Several ISO/TC 198 documents including ISO 11134 (Moist heat sterilization) are now in revision and ISO 11138-3 (Biological indicator, BI, moist heat sterilization) is not exceptional. New Technical Report for validation of cultivation period of BI is discussing to use injured microorganism cited several papers already published. Requirement of Biological Indicator Evaluator Resistometer (BIER) is also considered to revise. Approval range of D value for BI in revising ISO 11138-3, which will be restricted to Bacillus stearothermophilus ATCC 7953, will be narrower, probably from 1.5 to 1.9 min in terms of D value. Most of the requirement of ISO/DIS 14161 (Guidance for BI user) will be revised to the validation study done by the user according to Japan's proposal. The characteristic of some sort of BIs, mostly used for PDA facilities, is described. Parametric release scheduled to apply for moist heat sterilization, which PDA facilities will have concern, is described.

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  The high dosages that are often associated with the use of monoclonal antibodies for therapeutic purposes, necessitate the manufacture of large amounts of purified protein, whilst at the same time ensuring efficient recovery coupled with low manufacturing costs. Careful attention to the design of the recovery and purification process will contribute significantly to achieving these goals. The particular challenges associated with the design of a large industrial scale antibody manufacturing process are firstly, the efficient capture of the antibody from the very large volume of cell culture medium, and secondly, to achieve the high level of purity required of a therapeutic protein. The process must also ensure the removal of any potentially contaminating viruses. Product losses are incurred at each step of a recovery process, and it follows, therefore, that reducing the number of process steps by eliminating or combining them will improve the efficiency of a process. A process is described for which an ion-exchange capture step, which required pre-concentration of the cell culture filtrate followed by buffer exchange, was replaced by direct capture on PROSEP-A, a high throughput affinity adsorbent. The rest of the process involved integration of further chromatography steps (ion-exchange and hydrophobic interaction columns) by paying careful attention to the conditions under which each step was run, particularly in respect of the requirements of the next following step. This allowed the elimination of further buffer exchange steps, and significant overall process compression, leading to overall increases in process efficiency and significant cost reduction.

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  For both liquid and gas filters in aseptic processing, it has been stressed on the importance of integrity confirmation in site, before and after filtration. With newly developed water intrusion test (WI), only using water and gas, it is convenient to perform the test for hydrophobic air filters in site. In order to establish the WI procedure in site, here we pointed out on the followings: influential factors for WI results, test procedure, points to consider WI in site, and the case study with vacuum break filters of freeze dryer, especially installed in machine room. With regard to the influential factors for WI results, the changes in the temperature of test fluid and environment, test gas and water, and their introduction, filter cleanliness, filter types and size, air leakage in the upstream, test instrument and the stabilization time during the test etc. were described. According to WI, it is simple and different from the other kinds of test methods, especially on the wetting and drying procedure. Finally, from the test results using vacuum break filter installed in the machine room, it was convinced the importance of the temperature control between water and environment. In addition, in order to obtain high reproducible test results, and to do the effective trouble-shooting, it is important to be understood the influential factors and preliminary checking procedure, by the operators.

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  GMP for imported drugs (GMPI) has been issued in June and effective from August 1st in the last year. One of the most noteworthy issues is that the quality agreement with the foreign manufacturer has become a legal requirement. It is increasing to use the Third Party Manufacturer (TPM), in order to reduce business risks and total lifetime costs. All new TPM shall be assessed for GMP conformance and monitored for QA performance, in order to guarantee the product quality to be supplied. Quality agreement should be made as a part of business agreement, so that to guarantee the manufacturer's GMP conformance and mutual quality assurance on the product. As a sound business, the products and components or materials should be purchased from certified manufacturers and/or suppliers at the lowest life cycle cost. The lowest unit cost is not always necessary. The supplier should be reliable on their quality system, capable in supplying enough amount at the right time. Sound procurement system and TPM management will be required to assure the product quality and maintain a good supply chain. Quality agreement and continuous assessment on GMP compliance and QA performance of the manufacturers and/or suppliers should be a critical part of the procurement system and TPM management in the pharmaceutical companies.

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  This report introduces GMP guidance and inspection activities in Yamaguchi Prefecture, Japan. There are 21 manufacturing sites in Yamaguchi Prefecture, Japan, in which 431 pharmaceuticals are being manufactured. Among them, 189 products are active pharmaceutical ingredients. Half of the active pharmaceutical ingredients manufactured are exported. There are 5 inspectors for GMP in Yamaguchi Prefecture. All of manufacturing sites and products are inspected during 5 years. Before conducting site inspection, thorough document surveillance is performed. That surveillance contains physical characteristics, manufacturing methods, critical processes, and critical quality attributes of the product. During document surveillance, ambiguous points are clarified by communication with manufacturers. After the document surveillance, usually 2 inspectors visit the manufacturing site for two days, and perform the inspection based on the preliminary established inspection check list. Observed results are classified to 1) suggestion, 2) item(s) to be further considered, 3) item(s) to be corrected. Results of these inspections have been introduced in this report by classified to the above three categories.

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