Ministry of Health, Labour and Weltare has been conducting development of guidance for the approval process of brand-new medical products/development of guidance for medical devices in collaboration with Ministry of Economy, Trade and Industry as part of measures to promote practical use of brand-new medical products since 2005. The objective of this project is to expedite the processes from developmental process of medical devices to approval review and to introduce the medical devices to medical front quickly.. Ministry of Health, Labour and Welfare side has been making guidance for the guide in approval process of brand-new medical products and regeneration medicine products to aim at acceleration and facilitation of development and approval process of innovative medical products. Twenty-two of the guidance have been issued as director of the evaluation and licensing division. The evaluation index about safety and efficacy required for medical devices and regenerative medicine products in progress were put together in these guidance and useful for medical devices developer to understand the point at the approved review. Therefore, I think that the evaluation index could also contribute to the efficient product development. The guidance about implantable artificial heart is issued as the representative example which was useful in the approved review.
Chemical leukoderma is a skin depigmentation disorder known to occur in manufactural workplace through contact with chemicals, such as monobenzyl ether of hydroquinone (MBEH) and 4-tert- butylphenol (4-TBP). In the skin depigmented -legions induced by these chemicals, the number of melanocyte was severely decreased. Anti-melanoma agent 4-cysteaminylphenol (4-SCAP) and its derivatives are also known to cause leukoderma. Evidence has accumulated supporting that typical class of chemicals causing leukoderma is "4-alkyl/aryl-substituted phenols/catechols", which are structurally similar to melanin precursor tyrosine. Tyrosinase-mediated oxidation of these chemicals yields toxic ortho-quinones which bind to cellular proteins and produce reactive oxygen species. Accordingly, this tyrosinase-dependent metabolic activation is thought to cause melanocyte-specific damage and subsequent immune reactions toward melanocytes. Recently, rhododendrol, an inhibitor of tyrosinase developed for so-called lightening/whitening cosmetics, was shown to cause leukoderma in the users. In this review, I document the causes of known chemical leukoderma and rhododendrol- induced leukoderma, focusing on their common mechanisms underlying melanocyte loss.
Under the Chemical Substances Control Law (CSCL) in Japan, initial hazard information tor existing chemical substances has been collected by the Ministry of Health, Labour and Welfare, Japan (MHLW) to assess potential initial risks to human health. We have reviewed all collected toxicity information pertaining to acute toxicity, repeated dose toxicity, genotoxicity, and/or reproductive/developmental toxicity and performed hazard assessments. Approximately 150 substances are currently undergoing review and assessment. For clarification and evaluation of each toxicity study, we have created a dossier (a collection of study data containing a detailed summary of the methods, results, and conclusions of each study) in English using the International Uniform Chemical Information Database (IUCLID) version 5. The IUCLID dossier format is widely used and has been accepted as one of the most beneficial formats for providing summarized chemical substance toxicity assessments. In this report, as a contribution to our ongoing hazard assessment activity, we present summary hazard information related to the potential human health effects of the following 5 chemical substances: 4-chlorobenzoyl chloride (CAS: 122-01-0); benzenesulfonic acid, 4-hydroxy-, tin (2+) salt (CAS: 70974- 33-3); chlorocyclohexane (CAS: 542-18-7); 1,3-cyclohexanedimethanamine (CAS: 2579-20-6); and 1,3,5-triazine-2,4,6 (1H,3H,5H) -trithione (CAS: 638-16-4). The IUCLID dossiers created for these 5 chemical substances will be made available via the Japan Existing Chemical Data Base (JECDB) at . Additional human health hazard information on existing chemical substances will be provided using the same methodology and website when it is available.
An increasing number of inquiries about application of food additives have been made from businesses in and outside Japan. The Ministry of Health, Labour and Welfare (MHLW) is requested to expedite the procedure for designation and revision of use standards. In June 2014, the MHLW set up a center for consultation on application concerning food additives (Food Additive Designation Consultation Center, FADCC) in the National Institute of Health Sciences, aiming to smoothly and expeditiously handle clerical work for designation or revision of the use standards. FADCC gives advice on how to prepare documents on the information such as physicochemical characteristics, effectiveness, safety, daily intake and use standards, based on actual cases and experience.
Japan has published safety guideline on waterproof aerosol sprays. Furthermore, the Aerosol Industry Association of Japan has adopted voluntary regulations on waterproof aerosol sprays. Aerosol particles of diameter less than 10 µm are considered as "fine particles". In order to avoid acute lung injury, this size fraction should account for less than 0.6% of the sprayed aerosol particles. In contrast, the particle size distribution of aerosols released by hand-pump sprays containing fluorine-based or silicone-based compounds have not been investigated in Japan. Thus, the present study investigated the aerosol particle size distribution of 16 household hand-pump sprays. In 4 samples, the ratio of fine particles in aerosols exceeded 0.6%. This study confirmed that several hand-pump sprays available in the Japanese market can spray fine particles. Since the hand-pump sprays use water as a solvent and their ingredients may be more hydrophilic than those of aerosol sprays, the concepts related to the safety of aerosol-sprays do not apply to the hand pump sprays. Therefore, it may be required for the hand-pump spray to develop a suitable method for evaluating the toxicity and to establish the safety guideline.
When Rachel Carson wrote the "Silent Spring" in 1962, the toxicology society was influenced in an indirect way mainly on environmental effects of massive use of pesticides. However, at that time, for those who were studying DDT and other pesticides, the biological effect of such chemicals were understood as a result of their long-lasting toxicants with slow elimination rates from the body; bio- persistency and in some case bio- and environmentally accumulative. And the chronic effects became overt including complex endpoints not only liver toxicity but, reproductive, immune, and neuronal. The impact of Silent Spring on toxicology seems to have established the foundations for scientifically accepting the problems widely raised by the Theo Colborn's "Our stolen future", although its main target was reproductive mechanisms including oestrogen and androgen system. For basic receptor biologists, non-monotonic dose-response curve was a matter of course, but for toxicologists at tnat time, all dose-response curves should be monotonic. With further detailed discussion many toxicologists started to understand that there is a good plausibility that such non-monotonic and low dose effect can happen in wild life and may be in humans under certain conditions. Since then, many toxicologists including us have initiated research on the so-called endocrine disrupting chemicals under new paradigm of receptor mediated- or signal-toxicity. To handle this problem, it became clearer that toxicology has to be innovated towards more biologically mechanistic science. This thinking has linked to the trend of toxicogenomics, where classical pathological findings are used to confirm the results of comprehensive mechanistic analysis data. In contrast our idea of toxicogenomics, designated as Percellome Toxicogenomics Project, was to develop comprehensive and quantitative gene expression networks out of transcriptomic data alone. Existing biological knowledge is used to help understand the biological or toxicological meaning of the generated networks. As a whole, the author would like to outline the strategies to cope with the new paradigms and to combine them to construct a more robust toxicological research system under the concept of "signal toxicity". We believe that this activity should contribute to the development of more comprehensive, faster, cheaper (including less animal to use), and reliable system for the identification, and prediction of toxicity for any kind of agents entering our body and environment.
To investigate relationships between particle (as a model of aggregates) size in a nanomaterial test suspension and its cytotoxicity, a series of eleven sizes of polystyrene (PS) particles were tested in the cytotoxicity test and the chromosome aberration test by using a Chinese hamster cell line CHL. The PS particles were spheres with defined diameters ranging from 0.1 to 9.2 µm. A series of eight sizes of particles with diameters ranging from 0.92 to 4.45 µm showed stronger cytotoxicity than the others. There was a marked difference in cytotoxicity between the 4.45- and 5.26-µm particles. The 0.92- to 4.45-µm particles did not induce structural chromosome aberrations but induced a high frequency of polyploidy in the chromosome aberration test. The 5.26-µm particles showed very weak induction of polyploidy. The incorporation of the 4.45-µm particles into CHL cells was observed by scanning electron microscopy (SEM). Some cells incorporated more than 10 particles. The semi-quantitative measurement of incorporation of particles into cells was performed by flow cytometry with a parameter of side scattered light (SSC) intensity. It showed that CHL cells preferably incorporated the 4.45-µm particles to the 5.26-µm particles. These findings suggest that CHL cells may have a kind of size-recognition ability and incorporate a particular size of particles. The particles may prevent a normal cytokinesis resulting in polyploidy induction. Nanomaterials also may show size-dependent toxicity. Data on particle (or aggregate) size distribution in the test suspension should be provided to evaluate properly the results of toxicity tests of nanomaterials.
Monoclonal antibody products and monoclonal antibody-based biopharmaceuticals have shown considerable effectiveness in the treatment for variety of diseases; cancer, auto-immune/auto-inflammation diseases and so on. Significant advance in monoclonal antibody products for cancer treatments was made with antibody-drug conjugates (ADC), and antibodies for blockade of immune checkpoints. Already 3 ADCs and 2 anti-immune-checkpoint antibodies products have been approved, and these monoclonal antibody-related product pipelines reach over 30. On the other hand, EU approved first monoclonal-antibody biosimilar, RemsimaTM (infliximab), suggesting that other monoclonal-antibody biosmilars will follow to the market. In this paper, several new issues about monoclonal antibody products will be discussed.
In March, 2012, Japan made the application for membership of the Pharmaceutical Inspection convention and Pharmaceutical Inspection Co-operation scheme (PIC/S) which is an international body of a GMP inspection. The globalization of pharmaceutical manufacturing and sales has been a driving force behind the decision to become a PIC/S member. For the application for membership, Japan's GMP inspectorate needs to fulfill PIC/S requirements, for example, the inspection organization has to have a quality system as a global standard. One of the other requirements is that the GMP inspectorate can access Official Medicines Control Laboratories (OMCL) having high analytical skills and also have a quality system based on ISO 17025. I would like to describe the process to make up a quality system in the National Institute of Health Sciences and also the circumstances around the PIC/S application in Japan.
Recently, the development of nanomedicines is progressing. These are designed to ensure high stability and to optimize the pharmacokinetics in vivo. The polymeric micelles and lipid nanoparticles are typical such examples. Because the unique size-specific interaction with biological systems or biodistribution may have significant impacts on the efficacy and safety of nanomedicines, regulatory science researches of nanomedicines are required. In this review, the authors introduce our initiatives of the regulatory science researches of nanomedicines.
A well functioning immune system is essential in maintaining integrity of the organism, and malfunction may have severe health consequences. Environmental substances may pose direct toxicity to components of the immune system, often leading to immunosuppression and resulting reduced resistance to infections and tumors. Alternatively, such substances may be recognized by the immune system in a specific fashion, which may result in allergy and autoimmunity. A proper risk assessment of environmental substances in terms of immunotoxicity is necessary. In this manuscript, I reviewed recent three topics about immunotoxicity: (1) IPCS/WHO Guidance for immunotoxicity risk assessment for chemicals, (2) Intestinal immunotoxicity, and (3) Epicutaneous sensitization of food proteins.
In 2013, the Japanese Diet passed the Regenerative Medicine Promotion Act and the revisions to the Pharmaceutical Affairs Act, which was also renamed as the Therapeutic Products Act (TPA). One of the aims of the new/revised Acts is to promote the development and translation of and access to regenerative/cellular therapies. In the TPA, a product derived from processing cells is categorized as a subgroup of "regenerative medicine, cellular therapy and gene therapy products" (RCGPs), products distinct from pharmaceuticals and medical devices, allowing RCGPs to obtain a conditional and time- limited marketing authorization much earlier than that under the conventional system. To foster not only RCGPs, but also innovative pharmaceuticals and medical devices, the Ministry of Health, Labour and Welfare recently launched Translational Research Program for Innovative Pharmaceuticals, Medical Devices and RCGPs. This mini-review introduces contributions of the National Institute of Health Sciences (NIHS) to research projects on RCGPs in the Program.
Over the past decade, oligonucleotide-based therapeutics such as antisense oligonucleotides and small interfering RNAs (siRNAs) have been developed extensively. For example, mipomersen (Kynamro; ISIS Pharmaceuticals), which is a second-generation antisense oligonucleotide administered by subcutaneous injection, has recently been approved by the FDA for the treatment of homozygous familial hypercholesterolemia. On the other hands, methods for the evaluation of quality, efficacy and safety of oligonucleotide therapeutics have not been fully discussed. Furthermore, the regulatory guidance specific for oligonucleotide therapeutics has not been established yet. Under these circumstances, we started to collaborate with Osaka University and PMDA to discuss regulatory science focused on oligonucleotide therapeutics. Through the collaboration, we would like to propose the possible design of quality evaluation and preclinical safety-evaluation of oligonucleotide therapeutics.
In Japan's Specification and Standards for Food Additive, 8th edition, two identification tests involving isopropyl citrate for detecting isopropyl alcohol and citrate are stipulated. However, these identification tests use mercury compound, which is toxic, or require a time-consuming pretreatment process. To solve these problems, an identification test method using GC-FID for detecting isopropyl alcohol was developed. In this test, a good linearity was observed in the range of 0.1-40 mg/mL of isopropyl alcohol. While investigating the pretreatment process, we found that isopropyl alcohol could be detected using GC-FID in the distillation step only, without involving any reflux step. The study also showed that the citrate moiety of isopropyl citrate was identified using the solution remaining after conducting the distillation of isopropyl alcohol. The developed identification tests for isopropyl citrate are simple and use no toxic materials.
Division of Medical Devices has been conducting the projects to accelerate the practical use of innovative medical devices to collaborate with TWIns, Center for Advanced Biomedical Sciences, Waseda University and School of Engineering, The University of Tokyo. The TWIns has been studying to aim at establishment of preclinical evaluation methods by "Engineering Based Medicine", and established Regulatory Science Institute for Medical Devices. School of Engineering, The University of Tokyo has been studying to aim at establishment of assessment methodology for innovative minimally invasive therapeutic devices, materials, and nanobio diagnostic devices. This report reviews the exchanges of personnel, the implement systems and the research progress of these projects.
Biomarkers are useful tools to be utilized as indicators/predictors of disease severity and drug responsiveness/safety, and thus are expected to promote efficient drug development and to accelerate proper use of approved drugs. Many academic achievements have been reported, but only a small number of biomarkers are used in clinical trials and drug treatments. Regulatory sciences on biomarkers for their secure development and proper qualification are necessary to facilitate their practical application. We started to collaborate with Tohoku University and Nagoya City University for sample quality, biomarker identification, evaluation of their usage, and making guidances. In this short review, scheme and progress of these projects are introduced.
Azo colorants that generate primary aromatic amines (PAAs) have been recently deliberated as a controlled harmful substance by the "Act on the Control of Household Products Containing Harmful Substances" in Japan. Therefore, we examined an identification test for 22 kinds of PAAs originating from the azo colorants in commercial textile products and leather products using high performance liquid chromatography (HPLC). When a PAAs standard solution containing 2,4-xylidine and 2,6-xylidine was analyzed using the condition according to EN14362-1:2012 at 240 nm as a basic condition, we observed enough separation for all the PAAs to identify. However, in the some sample solutions, the peaks of several PAAs were overlapped with the interference peaks, and their identifications were difficult. In these cases, some PAAs were able to identify by alteration to suitable wavelength. Furthermore, the retention time of almost PAAs and interference peaks were changed by using acetonitrile as the organic solvent in eluent or phenyl type column. These modifications were helpful for identification of PAA which was overlapped to interference substances by the basic condition. Thus, we suggest the HPLC condition for an identification test is in accordance to that described in EN14362-1:2013. And we propose that the HPLC condition can be modified as necessary.
Gene therapy products are expected as innovative medicinal products for intractable diseases such as life-threatening genetic diseases and cancer. Recently, clinical developments by pharmaceutical companies are accelerated in Europe and the United States, and the first gene therapy product in advanced countries was approved for marketing authorization by the European Commission in 2012. On the other hand, more than 40 clinical studies for gene therapy have been completed or ongoing in Japan, most of them are conducted as clinical researches by academic institutes, and few clinical trials have been conducted for approval of gene therapy products. In order to promote the development of gene therapy products, revision of the current guideline and/or preparation of concept paper to address the evaluation of the quality and safety of gene therapy products are necessary and desired to clearly show what data should be submitted before First-in-Human clinical trials of novel gene therapy products. We started collaborative study with academia and regulatory agency to promote regulatory science toward clinical development of gene therapy products for genetic diseases based on lentivirus and adeno-associated virus vectors; National Center for Child Health and Development (NCCHD), Nippon Medical School and PMDA have been joined in the task force. At first, we are preparing pre-draft of the revision of the current gene therapy guidelines in this project.
In this study, we have standardized experimental protocols to evaluate the possibility of using cells differentiated from human induced pluripotent stem cells (hiPSCs) in the pre-clinical studies for the drug approval processes. Cells differentiated from hiPSC, especially cardiomyocytes, neurons and hepatocytes, are expected to be used as new pharmacological and toxicological assay tools. Current preclinical test methods have limitations for predicting clinical adverse drug reactions. This is because of the so-called 'problem of species difference'. Drug-induced arrhythmia, cognitive impairment and hepatotoxicity which can't be predicted in pre-clinical studies are major causes of the high rate attrition of new-drug candidates in clinical studies and of withdrawal of products from the market. The development of new pre-clinical test methods using cells differentiated from hiPSCs would resolve these problems, in addition to solving the issue of "the replacement, refinement and reduction (3Rs)" of animal experiments. From 2010 to 2011, we surveyed companies belonging to the Japan Pharmaceutical Manufacturers Association (JPMA) and academic researchers about the usage of differentiated cells in their laboratories. We found that studies were performed using differentiated cells from different cell lines of hiPSC with laboratory-specific differentiation methods. The cells were cultured in various conditions and their activities were measured using different methods. This resulted in a variety of pharmacological responses of the cells. It is therefore impossible to compare reproducibility and ensure reliability of experiments using these cells. To utilize the cells in the drug approval processes, we need robust, standardized test methods to accurately reproduce these methods in all laboratories. We will then be able to compare and analyze the obtained results. Based on the survey, the Ministry of Health, Labor and Welfare funded our study. In our study, we standardize pharmacological methods among several laboratories, including our laboratory, to develop robust tests, using the same lot of cells, the same culture conditions, reference compounds, experimental protocols, and analysis methodology. In conclusion, to standardize robust test methods, we need a consistent supply of high-quality differentiated cells. Further, indexes to quantify the quality of the differentiated cells will be needed for their effective usage in the pre-clinical safety studies.
Hydrolyzed wheat protein (HWP; hydrolyzed gluten) is used in various types of products worldwide. Several cases of wheat-dependent, exercise-induced anaphylaxis following exposure to HWP (Glupearl 19S) in cosmetics have been reported. Glupearl 19S was produced from the gluten after partial hydrolysis with hydrogen chloride, and its allergenicity is larger than that of gluten (Adachi R., Allergy 2012;67:1392-9.). It is considered that provocation of allergic manifestations is caused by deamidated gluten in food and/or non-food products. Moreover, an increasing number of studies have shown that HWP can induce IgE-mediated hypersensitivity by skin contact and/or food ingestion. However, the essential molecular properties and profiles of HWP are still unknown. In this study, bioinformatic and multivariate analyses using shotgun proteomics have revealed that 27 proteins significantly decreased in Glupearl 19S compared with intact gluten as shown by the ratio of ion signal intensity of tryptic peptides. In contrast, a single protein significantly increased in HWP compared with intact gluten as shown by the ratio of ion signal intensity of tryptic peptides. Furthermore, we have identified six Glupearl 19S-specific peptides using shotgun proteomics, database searches on Mascot Sequence Query, and de novo sequencing. The six peptides were identified as the specific markers of Glupearl 19S.
