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accept an NDA during the course of the long-term (3-year) storage testing if the interim results reveal a shelf-life of not less than 1 year, the accelerated testing estimates stability for at least 3 years, and the final long-term storage results will be submitted before approval [16]. Additionally, the bulk drug substance and the finished product should be studied under varying light, temperature, and humidity exposures. Any resultant degradation products must be identified as precisely as possible and their toxicity and general pharmacology tested. |
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Japan is a party to harmonization of stability requirements that has now reached Step 5 in the ICH process. The Koseisho has accepted protocols both for long-term stability testing (temperature and relative humidity 25°C and 60%, respectively) and for accelerated testing (40°C and 75%, respectively). However, there are no standards for light testing. Japan has taken a number of initiatives on this topic of standardization of light testing and an early draft guideline was issued in December 1993. This is an official ICH draft still designated as at Step 1. |
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A requirement unique to Japan was the need for an assay for the arsenic content of all medications. For medications that do not contain arsenic, the development and validation of such a test is difficult to justify. Through the ICH, Japan has agreed to forgo the requirement for an arsenic assay of bulk drug substance. |
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In Japan, pharmaceutical inspectors are prefectural government officials, and they have three major duties: to inspect in accordance with GMP, to watch for unlicensed and adulterated drugs, and to control false, exaggerated advertising. To meet these obligations, they conduct regular on-site inspections of manufacturers, importers, pharmacies, and all other premises where drugs are sold. If a problem is detected, the officials will conduct intensive inspections of the offender. Officials based at Japan's ports used to conduct detailed inspections of all imported drugs. As a result of international concern, this potential trade barrier has been significantly modified. Currently drugs with import approval and investigational drugs for clinical trials where the study protocol has been submitted to the MHW are cleared inwards through customs; however, the government insists that as part of quality assurance importers shall perform quality testing for each lot and retain the results in the import office. Since April 1994 it is no longer necessary to report the results to the pharmaceutical officials of the importer's prefecture. Such testing is likewise required of Japanese pharmaceutical companies who manufacture off-shore and subsequently import. Such off-shore manufacturing is common practice for several economic reasons. |
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A recent publication prepared under the supervision of the NDD of the PAB clearly discusses, with useful explanatory notes, the Japanese animal toxicology |
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