Harmonization of GMP has been intensively discussed in ICH, and the result is expected to emerge by the end of this year. Such kind of international harmonization is a pressing issue in the pharmaceutical industries, since the development of technology sometimes causes de-harmonization of regulations in various counties and area. Harmonization of regulations for pharmaceuticals have significance in deploying the worldwide research and development of new pharmaceuticals effectively. According to the harmonization of regulations for pharmaceuticals, activities of pharmaceutical industries have become rapidly global. In the area of quality control, “How to establish specifications” has been discussed in Q6A, and “Skip test,” “Process control” and “Parametric release” have reached to the agreement. These subjects were firstly discussed in the Joint Conference of Japan PDA and Association of Japan Pharm. Sci. in 1997 in Japan. “Parametric Release” has a close relation with validation, or it is a natural consequence of validation. It can be said, “Where there is Validation, there is Parametric Release. It should not be limited to “Sterility Test”, but should be applied to all of other specifications to determine the quality. As future issues of GMP in Japan, “Consultant” in ICH GMP Section 3(6), and FDA GMP Section 211-34 should be discussed in Japan, since there is no this section in Japan GMP. “Contract Manufacturing and Contract Laboratory” should also be discussed in future in Japan, since the concept of “Contract” is very much limited in the Japan GMP. “Complaint and Recall” should also be discussed from the view points of “Safety”, and results should be informed to the world with sound basis of safety. GMP inspection system should also be discussed in the world, after the agreement of written GMP. There seems to be significant differences in the written GMP, but there seems to be much differences in the implementation of GMP between men to men, area to area, country to country. Audit experiences of ISO 9000s show the importance of worldwide auditors' training. CTD (Common Technical Document), and various kinds of ISO Technical Requirements would have much influence to GMP. We have to watch these discussions. Under these circumstances, pharmaceutical industries in Japan are now expanding their activities from domestic to the world.

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  During 1987-1997, Nagoya City University Hospital experienced 22 cases of claim/complaint and recall of the pharmaceutical products. This included 9 cases of abnormality of container and package, 6 cases of contamination, 3 cases of content excess/shortage, and 2 cases of content abnormality and mislabeling. When observing from dosage form, a lot of complaint and recall were the injections of 9, and, next, the external preparations of 7. After enforcing PL law, claims/complains have increased in our hospital. We made the pharmaceutical companies claims of upgrading them and we got the improvement plans as the answer books of how these pharmaceutical companies resolved these problems as follows: contaminations of parts of manufacturing processes, insects, denatured ingredients etc. By using these answers from the companies, each reason of specific and interesting incident was observed and analyzed with the idea of Human Factors. As the results, reasons of most incidents were in the relationship between Liveware and Software.

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  Fluidized-bed granulation has many operational parameters to be optimized in comparison with other simple wet granulation such as kneading or agitating. In addition, these parameters are not independent of each other: a change in one parameter often influences other parameters. Therefore, difficulties are sometime experienced with scale-up study of fluidized-bed granulation. It is a fact, however, that this granulation method has considerable merits to prepare highly compressible granules which can prevent capping incidents. It is experimentally known that tablets prepared by fluidized-bed granulation have usually higher hardness than those prepared by any other granulation methods. In this study, the authors discussed a scale-up and granule size control strategy on fluidized-bed granulation focusing on the moisture in granulation.

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  Two major problems are expected to arise in the future in connection with plasma proteins. The first problem is the lack of source materials. The second problem is the risk of transmission of viral disease such as hepatitis, HIV or other yet-to-be identified viruses. Genetic engineering is the best approach to solve these problems. Plasma derived human serum albumin (pHSA) is one of the most useful plasma proteins. However, producing recombinant human serum albumin (rHSA) commercially via genetic engineering is not entirely straightforward. Two hurdles must be cleared in order to develop rHSA. One is cost and the other is quality. Albumin is typically administered in tens of gram quantities. At a purity level of 99.999% (a level considered sufficient for other recombinant protein preparations such as vaccine and cytokine), rHSA impurities on the order of one mg will still be injected into patients. So impurities from the host organism, in this case yeast, must be reduced to a minimum. Furthermore, purified rHSA must be identical to pHSA. Despite these stringent requirements, cost must be kept in check. One gram of pHSA costs a few dollars. Our goal is to produce rHSA at least as economically as pHSA. Thus to rein in rHSA costs, maximum quantities of albumin must be produced from minimum volumes of culture, and highly efficient, high-yield purification methods are required. Because of these special issues about rHSA development, purification methods were designed under conception described below. 1. Easy automatic control, 2. Easy scale up, 3. Use of no special materials, 4. Use of no complicated methods. The item No.1 is necessary for cost cutting and uniformity of quality. The item No. 2 is essential by the reason mentioned below. In the first stage of rHSA development, we examined purification methods based on 3 to 10 l fermentation scale. In the next stage of rHSA development, we confirmed and optimized purification methods established at the first stage using 1000 l fermentation scale. The final stage of rHSA development is commercial scale. We have the plan of fermentation scale being 50 m³. The purification methods of rHSA must be identical throughout these three stages. Easy scale up is a very important factor for process development. Column chromatography is the best approach to solve these problems. So we used a lot of column chromatography techniques in rHSA purification. The items No.3 and No.4 are necessary for the reason mentioned below. Affinity chromatography is usually a very efficient method. But in the case of rHSA, affinity chromatography is not efficient considering cost and capacity. Furthermore, gradient elution is a very efficient method for small size chromatography, but in rHSA purification, chromatography column is very large. Gel packing into large columns is much more difficult than in small ones, and also, chromatography patterns in large columns are often different from those of small ones. In other words, though impurities can be separated in small scale, separation efficiency becomes very low in large scale and thus the results of chromatography is different between large and small scales. Because of the reasons mentioned above, the media used in our process are very popular ones such as ion exchange, hydrophobic and gel filtration. The methods of chromatography we used are very simple, i.e., rHSA is adsorbed on the media, impurities are washed out, and then rHSA is eluted at a stretch. Or contrariwise, rHSA is flowed through the media while the impurities are adsorbed. In this way, scale up of chromatography is very simple. Same bed height and same linear flow give same results independent of gel volume.

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  The previous study has shown that stainless steel surfaces on piping could greatly be subject to rouging during the operation of high-purity water systems (Suzuki O et al.: Pharm Tech 22: 66-82, 1998). The follow-up study has hereupon been carried on to fed out what will potentially develop into such rouging on stainless steel, because the fouling-like rouging has always been an anxious matter to pharmaceutical engineers. The name of rouging is now given to a corrosive discoloration developed with various contaminants in the high-purity water treatment process, which will also occur in WFI (Water for Injection) systems or pure steam generators. Stainless steel elbow-piping sections, which surfaces were finished at such a high mill finish as mechanical polish and electropolish, were exposed to pure steam generated at 2 kg/cm²-g. The steam was also fed into the near-horizontal piping section not stagnant with distillate and the intentionally arranged section stagnant with distillate for 30 days. The inner surface after pure steam fed was visually inspected and analyzed by a physical technique of Auger electron spectroscopy so that rouging discoloration was detected to be mostly due to its surface oxidization of stainless steel. The oxidization is divided into two groups: namely, (1) reddish discoloration results from the vapor attack, and (2) blackish discoloration comes from long contact with condensate on stainless steel surfaces. The latter discoloration is further divided into two types in the chemical respect; namely, with carbon and without carbon. Although these kinds of discoloration may provide no deterioration for water quality because of very low solubility of metal oxides, a further study of this rouging mechanism should be made to acquire clear grounds for the final conclusion.

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  Detection method of microorganisms which has long been used, is one by counting the unit of colonies formed through naked eye or low magnified scope. On the other hand, there has been developed several rapid detection of microorganisms based on requirements various fields. Those developed methods including bioluminescence method are listed as impedance one, fluorescence one and fluorescence-laser scan one, etc. These methods are useful for specified market, but there has some issues to be resolved, for instance, necessity of increase sensitivity, elimination of false positive incidence and making brief sample preparation. This study was performed to establish a new rapid detection of microorganisms combined with specially modified membrane filter, gene engineering bioluminescence reagent and ultra low light detection equipment. This system: RMDS accord with end user's requirements that are rapid detection and elimination of false positive possibility and easy sample preparation. RMDS method was validated to produce reliability through the control of several elements, factors and so could produce quantitative function also. The test of high purity water by RMDS method has shown good recovery to conventional MF method with rapidity of microorganisms detection. Judging from evaluation results, this system is found to be applicable for monitoring process water and also monitoring of microorganism in the air and from solid surface.

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  This paper describes the effect of allowance for basic specifications of single particle counters on its counting results. Even particle counters meet requirement of Japanese Industrial Standard JIS-B-9921 (Light Scattering Automatic Particle Counter), they may show more than 40% differences in counting results. And we found that size resolution which is not specified in JIS-9921 is also important factor to get more accurate data from comparison test.

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