ICH Guideline “Specification: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances” (Q6A Guideline) reached consensus among USA, EU and Japan on November 1999. The objective of Q6A Guideline is to assist, to the extent possible, in the establishment of a single set of global specifications for new drug substances and new drug products. The most important features of this guideline are 1) new general concepts such as periodic/skip testing, in-process tests and parametric release, which have not been adopted in current drug approval - licensing system in Japan, are included, and 2) harmonization of test procedures among USP, EP and JP is strongly required. In order to support the implementation of this guideline in Japan, feasibility studies on the above three general concepts posed by Q6A guideline are now carrying out. In this speech, I would like to discuss the requirements for applying them in Japan based on the feasibility study reports of periodic/skip testing (1998) and in-process tests (1999). I'll also discuss the current status of pharmacopoeial harmonization on test procedures.
In recent years, in Japanese society, Medical practice, medicines, foods, and environmental accidents and natural disasters have been happening. The importance of “Danger management” has been realized, and its system has been strongly sought. On the other hand, even about contagious diseases, treatment with sulfa drugs and/or antibiotics, and inoculation with vaccines have advanced in development. In the developed countries, contagious disease had been thought to be almost conquered. Nevertheless, in the past 20 years about 30 new infectious diseases have appeared, and the previous diseases also have gained immunity to medicines by changing character and virology, reappearing as new diseases and are looked upon as problems. Especially concerning infectious diseases, the importance of controlling dangers such as HIV infected blood plasma goes without saying. With this background, concerning the increasingly sought biosafely, biological production facilities biohazards counterplans sighted as basic lectures are to be conducted. The lecture content is dealing with biohazards, and biosafety principles and practices, and biosafety guideline in bioproduction facilities.
When Toray company began gamma-ray sterilization of dializer in middle of 1970's, sterilization dose to realize 10−6 of SAL is set by D-value of B. pumilus's spore suspension and bioburden level. After then AAMI's B1 method was selected in accordance with the requirement of FDA. Currently ISO11137's method2, which is harmonized with AAMI's method 2, is selected in accordance with Japanese guideline of sterilization validation and related requirement. Parametric release is implemented for product release.
Spray drying is used as a very convenient means for drying liquid into powder instantly, continuously and economically in laboratory use and large production, but at high temperature, e.g. over 100°C as inlet air temperature. Freeze-drying is a typical drying technology for drying heat-sensitive products at 20-50°C during desorption drying, but for several hours. Due to invention of Four Fluid Nozzle (patented in USA, Europe and Japan), spray drying at low temperature closer to atmospheric temperature below 80°C as hot air temperature is possible and therefore a new drying technology as low temperature spray drying has been realized based on the principle of quicker drying speed by huge heating surface area of droplets minimized below abt. 10 μm by the new nozzle. The Four Fluid Nozzle, which was developed by the design concept of minimization and uniformity of droplet size for quicker drying speed and elimination of wet deposits on chamber wall, has a special acceleration zone on it for forming thin film of liquid just before atomization in addition to a focusing point of compressed air as a newly designed structure for removing loss of atomization energy. Thus, the droplet size distribution is in a very narrow range resulting in the uniform particle size distribution of dry powder all in a single micron. The smaller and uniform droplet size makes heating surface area bigger by abt. 10 times compared with conventional atomization systems and so such smaller droplets are dried quickly and completely before reaching chamber wall even at low temperature without wet deposits on chamber wall. The geometry of the new nozzle is quite the same even in smaller or larger types of the nozzles and so the quality of dried product is also the same even in case of the so-called circle nozzle for larger production scale, for example having the atomization capacity of max. 1000 Itr/h. There is a possibility that conventional low temperature drying technology like freeze-drying, vacuum drying, etc. can probably be replaced by the low temperature spray drying technology. Drying of parenteral drugs will also be possible by the new drying technology with Four Fluid Nozzle using CIP/SIP systems, powder recovery system with metal mesh cartridge filter and isolation technology as a validatable system in the near future.
In pharmaceutical manufacturing process, the contamination of particulate into drugs is a very important issue because of the adverse impacts upon human health & medical treatment. 7 commercially available Bio-cleanroom garments were tested and evaluated for characteristics related both to functionality and to contamination, according to the frequency of their clean laundry & sterilization cycles. Results are as follows: (1) Self-particle generation level from Bio-C.R. garments is higher than ICR C.R. garments. (2) Bio-C.R. garments are highly deteriorated by sterilization (Autoclave) . (3) Bio-C.R. garments shall be designed (i) to reinforce the strength of horizontal yarn, (ii) to weave high density of filaments by twill structure, (iii) to install E.C.F into a fiber by stripe, (iv) to make of plastic materials for zipper, (v) to make of plastic materials for Velcro fastener. (vi) to separate hood from C.R. garment itself.
In the pharmaceuticals water production process, the UF method is an effective way to remove pyrogen as well as the distillation and RO method. The UF module used for the production of WFI should have such properties as (1) Reliable bacteria and pyrogen removal (2) Biological safety (3) Excellent heat resistance (4) Excellent chemical compatibility (5) Sanitary structure (6) High water flux. Microza® UF “VIP-3017” module has been widely used, and is especially so steam sterilizable that the UF system incorporated with the UF modules is more reliable for this application. When the UF method is applied to the production of pharmaceuticals water including WFI, periodical analysis of UF permeate should be implemented to ensure the quality as the pharmaceuticals water and furthermore air leak test of the UF module should be performed from time to time. During the facility shutdown and steam sterilization of the UF system, a careful attention for the UF system operation should be paid in order to prevent from bacterial contamination at the UF permeate side. The UF method has been already approved in the JP for the production of WFI but is approved neither in the USP nor EP. It is desirable that enough information including data on this application in Japan is submitted to the USP and EP for international harmonization of pharmacopia.
During recent years, with respect to parenteral product containers, blow-fill-seal (BFS) plastic packages are receiving wide acceptance at medical treatment terminals due to various advantages on safety handling, foreign matter contamination and waste treatment aspects compared to glass containers. It is quite important to test leakage on the BFS package, as microbial contamination must be strictly avoided. At present, the highest sensitivity leakage detection method is direct current impressed high voltage leak detector (HVLD) system. It has been, however, required from the system that electric conductivity of the content to be not less than 20μS/cm for leakage detection. In the present work, pinhole sizes of 5-10μm were detected by the HVLD applied to water for injection of conductivity not more than 2μS/cm. Results indicate that the HVLD is feasible to apply for inline inspection of all products manufactured by the BFS process.