We are engaging the engineering and construction of many pharmaceutical factories, and facing increasing demand for properly treating the substances with the high pharmacological activity or toxicity. After the agreement of ICH Q7A API Guideline, the discussions on several issues including the containment of hazardous substances were raised broadly. Clarifying the requirement for the containment and the provision against the cross contamination was found very difficult. Issues and steps of countermeasures to establish the basis of containment facility obtained through the experience of the engineering and construction of containment facility is described in this report.

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  API GMP approved at the ICHQ7A meeting in San Diego held in November 2000 is coming nearly toward the mandatory step in Japan. In this API GMP, the Design Qualification for pharmaceutical facilities is clearly described as well as IQ, OQ and PQ. However, there has been no specific description of Design Qualification provided for us the pharmaceutical industry, except for European stipulations. The Validation Standard Code of MHLW, for instance, requires Design Qualification by no means. Very few procedural monographs on such Design Qualification have been found at least in Japan. Thereupon, the author will demonstrate how well we could have the Design Qualification function in the course of validation on the basis of some relevant literatures available in hand and his own experience through pharmaceutical manufacturing with process validation. Especially, what is required to cover Design Qualification is to be noted in relation to such specifications determined as applicable conditions, performance factors and characteristic mechanisms necessary for equipment and facilities with the procedures for the first step qualification as Design Qualification before IQ, OQ and PQ. Some important regulatory guides and references for equipment design will finally be detailed for your easier understanding.

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   Development of biopharmaceutical products can be accelerated by proper selection and application of membranes used during product and process development. This Report will discuss scalability, active product transmission and, filterability focusing on virus removal and DNA removal. Also, it will describe, how proper selection of test filters can eliminate or reduce further testing at pilot and production scales, thus reducing time to submission and marketing of the drug product.

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  It is recommended that organization shall have a reasonable timetable for promptly modifying any systems not in compliance (including legacy systems) to make them Part11 compliant, and shall be able to demonstrate progress in implementing their timetable. The reasons: 1. It takes not so much time to recognize Part11 requiring implementation of secure, computer-generated and time-stamped audit trails etc. as global standard. 2. The Japanese pharmaceutical companies are faces to important phase to decide the implementation of Part11 in their process of globalization. 3. It may take more time to modify the existing systems such as for R&D of new medicine, manufacturing and quality control management of products.

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  In 1997, FDA issued new reguration about electronic records/eletronic signature and handwritten signature at the behest of pharmaceutical industry. Advantage of this reguration, pharmaceutical company will have oppotunity of building paperless factory and also will take many benefit like searching large volume of data or speeding up inspection. On the other hand, there are problems that the risks of falsification are higher with electronic records than paper records. 21 CFR Part11 indicate requrement items which solve weakness of electronic records, but it still having many difficulties in actual implementation because of interpretation of Part11 rules and technical problems.

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  FDA issued a regulation in 1997 that outlines its criteria for acceptance of electronic records, electronic signatures, and handwritten signatures. The criteria were provided in response to industry requests. The regulation, 21 CFR Part11, allows electronic records to be considered equivalent to paper records and handwritten signatures. The rule applies to all industry segments regulated by FDA and includes good laboratory practice (GLP), good clinical practice (GCP), and current good manufacturing practice (CGMP). The new regulations primarily require analytical laboratories to use validated equipment and computer systems; secure retention of electronic records to instantly reconstruct analyses; userindependent, computer-generated, time-stamped audit trails; system and data security, data integrity, and confidentiality through limited authorized system access; secure electronic signatures for closed and open systems; and digital signatures for open systems. 21 CFR Part11 is adapted when exporting the tablet and original medicine which are medical supplies to the U.S. Agilent Technologies supplies the analytical instrument and NDS (Network Data System) corresponding to electronic record and electronic signature.

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  Requirements regarding electronic records and signatures were published in the United States Federal Register 21 CFR Part 11 in August 1997. These requirements regulate the control of records and signatures and associated security issues in order to respond to the movement towards paperless systems. In the QC lab, printouts from analytical equipment are often treated as raw data and especially for analytical equipment which are computer controlled, where the output is received via electronic media, compliance with the requirements of 21 CFR Part 11 is required to assure the output results. Taking QC lab circumstances into account and aiming towards compliance with 21 CFR Part 11, the preparations and planning, items for investigation and audit preparations are considered.

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  21 CFR Part 11 rule has been effective since August 1997. Pharmaceutical companies are still investigating how they comply with the rule. To comply with the rule around the current circumstances, pharmaceutical companies need to develop a compliance implementation plan, and establish company policies and procedures for compliance. Each site or division should prepare a site/division implementation plan and execute the plan for inventory list, assessment, procedural control and technical solution. From my viewpoint, I will describe some issues for pharmaceutical companies on scope, hybrid system, audit trail, long term retention of records, access control, and implementation plan.

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  A new method was developed to make water-based hydrophobic filter integrity tests (HydroCorr test) more reliable under varying temperature conditions. While water-based integrity tests including HydroCorr have been widely adopted in various sterile drug production processes, strict control of temperature of air and water (as test liquid) around the filter is required when using conventional integrity test instruments for this test. Changes in temperature directly affect water flow measurement by these instruments. Conducting the test for vacuum break filters on lyophilizers requires special considerations because filters are usually installed in machine rooms and are exposed to significant temperature changes throughout the process. This new In-line HydroCorr Test adopts a direct water flow measurement method with an accurate and in-line steamable water flow meter. Stability of the In-line HydroCorr Test incorporating this water flow meter is evaluated under various temperature conditions.

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