While the global pharmaceutical industry tends to be conservative in nature, its implementation of newer technologies for aseptic processing has been impressive — and nowhere more so than in Japan. Shibuya Kogyo (Kanazawa, Japan), in conjunction with La Calhene (Vendôme Cedex, France), introduced isolators for aseptic manufacturing into the Japanese market in 1994. Over the last dozen years, more than 40 isolator-based production lines have been installed and validated throughout the country.
Isolators are used in a wide variety of applications, including both large- and small-volume parenterals, lyophilized products, powder fills, combination products, medical devices as well as more typical liquid fills into a single container. In addition to advanced aseptic processing environments such as isolators, Japanese firms have been more aggressive than some of their international counterparts in the adoption of factory automation and robotics.
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Japan has also been very active over the same period of time in developing its regulatory guidance. In 2005, a task force comprised of industry, academic and government experts released “Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing.” This comprehensive 99-page document covers all aspects of aseptic processing including production facilities, utility systems, sterilization equipment and environmental management, process simulation and control. Additionally, it provides information pertinent to design and validation of advanced technologies such as isolators and blow/fill/seal.
Japanese standards regarding aseptic processing, notably those for environmental monitoring recommendations, media fill procedure/acceptance criteria and validation approaches, are all compatible with those of FDA and EMEA. This is not surprising since all three companies are members of the International Congress on Harmonization (ICH).
However, relatively little information is available in Europe and North America regarding aseptic processing requirements and facilities in Japan. This article will shed some light on Japanese aseptic practices and Japanese innovation in aseptic processing.
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.
Some of the noteworthy aspects of aseptic processing in Japan include:
- 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.
A case in point: Handai Biken
The following case study serves as an excellent example of a modern Japanese aseptic processing facility. This aseptic processing manufacturing line is installed at the Handai Biken facility in Kagawa, Japan, and is dedicated to the aseptic bottling of vaccines in vials. The Kagawa facility was built and the equipment installed in 2004, and commercial production of vaccines commenced in 2005. The facility can produce lyophilized and liquid filled vials.
All product filling, lyophilization and stoppering at the site are conducted in vertical unidirectional airflow isolators, which are designed and operated to comply with IS0 14644 Class 5 requirements. The environment surrounding the isolators complies with ISO Class 7 requirements. Handai Biken developed user requirement specifications (URS) for this project, in order to minimize the risk of contaminating the biological products. The production systems are designed to minimize particulate contamination as well as human intervention. Additionally, a number of design features were implemented to ensure high yields and minimal line stoppages.
The project consists of five isolator sections:
- Between the tunnel and filler (3.9 m3 total enclosed volume)
- Filling/stoppering machine (4.8 m3)
- Rubber stopper supply system (16.9 m3)
- Lyophilizer conveyor (3.9 m3)
- Automatic lyophilizer loading/unloading (17.0 m3)
The total enclosed isolator volume for these five sections is 47.4m3. To facilitate vapor hydrogen peroxide decontamination, the isolators are divided into two sections. The first section, which consists of the isolators described in items 1-4 above, has a total enclosed volume of 30.4 m3, while the second decontamination group consists only of the fifth isolator. Decontamination is accomplished by VHPM1000S vapor phase hydrogen peroxide generators sourced from Steris Corp. (Mentor, Ohio). The isolator network is divided into two sections for decontamination in order to ensure that the total volume and surface area to be treated is within the capacity of the vapor phase hydrogen peroxide generators.