[Specific aspects for virus safety of raw materials for cellular-based medicinal products]. / Spezifische Aspekte zur Virussicherheit von Produktionshilfsstoffen für somatische Zelltherapie-Arzneimittel.

Virus safety of cell-based medicinal products is a particular challenge. These products are frequently manufactured using various human- or animal-derived starting and raw materials (serum and feeder-cells) in cell culture, which are possible sources for viral contamination. For living or proliferating cells, no methods for virus inactivation (such as heat or chemical treatment) can be used and the options for testing these medicinal products for all possible viral contaminations are very limited. As a consequence, other safety measures, in particular careful selection and testing of starting and raw materials, are very important. For raw materials, attention should be paid to cell-culture additives of biological origin, such as human and bovine serum and porcine trypsin. Whenever possible, manufacturing steps for inactivation and removal of viruses should be introduced as an additional safety measure. In addition, recombinant products from animal cell cultures (such as growth factors, monoclonal antibodies for cell sorting, viral vectors) are used and have to be tested for virus safety.

Addressing parents' concerns: do vaccines contain harmful preservatives, adjuvants, additives, or residuals?

Vaccines often contain preservatives, adjuvants, additives, or manufacturing residuals in addition to pathogen-specific immunogens. Some parents, alerted by stories in the news media or information contained on the World Wide Web, are concerned that some of the substances contained in vaccines might harm their children. We reviewed data on thimerosal, aluminum, gelatin, human serum albumin, formaldehyde, antibiotics, egg proteins, and yeast proteins. Both gelatin and egg proteins are contained in vaccines in quantities sufficient to induce rare instances of severe, immediate-type hypersensitivity reactions. However, quantities of mercury, aluminum, formaldehyde, human serum albumin, antibiotics, and yeast proteins in vaccines have not been found to be harmful in humans or experimental animals.

Comparison of the formulation requirements of dosator and dosing disc automatic capsule filling machines.

The overall objective of this study was to provide 'semi-quantitative' or 'rigorous' definitions of the fluidity, lubricity and compactibility requirements of formulation for representative dosator and dosing disc capsule filling machines. To that end, model formulations were developed for those properties using Carr's compressibility index, ejection force, and plug breaking force at a specified compression force to gauge fluidity, lubricity, and compactibility, respectively. These formulations were each encapsulated on an Hofliger-Karg GKF-400 dosing disc machine and a Zanasi LZ-64 dosator machine. Each machine was instrumented to measure plug compression and ejection forces. The encapsulation process was evaluated for %CV of fill-weight, ejection force, plug breaking force and the dissolution of marker drugs incorporated in the formulations. The f2 metric was used to compare dissolution profiles. The results suggest: (1) formulations should meet different flow criteria for successful encapsulation on the two machines, (2) a relatively lower level of lubricant may be sufficient for the dosing disc machine, (3) a higher degree of formulation compactibility is needed for the dosator machine, and (4) transferring formulations between these machine types (same class, different subclass per FDA's SUPAC-IR/MR Manufacturing Equipment Addendum) could be challenging. In certain cases dissolution profiles for the same formulation filled on the two machines with equivalent compression force were different based on f2 < 50. Overall, the results of this study suggest a range of formulation characteristics appropriate for transferring formulations between these two types of machines.

Evaluation of the functional equivalence of crospovidone NF from different sources. II. Standard performance test.

Current NF monographs do not provide tests that reflect on the functionality of Crospovidone NF from multiple sources. Physical characterization studies such as particle size and distribution, surface area, porosity, and surface morphology revealed major differences among the crospovidones from different sources (Shah, U.; Augsburger, L.L. J. Pharm. Dev. Technol. 2001, 6 (1), 39-51). Differences in disintegration and dissolution were also observed for a model drug in an insoluble filler system (see Shah and Augsburger, 2001). The objective of this study was to determine the relationship between physical differences observed and disintegrant functionality and to develop standard performance test. Tests performed included settling volume studies, measurement of initial rate as well as extent of liquid uptake of the loose disintegrant powder, and simultaneous measurement of the axial and radial disintegrating forces along with the rate and extent of liquid uptake of the pure disintegrant compacts. Significant differences among the crospovidones were observed for all tests performed. Settling volume, liquid uptake, and disintegration force are recommended as standard performance tests to determine differences among crospovidones from different sources.

The suitability of some preservatives in chloroquine phosphate syrup.

In Third World countries chloroquine phosphate syrup is frequently prepared with chloroform as a preservative. Because of the toxic side effects of chloroform the suitability of a number of possible alternatives were investigated. If the chloroquine phosphate syrup is prepared as such, the combination of sorbic acid (1.5 g/l) and citric acid (2 g/l) is preferred. If, however, the chloroquine phosphate syrup is prepared from a stock solution of simple syrup, the relatively low pH may be undesirable, because it may negatively affect the stability or solubility of other medicinal compounds. For a stock solution of simple syrup the combination of methyl paraben (1.8 g/l) and propyl paraben (0.2 g/l) is preferred. Good care must be taken that a layer of condense water cannot be formed.

Corneal graft survival in the cat with prolonged preservation in McCarey-Kaufman and K-Sol media.

The effects of extended preservation on transplanted corneas were investigated using McCarey-Kaufman (M-K) and K-Sol media. Cat corneas were preserved in either M-K or K-Sol at 4 degrees C for 5, 10, 15, or 20 days and were subsequently transplanted. Postoperatively, transplants were observed via slit-lamp biomicroscopy and pachymetry and at postmortem examination by light and scanning electron microscopy. In this study, we found no difference in the corneal graft clarity, thickness, endothelial cell count, or morphologic features of corneal transplants preserved in either M-K or K-Sol media. Storage for more than ten days in either M-K or K-Sol media led to primary graft failure. This study demonstrated equivalent results in corneal preservation using either M-K or K-Sol media. The development of better preservation media may require changes in essential nutrients rather than changes in osmotic constituents.

Microbial contamination of a vitamin A formulation, prepared in local pharmacies, and its preservation against yeasts and moulds.

The microbial contamination of 44 samples of a vitamin A preparation in sucrose syrup was investigated. The contaminants were almost exclusively yeasts and moulds. Microbiological and physicochemical studies showed that sorbic acid was the preservative of choice for this formulation. The results are discussed with respect to the preservation of non-sterile pharmaceuticals.

Pseudomonas cepacia bacteraemia due to intrinsic contamination of an anaesthetic. Bacteriological and serological observations.

In November-December 1977 an epidemic of bacteraemia due to P. cepacia was observed in Odense, Denmark (nine patients), and in Nijmegen, Holland (seven patients). All patients recovered. The epidemic was traced to intrinsic contamination of two batches of the anaesthetic fentanyl. All isolates from the patients and from the two batches belonged to the same biotype, had identical sensitivity patterns, and identical antigens. The P. cepacia strain differed from stock strains in being able to grow in two passages in methyl-p-hydroxi-benzoate, 0.5 mg/ml, which promoted the growth of the microorganism: inocula of 2-20 cfu were sufficient to initiate growth in the drug or preservative. These facts indicate the inadvisability of using p-hydroxi-benzoates as preservatives in vials. The strain was inhibited at temperatures above 38.5 degrees C, corresponding to the recovery of the patients after a period with fever above 39 degrees C. Fourteen out of 15 patients examined had agglutinin titres greater than or equal to 320, while 36 blood donors had titres less than 40. Of 12 patients with postoperative fever in the same period whose blood cultures did not yield P. cepacia, three had titres greater than 320.