Journal of parenteral science and technology : a publication of the Parenteral Drug Association最新文献

Recovery of Neosartorya fischeri ascospores subjected to a dry heat treatment (DHT) at 95 degrees C, 50% relative humidity (RH) for 60 minutes increased exponentially as the initial temperature of the recovery buffer increased. Different diluents were evaluated and the same recovery pattern was obtained when water or dilute buffers were used to recover the DHT spores. However, when glycerol was added to the buffer, the number of spores recovered in solutions held in ice water increased with increasing glycerol concentration. When the DHT spores were exposed to an atmosphere saturated with water vapor (100% RH) before being placed in the buffer, the recovery was independent of the initial temperature of the buffer. This occurred even if the spores were subsequently dried before being introduced into the buffer. It is hypothesized that the temperature-dependent recovery was due to injury of the DHT spores during the sudden rehydration in dilute solutions at low temperatures.

During total parenteral nutrition, the intravenous infusion of large volumes over a prolonged period of time appears to involve risks of particle contamination for the patients. The aim of this work is to number, measure, and characterize inert particles in a standard ternary mixture prepared by sterile transfer technique. The distribution of particles is studied in each component of the admixture and in the final preparation using two different methods: the Coulter counter and an optical microscopic numbering after filtration. The nature and the origin of particles are determined by the use of scanning electron microscopy (SEM) coupled with a photon X spectrometer.

The use of different combinations of sterilization time and temperature in a pilot scale autoclave, GEV 612 AR-2 (Getinge Ab, Sweden), in optimizing the sterilization process was studied. All three programs used had the same sterilization efficacy (F0 = 15 minutes) but different sterilization temperatures (116, 121, and 126 degrees C) and total process times (98, 57, and 44 minutes). The heat distribution during the sterilization phase was, in all cases, very uniform, the greatest difference being 0.5 degrees C. Also the F0 values differed only by +/- 0.5 minutes from each other. The F0 value increases linearly with all programs until the beginning of the cooling phase. The main effect of different sterilization temperatures on the cumulative F0 curves is an increase in the slope of the curves with increasing sterilization temperature. First order temperature change constants were determined both for the heating phase and the cooling phase. The numeric values of the rate constants for the heating and the cooling phases were 0.20 +/- 0.03 and 0.046 +/- 0.005 min-1, respectively. It is concluded that the pilot autoclave used in this study controls the sterilization process very accurately. The observed variations between F0 values at different positions in the autoclave chamber are acceptable. On the basis of this study an accurately engineered and controlled autoclave is required in process optimization. It also is possible to use higher sterilization temperatures than usually suggested in pharmacopeias and thus to shorten the process time.

It is widely recognized that the level of particulate matter in an injectable product is one measure of quality, directly reflecting the success with which the manufacturer applies good quality control. The current USP XXII 1990 limits for particulate matter derived from knowledge that goes back to the 1970s but does not reflect the quality of the product available today. This presentation will discuss the purpose and background of proposed new limits intended to be adopted in the USP 23 revision cycle. The limits tests are structured in two stages for both Large-Volume and Small-Volume Injections, effectively employing an improved light obscuration method as a screening procedure. Product which fails this stage is then evaluated by a second stage, filtration and microscopic examination using a considerably improved procedure in which all of the container contents are sampled (or pooled to 25 mL) and the filter examined episcopically.

Quality of the final product largely depends on the freeze-drying process. In turn this largely depends on an adequate control of the amount of residual moisture after freeze-drying. Measuring this amount in the chamber of the freeze-dryer to determine the end point of sublimation and the end point of secondary drying provides a reliable control with regard to the methods traditionally used (for example rapid increase in product temperature). The purpose of this study is to evaluate the benefits and disadvantages of the different methods recommended for the monitoring of a freeze-drying cycle. Two systems for the measurement of the moisture in the freeze dryer are evaluated here: the Pirani vacuum gauge, and the moisture sensor. The moisture sensor appears to be the most sensitive and reliable way of determining both the end of sublimation and the end of secondary drying of the full load batch when placed on a freeze-dryer. The immediate benefit for the industry is to allow to scale-up without the risks of under or over estimating the freeze-drying cycle.

The effect of varying the pH and ionic strength on endotoxin removal (depyrogenation) from Water for Injections (WFI) was investigated. Studies using submicron filters showed that endotoxin aggregation and filter retention increased with increasing molarity and decreasing pH. Using a Sartorius 0.01 micron filter, greater than 98% endotoxin retention could be achieved with 10 endotoxin units (EU)/ml bulk solution, and greater than 97% endotoxin retention with the 500 EU/ml bulk solution. Depyrogenation of active and placebo solutions of the radiopaque, Iohexol (350 mgI/ml), using ultrafilters of varying nominal molecular weight limit (NMWL 10,000-300,000) and a Pall Posidyne 0.2 micron filter was also investigated. Results with the ultrafilters showed that it was possible to increase the molecular weight cut-off of an ultrafilter from 10,000 to 100,000, without affecting the efficiency of endotoxin removal, thereby increasing flow rate and reducing filtration time. The Posidyne filter was able to depyrogenate Iohexol active and placebo product. The use of submicron filtration in place of ultrafiltration would provide significant cost benefits in terms of filtration time and equipment costs, and they have been shown to be capable of efficient depyrogenation of these pharmaceutical products.

The kinetics of destruction by dry heat of two typical endotoxins, Escherichia coli 055:B5 (E. coli endotoxin) and Salmonella abortus equi (S. abortus equi endotoxin), were determined using the Limulus Amebocyte Lysate (LAL) and pyrogen assays. The efficiency of recovery of these endotoxins from carriers using a pyrogen assay was also determined simultaneously. In the LAL assay 0.1-10,000 EU was used and 10-1000 EU in the pyrogen assay. Recoveries of E. coli endotoxin and S. abortus equi endotoxin were, respectively, 49.7-92.0% and 27.0-70.1% by the LAL assay, and 31.1% and 60.6% by the pyrogen assay. Fourier transformation infrared (FT-IR) spectra demonstrated the presence of chemical structural differences between the two endotoxins. By dry heat (200 or 250 degrees C), there were no significant differences in the destruction kinetics between the two endotoxins; either endotoxin can therefore be adapted for use in the endotoxin challenge test. Destruction in the pyrogen assay was significantly quicker than that predicted by the LAL assay for each of the two endotoxins. In this endotoxin destruction system, 3 log cycle reduction (the United State Pharmacopeia (USP) recommendation for the depyrogenation process) could not be obtained by challenge with 10,000 EU of endotoxin under the depyrogenation conditions of 200 degrees C for 60 min (a set of conditions described in the European Pharmacopoeia (EP)), though little pyrogenicity remained. On the other hand, at 250 degrees C for 30 min (a set of conditions described in the EP, USP and Pharmacopoeia of Japan (JP)),a 3 log cycle reduction was achieved without any pyrogenicity remaining.

An ultrafiltration system is used to obtain an endotoxin-free buffer for the LAL test. The procedure is combined with a kinetic LAL reaction of high sensitivity. This approach allows for the easy determination of endotoxin levels in parenterals with LAL-interfering substances, reducing the maximum valid dilution necessary for use in product development.