume of aqueous solution to be treated is one-quarter its total capacity. The charged flask is rotated in a dry ice-acetone bath so that an even layer of frozen solution is obtained over the inside. The flask is immediately attached to the refrigerant chambers which are filled with a Cardice-acetone mixture. An oil vacuum pump is connected to the refrigerant chamber via the supplementary trap, which if possible should be immersed in a Dewar flask filled with liquid nitrogen such a cooled trap provides maximum protection for the vacuum pump. Vacuum is... 

A fundamental requirement for LC-MS/MS calibration materials is that matrix effects exerted by these materials are most similar to the matrix effects exerted by actual patients sample materials. Lyophilisation, virus inactivation and other procedures applied during the industrial production of calibration and control materials, may notably impact the ionization behaviour of extracts from such samples and can result in differential matrix effects in calibrators and actual patients samples. If the internal standard peak areas found for calibration samples systematically differ from those found in patients samples, inappropriateness of the calibration materials should be suspected. However, we have previously observed that calibration materials from different commercial sources lead to inaccurate tacrolimus results in an instrument specific manner, without showing deviations in the internal standard peak area. This effect was most likely related to ionization enhancement affecting the target analyte but not the homologue internal standard (ascomycin) ionization and being restricted to calibrator samples. This resulted in systematically low tacrolimus results of clinical samples in one instrument for one specific calibrator lot [52],... 

The product from Step 3 (0.75 mmol) was dissolved in 7.5 ml THE and 7.5 ml water to which was added lithium hydroxide monohydrate (0.83 mmol) and the mixture stirred overnight at ambient temperature. The organic solvent was removed, the aqueous phase acidified with 1 M HCl, and the product extracted twice with 50 ml CH2CI2. The organic phase was dried and evaporated under reduced pressure. The Z-isomer was isolated by lyophilisation from a mixture of methyl alcohol and water in 95% yield. H-NMR data supplied. 

The product from Step 6 (1.05 mmol) was dissolved in 5 ml ethyl alcohol, 1.00 ml 1 M sodium hydroxide solution added, and the mixture stirred 3 hours at ambient temperature. The clear solution was filtered, diluted with 6 ml water, then extracted twice with 7 ml t-butyl methyl ether. Approximately 2 ml water was distilled off and the remaining solution lyophilised yielding a slightly beige powder. NMR confirmed that the product of this Step was equivalent to the that of the commercial product, Huvastatin (5). 

A year later the same research group presented a second rather different approach [160] in which they described the production of abiotic receptors by imprinting of proteins. The basic idea was once again to induce a certain conformation into the tertiary structure of a protein using a template and then to freeze it in . Bovine serum albumin (BSA) was dissolved in water, containing either p-hydroxybenzoic acid or tartaric acid. After lyophilisation the protein was washed with anhydrous solvent to remove the template. The resultant imprinted proteins bound up to 30-fold more of the template in anhydrous... 

K. Nakahira Validation of deep vacuum vapor phase hydrogen peroxide sterilizer retrofit to a production lyophilizer. PDA Asian Symposium, Tokyo, 1994, pp. 16-616. M. Steiner, VHP—Sterilization of freeze-dryers. ISPE Seminar Lyophilisation (Antwerpen, Nov. 1994), International Society of Pharmaceutical Engineering (ISPE). 

Corveleyn, S. Remon, J.P. Formulation and production of rapidly disintegrating tablets by lyophilisation using hydrochlorothiazide as a model drug. Int. J. Pharm. 1997, 152, 215-225. 

One interesting feature of stability is that a product may have two shelf lives, one for the manufactured material and another for the reconstituted or opened pack. Methyl prednisolone sodium succinate lyophilised injection, for example, is stable for up to three years in the dry state but the reconstituted injection must be used within 12 hours. 

The present state of the art of Cr speciation leaves much to be desired and compels to improve quality assessment. In order to meet the requirements of the directives, the reliability of the methods needs to be improved substantially. Appropriate reference materials certified for Cr(III) and Cr(VI), which are at present non existing, would provide both an effective and economical way for the laboratories to check and improve their performance which justified the production of a lyophilised solution for the certification of Cr-species [36,37]. 

For biopharmaceuticals, storage conditions are critical to maintain activity. Normal ICH stability studies are conducted with reference to global climatic zones under standard and accelerated conditions over time periods of up to 5 years. For biopharmaceuticals, this may not be appropriate, and specific coohng conditions (2-8°C, <-20°C) may have to be provided to keep the product intact (see Section 1.4.6). Furthermore, the container and the closure system used for final market presentation (e.g., vial with mbber) must be investigated for interaction potential. Last -but not least - the stability of the reconstituted solution in the case of lyophilisate, or diluted solutions in the case of infusion therapy, must be characterized. 

The range of rubber materials includes natural and synthetic-based materials. Special designs of rubber (e.g. castellated) are available for lyophilised/freeze dried products. Surfaces may be coated, e.g. with PTFE or Parylene, to reduce any extractability risks. 

The following is a suggested programme for the evaluation of a plastic container for a liquid multidose injection product (not lyophilised). 

COC (cyclic olefin copolymer which includes Resin CZ from Daikyo Seiko and Topas from Ticona Mitsui) use for the former has already been found for vials for expensive lyophilised biotechnology products... 

After dissolving the lyophilisate in the added volume, incubation is an essential step to obtain the radiolabeled medicinal product. In this phase, the chemical reactions take place, resulting in Tc labeling. If incubation is inadequate, the labeling reaction may not be completed, and the radiopharmaceutical may not be suitable for administration. 

Where the quality of the product may be affected, air or any other gas admitted to an autoclave, hot air steriliser or lyophiliser or used to promote positive pressure for filtration should be filtered through a bacteria-retaining filter. 

Where a batch of product is sterilised as a series of lots, each of which is subjected to a separate sterilising cycle or is subjected in processing to different treatment which may affect its sterility, e.g. different lyophilisation cycles, then each lot should be tested for sterility. 

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