In the development or validation of sterilization process for terminally sterilized parenteral drugs, biological indicators (BIs) are used to evaluate the effectiveness of sterilization. Accurately determining the heat resistance of BIs (D value) in parenrteral solution is extremely important because the D value varies due to variations in the chemical composition of parenteral solutions. The steam BIER vessel can rigidly control the process variables such as exposure temperature and time and provide reproducible physical test conditions. It is possible to heat the BI suspension in capillary tube or small container with short time for come-up and cool-down by using the steam BIER vessel. Because of this advantage, the steam BIER vessel is useful for determination of the D value in parenteral solution. The steam BIER vessel can solve the problem concerning accuracy and procedures of determining the D value in parenteral solution and contribute to perform the high level sterilization process validation for parenteral drugs.

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  ISO 13408 Part 4 and Part 5 include requirements and guidance that are to be observed during cleaning in place (CIP) and sterilization in place (SIP). The purpose of this standard is standardization in the field of validation and routine control of CIP and SIP processes that are used for cleaning and sterilization of the systems that is used in the manufacture of health care products. The most important issue to consider in establishing CIP and SIP technologies is to ensure the design of the systems that are able to successfully clean and sterilize manufacturing systems to the desired sterility assurance level (SAL). The term “Steam-in-place” is used in ISO 13408 Part 1, and this term is sometimes abbreviated as SIP. However, in this part of ISO 13408 Part 5, “SIP” is used with a wider meaning and includes not only steam-in-place, but all kinds of sterilization used for the sterilization in-place. In this section, I introduce the important items mentioned about CIP, SIP and steam SIP from the system design point of view, according to the latest working draft of ISO 13408 Part 4 and Part 5.

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  A big point in standardization work of chemical indicators is the point that turned classification into six kinds according to performance (include a form). And a condition to change in a color after processing (endpoint) according to class including any kind of stated value (±).
1) Class 1: Process indicators It is a process indicator for so-called distinction, assortment. As a form, an indicator printed in sterilization back, indicator tape, indicator label are in this category. 2) Class 2: Indicators for use in specific tests Class 2 Bowie & Dick type indicators are intended to demonstrate the rapid and even penetration of steam and by implication the adequacy of air removal. (ISO 11140-3, 11140-4, 11140-5) 3) Class 3: Single parameter indicators A single parameter indicator shall be designed for one of the critical parameters (for example, high pressure steam sterilization, temperature of saturated steam). 4) Class 4: Multi-parameter indicators A multi-parameter indicator shall be designed for two (for example, EO sterilization, temperature and Gas conc.) or more of the critical parameters. 5) Class 5: Integrating indicators A 1 rank becomes of higher quality than Multi-parameter indicators with a thing reacting to all critical parameters (an indicator doing reaction in consideration of D value). 6) Class 6: Emulating indicators This is a thing reacting to all critical parameters, but it is it the highest-level indicator because standard width is smaller than integrating indicators. Please show Class 3 to 6 as follows, but it is reference in ISO 11140-1 about a detailed standard value.

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  Regulatory agencies in Japan, US and EU have been requiring validation for sterilizing filtration as part of aseptic processing to pharmaceutical industry. ISO 13408 offers guidance to filter users concerning general requirements for set up, validation and routine operation of a sterilizing filtration process, to be used for aseptic processing of health care products. ISO/TC 198/WG9 has been working for definition of requirements for filter selection, fluid specific selection criteria, filtration process, system design, routine process, documentation, maintenance &change control and operator training. At present, it is a step of Draft International Standard.

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  For decreasing particulate matter in sterile products, it is important to find the cause of the particulate contamination by containers as well as drugs. Particulate matter in laminated aluminum film, which is one of the multiple materials to be useful for the container of drugs, was investigated by various methods. It was found that the number of particles in the water increased with time by the particle counter when water was filled in a bag of laminated aluminum film. The number of the generated particles from the bag left for several hours exceeded that of the bag shaken sixty times. Besides, many white particles were detected under the microscope by filtrating water. The white particles weren't observed from the polyethylene film alone before lamination. And white particles was observed irrespective of treatment of heat-seal. Therefore, it was supposed lamination process was the cause of the particle formation. The number of particles in heat-sealed bag increased about twice as many as the number of particles in non-heat-seal bag (sealed by adhesive tape). Therefore, the treatment of heat-seal was also cause of the particle formation. In either case, film was held under high temperature and high pressure. Moreover, analyses of white particles showed that main ingredient in particles was same with an ingredient in polyethylene film which was soluble in ethanol. Therefore, it was presumed that the condition of high temperature and pressure caused the particle formation from an impurity in polyethylene, and particles appeared in water.

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  It is no doubt that media fill (simulation) test is the best method to evaluate aseptic processing. However, there are some problems concerning the acceptable criteria of “a contamination rate of less than 0.1% with 95% confidence limit”, which is specified in official compendia, such as JP,USP, EU GMP, WHO GMP, and ISO 13408 part 1 (General). In performing the media fill test, critical issues in performing media fills are the number of fills. Statistical validity of the observed contamination rate for the process has not been well explained hitherto. Problems associated with the “number” of criteria may not necessarily be treated with statistics, and personnel training and operation are sometimes major factors to cause contamination. However, dogma of “a contamination rate of less than 0.1% with 95% confidence limit” should be discussed further. Operation characteristic curves, which show the relationship between percent defectives and acceptance probability, clearly indicate that the more the number of fills, the higher the acceptable probability of contaminated units becomes in the range of contamination rate less than 0.1%. This means that the larger number of fills accept the worse average quality at the range of percent defectives less than 0.1%. According to a table of ISO 13408-1 (1998), which shows the relationship between the number of fills and the number of acceptable contaminated units, 10 positive units are accepted by 16970 fills' as the rate of contaminated units are less than 0.1% with a 95% confidence limit. However, the 95% confidential range of 4 positive units in 16970 fills is calculated to be 1/1970-6/16970. This means that zero (0) positive unit in 16970 fills, that is sterile prduct, is out-of control with a 95% confidence level. Even though the product meets the requirement of “less than 0.1% with a 95% confidence limit”, zero contamination unit in 16970 fills or asepsis must be very rare case. It means that sterile products become out-of-control according to the existing criteria. It is recommended that the dogmatic criteria such as less than 0.1% with 95% confidence limit should be revised. An example of a proposed new criteria is expressed as follows: “The result of media fill should show that the aseptic processing is consistently within the control limit (with a confidence limit of 95%) by using 3000 or more fills, and show the asepsis of the process or the validity of sterility of the product” in stead of “less than 0.1% with a 95% confidence limit.”

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