How Japan is different

Japan, like the other constituents of the ICH, has its own well-developed pharmaceutical manufacturing equipment industry, and is capable of supplying all of the equipment and facility infrastructure required for a modern aseptic processing facility. The country has also developed considerable capabilities in electronics, robotics, optics and in-process analysis. Japanese requirements for computer system validation have been pragmatic and objective, and have not prevented pharmaceutical manufacturers from using advanced process control technologies, robotics and machine automation.

[b]Some of the noteworthy aspects of aseptic processing in Japan include:

[COLOR=“blue”]•Automation of component supply feeding systems to reduce repetitive work and contamination risk. The use of automatically guided vehicles for logistics support, process line automation and automatic loading and unloading of lyophilizers is very common in new facilities.

•A high level of direct process monitoring for many production parameters such as throughput, fill volumes and component feed status. Japan has not had to deal with some of the circumstances related to 21 CFR Part 11 regarding validation of computerized process or information technology systems.

•Near paperless manufacturing with detailed operating instructions and all key inputs available on touch screens.

•Extremely high levels of process performance in terms of throughput, efficiency and reliability in all aspects of manufacturing process.

•The common use of video systems to enable direct visual monitoring of aseptic area operations. In addition, advanced facilities monitoring systems capable of measuring all key environmental parameters including airborne particle levels are also provided in a central control room.[/color][/b]


The following are basic elements of Japan’s “Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing.”

•Personnel: The guideline clearly states that human operators are the greatest source of contamination in aseptic processing and defines a comprehensive set of goals and objectives in personnel training. These include expertise in aseptic technique and a working knowledge of microbiology, including specific knowledge “regarding species likely to be encountered.” Additionally, personnel are to be comprehensively trained regarding gowning and evaluated regarding their gowning ability. Finally, workers are expected to have a working knowledge of the principles of cleaning and disinfection.

•Quality systems expectations are defined in the Guideline including systems for document control, organizational structure, risk analysis and qualification of equipment and processes.

•Requirements for facility design and room classification are set forth in detail. Critical areas are required to meet Grade A expectations for both total particulate and microbiological contamination. Support areas are to comply with Grade B requirements. The conditions stipulated for design, management and control of aseptic processing environments very much parallel those of the EU GMPs. Pressure differentials of 10-15 Pa are required between adjacent rooms of different classifications so that a proper air pressure cascade can be established and maintained.

•Disinfectants and sanitizing agents much be validated to be free of microbial contamination at the time of use, and the methods for their application must be verified/validated for effectiveness. Tests should also be conducted to ensure that residues can be reduced to a pre-defined level.

•Component washing must be validated to remove at least 99.9% (3-log reduction) of bacterial endotoxin.

•Environmental monitoring in Grade A critical zones for airborne contamination is to be done for each shift of operation. Operators are also to be sampled for microbial contamination once per shift. Surface monitoring is to be done at the end of each production operation. Particulate monitoring is to be done “throughout the entire aseptic procedure” in all Grade A environments.

•All product contact materials including container/closure systems and sample filters must be sterilized according to a validated process. The efficacy of the sterilization process is to be verified using biological indicators. Specific guidance is provided on all sterilization methods used in industry. A separate section is dedicated to directions for the use of Sterilization-in-Place systems.

•The Guideline suggests that isolator-equipped operations should keep “the number of half suits, gloves, transfer ports, and connections … to a minimum in order to reduce the chance of contamination.” Isolators are also required to have a minimum positive pressure differential of 17.5 Pa relative to the surrounding environment which is expected to meet Grade D requirements.

•Media fills must comprehensively challenge the entire process including all product contact equipment and must consist of 5,000 units as a general recommendation. All shifts must participate in media fill tests and all interventions must be included in each test. Media fills should cover the longest production time utilized in actual production.